Belbuca

Agents for Opioid Dependence
Agents for Opioid Withdrawal
Mixed Opiate Agonist-Antagonist

For storage information, see specific product information within the How Supplied section.

Oral Administration Oral Solid Formulations

For all transmucosal dosage forms (sublingual and buccal):
The risk for dental disease may be increased. Encourage all patients to receive consistent dental care and checkups while using these products.
Patients may lessen the risk of dental problems by swishing and swallowing water immediately after a dose is completely administered and dissolved. Patients should wait 1 hour before brushing teeth to avoid tooth damage.
 
Sublingual tablets (e.g., Subutex)
Completely dissolve under the tongue. Do not swallow or chew the tablets; swallowing the tablet will reduce the bioavailability of the drug.
For doses requiring more than 2 tablets, patients are advised to either place all the tablets at once under the tongue or, if they cannot fit more than 2 tablets comfortably, place 2 tablets at a time under the tongue. With either option, patients should hold the tablets under the tongue until they completely dissolve.
Prior to induction, determine the type of opioid dependence (i.e., long- or short-acting opioids).
Induction: To avoid precipitating withdrawal, induction with buprenorphine should be undertaken only after objective and clear signs of withdrawal are present.
Short-acting opioid: Administer first dose at least 4 hours or longer after the patient last used heroin or other short-acting opioid.
Longer-acting opioid (e.g., methadone): Administer first dose at least 24 hours or longer after the patient last long-acting opioid use.
Maintenance: Buprenorphine; naloxone combination products are preferred to buprenorphine single-ingredient products for maintenance treatment of OUD.
Storage: Keep buprenorphine secured in a location not accessible by others.
Disposal: Flush unused buprenorphine down the toilet when it is no longer needed if a drug take-back option is not readily available.

Other Oral Formulations

For all transmucosal dosage forms (sublingual and buccal):
The risk for dental disease may be increased. Encourage all patients to receive consistent dental care and checkups while using these products.
Patients may lessen the risk of dental problems by swishing and swallowing water immediately after a dose is completely administered and dissolved. Patients should wait 1 hour before brushing teeth to avoid tooth damage.
 
Buccal film (e.g., Belbuca)
Do not use if the package seal is broken or the film is cut, damaged, or changed in any way.
Use the tongue to wet the inside of the check or rinse the mouth with water to wet the area for placement.
Avoid applying the film to areas of the mouth with open sores or lesions.
Apply the film immediately after removal from the package.
Place the yellow side of the film against the inside of the cheek. Hold the film in place with clean, dry fingers for 5 seconds. Leave the film in place until it fully dissolves, usually within 30 minutes.
Do not manipulate the film with the tongue or fingers after it is in place. Avoid eating food and drinking liquids until the film has dissolved. Do not chew or swallow the film.
Abuse or misuse of the film by swallowing may cause choking, overdose, and death.
Storage: Keep buprenorphine secured in a location not accessible by others.
Disposal: Remove film from the foil packaging and flush unused medication down the toilet if a drug take-back option is not readily available.

Extemporaneous Compounding-Oral

Extemporaneous compounding instructions for 0.075 mg/mL sublingual buprenorphine solution
NOTE: Buprenorphine sublingual solution is not approved by the FDA.
Open a 0.3 mg/mL ampule of buprenorphine.
Add 1.26 mL of 95% ethanol to 0.3 mg buprenorphine (1 mL of the 0.3 mg/mL ampule solution).
Add simple syrup to obtain a final total volume of 4 mL.
Storage: The solution is stable in amber glass bottles (for 30 days) and oral dispensing syringes (for 7 days) when stored at room temperature at 68 to 77 degrees F (20 to 25 degrees C).
Administration
Using an oral syringe, place under the tongue for sublingual administration.
A pacifier may be placed in the neonate's mouth to maximize contact with the sublingual mucosa.
If the volume is more than 0.5 mL, divide into 2 administrations separated by at least 2 minutes.

Injectable Administration Intravenous Administration

Immediate-release injection solution (e.g., Buprenex)
No dilution is necessary. Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit.
Give by slow IV injection over 2 minutes directly into a vein or into the tubing of a freely flowing, compatible IV solution. Rapid IV injection may result in an increased frequency of adverse effects.
Do not exceed maximum of 0.3 mg/dose IV; if an adult patient (not in a high-risk category) requires a single dose more than 0.3 mg, then administer via the intramuscular route only.

Intramuscular Administration

Immediate-release injection solution (e.g., Buprenex)
No dilution is necessary. Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit.
May give the immediate-release injection solution of buprenorphine by deep IM injection.

Subcutaneous Administration

Extended-release once-monthly subcutaneous injection (i.e., Sublocade)
Only a health care professional should prepare and administer this injection.
Approved for use in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for at least 7 days, and are transitioning to this injection for maintenance treatment.
This product should be used as part of a comprehensive treatment program that includes counseling and psychosocial support.
Missed doses: Administer the patient's next dose as soon as possible, with the following dose given no less than 26 days later. Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect.
Sublocade injection Administration
Only for subcutaneous injection in the abdominal region. DO NOT administer intramuscularly, intravenously, or intradermally. Serious harm or death could result if administered intravenously.
Remove Sublocade from the refrigerator prior to administration. The product requires at least 15 minutes to reach room temperature. Do not open the foil pouch until the patient has arrived for his or her injection.
Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit. Each dose is a clear, colorless to yellow to amber solution.
Administer monthly with a minimum of 26 days between doses.
Only use the syringe and safety needle included with the product for administration. Do not attach the needle until the time of administration.
Choose an injection site in the abdominal region. Do not inject into an area where the skin is irritated, reddened, bruised, infected, or scarred in any way.
Do not rub the injection area after the injection. If bleeding occurs, use a gauze pad or bandage but only use minimal pressure.
Advise the patient that there may be a lump for several weeks after the injection that will decrease in size over time. Instruct the patient not to rub or massage the injection site and to be aware of the placement of any belts or clothing waistbands.
To avoid irritation, rotate the injection site with each monthly injection.
At the time of the next injection, examine the injection site for infection, evidence of tampering, or attempts to remove the depot.
Storage after removal from refrigeration: Once outside the refrigerator this product may be stored in its original packaging at room temperature, 15 to 30 degrees C (59 to 86 degrees F), for up to 7 days prior to administration. Discard the injection if left at room temperature for longer than 7 days.
 
Extended-release once-weekly or once-monthly subcutaneous injection (i.e., Brixadi)
Only a health care professional should prepare and administer this injection.
Patients appropriate for Brixadi (weekly) are adults who have tolerated a single 4 mg test dose of a transmucosal buprenorphine-containing product or who are currently receiving treatment with a transmucosal buprenorphine-containing product.
Patients appropriate for Brixadi (monthly) are adults who are currently receiving treatment with a transmucosal buprenorphine-containing product. Do not administer the monthly injection to those who are not currently receiving buprenorphine treatment.
This product should be used as part of a comprehensive treatment program that includes counseling and psychosocial support.
Weekly and monthly doses are different. Doses of the weekly formulation cannot be combined to yield an equivalent monthly dose.
Missed doses: Administer the patient's next dose as soon as possible. Brixadi (weekly) should be administered in 7-day intervals. Brixadi (monthly) should be administered in 28-day intervals. To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point, and the monthly dose may be administered up to 1 week before or after the monthly time point.
Brixadi injection Administration
Only for slow subcutaneous injection into the buttock, thigh, abdomen, or upper arm. Do NOT administer intravenously, intramuscularly, or intradermally. Serious harm or death could result if administered intravenously.
Remove the safety syringe components from the carton and assemble the safety syringe.
Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit. The liquid should be clear and yellowish to yellow in color.
Choose an injection site.
Do not administer weekly injections into the same site for at least 8 weeks. Administration of the weekly injection into the upper arm site should only be used after steady-state has been achieved (i.e., following 4 consecutive weekly doses).
No injection site rotation is required for monthly injections.
Administered the injection slowly to the selected area:
Pinch the skin at the injection site between your thumb and index finger. Hold the syringe in your other hand and insert the needle at an angle of approximately 90-degrees. Ensure the needle is fully inserted to enable the medication to reach the subcutaneous space.
Once the needle is fully inserted, release the pinched skin. Slowly press down the plunger head until it latches into the safety device "wings" to ensure all the medication has been injected. Continue to keep the plunger pressed down fully while holding the safety syringe in place for an additional 2 seconds.
Gently pull the needle straight out of the injection site, keeping the plunger fully depressed. Once fully removed from the skin, remove your thumb from the plunger and allow the syringe guard to automatically cover the exposed needle.
Dispose of the safety syringe immediately into an approved sharps container.
Do not rub the injection area after the injection. If bleeding occurs, press a gauze pad or cotton ball on the injection site. An adhesive bandage may be applied if needed.
Patient should be advised to notify their health care professional immediately if excessive swelling, redness, heat, or drainage develops at the injection site.
At the time of the next injection, examine the injection site for infection, evidence of tampering, or attempts to remove the depot.

Other Injectable Administration

Epidural Administration
NOTE: Buprenorphine is not FDA-approved for epidural administration.
This route of administration should only be used by specially trained health care professionals.
Placement of epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. For example, for thoracic surgery placement at T2 to T8, upper abdominal surgery, T4 to L1, lower abdominal surgery, T10 to L3, upper extremity surgery, C2 to C8 and lower extremity surgery, T12 to L3.
After ensuring proper placement of the needle or catheter, inject appropriate dose into the epidural space.

Topical Administration Transdermal Patch Formulations

Transdermal patch system (e.g., Butrans)
Apply to intact skin only.
Do not use if the pouch seal is broken or the patch is cut, damaged, or changed in any way. Do not cut the buprenorphine transdermal system.
Instruct patients to apply immediately after removal from the individually sealed pouch.
Each buprenorphine transdermal system is intended to be worn for 7 days.
Apply to the upper outer arm, upper chest, upper back, or the side of the chest. Rotate buprenorphine transdermal system application among the 8 described sites (each present on both sides of the body). After removal of the patch, wait a minimum of 21 days before reapplying to the same skin site.
Apply to a hairless or nearly hairless skin site. If necessary, hair should be clipped, not shaven. Do not apply to irritated skin.
If necessary, clean site with water only and allow to dry completely before application. Do not use soaps, alcohol, oils, lotions, or abrasive devices.
The patch may be worn while bathing or showering.
Avoid exposing the patch application site and surrounding areas to external heat sources (e.g., heating pads, electric blankets, heated water beds, hair dryers, tanning beds, hot baths or saunas, excessive sun exposure, or hot climate).
If the adhesive matrix (which contains buprenorphine) of the patch accidentally touches skin, wash the area with water. Do not use soap, alcohol, or other solvents to remove the adhesive; doing so may enhance drug absorption.
If problems arise with the adherence of the patch, the edges of the patch may be taped with first aid tape. If problems with the patch not sticking continue, cover the patch with special see-through adhesive dressings (e.g., Bioclusive or Tegaderm).
If the buprenorphine transdermal system falls off during the 7 day dosing interval, dispose of the patch properly and place a new patch at a different skin site.
Storage: Keep buprenorphine secured in a location not accessible by others.
Disposal: Dispose of damaged, used, and unneeded buprenorphine patches right away by folding patch in half so that the adhesive side is inward and immediately flush down the toilet. Alternatively, buprenorphine patches may be sealed in the Patch-Disposal Unit provided and then disposed of in the trash. Never dispose of a buprenorphine patch in the trash without sealing it in the Patch-Disposal Unit.

Other Administration Route(s)

Subdermal Implant Administration
Subdermal implant (Probuphine)
All prescribing health care providers performing implant insertions and/or removals must successfully complete a live training program on insertion and removal procedures, including demonstrating competency in procedures, and become certified in the associated risk management (REMS) program.
Patients eligible for the implant must currently be on a maintenance dose of 8 mg/day or less of a buprenorphine or buprenorphine/naloxone sublingual tablet or its transmucosal buprenorphine product equivalent (the dose of transmucosal buprenorphine providing blood levels comparable or lower than the level provided by buprenorphine subdermal implants) and have been stable on this dose without any need for supplemental dosing for 3 months or longer. Additionally, patients should be clinically stable as well as a suitable candidate for treatment (social support system, stable living environment, etc.).
The implants are inserted subdermally in the inner side of the upper arm. New implants may be inserted subdermally in an area of the inner side of either upper arm that has not been previously used at the time of removal. There is no experience with inserting additional implants into other sites in the arm to recommend an approach to a second insertion into a previously-used arm. Neither re-insertion into previously-used administration sites, nor into sites other than the upper arm, has been studied.
For details on insertion and removal of the inserts, see prescribing information.
In the case of spontaneous expulsion of the implant:
The patient should contact the prescribing health care provider as soon as possible.
Instruct the patient to place the implant in a plastic bag, store it safely out of reach of children, and to bring it to the health care provider office to determine whether the full implant has been expelled.
Prescriber must carefully monitor patient until the implant is replaced to evaluate for withdrawal or other clinical indicators that supplemental transmucosal buprenorphine may be needed.

