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Duragesic
Classes
Opiate Anesthetics
Opioid Agonists
Administration
Fentanyl products are not bioequivalent and are not interchangeable.
Transmucosal and sublingual formulations (Actiq, Fentora, Onsolis, Abstral, and Subsys) are not for use in the management of acute or postoperative pain. These products should only be used in opioid-tolerant patients.
Titrate initial dosage with caution and limit the initial quantity of medication prescribed.
Advise patients and caregivers that if an overdose is suspected to remove any remaining dosage formulation from the mouth and seek immediate medical help.
Abstral (sublingual tablets)
If mouth is dry, water may be used to moisten buccal mucosa before administration.
Dry hands before handling.
Immediately after removing from the blister pack, place tablet on the floor of the mouth directly under the tongue. Allow tablet(s) to dissolve completely.
Do not use more than 4 tablets at one time.
Instruct patients to not suck, chew, or swallow tablet. Further, instruct patients to avoid eating or drinking until tablet is dissolved.
Disposal: Dispose of any unneeded tablets as soon as no longer needed. Remove tablets from the blister cards and flush the tablets down the toilet. Do not dispose of blister cards, cartons, or other packaging in the toilet. Caregivers may also contact the product manufacturer or local DEA office for additional assistance in drug disposal if necessary.[43055]
Subsys (sublingual spray)
Open blister package with scissors immediately prior to use.
Carefully spray the entire contents of the unit into the mouth under the tongue.
Dispose of each used unit immediately after use by placing it into one of the disposable bags provided. Seal the bag and discard into a trash container out of the reach of children.
Consumed units are no longer protected by the child resistant blister package, but may contain enough medicine to be fatal to a child.
Disposal: Dispose of unused units into the provided charcoal-lined disposal pouch. Hold the charcoal-lined pouch with the opening facing up. Put the nozzle of the spray unit upside-down into the opening of the pouch. Squeeze your fingers and thumb together to spray the contents into the pouch. Dispose of the empty spray unit in a disposal bag. Repeat with any additional unused units. The pouch may be used for disposing of the contents of up to 10 spray units. Seal the pouch and place it in a disposal bag. Seal and discard the disposal bag in the trash out of the reach of children.[48165]
Actiq (oral lozenge)
Place between the cheek and lower gum, occasionally moving from one side of the mouth to the other using the handle. Patients should be instructed to suck but not chew the lozenges.
Consume over 15 minutes. Longer or shorter consumption times may produce less efficacy.
Using the handle, remove the unit after it has been consumed or after the patient has achieved the desired level of sedation or is experiencing respiratory depression.
Disposal: To dispose, remove the drug matrix from the handle by grasping it with tissue and separating it from the handle using a twisting motion. Flush the drug matrix down the toilet. If any of the drug matrix remains on the handle, remove it by placing the handle under warm running water until the drug matrix dissolves. During the disposal process, avoid contract with skin, eyes, or mucous membranes. Wash hands thoroughly when finished. Disposal must be consistent with state and federal regulations.[29763]
Fentora (buccal tablet)
Immediately before use, peel the blister backing away to expose the tablet. To avoid damaging the tablet, do NOT push the tablet through the blister.
Place the entire tablet either between the cheek and gum above a rear molar tooth or under the tongue. Do not break or split the tablet.
Allow to dissolve over 30 minutes. Sucking, chewing, or swallowing the tablet or any tablet fragments before 30 minutes have elapsed will produce less efficacy. Any remaining tablet may be swallowed after 30 minutes.
Have the patient spit out the tablet and rinse their mouth with water if the patient gets very sleepy, dizzy, or has slowed or labored breathing.
Disposal: Dispose of any unneeded tablets as soon as no longer needed. Remove tablets from the blister cards and flush the tablets down the toilet. Do not dispose of blister cards, cartons, or other packaging in the toilet. Caregivers may also contact the product manufacturer or local DEA office for additional assistance in drug disposal if necessary.[32731]
Onsolis (oral dissolving film)
This medication is applied to the inside of the cheek. Wet the affected area with tongue or rinse of water prior to application.
Immediately before use, open package with dry hands. Do not cut or tear the film prior to use.
Using the tip of a dry finger touching the white side of the film, place one film in the mouth with the pink side of the film facing the cheek; hold in place for approximately 5 second to adhere.
If using more than one film per dose, place films separately using both sides of the mouth as needed; do not overlap or stack films.
Allow the film(s) to dissolve over 15 to 30 minutes. If chewed and swallowed, lower peak concentrations and bioavailability are expected. Drinking liquids within 5 minutes after application, touching the film with fingers or tongue after placed, or eating before the film has fully dissolved may interfere with patch adherence and drug absorption.
Disposal: Dispose of any unneeded product as soon as no longer needed. Remove each film from the foil packaging and drop into the toilet, then flush when all unneeded films have placed in the toilet. Do not dispose of foil packs, cartons, or other packaging in the toilet. Caregivers may also contact the product manufacturer or local DEA office for additional assistance in drug disposal if necessary.[40943]
Only individuals trained in the administration of general anesthetics and the management of the respiratory effects of potent opioids should give the drug. Pulse oximetry or some other means for measuring respiratory function is recommended.
Resuscitative medications, including naloxone, and size-appropriate equipment for bag/valve/mask ventilation and intubation must be readily available.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
IV Push
Inject directly into a vein or into the tubing of a freely flowing IV solution slowly over 1 to 3 minutes. Rapid IV injection of fentanyl may result in apnea.
Continuous IV Infusion
May dilute in 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
Commonly used infusion concentration for adults: 10 mcg/mL.
ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 10 mcg/mL or 50 mcg/mL.
ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 10 mcg/mL or 50 mcg/mL.
Administer using a controlled-infusion device.
Adjust dose and infusion rate based on patient response.
Inject into a large muscle mass.
Inject subcutaneously taking care not to inject intradermally.
Fentanyl has been given as a subcutaneous continuous infusion in children weaning from prolonged sedation.
Epidural Administration
Epidural administration should only be used by specially trained health care professionals.
May be given as an intermittent bolus, continuous infusion, or patient-controlled epidural analgesia.
Before administration, an opioid antagonist and facilities for administration of oxygen and control of respiration should be available. The patient should be in a setting where adequate monitoring is possible.
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. Fentanyl only produces segmental analgesic effects and should only be used when the catheter tip is close to the incisional dermatome.
Intermittent Epidural Injection
After ensuring proper placement of the needle or catheter, inject the appropriate dose into the epidural space.
Monitor patients in a fully equipped and staffed environment for at least 24 hours after each dose.
Continuous Epidural Infusion
A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored in a fully equipped and staffed environment for several days after implantation of the device.
If dilution of the injection is necessary, 0.9% Sodium Chloride Injection is recommended.
Filling of the infusion device reservoir should only be done by fully trained and qualified health care professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5 micron (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdose.
To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, depletion of the reservoir should be avoided.
Monitor patients in a fully equipped and staffed environment.
Short-acting analgesics may be needed during the initial 24 hours of fentanyl patch application and for breakthrough pain.
Apply the patch immediately upon removal from the package. Do not use if the pouch seal is broken or the patch is damaged.
If skin needs preparation, use clear water and clip, do not shave, hair. Do not use soaps, oils, lotions, alcohol, or any other agents that may irritate the skin. Pat skin dry completely before applying patch.
Apply patch to a flat, intact, non-irritated, and non-irradiated area on the upper torso (e.g., chest, back, flank, or upper arm). Avoid cuts and sores.
In young children or those with cognitive impairment, place the patch on the upper back to minimize the potential of inappropriate patch removal. Adhesion of the patch should be closely monitored; patients or caregivers should frequently check that the patch has not fallen off, particularly after exercising, bathing, and sleeping.
Small children have removed patches on sleeping adults or found patches that have fallen off and ingested them or applied them to themselves (e.g., like a bandage); such cases have resulted in fatality. To limit curiosity and/or poor adhesion, patients should not apply patches in the company of young children, to an area of the body where young children can see it, or on areas of frequent movement.
Do not cut the patch to deliver partial doses. If it is necessary to use a smaller and commercially unavailable dosage, placing impermeable material (e.g., adhesive bandage) on the skin under the patch may block a proportional delivery of the drug.
Firmly press the patch onto the application site with the palm of the hand for 30 seconds. Make sure contact is complete and edges adhere to the skin. If there is difficulty with adhesion, the patch edges may be taped down with first aid tape or overlayed with a transparent adhesive film dressing (e.g., Tegaderm). Avoid other tight coverings over the patch.
When applying the patch, touch the adhesive side as little as possible. Exposure to the adhesive matrix may lead to serious adverse events such as respiratory depression and fatal overdose. If unintended skin contact occurs, thoroughly rinse exposed skin with large amounts of water; do not use soap, alcohol, or other solvents as this may enhance the drug's ability to penetrate the skin.
Wash hands with soap and water immediately after patch application.
Change patch at the same time of day every 3 days (72 hours); remove any patches in use prior to application of a new patch. Rotate patch application site.
If the patch falls off before 72 hours of use (including immediately after application) dispose of patch by folding in half so that the adhesive side is inward and immediately flushing down the toilet. Use a new patch at a different skin site.
Avoid contact with unwashed or unclothed application sites; this contact may result in secondary accidental exposure. Accidental exposure may occur during activities such as hugging, bed-sharing, or accidental caregiver skin contact during patch application and removal.
Avoid exposing the patch application site and surrounding areas to external heat sources (e.g., heating pads, electric blankets, heated water beds, tanning beds, hot baths or saunas, excessive sun exposure, or hot climate). Patients should also be counseled to avoid strenuous exercise, which can heat the body.
Storage: Instruct patients, caregivers, and family members to keep patches in a secure location out of the reach of children, pets, and others for whom the drug was not prescribed.
Disposal: Instruct patients, caregivers, and family members to dispose of damaged, used, or any patches remaining from a prescription when they are no longer needed. Improperly disposed of patches can cause serious illness or death, particularly to children or pets who might be inadvertently exposed. Unused patches should be removed from their pouch, folded in half so that the adhesive side is inward, and immediately flushed down the toilet.
Ionsys (iontophoretic transdermal system)
Apply only 1 system at any given time. Always wear gloves when handling the system.
Remove the foil pouch and the controller from the tray. Remove the drug unit from the foil pouch and place on a hard, flat surface.
Assemble the system. Align the matching shapes of the controller and the drug unit. Press on both ends of the device to ensure that the snaps at both ends are fully engaged. One or 2 clicks will be heard when the snaps are fully engaged.
After assembly, the digital display of the controller will complete a short self-test during which there is 1 audible beep, the red light will blink once, and the digital display will flash the number "88". Following the self-test, the display will show the number 0 and a green light will blink to indicate that the system is ready for application.
Choose an application site of healthy, unbroken skin on the upper outer arm or chest only. Clip excessive hair. Do not shave as this may irritate the skin.
Clean the administration site with alcohol and let dry. Do not use soaps, lotions, or other agents.
Peel off and discard the clear plastic liner covering the adhesive and hydrogels. Do not pull the red tab while preparing to apply the system; the red tab is only to be used during disposal.
Press and hold the system in place for 15 seconds or more with sticky side facing the skin. Make sure the edges adhere to the skin.
If the system loosens from the skin, secure it by pressing the edges or use a non-allergenic tape to secure the edges. Do not apply tape if skin is blistered or broken. Apply tape along the long edges of the system. Do not tape over the button, light, or digital display. After taping if the system beeps again, remove it and apply a new system on a different skin site.
To initiate administration of a dose, the patient should press the recessed button on the top housing of the system twice within 3 seconds. A single beep indicates the start of dose delivery that occurs over 10 minutes. During this time the system is locked-out and another dose cannot be delivered. When dose delivery is complete, the display will show the number of doses delivered.
Each system will function for 24 hours or 80 doses, whichever comes first. At this time, the green light will turn off and the number of doses delivered will flash on and off. To turn off the digital display, press the dosing button for 6 seconds.
Remove the system from the patient's skin. Ensure both hydrogels (1 contains fentanyl) remain within the removed system. If a hydrogel becomes separated during removal, use gloves or tweezers to remove it from the skin and properly dispose of in accordance with state and federal regulations for controlled substances.
Do not touch exposed hydrogel compartments or adhesive. If a hydrogel is touched accidentally, rinse the area with water. Do not use soap.
If additional analgesia is needed, a new system must be applied to a different site on the upper outer arm or chest.
Disposal: With gloves on, pull the red tab to separate the red bottom housing containing fentanyl from the system. Fold the red housing in half with the sticky side facing in. Dispose of the red housing per policies for disposal of schedule II drugs or by flushing it down the toilet. Hold the dosing button down until the display goes blank and then dispose of the remaining part of the system containing electronics in waste designated for batteries.
Lazanda (intranasal spray)
Confirm dosage before administration. Lazanda nasal spray is for use in opioid-tolerant adult patients only.
Prime before using for the first time. Remove the spray bottle from the child-resistant container. Remove the cap from the spray bottle. Aim the spray bottle tip into the provided pouch and depress the finger grips until "click" is heard then repeat for a total of 4 pumps; a green bar should appear in the counting window.The pump will remain primed for up to 5 days after priming or use. If the product has not been used for 5 days, re-prime by spraying once into the pouch. Retain and do not seal the medication pouch. Save the pouch and dispose of it at the appropriate time as directed in the MedGuide. Wash hands after priming.
Instruct the patient on the proper use according to MedGuide illustrated instructions.
Have patient sit during administration. If the nose is runny, blow nose prior to dosing. Place tip of the spray bottle in nostril (about one-half inch) while closing off the other nostril with a finger pressed to the side of the nose. Aim for the bridge of nose then depress finger grips until a "click" is heard. Spray may not be felt; an audible "click" and advancement of the dose counter confirm dose administration. Breathe gently in through the nose and out through the mouth one time. Repeat the steps in the other nostril if 2 sprays are needed for dose. If 4 sprays are needed for the dose, repeat the steps but alternate nostrils for each spray.
