Coricidin HPB Flu

Acetaminophen, Antihistamine, and Non-opioid Antitussive Combinations
Other Cough and Cold Combinations

Severe

seizures / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatic encephalopathy / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
renal papillary necrosis / Delayed / Incidence not known
renal failure / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
myocarditis / Delayed / Incidence not known
hearing loss / Delayed / Incidence not known
serotonin syndrome / Delayed / Incidence not known

Moderate

neuritis / Delayed / Incidence not known
hallucinations / Early / Incidence not known
excitability / Early / Incidence not known
confusion / Early / Incidence not known
euphoria / Early / Incidence not known
medication overuse headache / Delayed / Incidence not known
withdrawal / Early / Incidence not known
constipation / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hypoprothrombinemia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
hemolysis / Early / Incidence not known
thrombocytosis / Delayed / Incidence not known
erythema / Early / Incidence not known
contact dermatitis / Delayed / Incidence not known
palpitations / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
blurred vision / Early / Incidence not known
urinary retention / Early / Incidence not known
dysuria / Early / Incidence not known
wheezing / Rapid / Incidence not known

Mild

fatigue / Early / Incidence not known
paresthesias / Delayed / Incidence not known
drowsiness / Early / Incidence not known
anxiety / Delayed / Incidence not known
tremor / Early / Incidence not known
irritability / Delayed / Incidence not known
headache / Early / Incidence not known
restlessness / Early / Incidence not known
dizziness / Early / Incidence not known
insomnia / Early / Incidence not known
xerostomia / Early / Incidence not known
pyrosis (heartburn) / Early / Incidence not known
anorexia / Delayed / Incidence not known
vomiting / Early / Incidence not known
diarrhea / Early / Incidence not known
abdominal pain / Early / Incidence not known
nausea / Early / Incidence not known
malaise / Early / Incidence not known
urticaria / Rapid / Incidence not known
skin irritation / Early / Incidence not known
rash / Early / Incidence not known
maculopapular rash / Early / Incidence not known
hyperhidrosis / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
purpura / Delayed / Incidence not known
vertigo / Early / Incidence not known
tinnitus / Delayed / Incidence not known
diplopia / Early / Incidence not known
polyuria / Early / Incidence not known
nasal dryness / Early / Incidence not known
weakness / Early / Incidence not known
nasal congestion / Early / Incidence not known
bronchial secretions / Early / Incidence not known
chills / Rapid / Incidence not known

Coricidin HPB Flu, Diabetic Tussin Cold and Flu, Mapap Children's Cough and Sinus, PediaCare Children's Cough & Runny Nose, Triaminic Multi-Symptom Fever, Tylenol Children's Cold + Cold + Runny Nose, Tylenol Children's Plus Cough and Runny Nose, Vicks Formula 44, Vicks Nyquil Cold & Flu

OTC

Oral combination of an analgesic/antipyretic, antihistamine, and antitussive
Used for the treatment of symptoms due to the common cold or flu
May cause sedation; excitability may occur, especially in children

For the treatment of symptoms due to the common cold or flu, including cough, fever, headache, mild pain, rhinorrhea, sneezing, and sore throat. Oral dosage (tablets containing acetaminophen 325 mg, chlorpheniramine 2 mg, dextromethorphan 10 mg) Adults

2 tablets PO every 4 hours as needed. Max: 10 tablets/day. Discontinue use if fever worsens or does not improve within 3 days or pain or cough worsens or does not improve within 7 days.

Children and Adolescents 12 to 17 years

2 tablets PO every 4 hours as needed. Max: 10 tablets/day. Discontinue use if fever worsens or does not improve within 3 days or pain or cough worsens or does not improve within 7 days.

Oral dosage (liquid containing acetaminophen/chlorpheniramine/dextromethorphan 650 mg/4 mg/30 mg per 30 mL) Adults

30 mL PO every 6 hours as needed. Max: 120 mL/day. Discontinue use if fever worsens or does not improve within 3 days or pain or cough worsens or does not improve within 7 days.

Children and Adolescents 12 to 17 years

30 mL PO every 6 hours as needed. Max: 120 mL/day. Discontinue use if fever worsens or does not improve within 3 days or pain or cough worsens or does not improve within 7 days.

Oral dosage (suspension containing acetaminophen/chlorpheniramine/dextromethorphan 160 mg/1 mg/5 mg per 5 mL) Children 6 to 11 years or weighing 48 to 95 kg

10 mL PO every 4 hours as needed. Max: 50 mL/day. Discontinue use if fever worsens or does not improve within 3 days or pain or cough worsens or does not improve within 5 days.