Severe

coma / Early / 0-1.0
AV block / Early / 0-1.0
bradycardia / Rapid / 0-1.0
ileus / Delayed / 0-1.0
apnea / Delayed / 0-1.0
cyanosis / Early / 0-1.0
angioedema / Rapid / 0-1.0
anaphylactic shock / Rapid / 0-1.0
bronchospasm / Rapid / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
visual impairment / Early / 0-1.0
atrial fibrillation / Early / 0-0.2
cholecystitis / Delayed / 0-0.2
stroke / Early / 0-0.2
seizures / Delayed / Incidence not known
hepatic encephalopathy / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
increased intracranial pressure / Early / Incidence not known
SIADH / Delayed / Incidence not known
neonatal respiratory depression / Rapid / Incidence not known
neonatal opioid withdrawal syndrome / Delayed / Incidence not known
serotonin syndrome / Delayed / Incidence not known

Moderate

withdrawal / Early / 0-24.0
constipation / Delayed / 0-13.0
depression / Delayed / 0-11.0
erythema / Early / 3.0-10.0
hematoma / Early / 7.0-7.0
epiphora / Early / 3.0-7.0
migraine / Early / 0-5.0
hypotension / Rapid / 0-5.0
hypertension / Early / 0-5.0
angina / Early / 0-5.0
dyspnea / Early / 0-5.0
edema / Delayed / 5.0-5.0
elevated hepatic enzymes / Delayed / 0-5.0
peripheral edema / Delayed / 1.0-4.9
anemia / Delayed / 1.0-4.9
peripheral vasodilation / Rapid / 0-3.9
dysarthria / Delayed / 0-1.0
psychosis / Early / 0-1.0
memory impairment / Delayed / 0-1.0
hallucinations / Early / 0-1.0
confusion / Early / 0-1.0
dysphoria / Early / 0-1.0
sinus tachycardia / Rapid / 0-1.0
palpitations / Early / 0-1.0
orthostatic hypotension / Delayed / 0-1.0
QT prolongation / Rapid / 0-1.0
dehydration / Delayed / 0-1.0
dysphagia / Delayed / 0-1.0
hypoventilation / Rapid / 0-1.0
respiratory depression / Rapid / 0-1.0
wheezing / Rapid / 0-1.0
amblyopia / Delayed / 0-1.0
conjunctivitis / Delayed / 0-1.0
blurred vision / Early / 0-1.0
urinary retention / Early / 0-1.0
urinary incontinence / Early / 0-1.0
euphoria / Early / 0-1.0
chest pain (unspecified) / Early / 0-0.2
impaired cognition / Early / Incidence not known
hypoxia / Early / Incidence not known
jaundice / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
infertility / Delayed / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
physiological dependence / Delayed / Incidence not known
psychological dependence / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
glossitis / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
hyperalgesia / Delayed / Incidence not known

Mild

nausea / Early / 5.0-33.0
headache / Early / 1.0-29.1
insomnia / Early / 0-21.4
dizziness / Early / 1.5-15.0
asthenia / Delayed / 0-14.0
weakness / Early / 0-14.0
back pain / Delayed / 1.0-14.0
drowsiness / Early / 0-13.0
diaphoresis / Early / 1.0-12.6
anxiety / Delayed / 1.0-12.0
pruritus / Rapid / 0-12.0
abdominal pain / Early / 1.0-11.7
infection / Delayed / 1.0-11.7
rhinitis / Early / 0-11.0
vertigo / Early / 0-10.0
vomiting / Early / 1.0-9.0
chills / Rapid / 0-7.8
skin irritation / Early / 1.0-6.0
hypoesthesia / Delayed / 0-5.0
tremor / Early / 0-5.0
paresthesias / Delayed / 0-5.0
dyspepsia / Early / 0-5.0
anorexia / Delayed / 0-5.0
cough / Delayed / 0-5.0
rash / Early / 0-5.0
musculoskeletal pain / Early / 0-5.0
miosis / Early / 0-5.0
arthralgia / Delayed / 1.0-4.9
myalgia / Early / 1.0-4.9
fever / Early / 1.0-4.9
pharyngitis / Delayed / 1.0-4.9
lethargy / Early / 1.0-4.9
hyperhidrosis / Delayed / 1.0-4.9
flushing / Rapid / 0-4.9
sinusitis / Delayed / 0-4.9
syncope / Early / 0-1.0
emotional lability / Early / 0-1.0
restlessness / Early / 0-1.0
dysgeusia / Early / 0-1.0
tinnitus / Delayed / 0-1.0
agitation / Early / 0-1.0
nightmares / Early / 0-1.0
pallor / Early / 0-1.0
hiccups / Early / 0-1.0
flatulence / Early / 0-1.0
weight loss / Delayed / 0-1.0
hyperventilation / Early / 0-1.0
injection site reaction / Rapid / 0-1.0
urticaria / Rapid / 0-1.0
rhinorrhea / Early / 0-1.0
malaise / Early / 0-1.0
xerophthalmia / Early / 0-1.0
diplopia / Early / 0-1.0
libido decrease / Delayed / 0-1.0
ecchymosis / Delayed / 0-0.7
xerostomia / Early / 5.0
diarrhea / Early / 5.0
fatigue / Early / 3.9
amenorrhea / Delayed / Incidence not known
gonadal suppression / Delayed / Incidence not known
dental caries / Delayed / Incidence not known
dental pain / Delayed / Incidence not known

Accidental exposure, alcoholism, depression, opioid overdose, opioid use disorder, potential for overdose or poisoning, requires an experienced clinician, substance abuse

Opioid use requires an experienced clinician who is knowledgeable about the use of opioids, including the use of extended-release/long-acting opioids, and how to mitigate the associated risks. Opioids expose users to the risks of addiction, abuse, and misuse, which can occur at any dosage or duration. Although the risk of addiction in any individual is unknown, it can occur in persons appropriately prescribed opioids. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each individual's risk for opioid addiction, abuse, or misuse before prescribing an opioid, and monitor for the development of these behaviors or conditions. Risks are increased in persons with a personal or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression). The potential for these risks should not prevent the proper management of pain in any given individual. Persons at increased risk may be prescribed opioids, but use in such persons necessitates intensive counseling about the risks and proper use of the opioid along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse and addiction are separate and distinct from physical dependence and tolerance; persons with addiction may not exhibit tolerance and symptoms of physical dependence. Opioids are sought by drug abusers and persons with addiction disorders and are subject to criminal diversion. Abuse of opioids has the potential for overdose or poisoning and death. Consider these risks when prescribing or dispensing an opioid. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. The misuse of transdermal buprenorphine by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death. Abuse or misuse of the buccal film may cause choking, overdose, and death. Keep opioids out of the reach of pediatric persons, others for whom the drug was not prescribed, and pets as accidental exposure or improper use may cause respiratory failure and a fatal overdose. Accidental exposure of even a single dose of an opioid, especially by younger persons, can result in a fatal overdose. Because the risk of overdose increases as opioid dose increases, reserve titration to higher doses of an opioid for persons in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Do not use immediate-release opioids for an extended period unless the pain remains severe enough to require an opioid and for which alternative treatment options continue to be inadequate. Many acute pain conditions (e.g., pain occurring with surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid. Clinical guidelines on opioid prescribing for some acute pain conditions are available. Extended-release opioids are not intended for use in the management of acute pain or on an as-needed basis but rather only for the management of severe and persistent pain that requires an extended treatment period with a daily opioid and for which alternative treatment options are inadequate. Discuss the availability of naloxone with all persons and consider prescribing it in persons who are at increased risk of opioid overdose, such as persons who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental exposure or opioid overdose.[41235] [60270] [65733]

Acute intoxication of CNS depressants, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), CNS depression, coadministration with other CNS depressants, cor pulmonale, driving or operating machinery, emphysema, ethanol intoxication, obesity, psychosis, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

As with other opioid agonists, buprenorphine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as coadministration significantly increases the risk for respiratory depression, low blood pressure, and death. The potential risk of serious adverse effects with concomitant use of buprenorphine and other CNS depressants should not preclude medication-assisted treatment (MAT) with buprenorphine for opioid use disorder, since withholding MAT may increase the risk of morbidity and mortality from the opioid use disorder. Discontinuation of other CNS depressants is preferred in most cases; co-therapy may require more intensive counseling and monitoring, possible adjustments to induction procedures, gradual tapering of the CNS depressant to the lowest effective dose, and development of strategies to manage prescribed or illicit CNS depressant use. Educate patients at initiation of buprenorphine treatment about the risk of concurrent use of benzodiazepines, alcohol, and other CNS depressants. In patients receiving MAT with buprenorphine, benzodiazepines are not a preferred treatment for anxiety or insomnia. Prior to co-prescribing benzodiazepines, ensure there is an appropriate diagnosis for use, consider alternatives for insomnia or anxiety, develop a system for alerting other healthcare providers of the patient's buprenorphine treatment, coordinate care to minimize risks, and confirm the proper use of prescribed medication and assess for illicit benzodiazepine use through toxicology screening. There is no evidence to support dose limitations of buprenorphine to address benzodiazepine use in buprenorphine-treated patients; however, in patients who are sedated at the time of buprenorphine dosing, a medically-trained healthcare provider should evaluate the cause of sedation, and delay or omit the buprenorphine dose if needed. If buprenorphine must be administered to patients with pulmonary disease, use extreme caution and initiate treatment at the lowest effective dose. Clinically significant respiratory and CNS depression may occur with therapeutic doses of any form of buprenorphine; patients with pre-existing respiratory or CNS impairment may be at an increased risk of adverse events. Buprenorphine should be used with caution in patients with asthma; use of transdermal buprenorphine or the buccal film is contraindicated in patients with significant respiratory depression and/or acute or severe bronchial asthma (e.g., status asthmaticus) in an unmonitored setting or in the absence of resuscitative equipment. Use with caution in patients with compromised respiratory function such as occurs with chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, or pre-existing respiratory depression. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Prior to initiation of therapy, it is important to note that naloxone may not be effective in reversing buprenorphine effect. Proper dosing and titration are essential; patients should be monitored for respiratory depression, particularly during initiation or after a dose increase. Caution should be exercised when converting from a different opioid to buprenorphine for pain treatment, as overestimation of the buprenorphine dose may lead to fatal overdose. In patients with pulmonary disease such as chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, emphysema, chronic bronchitis, respiratory insufficiency, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to transdermal buprenorphine, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. If sublingual or intravenous buprenorphine are used in patients with compromised respiratory function, it is recommended that the dose be reduced by approximately one-half. Use buprenorphine with caution in patients with: an acute intoxication of CNS depressants (e.g., ethanol intoxication); a history of delirium tremens; cardiac failure; or obesity. Retention of carbon dioxide from respiratory depression may also aggravate the sedative effects of opioids. Use buprenorphine with caution in patients who have sleep apnea; opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia (hypoxia). Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dose using best practices for opioid tapering. Use buprenorphine with caution in patients who have kyphoscoliosis (a type of scoliosis), as the spine curvature may increase the risk of breathing difficulties. Patients with toxic psychosis may not be good candidates for buprenorphine receipt due to the possible CNS depressive effects. Caution is advised for use of buprenorphine in elderly, cachectic, or debilitated patients, who are more likely to a have a co-morbid disease that affects buprenorphine kinetics and since they may be more sensitive to the respiratory and CNS depressant effects of the drug. Careful monitoring is required, particularly when CYP450 3A4 inhibitors or inducers are used concomitantly; concurrent use of a CYP3A4 inhibitor or discontinuation of a concurrently used CYP3A4 inducer may increase plasma buprenorphine concentrations and potentiate the risk of fatal respiratory depression. Warn all patients that buprenorphine can impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. These effects may persist for varying periods of time after dosing. Impairment of mental or physical abilities may change during dosage adjustments.

Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

There have been no well-controlled studies of buprenorphine in pregnant women; buprenorphine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. As with other opioids, there is no consistent pattern of birth defects associated with opioid use during the first trimester. Reports of teratogenicity remain rare and account for a small increase in absolute risk. Limited published data on the use of buprenorphine immediate-release injection in pregnancy have not shown an increased risk of major malformations. The American College of Obstetricians and Gynecologists recommends early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Rely on validated screening tools, such as 4Ps, NIDA Quick Screen, and CRAFFT (for women 26 years or younger). Ensure opioids are appropriately indicated. For women using opioids for chronic pain, consider strategies to avoid or minimize the use of opioids, including alternative pain therapies (i.e., nonpharmacologic) and nonopioid pharmacologic treatments. Take a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids or other high-risk drugs such as benzodiazepines. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for neonatal opioid withdrawal syndrome, and how long-term opioid use may affect care during a future pregnancy. Opioid agonist pharmacotherapy is preferable to medically supervised withdrawal in pregnant women with opioid use disorder (OUD). Guidelines recommend discussing contraceptive use during OUD treatment to minimize the risk of unplanned pregnancy. Pregnant women receiving treatment for OUD may require dose adjustments of buprenorphine in order maintain abstinence from illicit drug use; closely monitor patients for withdrawal signs and symptoms and adjust dose as necessary. If the benefit of treatment with the subdermal implant (Probuphine) is determined to outweigh the risks during pregnancy, dosage adjustments cannot be made and the patient should be closely monitored to ensure adequate treatment. Because the implant dose cannot be adjusted, this formulation may not be an appropriate OUD treatment option to initiate in patients who are pregnant. The subcutaneous extended-release subcutaneous injection (Sublocade, Brixadi) may also not be the optimal dosage form for treatment of OUD during pregnancy. In published animal reproduction studies with an extended-release subcutaneous injection (Sublocade), administration to pregnant rabbits and rats during the period of organogenesis at the buprenorphine dose equivalent of 38 and 15 times (respectively) the maximum recommended human dose (MRHD) of 300 mg caused embryolethality, which appeared to be primarily attributable to the injection vehicle (Atrigel delivery system). Embryofetal death was also observed in both rats and rabbits when buprenorphine was administered during the period of organogenesis at doses 21 times and equal to (respectively) the mean daily dose of 4.6 mg buprenorphine delivered by the max doses of weekly and monthly extended-release subcutaneous injections of buprenorphine (Brixadi). In animal studies or oral buprenorphine, embryofetal death during organogenesis was observed in rats and rabbits given doses approximately 53 and 11 times the MRHD, respectively. Pre- and post-natal development studies in rats demonstrated increased neonatal death after oral and IM doses of approximately 4 and 3 times the MRHD, respectively. A pre- and postnatal development study in rats was also conducted using an extended-release subcutaneous injection (Sublocade), with no adverse effects noted for offspring survival, sexual maturation, behavioral assessment, or reproductive performance at up to 15 times the MRHD on an AUC basis. No teratogenic effects were observed in rats or rabbits given a range of doses more than the MRHD during organogenesis; however, events such as acephalus, omphalocele, and skeletal abnormalities have been reported in a few studies. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Further, prolonged maternal use of opioids, such as buprenorphine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. From postmarketing reports with sublingual use, the time to onset of neonatal withdrawal signs ranged from day 1 to day 8 of life with most cases occurring on day 1. Advise pregnant women receiving treatment for opioid dependence with buprenorphine of the risk of NOWS and ensure that appropriate treatment will be available. The risk for NOWS must be balanced against the risk of untreated opioid addiction in the mother which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. The safety of injectable buprenorphine given during labor and obstetric delivery has not been established. Pregnant patients on buprenorphine maintenance therapy for OUD may require additional analgesia during labor. Transdermal and buccal buprenorphine are not for analgesic use during and immediately prior to labor, when shorter acting analgesics or other therapies are more appropriate. Opioids can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.

Intravenous administration

Do not administer the extended-release buprenorphine subcutaneous injections (Sublocade or Brixadi) intravenously, intramuscularly, or intradermally. Intravenous administration of these products is contraindicated as it presents significant risk of serious harm or death because the injection solution forms a solid mass (Sublocade) or crystalline gel (Brixadi) upon contact with body fluids; venous occlusion, local tissue damage, and thromboembolic events, including life-threatening pulmonary emboli, could result. Buprenorphine extended-release subcutaneous injections are available only through restricted REMS programs due to the risk of serious harm or death that could result from intravenous self-administration. These programs ensure that health care settings and pharmacies are certified and that proper administration by a health care provider occurs.