After administration advise the patient to stay sitting for 1 minute and to avoid nose blowing for 30 minutes.
Return the bottle to the child-resistant container after each use. The bottle (in the child-resistant container) and the pouch should be stored in the cardboard carton and out of the reach of children or pets. Protect from light.
Wash hands with soap and water after handling the bottle and/or pouch.
Disposal:
Discard bottle if no longer needed, if all medication has been used, or if 60 days have passed since first use.
Follow the directions for proper disposal as indicated in the MedGuide. When a red number "8" appears in the counting window, the bottle is finished. Medicine remaining in the bottle is not enough for an accurate dose.
Dispose of medication by spraying the bottle into the pouch 4 times. The counter will stay on the red number "8"; no click will be heard once the bottle is empty.
Seal the pouch and put both the pouch and the empty bottle into the child-resistant container. Twist to close. Throw the child-resistant container into the trash, out of the reach of children and pets.
Fentanyl injectable solution
NOTE: There is currently no commercially available product that is FDA-approved for pediatric intranasal administration. The Lazanda nasal spray is for opioid-tolerant adults only and has not been studied in pediatric patients.
Pediatric studies have utilized the injectable solution off-label for intranasal administration at a concentration of 50 to 300 mcg/mL; however, only the 50 mcg/mL concentration is commercially available in the US.
In clinical practice, the parenteral solution is administered intranasally via drop installation with a needleless syringe or using a mucosal atomizer device. Use of the mucosal atomizer device improves absorption.
Clear the nasal passages prior to administration (e.g., suction or have the patient blow their nose).
Place the patient's head at 45 degrees.
Administer half of the dose to each nare. Do not use more than 0.5 to 1 mL of medication per nostril. If a higher dose is required, apply it in 2 separate doses a few minutes apart to allow for adequate absorption of the first dose.
The patient should remain in a semi-reclined position for several minutes after administration.
Adverse Reactions
hearing loss / Delayed / 0-1.0
ocular hemorrhage / Delayed / 0-1.0
oliguria / Early / 0-1.0
seizures / Delayed / 1.0
hematemesis / Delayed / 1.0
GI obstruction / Delayed / 1.0
GI bleeding / Delayed / 1.0
cardiac arrest / Early / 1.0
bradycardia / Rapid / 1.0
thrombosis / Delayed / 1.0
exfoliative dermatitis / Delayed / 2.0
pancytopenia / Delayed / 1.0
bone fractures / Delayed / 1.0
renal failure (unspecified) / Delayed / 1.0
laryngospasm / Rapid / Incidence not known
respiratory arrest / Rapid / Incidence not known
pleural effusion / Delayed / Incidence not known
pneumothorax / Early / Incidence not known
apnea / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
chest wall rigidity / Rapid / Incidence not known
ileus / Delayed / Incidence not known
atrial fibrillation / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
skin necrosis / Early / Incidence not known
SIADH / Delayed / Incidence not known
neonatal opioid withdrawal syndrome / Delayed / Incidence not known
serotonin syndrome / Delayed / Incidence not known
constipation / Delayed / 0-26.0
hypokalemia / Delayed / 0-15.0
hypoventilation / Rapid / 0-4.0
respiratory depression / Rapid / 0-1.0
myoclonia / Delayed / 0-1.0
aphasia / Delayed / 0-1.0
fecal incontinence / Early / 0-1.0
angina / Early / 0-1.0
phlebitis / Rapid / 0-1.0
hot flashes / Early / 0-1.0
prolonged bleeding time / Delayed / 0-1.0
myopathy / Delayed / 0-1.0
synovitis / Delayed / 0-1.0
amblyopia / Delayed / 0-1.0
hypoglycemia / Early / 0-1.0
tolerance / Delayed / 10.0
dyspnea / Early / 1.0
amnesia / Delayed / 1.0
hallucinations / Early / 1.0
confusion / Early / 1.0
depression / Delayed / 1.0
dysphoria / Early / 1.0
migraine / Early / 1.0
peripheral neuropathy / Delayed / 1.0
dysphonia / Delayed / 1.0
euphoria / Early / 1.0
dysphagia / Delayed / 1.0
stomatitis / Delayed / 1.0
glossitis / Early / 1.0
ascites / Delayed / 1.0
gastritis / Delayed / 1.0
sinus tachycardia / Rapid / 1.0
edema / Delayed / 1.0
hypertension / Early / 1.0
peripheral edema / Delayed / 1.0
chest pain (unspecified) / Early / 1.0
hypotension / Rapid / 1.0
blurred vision / Early / 1.0
urinary retention / Early / 1.0
bleeding / Early / 1.0
skin ulcer / Delayed / 1.0
erythema / Early / 1.0
oral ulceration / Delayed / 1.0
neutropenia / Delayed / 1.0
thrombocytopenia / Delayed / 1.0
anemia / Delayed / 1.0
leukopenia / Delayed / 1.0
hyponatremia / Delayed / 1.0
impotence (erectile dysfunction) / Delayed / 1.0
bone pain / Delayed / 1.0
elevated hepatic enzymes / Delayed / 1.0
jaundice / Delayed / 1.0
dehydration / Delayed / 1.0
hyperglycemia / Delayed / 1.0
hypocalcemia / Delayed / 1.0
hypercalcemia / Delayed / 1.0
hypoalbuminemia / Delayed / 1.0
hypomagnesemia / Delayed / 1.0
candidiasis / Delayed / 1.0
lymphadenopathy / Delayed / 1.0
conjunctivitis / Delayed / 1.0
urinary incontinence / Early / 1.0
vaginitis / Delayed / 1.0
dysuria / Early / 1.0
vaginal bleeding / Delayed / 1.0
hematuria / Delayed / 1.0
hypoxia / Early / Incidence not known
hemoptysis / Delayed / Incidence not known
wheezing / Rapid / Incidence not known
impaired cognition / Early / Incidence not known
ataxia / Delayed / Incidence not known
peripheral vasodilation / Rapid / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
burns / Early / Incidence not known
hyperesthesia / Delayed / Incidence not known
skin erosion / Delayed / Incidence not known
infertility / Delayed / Incidence not known
ejaculation dysfunction / Delayed / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
psychological dependence / Delayed / Incidence not known
physiological dependence / Delayed / Incidence not known
withdrawal / Early / Incidence not known
akathisia / Delayed / Incidence not known
dystonic reaction / Delayed / Incidence not known
hyperalgesia / Delayed / Incidence not known
vomiting / Early / 0-33.0
rash / Early / 0-8.0
abnormal dreams / Early / 0-3.0
miosis / Early / 0-1.0
cheilitis / Delayed / 0-1.0
maculopapular rash / Early / 0-1.0
urticaria / Rapid / 0-1.0
skin hyperpigmentation / Delayed / 0-1.0
skin discoloration / Delayed / 0-1.0
polyuria / Early / 0-1.0
nocturia / Early / 0-1.0
bladder discomfort / Early / 0-1.0
increased urinary frequency / Early / 0-1.0
cough / Delayed / 1.0
drowsiness / Early / 1.0
tremor / Early / 1.0
malaise / Early / 1.0
hypoesthesia / Delayed / 1.0
asthenia / Delayed / 1.0
dizziness / Early / 1.0
insomnia / Early / 1.0
anxiety / Delayed / 1.0
agitation / Early / 1.0
emotional lability / Early / 1.0
vertigo / Early / 1.0
headache / Early / 1.0
fatigue / Early / 1.0
paranoia / Early / 1.0
paresthesias / Delayed / 1.0
lethargy / Early / 1.0
anorexia / Delayed / 1.0
abdominal pain / Early / 1.0
dysgeusia / Early / 1.0
dyspepsia / Early / 1.0
gastroesophageal reflux / Delayed / 1.0
eructation / Early / 1.0
flatulence / Early / 1.0
diarrhea / Early / 1.0
nausea / Early / 1.0
syncope / Early / 1.0
pallor / Early / 1.0
pruritus / Rapid / 1.0
xerophthalmia / Early / 1.0
gingivitis / Delayed / 1.0
xerostomia / Early / 1.0
nasal congestion / Early / 1.0
rhinorrhea / Early / 1.0
nasal irritation / Early / 1.0
hyperhidrosis / Delayed / 1.0
alopecia / Delayed / 1.0
night sweats / Early / 1.0
skin irritation / Early / 1.0
epistaxis / Delayed / 1.0
weakness / Early / 1.0
chills / Rapid / 1.0
muscle cramps / Delayed / 1.0
ecchymosis / Delayed / 1.0
back pain / Delayed / 1.0
fever / Early / 1.0
weight loss / Delayed / 1.0
myalgia / Early / 1.0
arthralgia / Delayed / 1.0
ptosis / Delayed / 1.0
parosmia / Delayed / 1.0
tinnitus / Delayed / 1.0
laryngitis / Delayed / 1.0
infection / Delayed / 1.0
rhinitis / Early / 1.0
sinusitis / Delayed / 1.0
influenza / Delayed / 1.0
urinary urgency / Early / 1.0
hyperventilation / Early / Incidence not known
hiccups / Early / Incidence not known
diaphoresis / Early / Incidence not known
dental caries / Delayed / Incidence not known
flushing / Rapid / Incidence not known
xerosis / Delayed / Incidence not known
vesicular rash / Delayed / Incidence not known
gonadal suppression / Delayed / Incidence not known
amenorrhea / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
hypothermia / Delayed / Incidence not known
shivering / Rapid / Incidence not known
restlessness / Early / Incidence not known
Boxed Warning
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 an opioid. 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 opioids. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Keep opioids out of the reach of pediatric patients, 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. Advise patients and caregivers to wash hands after handling any fentanyl product or packaging and to seek immediate medical help if an accidental exposure occurs. Cases of pediatric accidental exposure to the patch have resulted in hospitalization and death; more than half of the cases evaluated by the FDA have involved children under the age of 2 years, indicating the mobility and curiosity of toddlers provides ample opportunity for finding improperly stored or discarded patches. Contact with unwashed or unclothed application sites from the transdermal patch can result in secondary exposure and should be avoided; examples include transfer of the drug to a child's body while hugging, sharing the same bed as the patient, or accidentally sitting on a patch. Used patches still may contain enough fentanyl to cause a fatal overdose in a child, adult, or pet. After 3 days of continuous use, a patch may contain approximately 30% to 85% of the original drug content. Placing a patch in the mouth, chewing it, or swallowing it may cause choking or overdose that may be fatal. Buccal absorption of fentanyl is increased more than 30-fold compared to transdermal absorption and allows large amounts of drug to rapidly enter the circulation. Swallowing an intact patch results in less rapid drug release, however, systemic absorption is still significant. To limit curiosity and/or poor adhesion, patches should not be applied in the company of children, to an area of the body where children can see it, or on areas of frequent movement. In addition, persons should frequently check that transdermal systems have not fallen off, particularly after exercising, bathing, and sleeping. Proper disposal out of reach or children or pets is essential. Dispose of the fentanyl patch by folding the adhesive side of the patch to itself, then flush the patch down the toilet. If an Abstral, Actiq, Fentora, Onsolis, Lazanda, or Subsys unit is not completely consumed or is no longer needed, it must be properly disposed of as soon as possible. Dispose of Abstral, Actiq, Fentora, Onsolis by flushing the medication down the toilet; do not flush foil packages or cartons. Discard fentanyl from Lazanda nasal spray and Subsys sublingual spray according to manufacturer instructions. Direct exposure to the adhesive gel in fentanyl patches or to the iontophoretic transdermal system or its hydrogel components may lead to serious adverse events such as respiratory depression and fatal overdose. If accidental skin contact occurs, thoroughly rinse exposed skin with large amounts of water; do not use soap, alcohol, or other solvents to remove the gel because they may enhance the drug's ability to penetrate the skin. If the iontophoretic transdermal system is not handled with gloves by health care providers, accidental overdose may occur. Because the risk of overdose increases as opioid doses increase, 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 patients and consider prescribing it in persons who are at increased risk of opioid overdose, such as those 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. [49933] [55856]
Nonparenteral fentanyl products are contraindicated for use in persons with acute or severe asthma (e.g., status asthmaticus) in unmonitored care settings or in the absence of resuscitative equipment.[29623] [29763] [32731] [43055] [44875] [48165] [59568] Fentanyl buccal tablets, lozenges, nasal spray, transdermal patches, and the iontophoretic transdermal system are contraindicated for use in persons with significant respiratory depression.[29623] [29763] [32731] [59568] Parenteral fentanyl use requires a clinician trained in the use of anesthetic drugs, airway management, and assisted ventilation. Parenteral fentanyl use also requires a specialized care setting. Adequate facilities for the management of postoperative respiratory depression must be available when using injectable fentanyl. Use of the fentanyl iontophoretic transdermal system requires medical personnel with expertise in pain management and the detection and management of hypoventilation, including close observation, supportive measures, and use of opioid antagonists if needed. The fentanyl iontophoretic transdermal system is for hospital use only by patients under medical supervision and direction; the fentanyl iontophoretic transdermal system must be removed prior to discharge. Avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in persons for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective dosages and minimum treatment durations needed. Monitor closely for signs or symptoms of respiratory depression and sedation. Persons with chronic obstructive pulmonary disease (COPD), cor pulmonale, respiratory insufficiency, hypoxemia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive even at recommended doses. Persons with advanced age, cachexia, or debilitation are also at an increased risk for opioid-induced respiratory depression. Monitor such persons closely, particularly when initiating and titrating the opioid; consider the use of non-opioid analgesics. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in persons with CSA. Respiratory depression, if left untreated, may cause respiratory arrest and death. Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Careful monitoring and dose titration are required, particularly when CYP3A4 inhibitors or inducers are used concomitantly. Concomitant use of a CYP3A4 inhibitor or discontinuation of a concurrently used CYP3A4 inducer may increase plasma fentanyl concentrations and potentiate the risk of fatal respiratory depression. Management of respiratory depression may include observation, necessary supportive measures, and opioid antagonist use when indicated. [61143]
Use fentanyl during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data are insufficient with fentanyl in human pregnancy to inform a drug-associated risk for major birth defects or miscarriage. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation, fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies. Fentanyl is not recommended for use during and immediately before labor when other analgesic techniques are more appropriate. Opioids can prolong labor and obstetric delivery by temporarily reducing the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. An opioid antagonist (e.g., naloxone) should be available for reversal of opioid-induced respiratory depression in the neonate. Further, prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Monitor the exposed neonate for withdrawal symptoms, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight, and manage accordingly. 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. Guidelines recommend early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Obtain 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 NOWS, and how long-term opioid use may affect care during a future pregnancy.[64838] [64909] In women undergoing uncomplicated normal spontaneous vaginal birth, consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, use in combination with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. Use immediate-release opioids instead of extended-release or long-acting opioids; order the lowest effective dosage and prescribe no greater quantity of opioids than needed for the expected duration of such pain severe enough to require opioids.[64909] 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. Opioid agonist pharmacotherapy (e.g., methadone or buprenorphine) is preferable to medically supervised withdrawal in pregnant women with opioid use disorder.[64838]
Application of transdermal patches to areas of preexisting skin abrasion can subject the patient to an additional risk of local adverse effects; patches are only for application to intact skin. Also, use only intact patches; use of damaged or cut patches can lead to a potentially fatal fentanyl dose due to rapid drug release. Serum concentrations of fentanyl could increase by approximately one-third in patients with fever more than 104 degrees F (40 degrees C) due to temperature dependent increase in fentanyl release from the transdermal system and increased skin permeability. Patients with fever who are wearing fentanyl transdermal patches should be carefully monitored for increased side effects and dosage adjustments may be necessary. Patients should avoid strenuous exertion that may increase core body temperature. Application of heat over fentanyl transdermal patches worn by healthy adults increased fentanyl mean serum concentration (Cmax) by 61% and mean systemic exposure (AUC) by 120%. Fatal overdose attributable to heat exposure has occurred. Patients should be advised to avoid exposing the transdermal application site to direct external heat sources, such as a heating pad, electric blankets, heat lamps, saunas, hot tubs, heated water beds, hot baths, sunbathing (including tanning beds and other sunlight (UV) exposure), conditions of ambient temperature increase, etc.