Hepatic Impairment

Use acetaminophen with caution in patients with hepatic dysfunction. In patients with chronic hepatic disease, acetaminophen can be used safely; use the smallest dose for the shortest duration necessary.  Use chlorpheniramine with caution in patients with severe hepatic impairment.

Renal Impairment

For patients with a CrCl less than 10 mL/minute, administer acetaminophen at a minimum interval of every 8 hours. Chronic use should be discouraged in patients with underlying renal disease. Use chlorpheniramine with caution in patients with severe renal impairment.

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Abiraterone: (Moderate) Abiraterone inhbits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. If dextromethorphan- related side effects occur, a dose reduction or discontinuation of dextromethorphan may be necessary. In an in vivo drug-drug interaction trial, the Cmax and AUC of the CYP2D6 substrate dextromethorphan were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily along with prednisone 5 mg twice daily. The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.
Acetaminophen; Caffeine; Dihydrocodeine: (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; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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; Dichloralphenazone; Isometheptene: (Moderate) Additive CNS depression may occur if dichloralphenazone is used concomitantly with any of the sedating H1 blockers. Use caution with this combination. Dosage reduction of one or both agents may be necessary.
Acetaminophen; Hydrocodone: (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; Oxycodone: (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.
Alfentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering alfentanil 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.
Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like sedating H1 blockers, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Amantadine: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Additive drowsiness may also occur.
Amikacin: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Aminoglycosides: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for chlorpheniramine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of chlorpheniramine. Celecoxib is a CYP2D6 inhibitor, and chlorpheniramine is a CYP2D6 substrate.
Amobarbital: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Amoxapine: (Moderate) Additive anticholinergic effects may be seen when amoxapine is used concomitantly with drugs are known to possess relatively significant antimuscarinic properties, including sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature Additive sedation may also occur.
Amphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
Amphetamine; Dextroamphetamine Salts: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
Amphetamine; Dextroamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
Antacids: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and chlorpheniramine could result in additive depressant effects. Careful monitoring is recommended during combined use. A dose reduction of one or both drugs may be warranted.
Aprepitant, Fosaprepitant: (Minor) Use caution if acetaminophen and aprepitant are used concurrently and monitor for an increase in acetaminophen-related adverse effects for several days after administration of a multi-day aprepitant regimen. Acetaminophen is a minor (10 to 15%) substrate of CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of acetaminophen. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Articaine; Epinephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of articaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Asenapine: (Moderate) Using drugs that can cause CNS depression, such as sedating H1-blockers, concomitantly with asenapine may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like sedating H1-blockers and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Aspirin, ASA; Carisoprodol: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant. (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.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Aspirin, ASA; Oxycodone: (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.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Atropine: (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Atropine; Difenoxin: (Moderate) An enhanced CNS depressant effect may occur when diphenoxylate/difenoxin is combined with other CNS depressants. Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as sedating H1 blockers, may produce additive effects with diphenoxylate/difenoxin if used concomitantly. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Azelastine: (Major) Avoid concomitant use of azelastine and sedating H1-blockers due to risk for additive CNS depression.
Azelastine; Fluticasone: (Major) Avoid concomitant use of azelastine and sedating H1-blockers due to risk for additive CNS depression.
Baclofen: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including skeletal muscle relaxants, such as baclofen.
Barbiturates: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Belladonna; Opium: (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. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
Benzhydrocodone; Acetaminophen: (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.
Benzodiazepines: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Benzphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers. This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
Benztropine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and benztropine use. Concomitant use may result in additive anticholinergic adverse effects.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Epinephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Buprenorphine: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Buprenorphine; Naloxone: (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concurrent use of sedating H1-blockers and buprenorphine is necessary, consider a dose reduction of one or both drugs because of the potential for additive pharmacological effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
Bupropion: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of bupropion is necessary. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Bupropion; Naltrexone: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of bupropion is necessary. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Busulfan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Butabarbital: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butorphanol: (Moderate) Concomitant use of butorphanol with sedating H1-blockers can potentiate the effects of butorphanol on CNS and/or respiratory depression. Use together with caution. If a CNS depressant needs to be used with butorphanol, use the smallest effective dose and the longest dosing frequency of butorphanol.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and sedating H1-blockers. CNS depressants can potentiate the effects of cannabidiol.
Capsaicin; Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants can potentiate the sedative effects of either agent.
Carbamazepine: (Minor) Carbamazepine may potentially accelerate the hepatic metabolism of acetaminophen. In addition, due to enzyme induction, carbamazepine may increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Clinicians should be alert to decreased effect of acetaminophen. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. 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. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Carisoprodol: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant.