Implant insertion and removal complications, infection, scleroderma

Buprenorphine implant for subdermal use (i.e., Probuphine) is associated with a risk of implant insertion and removal complications, including migration, protrusion, expulsion, and nerve damage resulting from the procedure. Administration and use requires an experienced clinician who is knowledgeable about the use of extended-release opioids and this implant dosage form. The buprenorphine implant should only be inserted subdermally, and intramuscular administration or other inadvertent administration may result in rare but serious complications (e.g., neural or vascular injury), difficult localization of the implant, or result in the need for a surgical procedure to remove the implant. Incomplete insertion or improper placement may lead to local migration, protrusion, and expulsion. Complicated removal can occur if the implant is not inserted correctly, is inserted too deeply (intramuscular or in the fascia), is not palpable, or has migrated. Injury to deeper neural or vascular structures in the arm may occur when removing deeply inserted implants. Infection may occur at the site of the insertion or removal, and infection may cause the implant to migrate, protrude, or expulse. Excessive palpation shortly after insertion of the implants or improper implant removal may increase the risk of infection. Buprenorphine implants should be used cautiously in patients with a history of recurrent MRSA infections. Because buprenorphine implants are administered subdermally, caution is recommended when using the implants in patients with a history of keloid formation or connective tissue disease (e.g., scleroderma).

Belbuca, Brixadi, Buprenex, Butrans, Probuphine, Sublocade, Subutex

Rx, schedule III

Semisynthetic mixed opiate agonist-antagonist; partial mu-receptor agonist with a ceiling to its pharmacological effects
Immediate-release parenteral form used for moderate to severe pain; transdermal and buccal forms used for continuous therapy for chronic severe pain
Sublingual tablets, dermal implant and extended-release subcutaneous injection products are used for treatment of opioid dependence

For the treatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequate. For the treatment of persistent, severe pain that requires an extended treatment period with a daily opioid and for which alternative treatments are inadequate.
NOTE: Transdermal and buccal buprenorphine should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Discontinue all other around-the-clock opioid drugs upon initiation of transdermal buprenorphine.
NOTE: Transdermal buprenorphine doses of 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, and 20 mcg/hour are for use in opioid-experienced patients only.
NOTE: Buccal doses of 600 mcg, 750 mcg, and 900 mcg are for use following titration from lower doses of the buccal film. Transdermal dosage for use as the first opioid analgesic (Butrans) Adults

5 mcg/hour transdermally every 7 days, initially. While the patch is intended to be worn for 7 days, doses may be titrated after a minimum interval of 72 hours; titrate dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than 2 patches of the 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour systems as needed to achieve adequate analgesia. Do not exceed a dose of 20 mcg/hour.

Transdermal dosage for conversion from other opioid agonist analgesics (Butrans)

NOTE: There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. Overestimating dose when converting from another opioid can be fatal with first dose.

Adults whose daily opioid dose is less than 30 mg oral morphine (or equivalent)

5 mcg/hour transdermally every 7 days, initially. Begin treatment with buprenorphine at the next dosing interval. Use extreme caution when converting patients from methadone as the ratio between methadone and other opioid agonists can vary widely. While the patch is intended to be worn for 7 days, doses may be titrated after a minimum interval of 72 hours; titrate dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than 2 patches of the 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour systems as needed to achieve adequate analgesia. Do not exceed a dose of 20 mcg/hour.

Adults whose daily opioid dose is 30 to 80 mg oral morphine (or equivalent)

10 mcg/hour transdermally every 7 days, initially. Taper the current around-the-clock opioid for up to 7 days to no more than 30 mg/day of oral morphine or equivalent before beginning transdermal buprenorphine. Begin treatment with buprenorphine at the next dosing interval. Use extreme caution when converting patients from methadone as the ratio between methadone and other opioid agonists can vary widely. While the patch is intended to be worn for 7 days, doses may be titrated after a minimum interval of 72 hours; titrate dose in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than 2 patches of the 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour systems as needed to achieve adequate analgesia. Do not exceed a dose of 20 mcg/hour.

Adults whose daily opioid dose is more than 80 mg oral morphine (or equivalent)

Consider the use of an alternate analgesic. The 20 mcg/hour transdermal buprenorphine may not provide adequate analgesia.

Transmucosal dosage for use as the first opioid analgesic (Belbuca) Adults

75 mcg transmucosally once daily, or every 12 hours if tolerated, placed against the inside of the cheek. After 4 days, increase dosage to 150 mcg every 12 hours. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half.

Transmucosal dosage for conversion from other opioid agonist analgesics (Belbuca)

NOTE: There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. Overestimating dose when converting from another opioid can be fatal with first dose.

Adults whose daily opioid dose is less than 30 mg oral morphine (or equivalent)

75 mcg transmucosally once daily, or every 12 hours if tolerated, placed against the inside of the cheek. After 4 days, increase dosage to 150 mcg every 12 hours. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half. Use extreme caution when converting patients from methadone as the potency ratio between methadone and other opioid agonists can vary widely.

Adults whose daily opioid dose is 30 to 89 mg oral morphine (or equivalent)

Taper the patient's current around-the-clock opioid to no more than 30 mg of oral morphine or equivalent per day before beginning transmucosal buprenorphine. Initiate 150 mcg transmucosally every 12 hours, placed against the inside of the cheek. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half. Use extreme caution when converting patients from methadone as the potency ratio between methadone and other opioid agonists can vary widely.

Adults whose daily opioid dose is 90 to 160 mg oral morphine (or equivalent)

Taper the patient's current around-the-clock opioid to no more than 30 mg of oral morphine or equivalent per day before beginning transmucosal buprenorphine. Initiate 300 mcg transmucosally every 12 hours, placed against the inside of the cheek. Titrate in increments of 150 mcg every 12 hours no more frequently than every 4 days to provide adequate analgesia. Maximum: 900 mcg every 12 hours. Do not exceed 900 mcg every 12 hours due to the potential for QT prolongation. For patients with known or suspected mucositis, reduce the starting dosage and titration dosage by half. Use extreme caution when converting patients from methadone as the potency ratio between methadone and other opioid agonists can vary widely.

Adults whose daily opioid dose is more than 160 mg oral morphine (or equivalent)

Consider the use of an alternate analgesic. The buccal/transmucosal film may not provide adequate analgesia.

Intravenous dosage

NOTE: A parenteral buprenorphine dose of 0.3 mg provides analgesia roughly equivalent to a parenteral morphine dose of 10 mg.

Adults

0.3 mg IV; may repeat dose at 30 to 60 minutes after the initial dose and then every 6 to 8 hours as needed. Max: 0.3 mg/dose IV.

Adolescents

0.3 mg IV; may repeat dose at 30 to 60 minutes after the initial dose and then every 6 to 8 hours as needed. Max: 0.3 mg/dose IV.

Children 2 to 12 years

2 to 6 mcg/kg/dose IV every 4 to 8 hours as needed.

Intramuscular dosage Adults

0.3 mg IM; may repeat dose at 30 to 60 minutes after the initial dose and then every 6 to 8 hours as needed. Occasionally, it may be necessary to administer single doses of up to 0.6 mg IM depending on pain severity and patient response.

Adolescents

0.3 mg IM; may repeat dose at 30 to 60 minutes after the initial dose and then every 6 to 8 hours as needed. Occasionally, it may be necessary to administer single doses of up to 0.6 mg IM depending on pain severity and patient response.

Children 2 to 12 years

2 to 6 mcg/kg/dose IM every 4 to 8 hours as needed.

For the treatment of opiate agonist dependence or opioid use disorder (OUD). For the treatment of opioid agonist dependence. Sublingual dosage Adults

2 to 4 mg SL as needed to achieve clinical effectiveness as rapidly as possible, then titrate dose by 2 to 4 mg to a level that holds the person in treatment and suppresses opioid withdrawal signs and symptoms. Target maintenance dose: 16 mg SL once daily. Usual dose range: 4 to 24 mg/day. Higher doses (i.e., 16 to 32 mg/day) may improve retention in treatment.

For the treatment of moderate to severe opioid use disorder (OUD) using the Sublocade injectable product in persons who have initiated treatment with a buprenorphine-containing product, followed by dose adjustment for at least 7 days.
NOTE: Before Sublocade use, persons should first undergo induction and stabilization by initiating a buprenorphine-containing product, delivering the equivalent of 8 to 24 mg/day of transmucosal buprenorphine for a minimum of 7 days.
Subcutaneous dosage (Sublocade extended-release injection) for initiation of treatment after induction Adults

300 mg subcutaneously once monthly for 2 months, then 100 mg subcutaneously once monthly. May increase the dose to 300 mg subcutaneously once monthly for persons who tolerate the 100 mg dose, but do not demonstrate a satisfactory clinical response, as evidenced by self-reported illicit opioid use or urine drug screens positive for illicit opioid use. A 2-month dosing interval may be considered in certain situations (e.g., extended travel) for persons established on 100 mg/month; in these instances, administer 300 mg subcutaneously once to cover the 2-month period, then resume 100 mg subcutaneously once monthly.

Subcutaneous dosage (Sublocade extended-release injection) for transition from long-term treatment with transmucosal buprenorphine Adults

300 mg subcutaneously once monthly for 1 month, then 100 mg subcutaneously once monthly for 8 to 18 mg/day of transmucosal buprenorphine and may consider 300 mg as the second dose in persons who experience craving or withdrawal symptoms after the initial 300 mg dose; 300 mg subcutaneously once monthly for 2 months, then 100 mg subcutaneously once monthly for 20 to 24 mg/day of transmucosal buprenorphine.

For maintenance treatment of opioid use disorder (OUD) with Probuphine Implants in persons who have achieved and sustained prolonged clinical stability on low-to-moderate doses of transmucosal buprenorphine (i.e., no more than 8 mg/day). Subdermal implant dosage (Probuphine Implants) Adults

4 implants (320 mg buprenorphine hydrochloride) subdermally in the inner side of the upper arm and leave in place for 6 months; remove implants by the end of the sixth month. New implants may be inserted if continued treatment is desired. If new implants are not inserted on the same day as the removal of old implants, maintain patients on their previous dose of transmucosal buprenorphine prior to insertion of the new implants. After implant insertion in each arm, most patients should be transitioned back to transmucosal buprenorphine for continued treatment. There is no experience with a second insertion into a previously-used administration site, other site on the arm, or a site other than the upper arm. Although some patients may require occasional supplemental dosing with buprenorphine, patients should not be provided with prescriptions for as-needed transmucosal buprenorphine; evaluate patients who feel the need for supplemental dosing promptly. Ongoing use of supplemental dosing with transmucosal buprenorphine indicates that the amount of buprenorphine delivered by the buprenorphine implant is not adequate for stable maintenance. In these cases, consider use of alternate buprenorphine products for maintenance of treatment.

Adolescents 16 to 17 years

4 implants (320 mg buprenorphine hydrochloride) subdermally in the inner side of the upper arm and leave in place for 6 months; remove implants by the end of the sixth month. New implants may be inserted subdermally if continued treatment is desired. If new implants are not inserted on the same day as the removal of old implants, maintain patients on their previous dose of transmucosal buprenorphine prior to insertion of the new implants. After implant insertion in each arm, most patients should be transitioned back to transmucosal buprenorphine for continued treatment. There is no experience with a second insertion into a previously-used administration site, other site on the arm, or a site other than the upper arm. Although some patients may require occasional supplemental dosing with buprenorphine, patients should not be provided with prescriptions for as-needed transmucosal buprenorphine; evaluate patients who feel the need for supplemental dosing promptly. Ongoing use of supplemental dosing with transmucosal buprenorphine indicates that the amount of buprenorphine delivered by the buprenorphine implant is not adequate for stable maintenance. In these cases, consider use of alternate buprenorphine products for maintenance of treatment.

For the treatment of moderate to severe opioid use disorder (OUD) using the Brixadi injectable product in persons who have initiated treatment with a single dose of a transmucosal buprenorphine-containing product.
NOTE: Before Brixadi use, patients not currently receiving buprenorphine treatment should be given a test dose of 4 mg of transmucosal buprenorphine to establish tolerability without precipitating withdrawal.
Subcutaneous dosage (Brixadi extended-release injection for weekly use) for initiation of treatment after induction Adults

Give 16 mg Brixadi (weekly) subcutaneously. Within 3 days, administer an additional dose of 8 mg subcutaneously to achieve the recommended 24 mg/week. If needed, may administer an additional 8 mg, waiting at least 24 hours after the previous injection, for a total dose of 32 mg/week. Base subsequent weekly injections on the total dosage established during Week 1. Make dosage adjustments at weekly appointments. Max: 32 mg/week. MISSED DOSE (Brixadi weekly): Give the next dose as soon as possible. Administer Brixadi (weekly) in 7-day intervals.

For the treatment of moderate to severe opioid use disorder (OUD) using the Brixadi injectable product in persons who are already being treated with a buprenorphine-containing product. Subcutaneous dosage (Brixadi extended-release injection) for transition from long-term treatment with buprenorphine Adults

For patients taking 6 mg/day or less of SL buprenorphine, initiate with Brixadi 8 mg/week subcutaneously. For 8 to 10 mg/day SL, switch to 16 mg/week or 64 mg/month subcutaneously. For 12 to 16 mg/day SL, switch to 24 mg/week or 96 mg/month subcutaneously. For 18 to 24 mg/day SL, switch to 32 mg/week or 128 mg/month subcutaneously. Brixadi Max: 32 mg/week or 128 mg/month. SWITCHING BETWEEN WEEKLY AND MONTHLY INJECTIONS: May transition from weekly to monthly dosing (or vice versa) based on clinical judgement. Suggested transitions: 16 mg/week = 64 mg/month; 24 mg/week= 96 mg/month; 32 mg/week = 128 mg/month. MISSED DOSES: Administer the next dose as soon as possible. To avoid missed doses, may give the weekly dose up to 2 days before or after the due date. The monthly dose may be administered up to 1 week before or after the monthly due date.

For the management of neonatal abstinence syndrome†. Sublingual dosage Neonates†

Initially, 13.2 to 15.9 mcg/kg/day sublingually divided every 8 hours. Titration schedules vary, but may be titrated by either 0.8 mcg/kg increments or by 25% per day based on targeted NAS scores (Max: 60 mcg/kg/day sublingually). Phenobarbital may be added when a maximum buprenorphine dose has been achieved or if unable to wean after 24 to 48 hours. Once symptoms are controlled, taper dosage. After infant symptoms have been stable for at least 24 to 48 hours, dosage may be decreased by 0.8 mcg/kg increments back down to 4.4 mcg/kg/dose every 8 hours for 3 doses, with additional fixed incremental reductions in dose and interval (2.6 mcg/kg/dose every 8 hours for 3 doses, 1.7 mcg/kg/dose every 8 hours for 3 doses, 1.7 mcg/kg/dose every 12 hours for 2 doses, and 1.7 mcg/kg/dose every 24 hours for 1 dose) or 10% per day until within 10% of starting dose. Dosage, interval, length of treatment, and taper schedule are variable and must be individualized to control symptoms of withdrawal. Weaning may take several weeks to months.