Common Brand Names
ABSTRAL, Actiq, Duragesic, Fentora, IONSYS, Lazanda, Sublimaze, SUBSYS
Dea Class
Rx, schedule II
Description
Phenylpiperidine synthetic opiate agonist
Used with general, regional, and spinal anesthesia; also for chronic and breakthrough pain
Formulations not interchangeable on a mcg-to-mcg basis, even those administered via same route, due to significant pharmacokinetic differences
Dosage And Indications
50 to 100 mcg IM, or by slow IV over 1 to 2 minutes, given 30 to 60 minutes before surgery.
50 to 100 mcg IM or slow IV over 1 to 2 minutes for the control of pain, tachypnea, and/or delirium. The dose may be repeated in 1 to 2 hours, as needed.
0.5 to 2 mcg/kg/dose (Max initial dose: 50 mcg/dose) IV or IM every 1 to 2 hours as needed. In general, young children require higher doses (e.g., 2 to 3 mcg/kg/dose) than older children and adolescents. Titrate dosage as needed to achieve adequate pain relief.
0.5 to 2 mcg/kg/dose IV or IM every 1 to 2 hours as needed. In general, young children require higher doses (e.g., 2 to 3 mcg/kg/dose) than infants and older children. Titrate dosage as needed to achieve adequate pain relief.
0.5 to 3 mcg/kg/dose IV every 2 to 4 hours as needed. Titrate dosage as needed to achieve adequate pain relief.
Initial bolus doses range 10 mcg to 100 mcg, depending on clinical condition for use. Typical fentanyl continuous epidural rate range for post-surgical pain control: 0.5 to 1 mcg/kg/hour epidurally. Standard epidural concentrations and dose regimens may vary with condition for use. Patients often receive concomitant epidural bupivacaine at concentrations of 0.0625% or 0.075%. Fentanyl has also been used in patient controlled epidural analgesia protocols (PCEA), with varied dosing regimens depending on the setting of use and if bupivacaine or ropivacaine are used concurrently in the epidural regimen. Use preservative-free solutions.
TO CONVERT OPIOID-TOLERANT ADULT PATIENTS FROM OTHER OPIATE AGONISTS TO FENTANYL TRANSDERMAL 72-HOUR SYSTEM: 1) Calculate the previous 24-hour opioid analgesic requirement; 2) Convert this amount to the equianalgesic oral morphine dose; 3) follow the FDA-approved conversion chart in the product label to convert 24-hour oral morphine equivalents dose to the corresponding transdermal fentanyl system dose. Initially, apply at minimum a 25 mcg/hour transdermal patch for patients receiving at least 60 mg/day oral morphine equivalents. Discontinue all other around-the-clock opioid drugs upon transdermal fentanyl initiation. 4) Change patch system every 72 hours. DOSE TITRATION: If adequate analgesia is not achieved, may titrate the initial dosage upward after 3 days (72 hours); subsequent titrations should be made no more frequently than every 6 days. Use short-acting opioid agonists as needed for 24 hours after initial application; breakthrough pain may require supplemental doses even after a transdermal dose is established. Appropriate transdermal system dosage adjustments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/day of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage. The patch should be changed every 72 hours; however, some patients may require patch application at 48-hour intervals to maintain adequate analgesia. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. DISCONTINUATION: To convert to another opioid, remove the fentanyl transdermal system and titrate the dose of the new analgesic to adequate pain relief. Once the patch is removed, 17 hours or more are required for a 50% decrease in fentanyl concentrations. To discontinue the transdermal system when not converting to another opioid, gradually decrease the system dose by 50% every 6 days. Monitor patients for withdrawal symptoms, as these are possible with dose conversion or adjustment. Transdermal fentanyl 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 otherwise provide inadequate pain management. Opioid-tolerant adult patients are defined as those taking, for a minimum of 1 week, at least 60 mg/day oral morphine, 30 mg/day oral oxycodone, 8 mg/day oral hydromorphone, or an equivalent dose of another opioid.
TO CONVERT OPIOID-TOLERANT PEDIATRIC PATIENTS FROM OTHER OPIATE AGONISTS TO FENTANYL TRANSDERMAL 72-HOUR SYSTEM: 1) Calculate the previous 24-hour opioid analgesic requirement; 2) Convert this amount to the equianalgesic oral morphine dose; 3) follow the FDA-approved conversion chart in the product label to convert 24-hour oral morphine equivalents dose to the corresponding transdermal fentanyl system dose. Initially, apply at minimum a 25 mcg/hour transdermal patch for patients receiving at least 60 mg/day oral morphine equivalents. Discontinue all other around-the-clock opioid drugs upon transdermal fentanyl initiation. Some experts suggest opioid-tolerant pediatric patients receiving 30 mg/day or more of oral morphine equivalents can be safely initiated on the 12.5 mcg/hour transdermal system. Open-label trials have started opioid-tolerant pediatric patients receiving 45 mg/day of oral morphine equivalents on a fentanyl transdermal system of 25 mcg/hour with a low incidence of adverse respiratory events. 4) Change patch system every 72 hours. DOSE TITRATION: If adequate analgesia is not achieved, may titrate the initial dosage upward after 3 days (72 hours); subsequent titrations should be made no more frequently than every 6 days. Use short-acting opioid agonists as needed for 24 hours after initial application; breakthrough pain may require supplemental doses even after a transdermal dose is established. Appropriate transdermal system dosage adjustments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/day of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage. Change patch system every 72 hours; dosing intervals less than this are not recommended in children and adolescents. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. DISCONTINUATION: To convert to another opioid, remove the fentanyl transdermal system and titrate the dose of the new analgesic to adequate pain relief. Once the patch is removed, 17 hours or more are required for a 50% decrease in fentanyl concentrations. To discontinue the transdermal system when not converting to another opioid, gradually decrease the system dose by 50% every 6 days. Monitor patients for withdrawal symptoms, as these are possible with dose conversion or adjustment.
Initially, a single 200-mcg lozenge (Actiq) placed between the cheek and lower gum as needed for breakthrough pain. The unit should be sucked, not chewed, over a period of 15 minutes. If pain is not relieved within 15 minutes after complete consumption, may repeat dose once. Max: 2 lozenge units/breakthrough pain episode. Do not repeat additional dosing for at least 4 hours. Max: 4 lozenge units/day. An initial titration supply of only six 200-mcg lozenge units should be prescribed to limit the number of units in the home and decrease the potential for confusion and overdose. Patients/caregivers should only have 1 strength of lozenge available. TITRATION: If several consecutive breakthrough pain episodes require more than 1 unit for treatment, practitioners should increase the dose to the next available strength. Evaluate the new dose over 1 to 2 days to determine if adequate pain relief and acceptable side effects occur. Re-evaluate maintenance opioid therapy if the patient experiences more than 4 episodes/day of breakthrough pain once an appropriate breakthrough dose is determined. If respiratory depression or signs of excessive sedation occur before unit is completely consumed, immediately remove unit from the patient's mouth; subsequent doses should be decreased.
Initially for a breakthrough pain episode, 100 mcg buccally (placed above a rear molar between the upper cheek and gum) until the buccal tablet has disintegrated. Patients must not suck, chew, or split the tablets. The patient may swallow any fragments that remain after 30 minutes. During an episode of breakthrough pain, one additional dose of the same strength, if needed, may be taken 30 minutes after the start of the previous administration, but no further doses may be used for the episode. At least 4 hours must elapse before treating the next breakthrough pain episode with Fentora. TITRATION: If treatment of several consecutive breakthrough pain episodes requires more than 1 dose/episode, increase the dose. For example, if more than 100 mcg is needed, place one 100 mcg tablet on each side of the mouth in the buccal cavity (total of two 100 mcg tablets). If this dose does not control the pain, place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate above 400 mcg/dose by 200 mcg increments. Once an effective dose has been achieved, use only one Fentora tablet of the correct dose strength per breakthrough pain episode and administer either via the buccal (between the upper cheek and gum above a rear molar) or sublingual (under the tongue) route. Once an appropriate breakthrough pain dose is determined, re-evaluate the maintenance (round-the-clock) opioid dose if there are more than 4 breakthrough pain episodes/day. SAFETY: To help prevent confusion and overdose, minimize the number of tablet strengths available to a patient at any time. Instruct patients to use all units of a particular strength before increasing to a higher dose. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.
Initially, place a 200-mcg film on the inside of the cheek. Conversion instructions are not available for any other fentanyl product; always initiate at the 200-mcg dose regardless of previous breakthrough pain medication use. Titrate by 200 mcg in each subsequent episode until the dose provides adequate analgesia with tolerable side effects. Separate doses by at least 2 hours. Use only one dose per episode of breakthrough pain. During titration, multiple films may be placed on both sides of the mouth; do NOT overlap or stack films on top of each other. Do not use more than four 200-mcg films simultaneously. Doses of 1,200 mcg are achieved by using one 1,200 mcg film. Maximum: 1,200 mcg/dose and not to exceed 4 doses per day. Once an adequate dose for breakthrough pain episodes is determined, re-evaluate the dose of the maintenance (around-the-clock) opioid if a patient has greater than 4 breakthrough pain episodes per day. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those who are taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.
Initially, 100 mcg sublingually until dissolved. Conversion instructions are not available for any other fentanyl product other than Actiq; therefore, except for patients already using Actiq, always initiate Abstral at the same dose (100 mcg) regardless of previous pain medication dosing. During an episode of breakthrough pain, 1 additional dose of the same strength, if needed, may be taken 30 minutes after the previous dose was given. Do not use more than 2 doses of Abstral per episode of breakthrough pain. At least 2 hours must elapse before treating another breakthrough pain episode. CONVERSION FROM ACTIQ: For patients on a current Actiq dose of 400 mcg or less, start Abstral at 100 mcg/dose and titrate using multiples of 100 mcg. For patients converting from an Actiq dose of 600 to 1200 mcg, start Abstral at 200 mcg/dose and titrate using multiples of 200 mcg. For patients converting from Actiq 1600 mcg, start Abstral 400 mcg/dose and titrate using multiples of 400 mcg. TITRATION: Titrate dose over consecutive episodes of breakthrough pain, as needed. In patients on a current Abstral dose of 100 to 300 mcg, titrate using multiples of 100 mcg. In patients on a current Abstral dose of 400 to 600 mcg, titrate using multiples of 200 mcg. Doses more than 800 mcg have not been studied. Do not exceed 4 sublingual tablets at a time. Do not treat more than 4 episodes of breakthrough pain in a day with Abstral. If a patient has greater than 4 breakthrough pain episodes per day once breakthrough pain dose is stable, re-evaluate the maintenance (around-the-clock) opioid dose. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those who are taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.
Initially, 100 mcg sprayed sublingually. Conversion instructions are not available for any other fentanyl product other than Actiq; therefore, except for patients already using Actiq, always initiate Subsys at the same dose (100 mcg) regardless of previous pain medication dosing. CONVERSION FROM ACTIQ: For patients converting from Actiq 400 mcg/dose or less, the initial dose is 100 mcg sprayed sublingually. For patients currently on Actiq 600 to 800 mcg per dose, the initial dose is 200 mcg sprayed sublingually. Patients previously using 1,200 to 1,600 mcg of Actiq should receive an initial dose of 400 mcg sprayed sublingually. TITRATION: During an episode of breakthrough pain, one additional dose of the same strength, if needed, may be taken 30 minutes after the previous dose. Do not use more than 2 doses of Subsys per episode of breakthrough pain. At least 4 hours must elapse before treating another breakthrough pain episode. Titrate the dose carefully in a stepwise manner, as needed, after a single administration of the current dose fails to adequately treat breakthrough pain during several consecutive episodes. Titration steps are 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,200 mcg, then 1,600 mcg per dose. To avoid overdose during titration, patients should have only 1 sublingual spray strength available at any time. Once titrated to an adequate dose, patients should use only one Subsys dose of the appropriate strength per breakthrough pain episode. Do not treat more than 4 episodes of breakthrough pain in a day. Once an appropriate breakthrough dose is determined, if a patient has greater than 4 breakthrough pain episodes per day, then re-evaluate the maintenance (around-the-clock) opioid dose. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those who are taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.
Initially, 1 spray (100 mcg/spray) intranasally in 1 nostril. Always initiate with a 100 mcg dose, regardless of previous pain medication dosing. If adequate analgesia is obtained within 30 minutes of administration, continue to treat subsequent episodes of breakthrough pain with this dose. At least 2 hours must elapse before another dose. If adequate analgesia is not obtained within 30 minutes of administration, may titrate at consecutive episodes of breakthrough pain. During any episode of breakthrough cancer pain, if there is inadequate pain relief after 30 minutes following Lazanda administration, or if a separate episode of breakthrough cancer pain occurs before the next dose is permitted (i.e. within 2 hours), the patients may use a rescue medication as directed by their healthcare provider. TITRATION: Titrate if needed to find a dose that provides adequate analgesia with tolerable side effects. At least 2 hours must elapse between each dose. First increase to 200 mcg/dose (1 spray of 100 mcg/spray in each nostril). If needed, subsequent titration to 400 mcg/dose (1 spray of 400 mcg/spray in 1 nostril), 600 mcg/dose (1 spray of 300 mcg/spray in each nostril), and then 800 mcg/dose (1 spray of 400 mcg/spray in each nostril) may be used. Maximum: 800 mcg/dose per breakthrough pain episode. Treat a maximum of 4 episodes or less daily with this medication. Once an appropriate breakthrough pain dose is determined, re-evaluate the maintenance (round-the-clock) opioid dose if there are more than 4 breakthrough pain episodes/day. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.
Use only after patients have been titrated to an acceptable level of analgesia using other opioid analgesics. One dose activation delivers 40 mcg transdermally over 10 minutes. Instruct patients on how to self-operate the system; patients should self-administer doses. Apply only 1 system at a time. A maximum of six 40-mcg doses may be administered per hour. Each system operates up to 24 hours or 80 doses, whichever comes first. Each subsequent system is applied to a different skin site. Maximum total duration of treatment should not exceed 3 days (72 hours). If inadequate analgesia occurs, provide breakthrough pain medication or replace with an alternate analgesic medication. If conversion to alternate analgesic is needed upon discontinuation of the system, titrate the dose of the new analgesic until adequate analgesia is obtained, considering that serum fentanyl concentrations will gradually decrease upon system removal.
2 mcg/kg IV or IM. Maintenance doses are infrequently needed.
2 mcg/kg IV or IM as a total "low" dose for induction and maintenance.
2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance. In general, young children require higher doses than older children and adolescents.
Limited data available. 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance, based on recommended doses in children 2 to 12 years of age. In general, young children require higher doses than neonates and infants.
NOTE: Respiratory depression at this dosage level requires artificial ventilation.
Intramuscular or Intravenous dosage Adults
2 to 20 mcg/kg IM or by slow IV. Additional doses may be required for maintenance if lightening of anesthesia or surgical stress becomes evident. Respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.
2 to 20 mcg/kg IV or IM as a total "moderate" dose for induction and maintenance. Respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.
2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance per the manufacturer. Larger weight-based dosing recommendations are discussed for a "moderate dose" (2 to 20 mcg/kg total dose) range, but may be excessive in this population. In general, young children require higher doses than older children and adolescents. With "moderate" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.
Limited data available. 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient based on dosing in children 2 to 12 years of age for induction and maintenance. Larger weight-based dosing recommendations are discussed for a "moderate dose" (2 to 20 mcg/kg total dose) range, but may be excessive in this population. In general, young children require higher doses than neonates and infants. With "moderate" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.
10 to 25 mcg as a single intrathecal bolus given in combination with other spinal analgesia to improve intraoperative analgesia.
20 to 50 mcg/kg IV or IM as a total "high" dose for induction. Maintenance dosage (ranging from 25 mcg to one half the initial loading dose) will be dictated by the changes in vital signs which indicate stress and lightening of analgesia. However, the additional dosage selected must be individualized especially if the anticipated remaining operative time is short. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this dosing is to produce "stress free" anesthesia.
20 to 50 mcg/kg IV or IM as a total "high" dose for induction and maintenance. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this dosing is to produce "stress free" anesthesia.
2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance per the manufacturer. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. In general, young children require higher doses than older children and adolescents. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.
Limited data available. 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance based on dosing in children 2 to 12 years of age. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. In general, young children require higher doses than neonates and infants. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.
50 to 100 mcg/kg by slow IV over 1 to 2 minutes or IM may be administered with oxygen and muscle relaxant, without the use of additional anesthetic agents. In certain cases, total doses up to 150 mcg/kg may be necessary to produce adequate anesthetic effect. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.
50 to 100 mcg/kg IV or IM as a total dose may be administered with oxygen and muscle relaxant, without the use of additional anesthetic agents. In certain cases, total doses up to 150 mcg/kg may be necessary to produce adequate anesthetic effect. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.
Limited data available for pediatrics 1 year of age and younger. Some experts describe fentanyl doses of 30 to 100 mcg/kg IV for cardiac surgery. Total doses of 50 to 100 mcg/kg IV or IM, administered with oxygen and a muscle relaxant but without the use of additional anesthetic agents may be sufficient based on dosing in children 2 to 12 years of age. In general, young children require higher doses than neonates and infants. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.
0.35 to 0.5 mcg/kg/dose IV every 30 to 60 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
50 to 100 mcg/dose IV every 30 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
1 to 2 mcg/kg/dose IV every 30 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
0.5 to 3 mcg/kg/dose IV every 30 minutes as needed. Adjust dose as needed to achieve target pain assessment score.
0.7 to 10 mcg/kg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
25 to 100 mcg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
1 to 10 mcg/kg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
0.5 to 2 mcg/kg/hour continuous IV infusion. Adjust dose as needed to achieve target pain assessment score.
1 to 3 mcg/kg IV over 1 to 2 minutes. Give dose 1 to 3 minutes prior to intubation.
2 to 3 mcg/kg IV over 1 to 2 minutes is a typical dose; however, a dose range of 1 to 5 mcg/kg has been recommended. Give dose 1 to 3 minutes prior to intubation. In general, infants, older children, and adolescents require lower doses than young children.
1 to 4 mcg/kg IV over at least 1 to 2 minutes has been recommended.
A dose of 25 mcg in 2 mL saline via nebulization has been administered to patients with improvements in respiratory rates and oxygen saturation, as well as overall patient perceptions of breathing.
Titrate slowly to achieve the desired effect. The usual dose is 25 mcg IV every 3 to 5 minutes as needed. Premedication with a benzodiazepine may potentiate the response to fentanyl; a reduced fentanyl dose may be needed. NOTE: Fentanyl should be administered as a inducing agent only by those trained in anesthesia. Monitor ventilation closely.
0.5 to 2 mcg/kg/dose IV (Max: 50 mcg/dose). May repeat in small increments (e.g., one-half of original dose, no more than 1 mcg/kg/dose) every 3 to 5 minutes as needed; titrate slowly to desired effect. Alternatively, a single dose of 25 to 50 mcg IV may be used. If needed, may repeat the full dose (up to 50 mcg) after 5 minutes. For particularly invasive/painful procedures (e.g., bone marrow aspiration), an additional 25 mcg may be given every 5 minutes for up to 4 to 5 additional doses if needed. Onset of analgesia is approximately 2 to 5 minutes with a duration of 20 to 60 minutes. Respiratory depressive effects usually outlast the opioid effects; close monitoring of ventilation is essential.
0.5 to 2 mcg/kg/dose IV (Max: 50 mcg/dose). May repeat in small increments (e.g., one-half of original dose, no more than 1 mcg/kg/dose) every 3 to 5 minutes as needed; titrate slowly to desired effect. Onset of analgesia is approximately 2 to 5 minutes, and the duration is about 20 to 60 minutes. Respiratory depressive effects usually outlast the opioid effects; close monitoring of ventilation is essential, particularly in younger patients.
Limited data available; most reports have been in patients weighing 10 kg or more. The injection solution was used for intranasal application as no commercially appropriate product is available. A single dose of 1 to 2 mcg/kg intranasally has been recommended. The usual maximum is 100 mcg/dose intranasally ; however, some experts recommend a maximum of 200 mcg/dose. Studies utilizing an initial dose of 1.4 mcg/kg allowed for additional doses of 15 mcg (0.2 to 1.2 mcg/kg/dose) administered every 5 minutes to a maximum total dose of 3 mcg/kg intranasally. Onset of analgesia is approximately 5 to 10 minutes with a duration of 30 minutes.
†Indicates off-label use
Dosing Considerations
Transdermal patches: Avoid use in severe hepatic impairment. Reduce the initial transdermal dose by 50% in patients with mild to moderate hepatic impairment and titrate to desired clinical effect.
Other dosage forms: Fentanyl dosage should be modified based on clinical response and degree of hepatic impairment. No quantitative recommendations are available.
Transdermal patches: Avoid use in severe renal impairment. Reduce the initial transdermal dose by 50% in patients with mild to moderate renal impairment and titrate to desired clinical effect.
Other dosage forms: Fentanyl dosage should be modified based on clinical response and degree of renal impairment. No quantitative recommendations are available.
Drug Interactions
Acetaminophen; Aspirin; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine 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.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine 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.
Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Acetaminophen; Dextromethorphan; Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Concomitant use of fentanyl with other CNS depressants, such as dichloralphenazone, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension.
Acetaminophen; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine 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.
Acetaminophen; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone 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. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine 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.
Acetaminophen; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
Acrivastine; Pseudoephedrine: (Major) Avoid coadministration of opioid agonists with acrivastine due to the risk of additive CNS depression.
Adagrasib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like adagrasib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If adagrasib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Almotriptan: (Moderate) If concomitant use of fentanyl and almotriptan 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.
Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. 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 fentanyl. 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 fentanyl. 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Amiodarone: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. If amiodarone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amiodarone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amiodarone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amitriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Amlodipine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amlodipine; Atorvastatin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amlodipine; Benazepril: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amlodipine; Celecoxib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amlodipine; Olmesartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amlodipine; Valsartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Amobarbital: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Amoxapine: (Major) Concomitant use of opioid agonists with amoxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with 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: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If clarithromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Amphetamines: (Moderate) If concomitant use of fentanyl 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.
Apalutamide: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with apalutamide is necessary. If apalutamide is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like apalutamide with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Apomorphine: (Major) Concomitant use of opioid agonists with apomorphine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with apomorphine 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. Dopaminergic agents like apomorphine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
Aprepitant, Fosaprepitant: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of a 3-day oral regimen of aprepitant is necessary. If aprepitant is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate and aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when aprepitant is added to a stable dose of fentanyl. If aprepitant is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
Aripiprazole: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole 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.
Armodafinil: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with armodafinil is necessary. If armodafinil is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like armodafinil with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Asciminib: (Minor) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of asciminib is necessary. If asciminib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like asciminib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If asciminib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Asenapine: (Moderate) Concomitant use of opioid agonists with asenapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with asenapine 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.
Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Concomitant use of fentanyl with orphenadrine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with orphenadrine 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.
Aspirin, ASA; Carisoprodol: (Major) Concomitant use of fentanyl with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol 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.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of fentanyl with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol 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.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone 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. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
Atazanavir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like atazanavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If atazanavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Atazanavir; Cobicistat: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like atazanavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If atazanavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Atenolol; Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Atropine: (Major) Reserve concomitant use of fentanyl 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 fentanyl 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) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
Avacopan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If avacopan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Azelastine: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine 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.
Azelastine; Fluticasone: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine 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.
Azilsartan; Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Baclofen: (Major) Concomitant use of fentanyl with baclofen may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with baclofen 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.
Barbiturates: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Belladonna; Opium: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Belumosudil: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of belumosudil is necessary. If belumosudil is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like belumosudil can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If belumosudil is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Belzutifan: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of belzutifan is necessary. If belzutifan is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like belzutifan with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with benzhydrocodone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of benzhydrocodone with opioid agonists 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 benzhydrocodone is initiated in a patient taking fentanyl, reduce initial dosage and titrate to clinical response. If fentanyl is prescribed in a patient taking benzhydrocodone, use a lower initial dose of fentanyl and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and fentanyl because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of fentanyl 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 fentanyl and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Benztropine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and benztropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Berotralstat: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like berotralstat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If berotralstat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
Bexarotene: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of bexarotene is necessary. If bexarotene is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like bexarotene with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Bicalutamide: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If bicalutamide is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. 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.
Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. 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.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. 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.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Bosentan: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with bosentan is necessary. If bosentan is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like bosentan with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Brexpiprazole: (Major) Concomitant use of opioid agonists with brexpiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brexpiprazole 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.
Brigatinib: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with brigatinib is necessary. If brigatinib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A4 inducer like brigatinib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
Brompheniramine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for who
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl 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 fentanyl; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bupivacaine; Meloxicam: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Buprenorphine: (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.