†Indicates off-label use

Hepatic Impairment

Immediate-release parenteral dosage forms (e.g., Buprenex or generic equivalent):
Specific guidelines for dosage adjustments in hepatic impairment are not available; however, dosage adjustments may be necessary. Adjust based on clinical response.
 
Extended-release subcutaneous injection (e.g., Sublocade, Brixadi, or generic equivalents):
Moderate to severe hepatic impairment (e.g., Child Pugh B or C): Use is not recommended.
Mild hepatic impairment (e.g., Child Pugh A): No dosage adjustments are needed.
 
Sublingual dosage form (e.g., Subutex or generic equivalents):
Severe hepatic impairment: Consider reducing the starting and titration incremental dose by half, and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.
Moderate hepatic impairment: No dosage adjustment is needed; however, patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.
Mild hepatic impairment: No dosage adjustment or specific monitoring is required.
 
Transdermal patch (e.g., Butrans):
In patients with mild to moderate hepatic impairment where the patch is the first opioid analgesic, initiate patients on 5 mcg/hour transdermally. Otherwise, cautiously select a dose that corresponds to the patient's oral morphine equivalents per day and other factors that influence initial patch selection (see manufacturer's literature). In some patients, alternate therapy should be considered. Closely monitor the patient for the first 24 to 72 hours of treatment with the patch for respiratory depression. Individually titrate the dose thereafter to a level that provides adequate analgesia and tolerable side effects. The buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment and is only intended for 7-day application. Consider the use of an alternate analgesic with more flexibility of dosing in patients with severe hepatic impairment.
 
Buccal film (e.g., Belbuca):
Severe hepatic impairment (Child-Pugh C): Reduce starting dose and titration dose by half that of patients with normal liver function, from 150 mcg to 75 mcg.
Mild to moderate hepatic impairment: No dose adjustment necessary.
 
Subdermal implant (i.e., Probuphine):
Moderate to severe hepatic impairment: Do not use as dose titration cannot be performed. Patients who develop moderate or severe hepatic impairment during treatment should be monitored for sedation and respiratory depression; implant removal may be necessary.
Mild hepatic impairment: No dose adjustment necessary.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed. Some manufacturers recommend cautious use in severe renal impairment.

Acetaminophen; Aspirin; Diphenhydramine: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as dihydrocodeine. Dihydrocodeine is found in several combination cough products. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression if buprenorphine is used with dihydrocodeine. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acetaminophen; Chlorpheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acetaminophen; Codeine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms.
Acetaminophen; Dextromethorphan: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Reserve concomitant prescribing of buprenorphine and doxylamine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Diphenhydramine: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Acetaminophen; Hydrocodone: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
Acetaminophen; Oxycodone: (Major) Avoid concomitant use of oxycodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of oxycodone and/or precipitation of withdrawal symptoms.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Acrivastine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Adagrasib: (Major) Avoid concomitant use of adagrasib and buprenorphine due to the potential for increased buprenorphine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a buprenorphine dosage reduction until stable drug effects are achieved. Monitor for respiratory depression and sedation at frequent intervals and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Buprenorphine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Alfentanil: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as alfentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Alfuzosin: (Major) Buprenorphine should be used cautiously and with close monitoring with should be used cautiously and with alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Alosetron: (Moderate) Concurrent use of buprenorphine and antidiarrheals can lead to severe constipation and possibly additive CNS depression.
Alprazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Amiloride: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Amiodarone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Antiarrhythmics with an established risk for QT prolongation and TdP include disopyramide, flecainide, propafenone, quinidine (including dextromethorphan; quinidine), procainamide, amiodarone, ibutilide, and sotalol. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as amiodarone may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with buprenorphine. Amisulpride causes dose- and concentration- dependent QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Amitriptyline: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Amoxapine: (Major) Concomitant use of buprenorphine with amoxapine may cause excessive sedation and somnolence. Limit the use of buprenorphine and amoxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Amphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Amphetamine; Dextroamphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Amphetamines: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Anagrelide: (Major) Buprenorphine should be used cautiously and with close monitoring with anagrelide. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of buprenorphine and anagrelide for cardiovascular effects and evaluate as necessary.
Apalutamide: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with apalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If apalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
Apomorphine: (Major) Use apomorphine and buprenorphine together with caution due to the risk of additive QT prolongation and CNS depression. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). The FDA-approved labeling for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval, such as apomorphine. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Aprepitant, Fosaprepitant: (Moderate) Use caution if buprenorphine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in buprenorphine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Buprenorphine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of buprenorphine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of aripiprazole and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of aripiprazole and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation, such as buprenorphine. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concomitant drug use is unavoidable, frequently monitor electrocardiograms.
Artemether; Lumefantrine: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If coadministration is necessary, consider ECG monitoring.
Asciminib: (Moderate) Concomitant use of buprenorphine and asciminib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when asciminib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping asciminib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If asciminib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and asciminib is a CYP3A inhibitor.
Asenapine: (Major) Buprenorphine should be avoided in combination with asenapine. Asenapine has been associated with QT prolongation. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). The manufacturer of asenapine recommends avoiding coadministration with with other agents also known to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) If concurrent use of orphenadrine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Aspirin, ASA; Carisoprodol: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms. (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Aspirin, ASA; Oxycodone: (Major) Avoid concomitant use of oxycodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of oxycodone and/or precipitation of withdrawal symptoms.
Atazanavir: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir.
Atazanavir; Cobicistat: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor.
Atomoxetine: (Major) Concomitant use of atomoxetine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atropine: (Major) Reserve concomitant use of buprenorphine and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atropine; Difenoxin: (Major) Reserve concomitant use of buprenorphine and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Buprenorphine is an opioid analgesic. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of buprenorphine and antidiarrheals, such as atropine; diphenoxylate, can lead to severe constipation and possibly additive CNS depression.
Avacopan: (Major) Concomitant use of buprenorphine and avacopan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when avacopan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping avacopan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If avacopan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and avacopan is a CYP3A inhibitor.
Azithromycin: (Major) Concomitant use of azithromycin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Baclofen: (Major) Reserve concomitant prescribing of buprenorphine and baclofen for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Barbiturates: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenobarbital may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. It is likely that all barbiturates exert the same effect as phenobarbital. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if any of these agents are added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. Additive CNS depression may be the more important issue initially when barbiturates are given with buprenorphine; the induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Bedaquiline: (Major) Buprenorphine should be used cautiously and with close monitoring with bedaquiline. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Bedaquiline has also been reported to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Coadministration may result in additive or synergistic prolongation of the QT interval. Monitor the ECG.
Belladonna; Opium: (Major) Avoid the concomitant use of buprenorphine and opiate agonists, such as opium. Mixed opiate agonist/antagonists may block the effects of opiate agonists and reduce analgesic effects. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use can also cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Belumosudil: (Moderate) Concomitant use of buprenorphine and belumosudil can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when belumosudil is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping belumosudil, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If belumosudil is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and belumosudil is a CYP3A inhibitor.
Belzutifan: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with belzutifan is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If belzutifan is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and belzutifan is a CYP3A inducer.
Benzhydrocodone; Acetaminophen: (Major) Avoid the concomitant use of buprenorphine and opiate agonists, such as benzhydrocodone, when buprenorphine is used for analgesia. Buprenorphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of buprenorphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. Opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as benzhydrocodone. Exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Benzphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Benztropine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and benztropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Berotralstat: (Moderate) Concomitant use of buprenorphine and berotralstat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when berotralstat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping berotralstat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If berotralstat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and berotralstat is a CYP3A4 inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including buprenorphine.
Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including buprenorphine or buprenorphine; naloxone.
Brompheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Brompheniramine; Phenylephrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Brompheniramine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Bumetanide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and buprenorphine; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Bupropion: (Moderate) If concomitant use of buprenorphine and bupropion is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving mixed opiate agonists/antagonists. Naltrexone will antagonize the therapeutic benefits of mixed opiate agonists/antagonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous o