Buprenorphine; Naloxone: (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.
Bupropion: (Moderate) If concomitant use of fentanyl 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 opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7-10 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 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 fentanyl 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 patients for signs and symptoms of serotonin syndrome during concomitant use of buspirone and fentanyl, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome.
Butabarbital: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Butalbital; Acetaminophen: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Butalbital; Acetaminophen; Caffeine: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as fentanyl. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Butorphanol may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of butorphanol 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.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication 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.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of opioid pain medications 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. Educate patients about the risks and symptoms of excessive CNS depression.
Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid pain medication 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 metaxalone and opioid agonists increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Carbamazepine: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of carbamazepine is necessary. If carbamazepine is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like carbamazepine with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine 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.
Cariprazine: (Moderate) Concomitant use of opioid agonists like fentanyl with cariprazine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cariprazine 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.
Carisoprodol: (Major) Concomitant use of fentanyl with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol 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.
Celecoxib; Tramadol: (Major) Concomitant use of tramadol with fentanyl may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cenobamate: (Moderate) Concomitant use of fentanyl with cenobamate may cause excessive sedation and somnolence. Limit the use of fentanyl 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, consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with cenobamate is necessary. If cenobamate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like cenobamate with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Ceritinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib is necessary. If ceritinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ceritinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ceritinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Cetirizine: (Major) Reserve concomitant use of opioids 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 opioids 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; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine 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.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine 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.
Chloramphenicol: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of chloramphenicol is necessary. If chloramphenicol is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like chloramphenicol can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If chloramphenicol is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorcyclizine 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.
Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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. (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Chloroprocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Chlorothiazide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpromazine: (Major) Concomitant use of opioid agonists with chlorpromazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorpromazine 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.
Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Chlorthalidone; Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Chlorzoxazone: (Major) Concomitant use of fentanyl with chlorzoxazone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with chlorzoxazone 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.
Cimetidine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cimetidine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cimetidine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ciprofloxacin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ciprofloxacin is necessary. If ciprofloxacin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ciprofloxacin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ciprofloxacin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Citalopram: (Moderate) Serotonin syndrome can occur during concomitant use of opiate agonists like fentanyl with serotonergic drugs, such as citalopram. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Clarithromycin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If clarithromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Clemastine: (Moderate) Concomitant use of opioid agonists with clemastine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clemastine 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.
Clevidipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with clevidipne. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving clevidipine.
Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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: (Moderate) Monitor for increased toxicity of fentanyl if used concomitantly with clofazimine. Concomitant use may increase the concentration of fentanyl, increasing the risk of adverse effects. Fentanyl is a CYP3A4 substrate that has a narrow therapeutic range; in vitro data suggest clofazimine inhibits CYP3A4.
Clomipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine 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.
Clopidogrel: (Moderate) Coadministration of opioid agonists, such as fentanyl, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Clozapine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as clozapine, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
Cobicistat: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; 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. (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
Codeine; Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; 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.
COMT inhibitors: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Limit the use of opioid pain medications with COMT inhibitors 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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Conivaptan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If conivaptan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Crizotinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A inhibitors like crizotinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If crizotinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
Cyclizine: (Moderate) Concomitant use of opioid agonists with cyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cyclizine 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.
Cyclobenzaprine: (Major) Concomitant use of fentanyl with cyclobenzaprine may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome and anticholinergic effects. Limit the use of opioid pain medication with cyclobenzaprine 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cyclosporine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine is necessary. If cyclosporine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cyclosporine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cyclosporine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Cyproheptadine: (Moderate) Concomitant use of opioid agonists with cyproheptadine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cyproheptadine 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.
Dabrafenib: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of dabrafenib is necessary. If dabrafenib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like dabrafenib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Dalfopristin; Quinupristin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of dalfopristin; quinupristin is necessary. If dalfopristin; quinupristin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like dalfopristin; quinupristin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If dalfopristin; quinupristin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Danazol: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of danazol is necessary. If danazol is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like danazol can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If danazol is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Dantrolene: (Major) Concomitant use of fentanyl with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene 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.
Daridorexant: (Major) Concomitant use of opiate agonists with daridorexant may cause excessive sedation and somnolence. Limit the use of opiates 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. Avoid prescribing cough medicines that contain opiates in patients taking daridorexant.
Darifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together 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. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Darunavir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If darunavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Darunavir; Cobicistat: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If darunavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If darunavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Deferasirox: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concomitant use of deferasirox is necessary. If deferasirox is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like deferasirox with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Delavirdine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of delavirdine is necessary. If delavirdine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like delavirdine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If delavirdine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
Desipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as desvenlafaxine and fentanyl. 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 serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine 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 deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Dexamethasone: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of dexamethasone is necessary. If dexamethasone is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like dexamethasone with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine 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.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine 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.
Dexchlorpheniramine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine 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.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine 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.
Dexmedetomidine: (Moderate) Concomitant use of opioid agonists with dexmedetomidine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with dexmedetomidine 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.
Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Dextromethorphan; Bupropion: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) If concomitant use of fentanyl 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.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Major) Reserve concomitant use of opioids and diphenhydramine 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Dextromethorphan; Quinidine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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. (Moderate) Quinidine increases fentanyl serum concentrations by inhibiting intestinal P-glycoprotein (P-gp). Receipt of fentanyl 2.5 mcg/kg orally 1 hour after a single dose of immediate-release quinidine 600 mg led to a fentanyl mean area under the plasma concentration-time curve (AUC) of 2.34 +/- 0.63 ng x hour/mL as compared with 0.9 +/- 0.47 ng x hour/mL with placebo. Elevated fentanyl serum concentrations can result in an increase in the pharmacologic effects of fentanyl, such as CNS or respiratory depression.
Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Dicyclomine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and dicyclomine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Difelikefalin: (Major) Avoid concomitant use of opioids and other CNS depressants, such as difelikefalin. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Diltiazem: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like diltiazem can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If diltiazem is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Dimenhydrinate: (Moderate) Concomitant use of opioid agonists with dimenhydrinate may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dimenhydrinate 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.
Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine 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.
Diphenhydramine; Ibuprofen: (Major) Reserve concomitant use of opioids and diphenhydramine 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.
Diphenhydramine; Naproxen: (Major) Reserve concomitant use of opioids and diphenhydramine 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.
Diphenhydramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Major) Reserve concomitant use of opioids and diphenhydramine 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.
Diphenoxylate; Atropine: (Major) Reserve concomitant use of fentanyl 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) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Doxepin: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine 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.
Doxylamine; Pyridoxine: (Major) Reserve concomitant use of opioids and doxylamine 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.
Dronabinol: (Moderate) Concomitant use of opioid agonists with dronabinol may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dronabinol 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.
Dronedarone: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. If dronedarone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like dronedarone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If dronedarone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Droperidol: (Major) Concomitant use of opioid agonists with droperidol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with droperidol 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.
Duloxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering duloxetine with other drugs that have serotonergic properties such as fentanyl. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and institute appropriate medical treatment if serotonin syndrome occurs.
Duvelisib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of duvelisib is necessary. If duvelisib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like duvelisib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If duvelisib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Efavirenz: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of efavirenz is necessary. If efavirenz is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like efavirenz with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of efavirenz is necessary. If efavirenz is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like efavirenz with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of efavirenz is necessary. If efavirenz is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like efavirenz with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Elagolix: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with elagolix is necessary. If elagolix is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like elagolix with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with elagolix is necessary. If elagolix is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like elagolix with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Elbasvir; Grazoprevir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir is necessary. If grazoprevir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like grazoprevir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If grazoprevir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Eletriptan: (Moderate) If concomitant use of fentanyl and eletriptan 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.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as fentanyl. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Emapalumab: (Moderate) Monitor for decreased efficacy of fentanyl and adjust the dose as needed during coadministration with emapalumab. Fentanyl is a CYP3A4 substrate with a narrow therapeutic range. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Enzalutamide: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with enzalutamide is necessary. If enzalutamide is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like enzalutamide with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Erythromycin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of erythromycin is necessary. If erythromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like erythromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If erythromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Escitalopram: (Moderate) Serotonin syndrome can occur during concomitant use of opiate agonists like fentanyl with serotonergic drugs, such as escitalopram. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Esketamine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine 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. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Eslicarbazepine: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of eslicarbazepine is necessary. If eslicarbazepine is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like eslicarbazepine with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Eszopiclone: (Major) Concomitant use of opioid agonists with eszopiclone may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with eszopiclone 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
Ethacrynic Acid: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and fentanyl; 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 opioids. Alcohol consumption may result in additive CNS depression and may increase the risk for opioid overdose. Consider the patient's use of alcohol when prescribing opioid medications. If the patient is unlikely to be compliant with avoiding alcohol, consider prescribing naloxone especially if additional risk factors for opioid overdose are present.
Etomidate: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic 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.
Etravirine: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with etravirine is necessary. If etravirine is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like etravirine with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Everolimus: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. If everolimus is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like everolimus can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If everolimus is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fedratinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. If fedratinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fedratinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fedratinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Felodipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with felodipine. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving felodipine.
Fenfluramine: (Moderate) Concomitant use of opioid agonists 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.
Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fesoterodine, an anticholinergic drug for overactive bladder is used with opiate agonists. The concomitant use of these drugs together 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. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Flavoxate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and flavoxate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Flibanserin: (Moderate) Concomitant use of opioid agonists with flibanserin may cause excessive sedation and somnolence. Limit the use of opioid pain medication with flibanserin 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.
Fluconazole: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of fluconazole is necessary. If fluconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fluconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fluoxetine: (Moderate) If concomitant use of fentanyl and fluoxetine 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.
Fluphenazine: (Moderate) Concomitant use of opioid agonists with fluphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with fluphenazine 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.
Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Fluvoxamine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluvoxamine is necessary. If fluvoxamine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluvoxamine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fluvoxamine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
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) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of fosamprenavir is necessary. If fosamprenavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like fosamprenavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fosamprenavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Fosphenytoin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of fosphenytoin is necessary. If fosphenytoin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like fosphenytoin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Fostamatinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of fostamatinib is necessary. If fostamatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fostamatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fostamatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Furosemide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and fentanyl; 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 opioid agonists with gabapentin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of opioid pain medications 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.
General anesthetics: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic 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.
Glycerol Phenylbutyrate: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of glycerol phenylbutyrate is necessary. If glycerol phenylbutyrate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like glycerol phenylbutyrate with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl 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 fentanyl and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Grapefruit juice: (Moderate) Patients should avoid or limit their intake of grapefruit juice during fentanyl treatment. Fentanyl is metabolized by CYP3A4. Grapefruit juice may increase fentanyl concentrations and/or decrease systemic clearance by inhibiting CYP3A4, leading to increased or prolonged effects, including a risk for significant respiratory depression. If concomitant use is necessary, consider dosage reduction of fentanyl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Sudden discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl
Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
Guanfacine: (Moderate) Concomitant use of opioid agonists with guanfacine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with guanfacine 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.
Haloperidol: (Moderate) Concomitant use of fentanyl with other central nervous system (CNS) depressants, such as haloperidol, can potentiate the effects of fentanyl and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of fentanyl 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. If these agents are used together, a reduced dosage of fentanyl and/or haloperidol is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and homatropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Hydromorphone: (Major) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as other opiate agonists, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of hydromorphone 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. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Hydroxyzine: (Major) Concomitant use of opioid agonists with hydroxyzine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with hydroxyzine 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.
Hyoscyamine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl 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 fentanyl 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 fentanyl 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) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone 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. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
Idelalisib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of idelalisib is necessary. If idelalisib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like idelalisib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If idelalisib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Iloperidone: (Moderate) Concomitant use of iloperidone with other centrally-acting medications such as opiate agonists, may increase both the frequency and the intensity of adverse effects including drowsiness, sedation, and dizziness.
Imatinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of imatinib is necessary. If imatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like imatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If imatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Imipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Indinavir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of indinavir is necessary. If indinavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like indinavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If indinavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Isavuconazonium: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of isavuconazonium is necessary. If isavuconazonium is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like isavuconazonium can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If isavuconazonium is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Isocarboxazid: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within the previous 14 days or are currently taking an MAOI due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small opioid doses to treat pain while closely monitoring blood pressure and signs and symptoms of serotonin syndrome and CNS and respiratory depression.
Isoflurane: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic 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.
Isoniazid, INH: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of isoniazid is necessary. If isoniazid is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like isoniazid can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If isoniazid is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of isoniazid is necessary. If isoniazid is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like isoniazid can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If isoniazid is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifampin is necessary. If rifampin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifampin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Isoniazid, INH; Rifampin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of isoniazid is necessary. If isoniazid is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like isoniazid can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If isoniazid is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifampin is necessary. If rifampin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifampin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Isradipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with isradipine. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving isradipine.
Istradefylline: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of istradefylline 40 mg daily is necessary. If istradefylline is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. Coadministration can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If istradefylline is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Itraconazole: (Major) Avoid use of fentanyl during and for 2 weeks after itraconazole therapy. Concomitant use may increase fentanyl plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of itraconazole could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If itraconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for CYP3A4. Itraconazole is a potent inhibitor of CYP3A4.
Ivacaftor: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ketamine: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic 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.
Ketoconazole: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ketoconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If clarithromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lapatinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lapatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Larotrectinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If larotrectinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lasmiditan: (Moderate) Concomitant use of fentanyl with lasmiditan may cause excessive sedation, somnolence, and serotonin syndrome. Limit the use of fentanyl 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.
Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of fentanyl-associated adverse reactions is advised with concomitant administration of ledipasvir. Fentanyl is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase fentanyl plasma concentrations.