piate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects (respiratory insufficiency or arrest or circulatory collapse) with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur. (Moderate) If concomitant use of buprenorphine and bupropion is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Buspirone: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant buprenorphine and buspirone use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms.
Butorphanol: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Cabotegravir; Rilpivirine: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of buprenorphine with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of buprenorphine with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Cannabidiol: (Moderate) Concomitant use of mixed opioid agonists/antagonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of mixed opioid agonists/antagonists with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opioid agonist/antagonist is initiated in a patient taking cannabidiol, reduce initial dosage and titrate to clinical response. If cannabidiol is initiated in a patient taking a mixed opioid agonist/antagonist, use a lower initial dose of cannabidiol and titrate to clinical response. Educate patients about the risks and symptoms of excessive CNS depression.
Capsaicin; Metaxalone: (Major) Concomitant use of buprenorphine with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of buprenorphine with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of buprenorphine and metaxalone increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Carbamazepine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with carbamazepine is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If carbamazepine is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and carbamazepine is a CYP3A4 inducer.
Carbidopa; Levodopa; Entacapone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Carbinoxamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including buprenorphine or buprenorphine; naloxone.
Carisoprodol: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Celecoxib; Tramadol: (Major) Avoid concomitant use of tramadol and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of tramadol and/or precipitation of withdrawal symptoms.
Cenobamate: (Moderate) Concomitant use of buprenorphine with cenobamate may cause excessive sedation and somnolence. Limit the use of buprenorphine with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Additionally, monitor for reduced efficacy of buprenorphine and signs of opioid withdrawal if coadministration with cenobamate is necessary; consider increasing the dose of buprenorphine as needed. If cenobamate is discontinued, consider a dose reduction of buprenorphine and frequently monitor for signs of respiratory depression and sedation. Buprenorphine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease buprenorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ceritinib: (Major) Avoid coadministration of ceritinib with buprenorphine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping ceritinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency; consider increasing buprenorphine dosage until stable drug effects are achieved and monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Ceritinib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation.
Cetirizine: (Major) Reserve concomitant use of buprenorphine and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cetirizine; Pseudoephedrine: (Major) Reserve concomitant use of buprenorphine and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chloramphenicol: (Major) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as chloramphenicol. During co-administration, use the lowest buprenorphine starting dose and slowly titrate to desired effect. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is advisable. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Chlorcyclizine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlordiazepoxide: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation. (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlordiazepoxide; Clidinium: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chloroquine: (Major) Avoid coadministration of chloroquine with buprenorphine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Chlorpheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Codeine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Dextromethorphan: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as dihydrocodeine. Dihydrocodeine is found in several combination cough products. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression if buprenorphine is used with dihydrocodeine. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Hydrocodone: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Phenylephrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpheniramine; Pseudoephedrine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorpromazine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of chlorpromazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Chlorpromazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of chlorpromazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Chlorzoxazone: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants, such as chlorzoxazone. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Cimetidine: (Minor) Since the metabolism of buprenorphine is mediated by the CYP3A4 isozyme, co-administration of drugs that inhibit CYP3A4, such as cimetidine, may cause decreased clearance of buprenorphine. Thus, there is a potential for excessive buprenorphine-related side effects.
Ciprofloxacin: (Major) Concomitant use of buprenorphine and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use can also increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ciprofloxacin is added after a stable buprenorphine dose is achieved. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ciprofloxacin, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ciprofloxacin is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a CYP3A4 substrate and ciprofloxacin is a CYP3A4 inhibitor.
Cisapride: (Contraindicated) Avoid concomitant use of cisapride and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Citalopram: (Major) Due to the potential for QT prolongation, avoid coadministration of citalopram and buprenorphine if possible. Citalopram causes dose-dependent QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. If concurrent therapy is considered essential, ECG monitoring is recommended. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Clarithromycin: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Class IA Antiarrhythmics: (Major) Buprenorphine should be avoided in combination with Class IA antiarrhythmics. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Clemastine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Clobazam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clofazimine: (Major) Concomitant use of clofazimine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Clonazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clorazepate: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Clozapine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of clozapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clozapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of clozapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Cobicistat: (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor.
Codeine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms.
Codeine; Guaifenesin: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms.
Codeine; Phenylephrine; Promethazine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms. (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Codeine; Promethazine: (Major) Avoid concomitant use of codeine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of codeine and/or precipitation of withdrawal symptoms. (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
COMT inhibitors: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Conivaptan: (Moderate) Concomitant use of buprenorphine and conivaptan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when conivaptan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping conivaptan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If conivaptan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and conivaptan is a CYP3A inhibitor.
Crizotinib: (Major) Avoid coadministration of crizotinib with buprenorphine due to the risk of QT prolongation. Buprenorphine exposure may also increase, resulting in increased or prolonged opioid effects, particularly when crizotinib is added after a stable dose of buprenorphine has been achieved. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Consider a dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping crizotinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If crizotinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Buprenorphine is a CYP3A4 substrate that has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Cyclizine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Cyclobenzaprine: (Major) Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Cyproheptadine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Daclatasvir: (Moderate) Systemic exposure of buprenorphine may be increased when administered concurrently with daclatasvir. Taking these drugs together could increase or prolong the therapeutic effects of buprenorphine. No dosage adjustments are recommended; however, close monitoring of patients for potential adverse effects is advised.
Dalfopristin; Quinupristin: (Moderate) Concomitant use of buprenorphine and dalfopristin; quinupristin can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when dalfopristin; quinupristin is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping dalfopristin; quinupristin, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If dalfopristin; quinupristin is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Dalfopristin; quinupristin is a CYP3A4 inhibitor.
Dantrolene: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Daridorexant: (Major) Concomitant use of opiate agonists-antagonists with daridorexant may cause excessive sedation and somnolence. Limit the use of opiate agonists-antagonists with daridorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Darunavir: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together.
Darunavir; Cobicistat: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor.
Dasatinib: (Major) Monitor for evidence of QT prolongation if coadministration of buprenorphine and dasatinib is necessary. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Degarelix: (Major) Concomitant use of buprenorphine and degarelix increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as buprenorphine, should be expected with concurrent use of delavirdine.
Desflurane: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of halogenated anesthetics and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Halogenated anesthetics have a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, during co-administration of buprenorphine with other CNS depressants, hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression. The buprenorphine dose may also need to be lowered when given with drugs that reduce hepatic blood flow, such as halothane, which causes a reduction in hepatic blood flow by about 30%.
Desipramine: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Desvenlafaxine: (Moderate) Concurrent use of opioids with other drugs that modulate serotonergic function, such as SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, levomilnacipran, venlafaxine), has resulted in serotonin syndrome in some cases. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
Deutetrabenazine: (Major) Avoid coadministration of buprenorphine with deutetrabenazine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Concomitant use of buprenorphine with deutetrabenazine may cause excessive sedation and somnolence. Limit the use of buprenorphine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Dexamethasone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with dexamethasone is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If dexamethasone is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and dexamethasone is a CYP3A inducer.
Dexchlorpheniramine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Dexmedetomidine: (Moderate) If concurrent use of dexmedetomidine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Monitor patients for sedation or respiratory depression.
Dextroamphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Bupropion: (Moderate) If concomitant use of buprenorphine and bupropion is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Guaifenesin: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; Quinidine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Diazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If parental diazepam is used with an opiate agonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Dicyclomine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and dicyclomine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diltiazem: (Moderate) Concomitant use of buprenorphine and diltiazem can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when diltiazem is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping diltiazem, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If diltiazem is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and diltiazem is a CYP3A4 inhibitor.
Dimenhydrinate: (Major) Reserve concomitant prescribing of buprenorphine and dimenhydrinate for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Ibuprofen: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Naproxen: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Phenylephrine: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenoxylate; Atropine: (Major) Reserve concomitant use of buprenorphine and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Buprenorphine is an opioid analgesic. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of buprenorphine and antidiarrheals, such as atropine; diphenoxylate, can lead to severe constipation and possibly additive CNS depression.
Dofetilide: (Major) Coadministration of dofetilide and buprenorphine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Dolasetron: (Major) Buprenorphine should be used cautiously and with close monitoring with dolasetron. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
Dolutegravir; Rilpivirine: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Donepezil: (Major) Buprenorphine should be used cautiously and with close monitoring with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
Donepezil; Memantine: (Major) Buprenorphine should be used cautiously and with close monitoring with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
Doxepin: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Doxylamine: (Major) Reserve concomitant prescribing of buprenorphine and doxylamine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Doxylamine; Pyridoxine: (Major) Reserve concomitant prescribing of buprenorphine and doxylamine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Dronabinol: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include dronabinol. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Dronedarone: (Contraindicated) Avoid concomitant use of dronedarone and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Droperidol: (Major) Mixed opiate agonists/antagonists have additive or potentiating effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant should be used.
Duloxetine: (Moderate) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as duloxetine, has resulted in serotonin syndrome in some cases. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
Efavirenz: (Major) If possible, avoid coadministration of efavirenz and buprenorphine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as buprenorphine. Efavirenz has been shown to decrease the AUC of buprenorphine by 50% and the norbuprenorphine AUC by 71%. No withdrawal symptoms have been reported and no dosage adjustments are recommended; however, monitor patients for withdrawal symptoms.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) If possible, avoid coadministration of efavirenz and buprenorphine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as buprenorphine. Efavirenz has been shown to decrease the AUC of buprenorphine by 50% and the norbuprenorphine AUC by 71%. No withdrawal symptoms have been reported and no dosage adjustments are recommended; however, monitor patients for withdrawal symptoms.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) If possible, avoid coadministration of efavirenz and buprenorphine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as buprenorphine. Efavirenz has been shown to decrease the AUC of buprenorphine by 50% and the norbuprenorphine AUC by 71%. No withdrawal symptoms have been reported and no dosage adjustments are recommended; however, monitor patients for withdrawal symptoms.
Elagolix: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with elagolix is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If elagolix is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with elagolix is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If elagolix is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer.
Elbasvir; Grazoprevir: (Moderate) Administering buprenorphine with elbasvir; grazoprevir may result in elevated buprenorphine plasma concentrations. Buprenorphine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and buprenorphine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buprenorphine, can increase buprenorphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Eliglustat: (Major) Buprenorphine should be used cautiously and with close monitoring with eliglustat. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor. (Moderate) The plasma concentrations of buprenorphine and its metabolite, norbuprenorphine, are elevated when administered concurrently with elvitegravir. Dose adjustments are not required; however clinical monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor. (Moderate) The plasma concentrations of buprenorphine and its metabolite, norbuprenorphine, are elevated when administered concurrently with elvitegravir. Dose adjustments are not required; however clinical monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Encorafenib: (Major) Avoid coadministration of encorafenib and buprenorphine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Entacapone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Entrectinib: (Major) Concomitant use of buprenorphine and entrectinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Enzalutamide: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with enzalutamide is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If enzalutamide is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
Eribulin: (Major) Buprenorphine should be used cautiously and with close monitoring with eribulin. Eribulin has been associated with QT prolongation. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If eribulin and buprenorphine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Erythromycin: (Major) Concomitant use of buprenorphine and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use can also increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when erythromycin is added after a stable buprenorphine dose is achieved. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping erythromycin, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If erythromycin is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a CYP3A4 substrate and erythromycin is a CYP3A4 inhibitor.
Escitalopram: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of escitalopram and buprenorphine is necessary. Escitalopram may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Esketamine: (Major) Closely monitor patients receiving esketamine and buprenorphine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Eslicarbazepine: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer, such as eslicarbazepine, is used with a CYP3A4 substrate, such as buprenorphine. Moderate to strong CYP3A4 inducers may increase the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if a CYP3A4 inducer is added. Conversely, buprenorphine doses may need to be decreased if the CYP3A4 inducer discontinued. The effect of CYP3A4 inducers on buprenorphine implants has not been studied.
Estazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Eszopiclone: (Moderate) If concurrent use of eszopiclone and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Ethacrynic Acid: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and buprenorphine; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Etomidate: (Major) If general anesthetics are required during treatment with buprenorphine, consider the potential for additive pharmacological effects during dose selection. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression.
Etravirine: (Moderate) Etravirine may decrease the systemic exposure and therapeutic efficacy of buprenorphine; monitor for potential reduction in efficacy or buprenorphine withdrawal symptoms. Buprenorphine is a CYP3A substrate, and etravirine is a moderate CYP3A inducer.
Everolimus: (Moderate) Concomitant use of buprenorphine and everolimus can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when everolimus is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping everolimus, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If everolimus is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Everolimus is a weak CYP3A4 inhibitor.
Fedratinib: (Moderate) Concomitant use of buprenorphine and fedratinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fedratinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fedratinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fedratinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and fedratinib is a moderate CYP3A4 inhibitor.
Fenfluramine: (Moderate) Concomitant use of opioid agonists-antagonists with fenfluramine may cause excessive sedation and somnolence. Limit the use of opioid agonists with fenfluramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fentanyl: (Major) Avoid concomitant use of fentanyl and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of fentanyl and/or precipitation of withdrawal symptoms.
Fingolimod: (Major) Buprenorphine should be used cautiously and with close monitoring with fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP), such as buprenorphine. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flavoxate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and flavoxate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Flecainide: (Major) Concomitant use of flecainide and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as mixed opiate agonists/antagonists or their combinations (e.g., buprenorphine; naloxone), may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
Fluconazole: (Contraindicated) Avoid concomitant use of fluconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fluconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fluconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fluconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and fluconazole is a CYP3A inhibitor.
Fluoxetine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Fluoxetine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Fluphenazine: (Moderate) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Flurazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome during concurrent use of fluvoxamine and buprenorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as fluvoxamine, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, coadministration of a moderate CYP3A4 inhibitor such as fluvoxamine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If coadministration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosamprenavir: (Moderate) Concomitant use of buprenorphine and fosamprenavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when fosamprenavir is added after a stable buprenorphine do se is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping fosamprenavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If fosamprenavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and fosamprenavir is a CYP3A inhibitor.
Foscarnet: (Major) Concomitant use of buprenorphine and foscarnet increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fosphenytoin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with fosphenytoin is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If fosphenytoin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and fosphenytoin is a CYP3A4 inducer.
Fostemsavir: (Major) Avoid coadministration of buprenorphine with fostemsavir. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Frovatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Furosemide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and buprenorphine; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Gabapentin: (Major) Concomitant use of buprenorphine with gabapentin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of buprenorphine with gabapentin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Gemifloxacin: (Major) Buprenorphine should be used cautiously and with close monitoring with gemifloxaicn. Gemifloxacin may prolong the QT interval in some patients. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and buprenorphine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Gilteritinib: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and buprenorphine is necessary. FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. Gilteritinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Glasdegib: (Major) Avoid coadministration of glasdegib with buprenorphine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Glycerol Phenylbutyrate: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with glycerol phenylbutyrate is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If glycerol phenylbutyrate is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer.
Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Glycopyrrolate; Formoterol: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Goserelin: (Major) Concomitant use of buprenorphine and goserelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Granisetron: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Granisetron also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as granisetron, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and ganisetron is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
Grapefruit juice: (Moderate) Since the metabolism of buprenorphine is mediated by CYP3A4, consumption of grapefruit juice, a strong CYP3A4 inhibitor, may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. Dose adjustments of buprenorphine may be necessary in patients who regularly consume grapefruit juice. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Guaifenesin; Hydrocodone: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
Halogenated Anesthetics: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of halogenated anesthetics and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Halogenated anesthetics have a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, during co-administration of buprenorphine with other CNS depressants, hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression. The buprenorphine dose may also need to be lowered when given with drugs that reduce hepatic blood flow, such as halothane, which causes a reduction in hepatic blood flow by about 30%.
Haloperidol: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of haloperidol and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Haloperidol has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of haloperidol and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Histrelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving buprenorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and homatropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydrocodone: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
Hydrocodone; Ibuprofen: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
Hydrocodone; Pseudoephedrine: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
Hydromorphone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydromorphone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of hydroxyzine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, if concomitant use is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Hyoscyamine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Ibuprofen; Oxycodone: (Major) Avoid concomitant use of oxycodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of oxycodone and/or precipitation of withdrawal symptoms.
Ibutilide: (Major) Buprenorphine should be avoided in combination with ibutilide. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Ibutilide, a class III antiarrhythmic, has an established risk for QT prolongation and TdP and caution is recommended if concurrent use with buprenorphine is required. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Idelalisib: (Major) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as idelalisib. During co-administration, use the lowest buprenorphine starting dose and slowly titrate to desired effect. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is advisable. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Iloperidone: (Major) Buprenorphine should be avoided in combination with iloperidone. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Iloperidone also has a possible risk for QT prolongation and TdP. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of iloperidone and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Imatinib: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as imatinib, STI-571 may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Imipramine: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Indapamide: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when indapamide is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Indinavir: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of strong CYP3A4 inhibitors such as anti-retroviral protease inhibitors (e.g., amprenavir, fosamprenavir, indinavir, nelfinavir) may result in increased systemic exposure to buprenorphine, with the potential for excessive buprenorphine-related side effects; however, studies have shown that nelfinavir has little effect on buprenorphine pharmacokinetics and no significant pharmacodynamic effects. In general, if a protease inhibitor and buprenorphine are used concurrently, monitor accordingly for sedation and respiratory depression and adjust the buprenorphine dosage if needed. Consider conservative buprenorphine therapy in patients already on a CYP3A4 inhibitor. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with buprenorphine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with buprenorphine may result in increased serum concentrations of buprenorphine. Buprenorphine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of halogenated anesthetics and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Halogenated anesthetics have a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, during co-administration of buprenorphine with other CNS depressants, hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression. The buprenorphine dose may also need to be lowered when given with drugs that reduce hepatic blood flow, such as halothane, which causes a reduction in hepatic blood flow by about 30%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Isoniazid, INH; Rifampin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Itraconazole: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of itraconazole and buprenorphine is necessary. Buprenorphine and itraconazole have been associated with QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, coadministration of a strong CYP3A4 inhibitor such as itraconazole may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Ivacaftor: (Moderate) Use caution when administering ivacaftor and buprenorphine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buprenorphine, can increase buprenorphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with buprenorphine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Ketamine: (Major) If general anesthetics are required during treatment with buprenorphine, consider the potential for additive pharmacological effects during dose selection. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Monitor patients for sedation or respiratory depression.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ketoconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ketoconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ketoconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and ketoconazole is a CYP3A inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with buprenorphine is necessary; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Lasmiditan: (Moderate) Concomitant use of buprenorphine with lasmiditan may cause excessive sedation, somnolence, and serotonin syndrome. Limit the use of buprenorphine with lasmiditan to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Lefamulin: (Major) Avoid coadministration of lefamulin with buprenorphine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Lemborexant: (Moderate) Concomitant use of opiate agonists-antagonists with lemborexant may cause excessive sedation and somnolence. Limit the use of the opiate agonists-antagonist with lemborexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
Lenacapavir: (Moderate) Concomitant use of buprenorphine and lenacapavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when lenacapavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping lenacapavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If lenacapavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and lenacapavir is a CYP3A inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with buprenorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of buprenorphine; monitor for potential reduction in efficacy. Buprenorphine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of buprenorphine; monitor for potential reduction in efficacy. Buprenorphine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) Concomitant use of buprenorphine and letermovir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when letermovir is added after a stable buprenorphine dose is achieved. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping letermovir, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If letermovir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving buprenorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving buprenorphine. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
Levocetirizine: (Major) Reserve concomitant use of buprenorphine and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Levofloxacin: (Major) Concomitant use of levofloxacin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ketoconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ketoconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ketoconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and ketoconazole is a CYP3A inhibitor.
Levomilnacipran: (Moderate) If concomitant use of buprenorphine and levomilnacipran is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Levorphanol: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as levorphanol. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Linezolid: (Major) Avoid concomitant use of buprenorphine in patients receiving linezolid or within 14 days of stopping treatment with linezolid due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
Lisdexamfetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Lithium: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of lithium and buprenorphine is necessary. Lithium may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as lithium, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with buprenorphine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration. Lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval and there are postmarketing reports of TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommends avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In electrophysiology studies, lofexidine (2.88 mg/day) coadministered with buprenorphine (16 to 24 mg/day) resulted in a maximum mean QTcF increase of 15 (5.6) msec from buprenorphine-alone baseline.
Lonafarnib: (Moderate) Concomitant use of buprenorphine and lonafarnib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when lonafarnib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping lonafarnib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If lonafarnib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and lonafarnib is a CYP3A4 inhibitor.
Loop diuretics: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and buprenorphine; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Loperamide: (Major) Concomitant use of loperamide and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Loperamide; Simethicone: (Major) Concomitant use of loperamide and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lopinavir; Ritonavir: (Major) Concomitant use of lopinavir and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor.
Lorazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lorcaserin: (Moderate) If concomitant use of buprenorphine and lorcaserin is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Lorlatinib: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with lorlatinib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If lorlatinib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of buprenorphine by decreasing its systemic exposure; use together with caution and consider buprenorphine dosage adjustment if necessary. Buprenorphine is a primary substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and buprenorphine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buprenorphine, can increase buprenorphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and buprenorphine. Concurrent use may result in additive CNS depression.
Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as buprenorphine.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as buprenorphine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Maprotiline: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include maprotiline. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Maribavir: (Moderate) Concomitant use of buprenorphine and maribavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when maribavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping maribavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If maribavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and maribavir is a weak CYP3A inhibitor.
Mavacamten: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with mavacamten is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If mavacamten is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and mavacamten is a CYP3A inducer.
Meclizine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Mefloquine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as mefloquine. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Meperidine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as meperidine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Meprobamate: (Moderate) If concurrent use of meprobamate and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Metaxalone: (Major) Concomitant use of buprenorphine with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of buprenorphine with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of buprenorphine and metaxalone increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Methadone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Methadone has a possible risk for QT prolongation and TdP and use with buprenorphine should be avoided if possible. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as methadone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Methamphetamine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Methocarbamol: (Major) Reserve concomitant prescribing of buprenorphine and methocarbamol for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Methscopolamine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and methscopolamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Methylene Blue: (Major) Avoid concomitant use of buprenorphine in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
Methylphenidate Derivatives: (Moderate) If concomitant use of buprenorphine and methylphenidate derivatives is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Metronidazole: (Major) Concomitant use of metronidazole and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Midostaurin: (Major) Concomitant use of midostaurin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mifepristone: (Major) Concomitant use of buprenorphine and mifepristone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use can also increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when mifepristone is added after a stable buprenorphine dose is achieved. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping mifepristone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If mifepristone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a CYP3A4 substrate and mifepristone is a CYP3A4 inhibitor.
Milnacipran: (Moderate) If concomitant use of buprenorphine and milnacipran is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as buprenorphine. Caution should be exercised when using these agents concurrently.