Lefamulin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of oral lefamulin is necessary. If oral lefamulin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like oral lefamulin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. An interaction is not expected with intravenous lefamulin. If oral lefamulin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lemborexant: (Moderate) Concomitant use of fentanyl with lemborexant may cause excessive sedation and somnolence. Limit the use of fentanyl 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) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lenacapavir is necessary. If lenacapavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like lenacapavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lenacapavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lesinurad: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of lesinurad is necessary. If lesinurad is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like lesinurad with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Lesinurad; Allopurinol: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of lesinurad is necessary. If lesinurad is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like lesinurad with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Letermovir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of letermovir is necessary; the magnitude of this interaction may be amplified if the patient is also receiving cyclosporine. If letermovir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like letermovir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If letermovir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Levamlodipine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Levocetirizine: (Major) Reserve concomitant use of opioids 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.
Levoketoconazole: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ketoconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Levomilnacipran: (Moderate) If concomitant use of fentanyl 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.
Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lidocaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lidocaine; Prilocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Linezolid: (Major) Avoid concomitant use of fentanyl 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.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Lithium: (Moderate) If concomitant use of fentanyl and lithium 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.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and fentanyl. Lofexidine can potentiate the effects of CNS depressants.
Lonafarnib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lonafarnib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Loop diuretics: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and fentanyl; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Lopinavir; Ritonavir: (Major) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ritonavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%).
Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Lorcaserin: (Moderate) If concomitant use of fentanyl 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) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with lorlatinib is necessary. If lorlatinib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like lorlatinib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Loxapine: (Moderate) Concomitant use of opioid agonists, such as fentanyl, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine 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.
Lumacaftor; Ivacaftor: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lumacaftor; ivacaftor is necessary. If lumacaftor; ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lumacaftor; ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lumacaftor; Ivacaftor: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lumacaftor; ivacaftor is necessary. If lumacaftor; ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lumacaftor; ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Lumateperone: (Moderate) Concomitant use of opioid agonists like fentanyl with lumateperone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lumateperone 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.
Lurasidone: (Moderate) Concomitant use of opioid agonists like fentanyl with lurasidone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lurasidone 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.
Maprotiline: (Major) Concomitant use of opioid agonists with maprotiline may cause excessive sedation and somnolence. Limit the use of opioid pain medications with maprotiline 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.
Maribavir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of maribavir is necessary. If maribavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like maribavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If maribavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Mavacamten: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of mavacamten is necessary. If mavacamten is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like mavacamten with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Melatonin: (Moderate) Concomitant use of opioid agonists with melatonin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with melatonin 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.
Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Meprobamate: (Moderate) Concomitant use of fentanyl with meprobamate may cause respiratory depression, hypotension, and profound sedation. A coma could result in some circumstances. If concurrent use is desired, significantly reduce the dose of fentanyl and/or meprobamate. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid pain medication 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 metaxalone and opioid agonists increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Methadone: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone 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. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid concomitant use of fentanyl 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 fentanyl and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Methocarbamol: (Major) Concomitant use of fentanyl with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant 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.
Methohexital: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Methscopolamine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and methscopolamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Methyclothiazide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa 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.
Methylene Blue: (Major) Avoid concomitant use of fentanyl 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 fentanyl and methylphenidate or its 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.
Metoclopramide: (Moderate) The effects of metoclopramide on gastrointestinal motility are antagonized by narcotic analgesics. Concomitant use of opioid agonists with metoclopramide may also cause excessive sedation and somnolence. Limit the use of opioid pain medications with metoclopramide 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.
Metolazone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Metreleptin: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and fentanyl concomitantly; fentanyl dosage should be carefully selected and titrated. Upon initiation or discontinuation of metreleptin, carefully monitor patients for therapeutic and adverse effects of fentanyl and adjust the dosage as necessary. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as fentanyl.
Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
Midazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Mifepristone: (Contraindicated) Coadministration of fentanyl is contraindicated when mifepristone is used chronically, such as in the treatment of Cushing's syndrome or other hormonal conditions. Mifepristone inhibits CYP3A4. Coadministration of mifepristone may lead to a significant increase in serum concentrations of drugs that are CYP3A4 substrates and that have a narrow therapeutic index, such as fentanyl. The increase in fentanyl concentrations can increase the risk for serious CNS depression and respiratory depression, particularly when mifepristone is added after a stable dose of fentanyl is achieved. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Milnacipran: (Moderate) If concomitant use of fentanyl 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 opiate agonists. Caution should be exercised when using these agents concurrently.
Mirtazapine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Mitapivat: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of mitapivat is necessary. If mitapivat is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like mitapivat with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Mitotane: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of mitotane is necessary. If mitotane is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like mitotane with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Mobocertinib: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of mobocertinib is necessary. If mobocertinib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like mobocertinib with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Modafinil: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of modafinil is necessary. If modafinil is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like modafinil with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Molindone: (Moderate) Concomitant use of opioid agonists like fentanyl with molindone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with molindone 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.
Monoamine oxidase inhibitors: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within the previous 14 days or are currently taking an MAOI due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small opioid doses to treat pain while closely monitoring blood pressure and signs and symptoms of serotonin syndrome and CNS and respiratory depression.
Morphine: (Major) Concomitant use of morphine with fentanyl can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may al so occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or fentanyl is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
Morphine; Naltrexone: (Major) Concomitant use of morphine with fentanyl can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or fentanyl is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
Nabilone: (Major) Avoid coadministration of opioid agonists with nabilone due to the risk of additive CNS depression.
Nafcillin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of nafcillin is necessary. If nafcillin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like nafcillin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Nalbuphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as fentanyl. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine 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.
Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7-10 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 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) If concomitant use of fentanyl and naratriptan 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.
Nefazodone: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone 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. If nefazodone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nefazodone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If nefazodone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. 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.
Nelfinavir: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of nelfinavir is necessary. If nelfinavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nelfinavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If nelfinavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Neostigmine; Glycopyrrolate: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If netupitant is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) If concomitant use of fentanyl 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.
Nevirapine: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of nevirapine is necessary. If nevirapine is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like nevirapine with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Nicardipine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of nicardipine is necessary. If nicardipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nicardipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If nicardipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Nifedipine: (Moderate) Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.
Nilotinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If nilotinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Nimodipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with nimodipine. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving nimodipine.
Nirmatrelvir; Ritonavir: (Major) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ritonavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%). (Major) Consider withholding fentanyl, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the fentanyl dose. Coadministration may increase fentanyl exposure resulting in adverse events, including potentially fatal respiratory depression. Fentanyl is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Nisoldipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with nisoldipine. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving nisoldipine.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
Nortriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Odevixibat: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of odevixibat is necessary. If odevixibat is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A inducer like odevixibat with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Olanzapine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine 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.
Olanzapine; Fluoxetine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine 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. (Moderate) If concomitant use of fentanyl and fluoxetine 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.
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) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine 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.
Oliceridine: (Major) Concomitant use of oliceridine with fentanyl may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of oliceridine with fentanyl 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.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Olutasidenib: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of olutasidenib is necessary. If olutasidenib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like olutasidenib with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Omaveloxolone: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of omaveloxolone is necessary. If omaveloxolone is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like omaveloxolone with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifabutin is necessary. If rifabutin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifabutin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Ondansetron: (Moderate) If concomitant use of fentanyl and ondansetron 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.
Oritavancin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of oritavancin is necessary. If oritavancin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like oritavancin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Orphenadrine: (Major) Concomitant use of fentanyl with orphenadrine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with orphenadrine 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.
Osilodrostat: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of osilodrostat is necessary. If osilodrostat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like osilodrostat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If osilodrostat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Oxazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Oxcarbazepine: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of oxcarbazepine is necessary. If oxcarbazepine is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like oxcarbazepine with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Oxybutynin: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and oxybutynin use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone 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. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
Oxymetazoline: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., oxymetazoline); do not titrate fentanyl nasal spray dose in such patients. Oxymetazoline use results in a decrease in the rate and extent of fentanyl absorption through the nasal mucosa. Measured fentanyl pharmacokinetic values decreased as follows in patients treated concurrently with oxymetazoline: mean Cmax decreased approximately 32-40% and mean AUC decreased 10-17%. Further, the mean time to maximum fentanyl plasma concentration was 0.75-1.25 h (range 0.08-3 h) for oxymetazoline-treated patients as compared to 0.25-0.33 h (range 0.17-2 h) in patients who did not receive the drug. This interaction is not expected with other fentanyl administration routes.
Oxymorphone: (Major) Concomitant use of fentanyl with oxymorphone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of fentanyl with oxymorphone to only patients for whom alternative treatment options are inadequate. Oxymorphone and fentanyl should be used in reduced dosages if used concurrently. Initiate oxymorphone at 1/3 to 1/2 the usual dosage. Titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Ozanimod: (Major) When possible, fentanyl should not be used in patients taking MAOIs or within 14 days of stopping such treatment. An active metabolite of ozanimod inhibits MAO-B. MAO inhibitor interactions with fentanyl may manifest as serotonin syndrome, hypertensive crisis, or opioid toxicity (e.g., respiratory depression, coma). If concurrent use is absolutely necessary, use the lowest possible doses of fentanyl, and monitor blood pressure and for serotonergic symptoms closely. 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.
Pacritinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of pacritinib is necessary. If pacritinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like pacritinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If pacritinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Palbociclib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of palbociclib is necessary. If palbociclib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like palbociclib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If palbociclib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Paliperidone: (Major) Concomitant use of opiate agonists with paliperidone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with paliperidone 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 paliperidone, use a lower initial dose of the opiate and titrate to clinical response. If paliperidone is prescribed for a patient taking an opiate agonist, use a lower initial dose of paliperidone and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Palonosetron: (Moderate) If concomitant use of fentanyl 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.
Paroxetine: (Moderate) If concomitant use of fentanyl 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.
Pazopanib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of pazopanib is necessary. If pazopanib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like pazopanib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If pazopanib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Pegvisomant: (Moderate) In clinical trials, patients taking opiate agonists often required higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opiate agonists. The mechanism of this interaction is unknown.
Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as fentanyl. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine 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.
Pentazocine; Naloxone: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as fentanyl. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine 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.
Pentobarbital: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Perampanel: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel 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.
Perindopril; Amlodipine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Perphenazine: (Moderate) Concomitant use of opioid agonists with perphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perphenazine 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.
Perphenazine; Amitriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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. (Moderate) Concomitant use of opioid agonists with perphenazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perphenazine 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.
Pexidartinib: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of pexidartinib is necessary. If pexidartinib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like pexidartinib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Phenelzine: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within the previous 14 days or are currently taking an MAOI due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small opioid doses to treat pain while closely monitoring blood pressure and signs and symptoms of serotonin syndrome and CNS and respiratory depression.
Phenobarbital: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate. (Major) Reserve concomitant use of fentanyl 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 fentanyl 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 fentanyl and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Phentermine; Topiramate: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of topiramate is necessary. If topiramate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like topiramate with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
Phenytoin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of phenytoin is necessary. If phenytoin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like phenytoin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Pimozide: (Moderate) Concomitant use of fentanyl with other central nervous system (CNS) depressants, such as pimozide, can potentiate the effects of fentanyl and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of fentanyl 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. If these agents are used together, a reduced dosage of fentanyl and/or pimozide may be required. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Pirtobrutinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If pirtobrutinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Posaconazole: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of posaconazole is necessary. If posaconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like posaconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If posaconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Pramipexole: (Major) Concomitant use of opioid agonists with pramipexole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pramipexole 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. Dopaminergic agents like pramipexole have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Pramlintide: (Major) Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications with the potential to slow GI motility, such as opiate agonists, should be used with caution, if at all, with pramlintide until more data are available from the manufacturer. Monitor blood glucose.
Prasugrel: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
Pregabalin: (Major) Concomitant use of opioid agonists with pregabalin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of opioid pain medications 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.
Prilocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Prilocaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Primidone: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Procarbazine: (Major) In theory, procarbazine potentiates the CNS depression and hypotension caused by opiate agonists such as fentanyl. Procarbazine has MAOI activity; the manufacturers of fentanyl do not recommend its use within 14 days of an MAO Inhibitor. Caution is advised until more data are available.
Prochlorperazine: (Major) Concomitant use of opioid agonists with prochlorperazine may cause excessive sedation and somnolence. Concurrent administration of prochlorperazine is contraindicated in patients receiving large doses of opiate agonists. Limit the use of opioid pain medications with prochlorperazine 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.
Promethazine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; 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.
Promethazine; Dextromethorphan: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; 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. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. 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.
Promethazine; Phenylephrine: (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; 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. (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
Propantheline: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl and propantheline use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Propofol: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic 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.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Protriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Pseudoephedrine; Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine 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.
Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine 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.
Quazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Quetiapine: (Major) Concomitant use of opioid agonists with quetiapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with quetiapine 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.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Quinidine: (Moderate) Quinidine increases fentanyl serum concentrations by inhibiting intestinal P-glycoprotein (P-gp). Receipt of fentanyl 2.5 mcg/kg orally 1 hour after a single dose of immediate-release quinidine 600 mg led to a fentanyl mean area under the plasma concentration-time curve (AUC) of 2.34 +/- 0.63 ng x hour/mL as compared with 0.9 +/- 0.47 ng x hour/mL with placebo. Elevated fentanyl serum concentrations can result in an increase in the pharmacologic effects of fentanyl, such as CNS or respi ratory depression.
Quinine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of quinine is necessary. If quinine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like quinine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If quinine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ramelteon: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon 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.
Ranolazine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ranolazine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ranolazine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Rasagiline: (Major) Avoid concomitant use of fentanyl 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.