Mirtazapine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), serotonin syndrome, or CNS depression during concurrent use of mirtazapine and buprenorphine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments; discontinue serotonergic agents if serotonin syndrome occurs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, the patient's overall response to treatment, and potential use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Mitapivat: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with mitapivat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If mitapivat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and mitapivat is a CYP3A inducer.
Mitotane: (Moderate) Use caution if mitotane and buprenorphine are used concomitantly, and monitor for decreased efficacy of buprenorphine and possible onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. Mitotane is a strong CYP3A4 inducer and buprenorphine is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of buprenorphine. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun; buprenorphine doses may need to be increased. Conversely, buprenorphine doses may need to be decreased if mitotane is discontinued, as buprenorphine plasma concentrations may increase and serious respiratory depression could occur.
Mobocertinib: (Major) Concomitant use of mobocertinib and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with mobocertinib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If mobocertinib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and mobocertinib is a CYP3A inducer.
Molindone: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include molindone. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Monoamine oxidase inhibitors: (Major) Avoid concomitant use of buprenorphine in patients receiving monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
Morphine: (Major) Avoid concomitant use of morphine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of morphine and/or precipitation of withdrawal symptoms.
Morphine; Naltrexone: (Major) Avoid concomitant use of morphine and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of morphine and/or precipitation of withdrawal symptoms.
Moxifloxacin: (Major) Concomitant use of buprenorphine and moxifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Nabilone: (Major) The use of nabilone with opiate agonist/antagonists may lead to additive CNS or respiratory depression, profound sedation, or coma. If these agents are used together, a reduced dosage of either drug may be advisable. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Cross-tolerance may occur between these drugs over time. Consider the patient's use of alcohol or illicit drugs. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
Nalbuphine: (Major) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Nalmefene: (Major) Naloxone, nalmefene, and naltrexone act as opiate antagonists at all opiate receptors. Administration of an opiate antagonist will override the actions of mixed opiate agonist/antagonists and precipitate opioid withdrawal effects. While opiate antagonism may be desirable in a patient with respiratory depression caused by the mixed opiate agonist/antagonist, severe pain can be unmasked and opiate withdrawal symptoms may occur in patients who have received chronic opiate agonist therapy.
Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving mixed opiate agonists/antagonists. Naltrexone will antagonize the therapeutic benefits of mixed opiate agonists/antagonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7 to 10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects (respiratory insufficiency or arrest or circulatory collapse) with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
Naratriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Nefazodone: (Major) The plasma concentrations of CYP3A4 substrates such as buprenorphine and its metabolite, norbuprenorphine, may be elevated when administered concurrently with strong CYP3A4 inhibitors such as nefazodone. If concurrent use of nefazodone and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Nelfinavir: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of strong CYP3A4 inhibitors such as anti-retroviral protease inhibitors (e.g., amprenavir, fosamprenavir, indinavir, nelfinavir) may result in increased systemic exposure to buprenorphine, with the potential for excessive buprenorphine-related side effects; however, studies have shown that nelfinavir has little effect on buprenorphine pharmacokinetics and no significant pharmacodynamic effects. In general, if a protease inhibitor and buprenorphine are used concurrently, monitor accordingly for sedation and respiratory depression and adjust the buprenorphine dosage if needed. Consider conservative buprenorphine therapy in patients already on a CYP3A4 inhibitor. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
Neostigmine; Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) If concomitant use of buprenorphine and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as buprenorphine. The plasma concentrations of buprenorphine can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nevirapine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with nevirapine is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If nevirapine is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and nevirapine is a CYP3A inducer.
Nilotinib: (Major) Buprenorphine should be avoided in combination with nitlotinib. Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval is not advised. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with nilotinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Nirmatrelvir; Ritonavir: (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor.
Nortriptyline: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Odevixibat: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with odevixibat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If odevixibat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Ofloxacin: (Major) Concomitant use of ofloxacin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Olanzapine; Fluoxetine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Fluoxetine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Olanzapine; Samidorphan: (Contraindicated) Salmidorphan is contraindicated in patients who are using opiate agonists or undergoing acute opioid withdrawal. Salmidorphan increases the risk of precipitating acute opioid withdrawal in patients dependent on opioids. Before initiating salmidorphan, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations, if a salmidorphan-treated patient requires opiates for anesthesia or analgesia, discontinue salmidorphan. The opiate agonist should be administered by properly trained individual(s), and the patient properly monitored in a setting equipped and staffed for cardiopulmonary resuscitation. In non-emergency situations, if a salmidorphan-treated patient requires opiate agonist treatment (e.g., for analgesia) discontinue salmidorphan at least 5 days before opioid treatment. Salmidorphan, as an opioid antagonist, may cause opioid treatment to be less effective or ineffective shortly after salmidorphan discontinuation. (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Oliceridine: (Major) Avoid concomitant use of oliceridine with opioid agonists-antagonists. Coadministration may reduce the analgesic effect of oliceridine and/or precipitate withdrawal symptoms.
Olutasidenib: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with olutasidenib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If olutasidenib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and olutasidenib is a CYP3A inducer.
Omaveloxolone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with omaveloxolone is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If omaveloxolone is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and omaveloxolone is a CYP3A inducer.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Ondansetron: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of ondansetron and buprenorphine is necessary. Ondansetron may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. ECG monitoring is recommended if these drugs are used concurrently. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as ondansetron, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Opicapone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Oritavancin: (Moderate) Buprenorphine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of buprenorphine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) If concurrent use of orphenadrine and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Osilodrostat: (Major) Concomitant use of buprenorphine and osilodrostat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when osilodrostat is added after a stable buprenorphine dose is achieved. Additionally, additive QT prolongation can occur. If concurrent use is necessary, monitor ECGs and consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping osilodrostat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If osilodrostat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Osilodrostat is a weak CYP3A4 inhibitor that is associated with dose-dependent QT prolongation. Buprenorphine is a CYP3A4 substrate that has been associated with QT prolongation and has a possible risk of torsade de pointes. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Osimertinib: (Major) Concomitant use of osimertinib and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Oxaliplatin: (Major) Concomitant use of oxaliplatin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Oxazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Oxcarbazepine: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer, such as oxcarbazepine, is used with a CYP3A4 substrate, such as buprenorphine. Moderate to strong CYP3A4 inducers may increase the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if a CYP3A4 inducer is added. Conversely, buprenorphine doses may need to be decreased if the CYP3A4 inducer discontinued.
Oxybutynin: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and oxybutynin use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Oxycodone: (Major) Avoid concomitant use of oxycodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of oxycodone and/or precipitation of withdrawal symptoms.
Oxymorphone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as oxymorphone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Ozanimod: (Major) In general, do not initiate buprenorphine in patients taking ozanimod or vice-versa due to the risk of additive serotonergic effects, bradycardia, QT prolongation, and torsade de pointes (TdP). There is also a potential for increased blood pressure. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension. Some buprenorphine dosage forms should not be used in patients taking MAOIs or within 14 days of stopping them. An active metabolite of ozanimod inhibits MAO-B. MAO inhibitor interactions with meperidine may manifest as serotonin syndrome, hypertensive crisis, or opioid toxicity (e.g., respiratory depression, coma). Although a small number of patients treated with ozanimod were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from coadministration. Ozanimod may also result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Buprenorphine is associated with QT prolongation and has a possible risk of TdP.
Pacritinib: (Major) Concomitant use of buprenorphine and pacritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase buprenorphine exposure resulting in increased or prolonged opioid effects, particularly when pacritinib is added after a stable buprenorphine dose is achieved. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concurrent use is necessary, consider a dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping pacritinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If pacritinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Buprenorphine is a substrate of CYP3A4 and pacritinib is a CYP3A4 inhibitor.
Palbociclib: (Moderate) Consider a reduced dose of buprenorphine with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the buprenorphine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Buprenorphine is a CYP3A4 substrate and palbociclib is a weak, time dependent CYP3A4 inhibitor. Coadministration can increase buprenorphine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of buprenorphine If palbociclib is discontinued, buprenorphine plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to buprenorphine.
Paliperidone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, coadministration of buprenorphine and paliperidone should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Paliperidone also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of paliperidone and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation.
Palonosetron: (Moderate) If concomitant use of buprenorphine and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Panobinostat: (Major) Concomitant use of panobinostat and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paroxetine: (Moderate) If concomitant use of buprenorphine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Pasireotide: (Major) Concomitant use of pasireotide and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and buprenorphine have been reported to prolong the QT interval. If pazopanib and buprenorphine must be used, closely monitor the patient for QT prolongation. In addition, pazopanib is a weak inhibitor of and substrate for CYP3A4, and buprenorphine is a CYP3A4 substrate. Concurrent administration of buprenorphine and pazopanib may result in increased pazopanib concentrations and/or increased buprenorphine concentrations. Dose reduction of one or both medications should be considered when coadministration of pazopanib and buprenorphine is necessary.
Pentamidine: (Major) Concomitant use of pentamidine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pentazocine: (Major) Avoid concomitant use of pentazocine with buprenorphine. Coadministration may reduce the analgesic effect of either drug and/or precipitate withdrawal symptoms.
Pentazocine; Naloxone: (Major) Avoid concomitant use of pentazocine with buprenorphine. Coadministration may reduce the analgesic effect of either drug and/or precipitate withdrawal symptoms.
Perphenazine: (Moderate) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Perphenazine; Amitriptyline: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Moderate) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Pexidartinib: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with pexidartinib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If pexidartinib is discontinued, consider a buprenorphine dose reduction, and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and pexidartinib is a CYP3A4 inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Reserve concomitant use of buprenorphine and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Major) Reserve concomitant use of buprenorphine and scopolamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Phenytoin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with phenytoin is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If phenytoin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and phenytoin is a CYP3A4 inducer.
Pimavanserin: (Major) Concomitant use of pimavanserin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pimozide: (Contraindicated) Avoid concomitant use of pimozide and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Pirtobrutinib: (Moderate) Concomitant use of buprenorphine and pirtobrutinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when pirtobrutinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping pirtobrutinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If pirtobrutinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and pirtobrutinib is a CYP3A inhibitor.
Pitolisant: (Major) Concomitant use of pitolisant and buprenophine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking buprenorphine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP.
Posaconazole: (Contraindicated) Concurrent use of buprenorphine and posaconazole is considered contraindicated. Buprenorphine, a CYP3A4 substrate, and posaconazole, a CYP3A4 inhibitor, are both associated with a risk for QT prolongation and torsade de pointes (TdP). The combined use of two drugs that can cause QT prolongation and TdP, along with a possible increased risk for these effects due to elevated plasma concentrations of buprenorphine via CYP3A4 inhibition by posaconazole, warrants a contraindication for concurrent use.
Pramipexole: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include pramipexole. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Pregabalin: (Major) Concomitant use of buprenorphine with pregabalin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of buprenorphine with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Primaquine: (Major) Concomitant use of primaquine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Prochlorperazine: (Moderate) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Promethazine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Promethazine; Dextromethorphan: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Promethazine; Phenylephrine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, caution and close monitoring are advisable if concurrent use of promethazine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Promethazine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of promethazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Propafenone: (Major) Concomitant use of propafenone and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propantheline: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and propantheline use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Protriptyline: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Pseudoephedrine; Triprolidine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Pyrilamine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Quazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Quetiapine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of quetiapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Quetiapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of quetiapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Quinine: (Major) Buprenorphine should be avoided in combination with quinine. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP) and should be avoided in combination with other drugs that prolong the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with quinine, a CYP3A4 inhibitor, further increasing the risk of toxicity. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Quizartinib: (Major) Concomitant use of quizartinib and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ramelteon: (Moderate) If concurrent use of ramelteon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Ranolazine: (Moderate) Concomitant use of buprenorphine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Rasagiline: (Major) Avoid concomitant use of buprenorphine in patients receiving rasagiline or within 14 days of stopping treatment with rasagiline due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
Relugolix: (Major) Concomitant use of relugolix and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Relugolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of relugolix and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Remifentanil: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as remifentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Remimazolam: (Major) Concomitant use of opioid agonists-antagonists with remimazolam may cause respiratory depression, hypotension, profound sedation, and death. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Ribociclib: (Major) Avoid coadministration of ribociclib with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when ribociclib is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when ribociclib is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Rifampin: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Rifamycins: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Rifapentine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with rifamycins is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If the rifamycin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and rifamycins are CYP3A4 inducers.
Rilpivirine: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Risperidone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of risperidone and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Risperidone has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of risperidone and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Ritlecitinib: (Moderate) Concomitant use of buprenorphine and ritlecitinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritlecitinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritlecitinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritlecitinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and ritlecitinib is a CYP3A inhibitor.
Ritonavir: (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor.
Rizatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Romidepsin: (Major) Concomitant use of romidepsin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ropinirole: (Moderate) Concomitant use of buprenorphine with other CNS depressants, such as ropinirole, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Rotigotine: (Moderate) Concomitant use of rotigotine with other CNS depressants, such as opiate agonists-antagonists, can potentiate the sedation effects of rotigotine.
Rucaparib: (Moderate) Concomitant use of buprenorphine and rucaparib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when rucaparib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping rucaparib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If rucaparib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and rucaparib is a CYP3A4 inhibitor.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as buprenorphine, may occur during concurrent use with rufinamide.
Safinamide: (Contraindicated) Concomitant use of safinamide with opioids is contraindicated due to the risk of serotonin syndrome. Allow at least 14 days between discontinuation of safinamide and initiation of treatment with opioids.
Saquinavir: (Major) Buprenorphine should be avoided in combination with saquinavir. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as saquinavir may decrease the clearance of buprenorphine further increasing the risk of QT prolongation and prolonged or increased opioid effects. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Scopolamine: (Major) Reserve concomitant use of buprenorphine and scopolamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Selegiline: (Major) Avoid concomitant use of buprenorphine in patients receiving selegiline or within 14 days of stopping treatment with selegiline due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
Selpercatinib: (Major) Avoid coadministration of selpercatinib with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when selpercatinib is added after a stable buprenorphine dose is achieved. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Additionally, consider a dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping selpercatinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If selpercatinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Selpercatinib is a weak CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner.
Serotonin-Receptor Agonists: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sertraline: (Major) Cautious use and close monitoring are advisable if concurrent use of sertraline and buprenorphine is necessary due to possible serotonin syndrome or QT prolongation. Buprenorphine has caused QT prolongation in some patients during clinical trials. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease. Concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has also resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Sevoflurane: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of halogenated anesthetics and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Halogenated anesthetics have a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, during co-administration of buprenorphine with other CNS depressants, hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects. Monitor patients for sedation or respiratory depression. The buprenorphine dose may also need to be lowered when given with drugs that reduce hepatic blood flow, such as halothane, which causes a reduction in hepatic blood flow by about 30%.
Siponimod: (Major) Concomitant use of siponimod and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sodium Oxybate: (Major) Concomitant use of buprenorphine with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of buprenorphine with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with taurursodiol is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If taurursodiol is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and taurursodiol is a CYP3A inducer.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as solifenacin. Solifenacin has been associated dose-dependent prolongation of the QT interval. TdP has been reported with post-marketing use, although causality was not determined. Additionally, monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Sorafenib: (Major) Concomitant use of sorafenib and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotalol: (Major) Concomitant use of sotalol and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with sotorasib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If sotorasib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer.
Spironolactone: (Moderate) Concomitant use of buprenorphine and spironolactone can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when spironolactone is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping spironolactone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If spironolactone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and spironolactone is a CYP3A4 inhibitor. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of buprenorphine and spironolactone can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when spironolactone is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping spironolactone, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If spironolactone is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and spironolactone is a CYP3A4 inhibitor. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with buprenorphine. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
St. John's Wort, Hypericum perforatum: (Moderate) The use of St. John's wort with buprenorphine is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of buprenorphine and also for signs of opioid withdrawal in patients who have developed physical dependence to buprenorphine. Buprenorphine is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Also monitor patients for the emergence of serotonin syndrome; both agents have serotonergic activity. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Stiripentol: (Major) Concomitant use of buprenorphine with stiripentol may cause excessive sedation and somnolence. Limit the use of buprenorphine with stiripentol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If buprenorphine is initiated in a patient taking stiripentol, reduce initial dosage and titrate to clinical response. If stiripentol is initiated a patient taking buprenorphine, use a lower initial dose of stiripentol and titrate to clinical response. Educate patients about the risks and symptoms of excessive CNS depression. Consider a dose adjustment of buprenorphine when coadministered with stiripentol. Coadministration may alter plasma concentrations of buprenorphine resulting in an increased risk of adverse reactions and/or decreased efficacy. Buprenorphine is a substrate of CYP3A4. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Concomitant use of buprenorphine and dalfopristin; quinupristin can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when dalfopristin; quinupristin is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping dalfopristin; quinupristin, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If dalfopristin; quinupristin is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4. Dalfopristin; quinupristin is a CYP3A4 inhibitor.
Sufentanil: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as sufentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
Sumatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sumatriptan; Naproxen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sunitinib: (Major) Concomitant use of sunitinib and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Suvorexant: (Moderate) If concurrent use of suvorexant and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Sedation, coma, or respiratory depression may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Tacrolimus: (Major) Both buprenorphine and tacrolimus have been associated with QTc prolongation, and both are CYP3A4 substrates. The manufacturer of tacrolimus recommends reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Tamoxifen: (Major) Concomitant use of tamoxifen and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tapentadol: (Major) Avoid the concomitant use of tapentadol and opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, or pentazocine). Opiate agonists/antagonists may partially block the analgesic, respiratory depressant, and CNS depressant effects of tapentadol. Due to their antagonistic properties, opiate agonists/antagonists may cause withdrawal symptoms in patients receiving chronic opiate agonists. These agents may also be used concurrently with some opiate agonists and cause additive CNS, respiratory, and hypotensive effects. Consider dose reduction of the opiate agonist in situations of concomitant prescription. The additive or antagonistic effects are dependent upon the dose of pure opiate agonist used; antagonistic effects are more common at low to moderate doses of the pure opiate agonist.
Tasimelteon: (Moderate) If concurrent use of tasimelteon and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Tedizolid: (Major) Avoid concomitant use of buprenorphine in patients receiving tedizolid or within 14 days of stopping treatment with tedizolid due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
Telavancin: (Major) Concomitant use of telavancin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telotristat Ethyl: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with telotristat is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If telotristat is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and telotristat is a CYP3A4 inducer.
Temazepam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tetrabenazine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, coadministration of tetrabenazine and buprenorphine should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tetrabenazine also has a possible risk for QT prolongation and TdP. Some buprenorphine labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of tetrabenazine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and buprenorphine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as buprenorphine, can increase buprenorphine exposure leading to increased or prolonged therapeutic effects and adverse events.
Thiazide diuretics: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and buprenorphine; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Thioridazine: (Contraindicated) Avoid concomitant use of thioridazine and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Tipranavir: (Minor) Although no significant effects have been noted, buprenorphine AUC, Cmax, and Cmin may be decreased by about 80% when coadministered with tipranavir plus ritonavir. Tipranavir trough concentrations may be decreased by 19 to 40% and serum concentration monitoring may be warranted.
Tizanidine: (Major) Concomitant use of buprenorphine and tizanidine can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant use of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation.
Tolcapone: (Major) Concomitant use of opiate agonists-antagonists with other central nervous system (CNS) depressants, such as COMT inhibitors, can potentiate the effects of the opiate agonists-antagonist and may lead to additive CNS or respiratory depression. Prior to concurrent use of a mixed opiate agonist-antagonist in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. If these agents are used together, reduced dosages may be necessary. Carefully monitor the patient for hypotension and CNS depression.
Tolterodine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Additionally, monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Toremifene: (Major) Concomitant use of toremifene and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Torsemide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and buprenorphine; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Tramadol: (Major) Avoid concomitant use of tramadol and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of tramadol and/or precipitation of withdrawal symptoms.
Tramadol; Acetaminophen: (Major) Avoid concomitant use of tramadol and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of tramadol and/or precipitation of withdrawal symptoms.
Trandolapril; Verapamil: (Moderate) Concomitant use of buprenorphine and verapamil can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when verapamil is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping verapamil, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If verapamil is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and verapamil is a CYP3A4 inhibitor.
Trazodone: (Major) Due to the potential for QT prolongation, additive CNS depressant effects, and a potential for serotonin syndrome, cautious use and close monitoring are advisable if concurrent use of trazodone and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Trazodone has a possible risk for QT prolongation. FDA-approved labeling for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking trazodone, use a lower initial dose of the opiate and titrate to clinical response. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Triamterene: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a triamterene and buprenorphine; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a triamterene and buprenorphine; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Triazolam: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Triclabendazole: (Major) Concomitant use of triclabendazole and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
T ricyclic antidepressants: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Trifluoperazine: (Moderate) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of phenothiazines and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Phenothiazines including fluphenazine, perphenazine, prochlorperazine, and trifluoperazine are associated with a possible risk for QT prolongation. Theoretically, these phenothiazines may increase the risk of QT prolongation if co-administered with drugs with a risk of QT prolongation. Also, concomitant use of buprenorphine with other CNS depressants, such as phenothiazines, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Trihexyphenidyl: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant buprenorphine and trihexyphenidyl use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like buprenorphine, may potentiate the effects of either trimethobenzamide or buprenorphine.
Trimipramine: (Major) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Triprolidine: (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Triptorelin: (Major) Concomitant use of triptorelin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trofinetide: (Moderate) Concomitant use of buprenorphine and trofinetide can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when trofinetide is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping trofinetide, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If trofinetide is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and trofinetide is a CYP3A inhibitor.
Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug, such as trospium. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Tucatinib: (Moderate) Concomitant use of buprenorphine and tucatinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when tucatinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping tucatinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If tucatinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and tucatinib is a CYP3A4 inhibitor.
Vandetanib: (Major) Concomitant use of vandetanib and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vardenafil: (Major) Concomitant use of vardenafil and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of vemurafenib and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Vemurafenib also has a possible risk for QT prolongation and TdP. Some buprenorphine labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If buprenorphine and vemurafenib must be coadministered, must be coadministered, ECG monitoring is recommended. In addition, vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as buprenorphine, could be expected with concurrent use. Decreased buprenorphine efficacy or buprenorphine withdrawal symptoms are possible. Use caution, and monitor therapeutic effects of buprenorphine when co-administered with vemurafenib. The effect of CYP3A4 inducers on buprenorphine implants has not been studied.
Venlafaxine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of venlafaxine and buprenorphine is necessary. Venlafaxine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SNRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Verapamil: (Moderate) Concomitant use of buprenorphine and verapamil can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when verapamil is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping verapamil, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If verapamil is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and verapamil is a CYP3A4 inhibitor.
Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with buprenorphine.
Vilazodone: (Moderate) Concomitant use of buprenorphine with vilazodone may cause sedation, somnolence, and increased risk of serotonin syndrome. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Viloxazine: (Moderate) Concomitant use of buprenorphine and viloxazine can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when viloxazine is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping viloxazine, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If viloxazine is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and viloxazine is a CYP3A4 inhibitor.
Voclosporin: (Major) Concomitant use of voclosporin and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with voclosporin is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Vonoprazan; Amoxicillin: (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration. (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Voriconazole: (Major) Avoid coadministration of voriconazole with buprenorphine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of buprenorphine may also be increased, resulting in increased or prolonged opioid effects, particularly when voriconazole is added after a stable buprenorphine dose is achieved. Buprenorphine is a substrate of CYP3A4 that has been associated with QT prolongation and has a possible risk of TdP. Voriconanzole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of TdP, cardiac arrest, and sudden death. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Major) Concomitant use of vorinostat and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vortioxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with vortioxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Voxelotor: (Moderate) Concomitant use of buprenorphine and voxelotor can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when voxelotor is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. When stopping voxelotor, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If voxelotor is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and voxelotor is a CYP3A4 inhibitor.
Zafirlukast: (Moderate) Concomitant use of buprenorphine and zafirlukast can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when zafirlukast is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping zafirlukast, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If zafirlukast is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and zafirlukast is a CYP3A inhibitor.
Zaleplon: (Major) Reserve concomitant prescribing of buprenorphine and zaleplon for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Ziconotide: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Ziprasidone: (Major) Avoid the use of buprenorphine and ziprasidone together due to a risk for QT prolongation; additive sedation and CNS depression may also occur. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The prescribing information for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval.
Zolmitriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine with serotonergic-receptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Zolpidem: (Major) Reserve concomitant prescribing of buprenorphine and zolpidem for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Limit the dose of Intermezzo sublingual tablets to 1.75 mg/day. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Belbuca Buccal Film: 75mcg, 150mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcg
Belbuca Transmucosal Film: 75mcg, 150mcg, 300mcg, 450mcg, 600mcg, 750mcg, 900mcg
Brixadi/Sublocade Subcutaneous Inj Sol: 0.5mL, 1mL, 50mg, 100mg, 356mg
Buprenex/Buprenorphine/Buprenorphine Hydrochloride Intramuscular Inj Sol: 0.3mg, 1mL
Buprenex/Buprenorphine/Buprenorphine Hydrochloride Intravenous Inj Sol: 0.3mg, 1mL
Buprenorphine/Buprenorphine Hydrochloride/Subutex Sublingual Tablet, SL: 2mg, 8mg
Buprenorphine/Butrans Transdermal Film ER: 1h, 5mcg, 7.5mcg, 10mcg, 15mcg, 20mcg
Probuphine Subdermal Imp: 74.2mg