Remimazolam: (Major) Concomitant use of opioid agonists 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: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ribociclib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ribociclib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ribociclib; Letrozole: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ribociclib is necessary. If ribociclib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ribociclib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ribociclib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Rifabutin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifabutin is necessary. If rifabutin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifabutin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Rifampin: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of rifampin is necessary. If rifampin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like rifampin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Rifapentine: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with rifapentine is necessary. If rifapentine is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like rifapentine with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Risperidone: (Moderate) Concomitant use of fentanyl with other central nervous system (CNS) depressants such as risperidone can potentiate the effects of fentanyl and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of fentanyl 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. If these agents are used together, a reduced dosage of fentanyl and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Ritlecitinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ritlecitinib is necessary. If ritlecitinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like ritlecitinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ritlecitinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ritonavir: (Major) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ritonavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%).
Rizatriptan: (Moderate) If concomitant use of fentanyl and rizatriptan 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.
Ropinirole: (Major) Concomitant use of opioid agonists with ropinirole may cause excessive sedation and somnolence. Limit the use of opioid pain medication with ropinirole 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. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Ropivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Rotigotine: (Major) Concomitant use of opioid agonists with rotigotine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with rotigotine 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. Dopaminergic agents like rotigotine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Rucaparib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of rucaparib is necessary. If rucaparib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate and rucaparib is a weak CYP3A4 inhibitor. Coadministration can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If rucaparib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
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.
Sarilumab: (Moderate) Monitor for evidence of reduced pain control or opioid withdrawal if fentanyl coadministration with sarilumab is necessary; fentanyl dosage adjustment may be needed. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fentanyl, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fentanyl is a CYP3A4 substrate and narrow therapeutic index drug.
Scopolamine: (Major) Reserve concomitant use of fentanyl 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.
Secobarbital: (Major) Concomitant use of fentanyl with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate 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. Additionally, concurrent use of fentanyl with a barbiturate may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; fentanyl is a CYP3A4 substrate.
Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking fentanyl, monitor for altered patient response to fentanyl; fentanyl dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as fentanyl.
Selegiline: (Major) Avoid concomitant use of fentanyl 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: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of selpercatinib is necessary. If selpercatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like selpercatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If selpercatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Sertraline: (Moderate) If concomitant use of fentanyl and sertraline 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.
Sevoflurane: (Major) Concomitant use of fentanyl with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a general anesthetic 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.
Siltuximab: (Moderate) Monitor for evidence of reduced pain control or opioid withdrawal if fentanyl coadministration with siltuximab is necessary; fentanyl dosage adjustment may be needed. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fentanyl, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fentanyl is a CYP3A4 substrate and narrow therapeutic index drug.
Sodium Oxybate: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication 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) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of taurursodiol is necessary. If taurursodiol is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like taurursodiol with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Solifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of fentanyl 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.
Sotorasib: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of sotorasib is necessary. If sotorasib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like sotorasib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Spironolactone: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like spironolactone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If spironolactone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with fentanyl. 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) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of spironolactone is necessary. If spironolactone is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like spironolactone can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If spironolactone is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Additionally, monitor for decreased diuretic efficacy and additive orthostatic hypotension when spironolactone is administered with fentanyl. 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
St. John's Wort, Hypericum perforatum: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with St. John's wort is necessary. If St. John's wort is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like St. John's wort with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression. Additive serotonergic effects are also possible with this drug-herb combination. Caution and careful monitoring, particularly during treatment initiation and dose adjustment, is recommended due to the potential for serotonin syndrome. Serotonin syndrome may occur within the recommended dosage range. Discontinue fentanyl if serotonin syndrome is suspected. 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. Monitor the patient closely if use of St. John's wort is reported pre-operatively. The American Society of Anesthesiologists has recommended that, if possible, patients should stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Stiripentol: (Moderate) Concomitant use of opioid agonists with stiripentol may cause excessive sedation and somnolence. Limit the use of opioid pain medications 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. Educate patients about the risks and symptoms of excessive CNS depression. Coadministration may alter plasma concentrations of fentanyl resulting in an increased risk of adverse reactions and/or decreased efficacy. Fentanyl is a CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of dalfopristin; quinupristin is necessary. If dalfopristin; quinupristin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like dalfopristin; quinupristin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If dalfopristin; quinupristin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Sumatriptan: (Moderate) If concomitant use of fentanyl and sumatriptan 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.
Sumatriptan; Naproxen: (Moderate) If concomitant use of fentanyl and sumatriptan 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.
Suvorexant: (Moderate) Concomitant use of opioid agonists with suvorexant may cause excessive sedation and somnolence. Limit the use of opioid pain medications with suvorexant 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.
Tapentadol: (Major) Concomitant use of tapentadol with fentanyl may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of tapentadol with fentanyl 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.
Tasimelteon: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon 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.
Tazemetostat: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with tazemetostat is necessary. If tazemetostat is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A4 inducer like tazemetostat with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Tecovirimat: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of tecovirimat is necessary. If tecovirimat is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like tecovirimat with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Tedizolid: (Major) Avoid concomitant use of fentanyl 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.
Telmisartan; Amlodipine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Telotristat Ethyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of telotristat ethyl is necessary. If telotristat ethyl is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like telotristat ethyl with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Temazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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) Concomitant use of opiate agonists with tetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with tetrabenazine 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 tetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. If tetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of tetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tetracaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics 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. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tezacaftor; Ivacaftor: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. If ivacaftor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ivacaftor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Thalidomide: (Major) Avoid coadministration of opioid agonists with thalidomide due to the risk of additive CNS depression.
Thiazide diuretics: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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: (Major) Concomitant use of opioid agonists with thioridazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with thioridazine 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.
Thiothixene: (Moderate) Concomitant use of opioid agonists like fentanyl with thiothixene may cause excessive sedation and somnolence. Limit the use of opioid pain medication with thiothixene 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.
Ticagrelor: (Moderate) Coadministration of opioid agonists, such as fentanyl, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
Tizanidine: (Major) Concomitant use of fentanyl with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant 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.
Tocilizumab: (Moderate) Monitor for evidence of reduced pain control or opioid withdrawal if fentanyl coadministration with tocilizumab is necessary; fentanyl dosage adjustment may be needed. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fentanyl, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fentanyl is a CYP3A4 substrate and narrow therapeutic index drug.
Tolterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of fentanyl 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.
Topiramate: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of topiramate is necessary. If topiramate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like topiramate with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Torsemide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and fentanyl; 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) Concomitant use of tramadol with fentanyl may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Tramadol; Acetaminophen: (Major) Concomitant use of tramadol with fentanyl may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Trandolapril; Verapamil: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If verapamil is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Tranylcypromine: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within the previous 14 days or are currently taking an MAOI due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small opioid doses to treat pain while closely monitoring blood pressure and signs and symptoms of serotonin syndrome and CNS and respiratory depression.
Trazodone: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering fentanyl with trazodone. Limit the use of opiod 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. 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 triamterene and fentanyl; increase the dosage of triamterene 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 thiazide diuretic and fentanyl; 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of triamterene and fentanyl; increase the dosage of triamterene as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Triazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, 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.
Tricyclic antidepressants: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Trifluoperazine: (Moderate) Concomitant use of opioid agonists with trifluoperazine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with trifluoperazine 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.
Trihexyphenidyl: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant fentanyl 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 opiate agonists, may potentiate the effects of either trimethobenzamide or the opiate agonist.
Trimipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tricyclic antidepressants 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.
Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine 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.
Trofinetide: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If trofinetide is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when trospium, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together 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. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Tucatinib: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of tucatinib is necessary. If tucatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like tucatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If tucatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Valerian, Valeriana officinalis: (Moderate) Concomitant use of opioid agonists with valerian may cause excessive sedation and somnolence. Limit the use of opioid pain medication with valerian 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.
Valproic Acid, Divalproex Sodium: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid 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.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and fentanyl; 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.
Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions. Infusion-related events may be minimized by the administration of vancomycin as a 60-minute infusion prior to anesthetic induction.
Venlafaxine: (Moderate) If concomitant use of fentanyl and venlafaxine 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.
Verapamil: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of verapamil is necessary. If verapamil is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like verapamil can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If verapamil is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
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 opiate agonists.
Vilazodone: (Moderate) Because of the potential risk and severity of excessive sedation, respiratory depression, and serotonin syndrome, caution should be observed when administering fentanyl with vilazodone. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. 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.
Viloxazine: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of viloxazine is necessary. If viloxazine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like viloxazine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If viloxazine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Vonoprazan; Amoxicillin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If vonoprazan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like clarithromycin can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If clarithromycin is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If vonoprazan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Voriconazole: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of voriconazole is necessary. If voriconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voriconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If voriconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Vortioxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome, caution should be observed when administering fentanyl with vortioxetine. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. 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:< /strong> (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of voxelotor is necessary. If voxelotor is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like voxelotor can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If voxelotor is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Zafirlukast: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. If zafirlukast is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If zafirlukast is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Zaleplon: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with zaleplon 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.
Ziconotide: (Moderate) Concurrent use of ziconotide and opiate agonists 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: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering fentanyl with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Zolmitriptan: (Moderate) If concomitant use of fentanyl and zolmitriptan 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.
Zolpidem: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.
How Supplied
ABSTRAL/Fentanyl Citrate/Fentora Sublingual Tablet, SL: 100mcg, 200mcg, 300mcg, 400mcg, 600mcg, 800mcg
Actiq/Fentanyl Citrate Buccal Lozenge: 200mcg, 400mcg, 600mcg, 800mcg, 1200mcg, 1600mcg
Actiq/Fentanyl Citrate Transmucosal Lozenge: 200mcg, 400mcg, 600mcg, 800mcg, 1200mcg, 1600mcg
Duragesic/Fentanyl Transdermal Film ER: 1h, 12mcg, 25mcg, 37.5mcg, 50mcg, 62.5mcg, 75mcg, 87.5mcg, 100mcg
Fentanyl Citrate/Fentora Buccal Tablet, SL: 100mcg, 200mcg, 400mcg, 600mcg, 800mcg
Fentanyl Citrate/Fentora Transmucosal Tablet, SL: 100mcg, 200mcg, 400mcg, 600mcg, 800mcg
Fentanyl Citrate/Sublimaze Intramuscular Inj Sol: 1mL, 50mcg
Fentanyl Citrate/Sublimaze Intravenous Inj Sol: 1mL, 50mcg
IONSYS Transdermal Patch, Electrically Controlled: 1actuation, 40mcg
Lazanda Nasal Spray Met: 1actuation, 100mcg, 300mcg, 400mcg
Lazanda Transmucosal Spray Met: 1actuation, 100mcg, 300mcg, 400mcg
SUBSYS Sublingual Spray Met: 1actuation, 100mcg, 200mcg, 400mcg, 600mcg, 800mcg
Maximum Dosage
4 doses/day of Actiq, Fentora, or Onsolis transmucosal; 800 mcg/dose, 2 doses/break-thru pain episode, and 4 treated episodes/day of Abstral sublingual; 1600 mcg/dose, 2 doses/break-thru pain episode, and 4 treated episodes/day of Subsys sublingual; 800 mcg/dose and 4 doses/day of Lazanda nasal spray; 40 mcg/dose and 80 doses/day with Ionsys; with appropriate dosage titration, there is no maximum dose of other dosage forms.
Geriatric4 doses/day of Actiq, Fentora, or Onsolis transmucosal; 800 mcg/dose, 2 doses/break-through pain episode, and 4 treated episodes/day of Abstral sublingual; 1600 mcg/dose, 2 doses/break-thru pain episode, and 4 treated episodes/day of Subsys sublingual; 800 mcg/dose and 4 doses/day of Lazanda nasal spray; 40 mcg/dose and 80 doses/day with Ionsys; with appropriate dosage titration, there is no maximum dose of other dosage forms.
Adolescents16 to 17 years: 4 units/day of fentanyl transmucosal lozenge (i.e., Actiq). With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
13 to 15 years: With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
2 to 12 years: With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
1 year: With appropriate dosage titration, there is no maximum dose of intravenous fentanyl The safety and efficacy of other dosage forms have not been established.
With appropriate dosage titration, there is no maximum dose of intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
NeonatesWith appropriate dosage titration, there is no maximum dose of intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
Mechanism Of Action
Similar to morphine, fentanyl is a strong agonist at mu- and kappa-opiate receptors, which have been reclassified by an International Union of Pharmacology subcommittee as OP2 (kappa) and OP3 (mu). These receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase3 C (PLC)-intositol 1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2).
Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (mu2-, delta-, kappa-receptors) and higher levels in the CNS (mu1- and kappa3 receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opioids close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (mu and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. 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 of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opioids decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.
The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood. Possible mechanisms including differential susceptibility of the opioid receptor to desensitization or activation of more than one G-protein system or subunit (one excitatory and one inhibitory) by an opioid receptor.
The actions of fentanyl are similar to those of morphine, although fentanyl is much more lipophilic as compared to morphine (580:1) and has a more rapid onset of action. Clinically, stimulation of mu-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, as well as, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Opiate-induced respiratory depression is caused by direct action on respiratory centers in the brain stem. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention. Fentanyl exhibits little hypnotic activity and rarely stimulates histamine release. Bradycardia is due to medullary vasomotor center depression and vagal nucleus stimulation and may lead to decreased cardiac output. Myocardial contractility is not affected by fentanyl. Muscle rigidity of the chest and abdominal muscles is often seen with opiate agonist anesthesia. This effect may be due to opiate stimulation of spinal reflexes or interference with basal ganglia integration. When used as part of anesthesia, opiate agonists provide analgesic protection against hemodynamic responses to surgical stress by attenuating the catecholamine response.
Pharmacokinetics
Fentanyl is administered via transmucosal, parenteral, transdermal, and intranasal routes. Analgesic effects are related to the fentanyl blood concentration.