Adults

0.6 mg/dose IM, 0.3 mg/dose IV, 20 mcg/hour transdermally, or 900 mcg transmucosal every 12 hours for pain; for opioid use disorder: 24 mg/day SL, 32 mg/week extended-release subcutaneous injection (Brixadi), 128 mg/month (Brixadi) or 300 mg/month (Sublocade) extended-release subcutaneous injection, or 4 implants/6 months (Probuphine) subdermally (each implant contains 74.2 mg of buprenorphine).

Geriatric

0.6 mg/dose IM, 0.3 mg/dose IV, 20 mcg/hour transdermally, or 900 mcg transmucosal every 12 hours for pain; for opioid use disorder: 24 mg/day SL, 32 mg/week extended-release subcutaneous injection (Brixadi), 128 mg/month (Brixadi) or 300 mg/month (Sublocade) extended-release subcutaneous injection, or 4 implants/6 months (Probuphine) subdermally (each implant contains 74.2 mg of buprenorphine).

Adolescents

16 to 17 years: 0.6 mg/dose IM and 0.3 mg/dose IV for pain. For opioid use disorder: 4 implants/6 months (Probuphine) subdermally (each implant contains 74.2 mg of buprenorphine). Safety and efficacy of other dosage forms have not been established.
13 to 15 years: 0.6 mg/dose IM and 0.3 mg/dose IV for pain. Safety and efficacy of other dosage forms have not been established.

Children

2 to 12 years: 6 mcg/kg/dose IV/IM every 4 to 8 hours for pain. Safety and efficacy of other dosage forms have not been established.
Less than 2 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

60 mcg/kg/day sublingually has been used off-label for neonatal abstinence syndrome.

Buprenorphine is a mixed agonist-antagonist narcotic. It acts as a partial agonist at the mu-opioid receptor, an antagonist at the kappa-opioid receptor, an agonist at the delta-opioid receptor, and a partial agonist at the ORL-1 (nociceptin/orphanin FQ) receptor. Opiate agonists are believed to exert their effects by stimulating specific opiate receptors, designated as mu, kappa, delta, and ORL-1 which have been reclassified by an International Union of Pharmacology subcommittee as DOP (delta), KOP (kappa), MOP (mu), and NOP (ORL-1). Mu-receptors, where buprenorphine is an agonist, are considered the classic morphine-receptor type, as stimulation at this receptor produces supraspinal analgesia, respiratory depression, euphoria, and physical dependence. Actions at kappa-receptors, where buprenorphine is an antagonist, are believed to produce alterations in the perception of pain and the emotional response to pain. Dysphoria is often experienced from kappa-receptor activation. It is hypothesized that patients with opioid or cocaine drug dependence have increased kappa-receptor activity to modulate the mu-receptor agonistic effects. Patients with dependence to full opioid agonists are more likely to experience euthymia following administration of buprenorphine, which increases mu-receptor activity and blocks kappa-receptor activity, as compared to following administration of a pure mu-receptor antagonist (i.e., naloxone or naltrexone), which block mu-receptors while leaving the full agonist effects of kappa-receptor activation unopposed. The effect of buprenorphine activity at delta and ORL-1 (NOP) receptors is not fully elucidated. Buprenorphine binds mu-receptors with high affinity; however, buprenorphine has less intrinsic activity at mu-receptors than do full opioid agonists. Blockade of the effects of full mu-receptor agonists occurs after acute administration of buprenorphine. Buprenorphine very slowly dissociates from the mu-receptor, which likely accounts for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifested physical dependence. Partial agonist typically have a ceiling effect on both respiratory depression and analgesic effect; the analgesic ceiling effect has been demonstrated with sublingual buprenorphine.
 
The pharmacologic effects observed after opiates bind to their receptors involve a second messenger such as cyclic AMP, which is synthesized by adenylate cyclase. Opioid receptors are coupled to these second messenger systems through an inhibitory G-protein (guanine nucleotide-binding protein). G-proteins are located at the cell surface along with many other receptors, including opioid receptors. G-proteins are thought to interact with opiate receptors, giving the receptor a higher affinity for the opiate. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case, the effector system is adenylate cyclase and cyclic AMP located at the inner surface of the plasma membrane. Opioid agonists effectively inhibit adenylate cyclase and cause a decrease in intracellular cyclic AMP levels. Other research has shown that mu-, delta-, and kappa-receptors are associated with ion channels and control the influx of cations into the cell. Mu- and delta-receptor stimulation is associated with increasing potassium influx and kappa-receptor activity is associated with reducing calcium influx in cells located in various human and animal nerve systems. All of these effects appear to ultimately reduce transmitter release and may also be mediated through G-proteins.

Buprenorphine is administered orally via the sublingual or buccal route, transdermally by subdermal implant, parenterally by intravenous (IV), intramuscular (IM), or epidural injection, and via extended-release subcutaneous injectable formulations. Within the systemic circulation, buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. The drug undergoes N-dealkylation metabolism by CYP3A4 isozymes to an active metabolite, norbuprenorphine. A portion of the norbuprenorphine then undergoes further glucuronidation metabolism. The clearance of buprenorphine is related to hepatic blood flow; when administered with drugs that decrease this flow (e.g., some general anesthetics) buprenorphine elimination may be impaired. As determined in a pharmacokinetic study involving radiolabeled drug, buprenorphine is primarily eliminated in the feces (69%) with 31% eliminated in the urine; collected compounds included buprenorphine, norbuprenorphine, and 2 unidentified buprenorphine metabolites.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
Buprenorphine is metabolized to its major metabolite, norbuprenorphine, primarily by CYP3A4. Based on studies using transmucosal buprenorphine, patients receiving concomitant treatment with CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors, macrolide antibiotics) or CYP3A4 inducers (e.g., phenobarbital, phenytoin, carbamazepine, rifampicin) should be monitored for alterations in buprenorphine plasma concentrations, regardless of the product administered. Buprenorphine has been shown to be a CYP3A4 and CYP2D6 inhibitor and in vitro studies have shown that norbuprenorphine is a modest CYP2D6 inhibitor; however, clinically relevant interactions of buprenorphine with CYP2D6 substrates are not expected.

Oral Route

Sublingual Route (e.g., Subutex and generic equivalents): Buprenorphine displays poor oral bioavailability; however, bioavailability improves with sublingual administration. Plasma concentrations (Cmax) and drug exposure (AUC) of buprenorphine increase linearly, though not in direct dose proportionality, with increasing sublingual dose over a range of 4 to 16 mg. Opioid agonist effects of sublingual buprenorphine are limited by a ceiling effect which occurs between 8 and 16 mg; doses above this maximum produced no additional effect. The mean elimination half-life of sublingually administered buprenorphine is 37 hours.
 
Transmucosal Route (Belbuca): The absolute bioavailability of buprenorphine with transmucosal administration ranges from 46 to 65%. With multiple dose administration, steady-state plasma concentrations were achieved prior to the sixth dose. Steady-state Cmax and AUC increase proportionally to dose. Administration of the film with cold, hot, or room temperature water reduced systemic buprenorphine exposure by 23 to 27%. Low pH liquids such as decaffeinated cola decreased drug exposure by 37%.

Intravenous Route

The onset of action and time to peak effect of buprenorphine are more rapid with IV administration as compared to IM or epidural administration. The elimination half-life of intravenous buprenorphine (0.3 mg IV) is 1.2 to 7.2 hours with an average of 2.2 hours.

Intramuscular Route

Pharmacological effects of buprenorphine occur as soon as 15 minutes after IM injection and usually last for 6 to 10 hours. Peak pharmacologic effects usually are observed at 1 hour. As expected, time to onset of action and peak effect are shorter with IV administration.

Subcutaneous Route

Subcutaneous depot extended-release injection (Sublocade): After subcutaneous injection of this product, the median time to maximum concentration (median Tmax) occurred at 24 hours post-dose. The product is injected subcutaneously as a liquid, with subsequent precipitation into a solid depot that contains buprenorphine. Buprenorphine is then released via diffusion from the biodegradation of the depot. Steady-state is reached in 4 to 6 months. The steady-state concentrations of the major metabolite, norbuprenorphine, are low compared to buprenorphine. The terminal half-life of buprenorphine extended-release subcutaneous injection has a range of 43 to 60 days due to slow release from the subcutaneous depot. Patients who discontinue the drug may have detectable plasma and urine concentrations of buprenorphine for 12 months or longer. Therefore, patients who discontinue treatment should be monitored for several months for signs and symptoms of withdrawal and treated appropriately. Buprenorphine may be detected in plasma and urine 22 to 38 months following last exposure, and it is expected that buprenorphine will be detected in patients for a longer time in urine than in plasma. Mean buprenorphine plasma concentrations for Cavg, Cmax, and Ctrough at steady-state for this product have been compared to daily transmucosal buprenorphine; consult the manufacturer literature for comparison tables.
Subcutaneous extended-release injection (Brixadi): Following subcutaneous injection, the extended-release formulation transforms from a low viscous solution to a liquid crystalline gel that encapsulates buprenorphine and releases it at a steady rate as the depot biodegrades. After administration, the buprenorphine plasma concentration increases with a median Tmax of about 24 hours for the weekly formulation and 6 to 10 hours for the monthly formulation. Based on trough levels after each dose, steady-state exposure is reached at administration of the fourth weekly or monthly dose. Norbuprenorphine steady-state plasma concentrations after subcutaneous injection of the weekly or monthly formulations are low compared to buprenorphine (AUC norbuprenorphine/buprenorphine ratio of 0.35). After multiple dose subcutaneous injections of the 32 mg/week buprenorphine product at different injection sites (abdomen, thigh, buttock, or upper arm), a comparable PK exposure was observed. However, injection into the upper arm was associated with approximately 10% lower plasma levels than other sites. The terminal plasma half-life of the subcutaneous buprenorphine formulation ranged from 3 to 5 days for the weekly injection and 19 to 26 days for the monthly injection. Mean buprenorphine plasma concentrations for Cavg, Cmax, and Ctrough at steady-state for this product have been compared to daily transmucosal buprenorphine; consult the manufacturer literature for comparison tables.

Topical Route

Transdermal Route (Butrans)
The proportion of buprenorphine mixed in the adhesive matrix is the same in each of the three different strengths of the buprenorphine transdermal system. The amount of buprenorphine released from the system per hour is proportional to the active surface area of the system. The 5, 10, and 20 mcg/hour patches provide dose-proportional buprenorphine AUCs after 7-day applications. Additionally, the pharmacokinetic profile is similar when applied to each of the suggested application sites; the skin is the limiting barrier to diffusion from the system into the bloodstream. Data from clinical studies suggest that the median time for the buprenorphine 10 mcg/hour transdermal system to deliver quantifiable buprenorphine concentrations (>= 25 pg/mL) is approximately 17 hours. The bioavailability relative to intravenous administration after a 7-day application is approximately 15% for all doses. Application of a heating pad directly to the buprenorphine transdermal system increased buprenorphine blood concentrations by 26 to 55%. Concentrations returned to normal within 5 hours after the heat was removed. Similarly, fever may increase the permeability of the skin and lead to increased buprenorphine concentrations; however, in a crossover study of healthy subjects, the AUC and Cmax did not change significantly in patients with a mild fever. A minimum rest period of 21 days is required before reapplication to the same site, in order to avoid variability in drug absorption. Steady state is achieved by day 3 after application. After dose titration, plasma buprenorphine concentrations show no further change over a 60-day study period. Buprenorphine metabolism in the skin after transdermal application is negligible. After removal of the system, mean buprenorphine concentrations decreased by 50% within 10 to 24 hours. The terminal half-life is approximately 26 hours.

Other Route(s)

Epidural Route
The duration of epidurally administered buprenorphine analgesic effect appears to be dose-dependent. In a double-blind controlled trial (n = 158), postoperative analgesia, as measured by patient report every 3 hours, was greater than placebo for 6 hours in patients administered 0.15 mg buprenorphine at the end of surgery (p less than 0.05) and for 12 hours in patients administered 0.3 mg buprenorphine at the end of surgery (p less than 0.05); no statistically significant differences in adverse events were reported between the groups.
 
Subdermal Implant Route (Probuphine)
After insertion of the buprenorphine implants, an initial buprenorphine peak was observed and the median time to maximum concentration (Tmax) occurred at 12 hours. After the initial peak, the plasma buprenorphine concentration slowly declined and steady-state plasma buprenorphine concentrations were reached by about Week 4. Mean steady-state plasma buprenorphine concentrations were about 0.5 to 1 ng/mL and were maintained for approximately 20 weeks (Week 4 through Week 24) in a 24-week treatment period. At steady state, the buprenorphine concentrations were stable and comparable to the trough buprenorphine concentration of 8 mg/day of sublingual buprenorphine at steady-state. In one pharmacokinetics study, subjects received 16 mg/day of sublingual buprenorphine for a minimum of 5 consecutive days, followed by 4 implants of buprenorphine (total of 320 mg buprenorphine HCl). Overall peak plasma buprenorphine concentrations were significantly lower after buprenorphine implant insertion than after dosing with sublingual buprenorphine. The average steady-state concentration of buprenorphine implant on Day 28 was about 8% and 52%, respectively, of the peak and trough concentrations of sublingual buprenorphine at steady-state.

Pregnancy

There have been no well-controlled studies of buprenorphine in pregnant women; buprenorphine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. As with other opioids, there is no consistent pattern of birth defects associated with opioid use during the first trimester. Reports of teratogenicity remain rare and account for a small increase in absolute risk. Limited published data on the use of buprenorphine immediate-release injection in pregnancy have not shown an increased risk of major malformations. The American College of Obstetricians and Gynecologists recommends early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Rely on validated screening tools, such as 4Ps, NIDA Quick Screen, and CRAFFT (for women 26 years or younger). Ensure opioids are appropriately indicated. For women using opioids for chronic pain, consider strategies to avoid or minimize the use of opioids, including alternative pain therapies (i.e., nonpharmacologic) and nonopioid pharmacologic treatments. Take a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids or other high-risk drugs such as benzodiazepines. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for neonatal opioid withdrawal syndrome, and how long-term opioid use may affect care during a future pregnancy. Opioid agonist pharmacotherapy is preferable to medically supervised withdrawal in pregnant women with opioid use disorder (OUD). Guidelines recommend discussing contraceptive use during OUD treatment to minimize the risk of unplanned pregnancy. Pregnant women receiving treatment for OUD may require dose adjustments of buprenorphine in order maintain abstinence from illicit drug use; closely monitor patients for withdrawal signs and symptoms and adjust dose as necessary. If the benefit of treatment with the subdermal implant (Probuphine) is determined to outweigh the risks during pregnancy, dosage adjustments cannot be made and the patient should be closely monitored to ensure adequate treatment. Because the implant dose cannot be adjusted, this formulation may not be an appropriate OUD treatment option to initiate in patients who are pregnant. The subcutaneous extended-release subcutaneous injection (Sublocade, Brixadi) may also not be the optimal dosage form for treatment of OUD during pregnancy. In published animal reproduction studies with an extended-release subcutaneous injection (Sublocade), administration to pregnant rabbits and rats during the period of organogenesis at the buprenorphine dose equivalent of 38 and 15 times (respectively) the maximum recommended human dose (MRHD) of 300 mg caused embryolethality, which appeared to be primarily attributable to the injection vehicle (Atrigel delivery system). Embryofetal death was also observed in both rats and rabbits when buprenorphine was administered during the period of organogenesis at doses 21 times and equal to (respectively) the mean daily dose of 4.6 mg buprenorphine delivered by the max doses of weekly and monthly extended-release subcutaneous injections of buprenorphine (Brixadi). In animal studies or oral buprenorphine, embryofetal death during organogenesis was observed in rats and rabbits given doses approximately 53 and 11 times the MRHD, respectively. Pre- and post-natal development studies in rats demonstrated increased neonatal death after oral and IM doses of approximately 4 and 3 times the MRHD, respectively. A pre- and postnatal development study in rats was also conducted using an extended-release subcutaneous injection (Sublocade), with no adverse effects noted for offspring survival, sexual maturation, behavioral assessment, or reproductive performance at up to 15 times the MRHD on an AUC basis. No teratogenic effects were observed in rats or rabbits given a range of doses more than the MRHD during organogenesis; however, events such as acephalus, omphalocele, and skeletal abnormalities have been reported in a few studies. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Further, prolonged maternal use of opioids, such as buprenorphine, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. From postmarketing reports with sublingual use, the time to onset of neonatal withdrawal signs ranged from day 1 to day 8 of life with most cases occurring on day 1. Advise pregnant women receiving treatment for opioid dependence with buprenorphine of the risk of NOWS and ensure that appropriate treatment will be available. The risk for NOWS must be balanced against the risk of untreated opioid addiction in the mother which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. The safety of injectable buprenorphine given during labor and obstetric delivery has not been established. Pregnant patients on buprenorphine maintenance therapy for OUD may require additional analgesia during labor. Transdermal and buccal buprenorphine are not for analgesic use during and immediately prior to labor, when shorter acting analgesics or other therapies are more appropriate. Opioids can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.