Fentanyl is 80 to 85% protein bound mainly to alpha-1-acid glycoprotein, but free fractions of the drug increase with acidosis. Fentanyl is highly lipophilic. It is rapidly distributed to the brain, heart, lungs, kidneys and spleen, with slower redistribution to skeletal muscle and fat where it is released slowly into the blood. Slow release of unchanged fentanyl from peripheral compartments into the blood may cause a rebound in serum fentanyl concentrations ("secondary peaks") even after drug discontinuation. In addition, alterations in pH may affect the drug's distribution into the central nervous system (CNS). Volume of distribution varies with age and is larger in neonates and young infants; mean Vd in adults is 4 L/kg (range 3 to 8 L/kg). Fentanyl is metabolized in the liver and intestinal mucosa via cytochrome P450 3A4 by oxidative N-dealkylation to norfentanyl (inactive metabolite). Approximately 75% of the administered dose is excreted in the urine, primarily as metabolites with less than 10% as unchanged drug. Less than 10% of the administered dose is recovered in the feces as metabolites.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
Fentanyl is primarily metabolized by the CYP3A4 isoenzyme system. Concurrent administration of drugs that induce CYP3A4 may reduce the efficacy of fentanyl, and concurrent administration of drugs that inhibit CYP3A4 may increase fentanyl plasma concentrations, resulting in increased or prolonged adverse drug effects and potentially fatal respiratory depression. Fentanyl is also a substrate for P-glycoprotein (P-gp).
Sublingual Administration (Abstral tablet; Subsys spray): Due to pharmacokinetic differences, transmucosal products, including sublingual tablets and sprays, are not equivalent on a mcg to mcg basis. After sublingual administration, absorption occurs primarily through the oral mucosa, with a resultant bioavailability of approximately 54% for the sublingual tablet and 76% for the sublingual spray. The pharmacokinetic profile and bioavailability depend on the fraction of the dose that is absorbed through the sublingual mucosa and the fraction swallowed. In a study comparing the sublingual spray to oral transmucosal fentanyl citrate (OTFC), the rate and extent of the sublingual spray was greater than that of OTFC with a 34% greater Cmax and a 38% greater AUC. The mean time to maximum plasma concentrations (Tmax) is 0.5 to 1 hour after sublingual tablet administration and 0.67 to 1.5 hours after sublingual spray administration. Sublingual tablet dose proportionality exists across the 200 mcg to 800 mcg dose range and across 800 mcg to 1600 mcg supra-therapeutic dose range. Sublingual spray dose proportionality exists across the 5 available strengths (100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg). Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets of the equivalent dose. The mean maximum concentration (Cmax) was 0.187 ng/mL for the 100 mcg sublingual tablet, 0.302 ng/mL for the 200 mcg tablet, 0.765 ng/mL for the 400 mcg tablet, and 1.42 ng/mL for the 800 mcg tablet. The mean Cmax was 0.202 ng/mL for the 100 mcg sublingual spray dose, 0.378 ng/mL for the 200 mcg dose, 0.8 ng/mL for the 400 mcg dose, 1.17 ng/mL for the 600 mcg dose, and 1.610 ng/mL for the 800 mcg dose. Peak concentrations and total exposure with the sublingual spray is not affected by pretreatment with hot or iced water or with low or high pH beverages. In a study with the sublingual spray, cancer patients with Grade 1 mucositis (n = 7) had a 73% greater Cmax and a 52% greater AUC in comparison to patients without mucositis. In 2 patients with Grade 2 mucositis, there was a 4- to 7-fold higher Cmax and a 3-fold or higher AUC compared to patients without mucositis.
Transmucosal Administration (Actiq): Due to pharmacokinetic differences, transmucosal products are not equivalent on a mcg to mcg basis. If administered as directed, approximately 25% of the fentanyl transmucosal lozenge dose is rapidly absorbed from the buccal mucosa. The remaining 75% is swallowed with the saliva and is slowly absorbed from the gastrointestinal tract. About one-third of this amount (25% of the total dose) avoids hepatic first-pass elimination and becomes systemically available. Thus, absolute bioavailability is approximately 50%. If the lozenge is improperly administered (i.e., chewed and swallowed), lower peak serum concentrations result and pain may not be adequately controlled. Onset of analgesia occurs as early as 4 minutes after administration. Dose proportionality exists for 4 available dosage strengths of Actiq: 200 mcg, 400 mcg, 800 mcg, and 1600 mcg. In adult pharmacokinetic studies, the mean Cmax was 0.39 ng/mL, 0.75 ng/mL, 1.55 ng/mL, and 2.51 ng/mL, respectively. The mean AUC was 102 ng x minute/mL, 243 ng x minute/mL, 573 ng x minute/mL, and 1026 ng x minute/mL for each dosage form, respectively. Administration of the 200 mcg unit appears to have a longer Tmax and a shorter half-life compared to other dosage strengths. The median Tmax for the 200 mcg lozenge was 40 minutes after the start of administration, vs. a mean of 20 to 25 minutes (range 20 to 480 minutes) with the higher dosage strengths. Mean half-life for the 200 mcg lozenge was 193 minutes, compared to 358 to 386 minutes with the higher dosage strengths. Duration of analgesia was 145 minutes for the 200 mcg unit and 215 minutes for the 800 mcg unit.
Transmucosal Administration (Fentora): Due to pharmacokinetic differences, transmucosal products are not equivalent on a mcg to mcg basis. Fentanyl is readily absorbed after buccal administration with an absolute bioavailability of 65%. Peak plasma concentrations are generally attained within an hour of buccal administration. Tablet disintegration usually takes 14 to 25 minutes, and the amount of time needed for the tablet to fully disintegrate does not appear to affect early systemic exposure. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract. Systemic exposure to buccal and sublingual fentanyl is equivalent and increases linearly in an approximate dose-proportional manner over the 100 mcg to 800 mcg dose range. The mean Cmax after administration of each dosage strength was 0.25 ng/mL, 0.4 ng/mL, 0.97 ng/mL, and 1.59 ng/mL, respectively. A 400 mcg tablet is not bioequivalent to four 100 mcg tablets, as the maximum serum concentration was 12% higher, and the systemic exposure was 13% higher with the four 100 mcg tablets. Consequently, patients converting from four 100 mcg tablets to one 400 mcg tablet would be expected to experience a decrease in fentanyl plasma concentration.
NOTE: In a comparative study of Actiq and Fentora, the rate and extent of fentanyl absorption were approximately 30% greater with Fentora, and exposure was approximately 50% greater with Fentora in another study. Further, the median Tmax with Fentora 400 mcg was 46.8 minutes (range, 20 to 240 minutes) as compared with 90.8 minutes (range, 35 to 240 minutes) with Actiq.
Transmucosal Administration (Onsolis): Due to pharmacokinetic differences, transmucosal products are not equivalent on a mcg to mcg basis. When administrated correctly, the absolute bioavailability of fentanyl from this formulation of transmucosal film is 71%; approximately 51% of dose is rapidly absorbed via the buccal membrane and an additional 20% of dosage is delivered systemically after swallowing, slow absorption from the gastrointestinal tract, and first pass elimination. The time to Cmax is approximately 1 hour and may be longer in patients with mucositis (range, 0.5 to 4 hours) compared to those with no mucositis (range, 0.5 to 1.5 hours). Plasma concentration curves, Cmax, and AUC values are proportional over a dosing range of 200 to 1200 mcg, with mean Cmax values of 0.38 ng/mL after a 200 mcg dose, 1.16 ng/mL after a 600 mcg dose, and 2.19 ng/mL after a 1200 mcg dose.
NOTE: In a comparative study of Actiq and Onsolis, the rate and extent of fentanyl absorption were greater with Onsolis, with a 62% greater Cmax and a 40% greater systemic exposure after single doses of 800 mcg. Further, the median Tmax with Onsolis 800 mcg was 1 hour (range, 0.75 to 4 hours) compared to 2 hours (range, 0.5 to 4 hours) with Actiq 800 mcg.
After IV administration of fentanyl, peak analgesia occurs within minutes and lasts for 30 to 60 minutes after a single dose. Respiratory depressant effects persist longer than analgesic actions, and residual fentanyl from 1 dose can potentiate the effect of subsequent doses.
Intramuscular RouteAfter IM administration of fentanyl, onset of analgesia is within 7 to 8 minutes and lasts for 1 to 2 hours. Respiratory depressant effects persist longer than analgesic actions, and residual fentanyl from 1 dose can potentiate the effect of subsequent doses.
Topical RouteTransdermal Administration (Duragesic): Fentanyl is released from the drug-in-adhesive matrix patch at a nearly constant rate into the skin, where a depot of fentanyl accumulates in the upper epidermis. From this depot the drug is systemically absorbed. Onset of analgesia is 12 to 24 hours after initial application. Serum fentanyl concentrations gradually increase over the first 12 to 24 hours after application; concentrations remain relatively constant for the remainder of the 72-hour application period. Peak concentrations occur 20 to 72 hours after initial application. With sequential use, serum fentanyl concentrations reach steady state by the end of the second 72-hour patch application. After removal, serum fentanyl concentrations decrease slowly due to absorption of residual drug concentrations in the skin. The average half-life of fentanyl transdermal patch is 17 hours after patch removal; analgesia may persist for up to 12 hours after patch removal. Fentanyl does not appear to be metabolized in the skin, as 92% of a transdermal dose can be found unchanged in systemic circulation. Exposure to external heat sources (e.g., heating pads, saunas, hot tubs, sunbathing) may increase fentanyl absorption from the transdermal system. In a study of healthy adult patients, direct heat application over the patch increased mean fentanyl exposure by 120% and average fentanyl concentrations by 61%.
Transdermal Administration (Ionsys): At initiation of each dose, electrical current is activated for 10 minutes which moves a dose of fentanyl through the skin and into systemic circulation. Blood concentrations increase slowly and continue to increase for approximately 5 minutes after completion of the 10 minute current. Systemic absorption increases as a function of time independent of dosing frequency. Following 48 doses (2 sequential doses every hour for approximately 23 hours), the AUC per on demand dose was 0.57 +/- 0.13 ng/mL, while the Cmax was 1.3 +/- 0.3 ng/mL. This regimen is representative of dosing regimens administered during phase 3 clinical trials.
Epidural Route
Following epidural administration, the onset of analgesia occurs within 10 to 15 minutes and lasts 2 to 3 hours. The high lipid solubility leads to rapid clearance from the CSF and less rostral or 'hook-like' spread than hydrophilic agents such as morphine. Fentanyl does not provide analgesia at distant sites from where it was administered; thus, epidural catheter placement is of great importance. Epidural administration is more effective than IM administration in producing lower spontaneous and provoked pain scores. Transfer to the placenta occurs rapidly. Eight pregnant women at term received epidural administration of 2 mL of 0.05 mg/mL fentanyl citrate along with 15 mL of 0.5% bupivacaine hydrochloride with 1:200,000 epinephrine, and 10 mL 2% lidocaine hydrochloride without a vasoconstrictor. Babies were born by Cesarean section a median of 28.5 minutes after epidural drug administration, and the median fetal/maternal plasma concentration ratio was 0.892 at birth. The median fetal plasma fentanyl concentration was 0.25 ng/mL as compared with the median maternal plasma concentration of 0.31 ng/mL. All babies had an Apgar score of 10 at the 5 minute time point.
Intranasal Route (e.g., Lazanda)
Fentanyl bioavailability is more than 50% after administration of the fentanyl nasal spray ; more precisely, systemic bioavailability after nasal application has been reported to be as high as 71 to 89%. In addition, the nasal spray has a 20% greater bioavailability than that of a compared (unspecified) oral transmucosal product. Onset of analgesia is within 10 minutes. Time to maximum plasma concentration occurs 15 to 21 minutes after administration. AUC and Cmax values are linear over a dosing range of 100 to 800 mcg (100 mcg, 200 mcg, 400 mcg, and 800 mcg). During adult pharmacokinetic studies, the mean Cmax after administration of each dosage was 0.35 ng/mL, 0.78 ng/mL, 1.55 ng/mL, and 2.84 ng/mL, respectively. The mean AUC was 2.46 ng x hour/mL, 4.36 ng x hour/mL, 7.51 ng x hour/mL, and 17.27 ng x hour/mL for each dosage, respectively. Repeat dosing in the same nostril results in increased Cmax. As compared to the first dose Cmax, the second dose Cmax was 30% greater with a 1-hour dosing interval, 25% greater with a 2-hour interval, and 10% greater with a 4-hour interval. The median Tmax ranged from 0.25 to 0.35 hours. Mean half-life ranges from 15 to 25 hours. Analgesic effects persist for 30 to 60 minutes. Allergic rhinitis does not appear to affect the rate or extent of absorption.
Pregnancy And Lactation
Use fentanyl during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data are insufficient with fentanyl in human pregnancy to inform a drug-associated risk for major birth defects or miscarriage. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation, fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies. Fentanyl is not recommended for use during and immediately before labor when other analgesic techniques are more appropriate. Opioids can prolong labor and obstetric delivery by temporarily reducing the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. An opioid antagonist (e.g., naloxone) should be available for reversal of opioid-induced respiratory depression in the neonate. Further, prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Monitor the exposed neonate for withdrawal symptoms, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight, and manage accordingly. 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. Guidelines recommend early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Obtain 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 NOWS, and how long-term opioid use may affect care during a future pregnancy.[64838] [64909] In women undergoing uncomplicated normal spontaneous vaginal birth, consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, use in combination with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. Use immediate-release opioids instead of extended-release or long-acting opioids; order the lowest effective dosage and prescribe no greater quantity of opioids than needed for the expected duration of such pain severe enough to require opioids.[64909] 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. Opioid agonist pharmacotherapy (e.g., methadone or buprenorphine) is preferable to medically supervised withdrawal in pregnant women with opioid use disorder.[64838]