Celecoxib: (Moderate) A dosage adjustment may be warranted for chlorpheniramine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of chlorpheniramine. Celecoxib is a CYP2D6 inhibitor, and chlorpheniramine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Moderate) A dosage adjustment may be warranted for chlorpheniramine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of chlorpheniramine. Celecoxib is a CYP2D6 inhibitor, and chlorpheniramine is a CYP2D6 substrate. (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.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and sedating H1-blockers. Concomitant use may result in additive CNS depression or anticholinergic effects.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and sedating H1-blockers. Concomitant use may result in additive CNS depression or anticholinergic effects.
Charcoal: (Minor) Activated charcoal binds many drugs within the gut. Administering charcoal dietary supplements at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen. Charcoal is mostly used in the setting of acetaminophen overdose; however, patients should never try to treat an acetaminophen overdose with charcoal dietary supplements. Advise patients to get immediate medical attention for an acetaminophen overdose.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Chlorpheniramine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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: (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: (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: (Moderate) Additive anticholinergic and sedative effects may be seen when chlorpromazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
Cholestyramine: (Moderate) Cholestyramine has been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved.
Choline Salicylate; Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
Citalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with citalopram. 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.
Clobazam: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
Clozapine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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.
Codeine; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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.
Codeine; Phenylephrine; Promethazine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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.
Codeine; Promethazine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine 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.
COMT inhibitors: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. 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. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Cyclobenzaprine: (Moderate) Cyclobenzaprine and sedating antihistamines such as chlorpheniramine both exhibit anticholinergic activity, and anticholinergic side effects can be additive. Monitor for anticholinergic-related effects such as constipation and urinary retention. Additive CNS depression causing sedation and/or dizziness is also possible. Dosage adjustments of either or both drugs may be necessary.
Dacomitinib: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of dacomitinib is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and dacomitinib is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dantrolene: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
Dapsone: (Moderate) Coadministration of dapsone with acetaminophen may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Daratumumab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Darifenacin: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Delavirdine: (Moderate) Use of dextromethorphan with delavirdine may result in increased dextromethorphan exposure. Delavirdine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of desloratadine with CNS depressants such as other H1-blockers.
Desloratadine; Pseudoephedrine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of desloratadine with CNS depressants such as other H1-blockers.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Desvenlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with desvenlafaxine. 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. In addition, the manufacturer of desvenlafaxine recommends that the dose of CYP2D6 substrates, such as dextromethorphan, be reduced by up to 50% if used with desvenlafaxine 400 mg/day, a CYP2D6 inhibitor.
Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as chlorpheniramine, may have additive effects and worsen drowsiness or sedation.
Dexmedetomidine: (Moderate) Consider a dosage reduction for dexmedetomidine or the sedating antihistamine during concomitant use due to the risk of additive CNS effects.
Dextroamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
Dextromethorphan; Bupropion: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of bupropion is necessary. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Quinidine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of quinidine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and quinidine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dicyclomine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and dicyclomine use. Concomitant use may result in additive anticholinergic adverse effects.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diflunisal: (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.
Diphenoxylate; Atropine: (Moderate) An enhanced CNS depressant effect may occur when diphenoxylate/difenoxin is combined with other CNS depressants. Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as sedating H1 blockers, may produce additive effects with diphenoxylate/difenoxin if used concomitantly. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Disopyramide: (Moderate) The anticholinergic effects of sedating H1-blockers may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including disopyramide. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Donepezil: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
Donepezil; Memantine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
Doxorubicin Liposomal: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Doxorubicin: (Major) Chlorpheniramine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of chlorpheniramine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with antihistamines is necessary. Concurrent use of dronabinol, THC with antihistamines may result in additive drowsiness, hypertension, tachycardia, and possibly cardiotoxicity.
Dronedarone: (Moderate) Dronedarone is an inhibitor of CYP2D6. Chlorpheniramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Droperidol: (Moderate) Sedating H1-blockers have additive or potentiating sedative and other CNS effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant may need to be used.
Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Duloxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. 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.
Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as chlorpheniramine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Efavirenz: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavir

enz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efgartigimod Alfa; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of scheduled chlorpheniramine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily during the course of antihistamine treatment; however, coadministration of eliglustat with both chlorpheniramine and a strong or moderate CYP3A inhibitor is contraindicated. It is unclear whether a single dose of chlorpheniramine warrants modification of eliglustat therapy. Chlorpheniramine is a substrate and moderate inhibitor of CYP2D6; eliglustat is also a substrate and inhibitor of CYP2D6 as well as a CYP3A substrate. Coadministration of eliglustat with CYP2D6 inhibitors, such as chlorpheniramine, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); the effects of a single chlorpheniramine dose are unknown. In addition, coadministration of eliglustat with CYP2D6 substrates (e.g., chlorpheniramine) may result in increased concentrations of the concomitant drug; monitor patients closely for anticholinergic adverse events. (Moderate) Use of dextromethorphan with eliglustat may result in increased dextromethorphan exposure. Eliglustat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Acetaminophen is a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of acetaminophen are possible. Monitor patients for adverse reactions if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. 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. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Epinephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine.
Escitalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with escitalopram. 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.
Esketamine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Eszopiclone: (Moderate) A reduction in the dose of eszopiclone and concomitantly administered CNS depressants, such as sedating H1-blockers, should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume alcohol. Patients who drink more than 3 alcohol-containing drinks a day and take acetaminophen are at increased risk of developing hepatotoxicity. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume alcohol regularly.
Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Etomidate: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Everolimus: (Moderate) Monitor for an increase in chlorpheniramine-related adverse reactions if coadministration with everolimus is necessary. Chlorpheniramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor.
Exenatide: (Minor) Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
Fedratinib: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and chlorpheniramine. Concurrent use may result in additive CNS depression. (Moderate) Use fenfluramine and dextromethorphan with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fentanyl: (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.
Flavoxate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and flavoxate use. Concomitant use may result in additive anticholinergic adverse effects.
Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as sedating H1-blockers, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
Fluoxetine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Fluphenazine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Fluvoxamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. 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.
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.
Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of chlorpheniramine and gabapentin. Concurrent use may result in additive CNS depression.
Galantamine: (Moderate) Concurrent use of sedating H1-blockers and galantamine should be avoided if possible. Galantamine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of galantamine.
Gentamicin: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Givosiran: (Moderate) If possible, avoid concomitant use of dextromethorphan with givosiran due to the risk of increased dextromethorphan-related adverse reactions. If use is necessary, consider decreasing the dextromethorphan dose. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Dextromethorphan is a sensitive CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Glycopyrrolate; Formoterol: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Grapefruit juice: (Minor) Intake of grapefruit juice or seville orange juice increased dextromethorphan bioavailability in one study. Patients with increased concentrations of dextromethorphan may experience drowsiness or serotonergic side effects (dizziness, nervousness or restlessness, nausea, vomiting, stomach upset) not usually noted with prescribed or nonprescription product doses. Grapefruit juice and seville orange juice contain compounds that can inhibit P-glycoprotein in the intestinal wall, and dextromethorphan absorption may be affected by P-glycoprotein activity. Dextromethorphan is largely metabolized by CYP2D6, so this particular interaction with grapefruit juice may be more relevant in patients who are poor CYP2D6 metabolizers.
Guaifenesin; Hydrocodone: (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.
Halogenated Anesthetics: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as the sedating H1-blockers. Additive anticholinergic effects may occur. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or CNS effects may also occur.
Heparin: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Homatropine; Hydrocodone: (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. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and homatropine use. Concomitant use may result in additive anticholinergic adverse effects.
Hyaluronidase, Recombinant; Immune Globulin: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Hydrocodone: (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.
Hydrocodone; Ibuprofen: (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.
Hydrocodone; 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.
Hydromorphone: (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.
Hyoscyamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Ibuprofen; Oxycodone: (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.
Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications, such as sedating H1-blockers.
Imatinib: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Use of dextromethorphan with imatinib may result in increased dextromethorphan exposure. Imatinib inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Insulin Glargine; Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with acetaminophen may result in increased serum concentrations of acetaminophen. Acetaminophen is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites.
Isoniazid, INH: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
Isoniazid, INH; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
Isoproterenol: (Moderate) Monitor hemodynamic parameters during concomitant isoproterenol and chlorpheniramine use; dosage adjustments may be necessary. Chlorpheniramine may potentiate the effects of isoproterenol.
Ketamine: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Lamotrigine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and sedating H1-blockers. Concurrent use may result in additive CNS depression. (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and sedating antihistamines (H1-blockers). Dosage adjustments of lemborexant and sedating H1-blockers may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants. Patients should generally avoid nonprescription antihistamine products that are marketed as sleep-aids concurrently with lemborexant.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and sedating H1-blockers. Concomitant use may result in additive CNS depression or anticholinergic effects.
Levomilnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with levomilnacipran. Dextromethorphan has serotonergic activity. 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.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Levorphanol: (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.
Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Linezolid: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering linezolid with dextromethorphan. Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor and has potential to interact with serotonergic agents. Dextromethorphan has serotonergic activity. However, the potential for interaction has been studied. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
Lithium: (Moderate) Because lithium has the potential to impair cognitive and motor skills, caution is advisable during concurrent use of other medications with centrally-acting effects including the sedating antihistamines.
Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day PO for >= 3 days/week). The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Lopinavir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as other H1-blockers.
Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as other H1-blockers.
Lorcaserin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with lorcaserin. Both medications have serotonergic activity. 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. In addition, lorcaserin inhibits CYP2D6-mediated metabolism of dextromethorphan, increasing dextromethorphan Cmax by approximately 76% and AUC by approximately 2-fold. Increased dextromethorphan exposure may result in adverse effects consistent with the serotonin syndrome.
Loxapine: (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and chlorpheniramine. Concurrent use may result in additive CNS depression.
Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications. Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur.
Maprotiline: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
Meclizine: (Major) Meclizine is an H1-blocker which exhibits significant anticholinergic effects. The anticholinergic effects of meclizine may be enhanced when combined with other drugs with antimuscarinic activity, including other sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive sedation may also occur.
Melatonin: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of melatonin and sedating H1-blockers due to the risk for additive CNS depression.
Memantine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
Meperidine: (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.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including sedating H1-blockers.
Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants can potentiate the sedative effects of either agent.
Methadone: (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.
Methamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of sedating H1-blockers. This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine. Coadminister with caution and monitor for altered response to drug therapy.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants such as sedating H1-blockers. Combination therapy can cause additive effects of sedation and dizziness, which can impair the patient's ability to undertake tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary.
Methohexital: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Methscopolamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and methscopolamine use. Concomitant use may result in additive anticholinergic adverse effects.
Methylene Blue: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
Metyrapone: (Major) Coadministration of metyrapone and acetaminophen may result in acetaminophen toxicity. Acetaminophen glucuronidation is inhibited by metyrapone. It may be advisable for patients to avoid acetaminophen while taking metyrapone. (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as sedating H1-blockers, should be used with caution. Additive drowsiness and/or dizziness is possible.
Metyrosine: (Moderate) The concomitant administration of metyrosine with sedating H1-blockers can result in additive sedative effects.
Milnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with milnacipran. Dextromethorphan has serotonergic activity. 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.
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 sedating H1-blockers. Caution should be exercised when using these agents concurrently.
Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary. (Minor) Use of dextromethorphan with mirabegron may result in increased dextromethorphan exposure. Mirabegron moderately inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Mirtazapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Mitotane: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
Molindone: (Moderate) An enhanced CNS depressant effect may occur when sedating h1-blockers are combined with other CNS depressants including molindone.
Monoamine oxidase inhibitors: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites.
Morphine: (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.
Morphine; Naltrexone: (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.
Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nabilone on respiratory depression.
Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with chlorpheniramine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as chlorpheniramine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nefazodone: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. 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.
Neostigmine; Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Niraparib; Abiraterone: (Moderate) Abiraterone inhbits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. If dextromethorphan- related side effects occur, a dose reduction or discontinuation of dextromethorphan may be necessary. In an in vivo drug-drug interaction trial, the Cmax and AUC of the CYP2D6 substrate dextromethorphan were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily along with prednisone 5 mg twice daily. The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.
Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Olanzapine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Olanzapine; Fluoxetine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Olanzapine; Samidorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Oliceridine: (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. (Moderate) If concomitant use of oliceridine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Omeprazole; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Opiate Agonists: (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.
Opicapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. 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. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Oritavancin: (Moderate) Administration of oritavancin, a weak inducer of CYP2D6 and CYP3A4, with dextromethorphan resulted in a 31% reduction in the ratio of dextromethorphan to dextrorphan concentrations in the urine. The efficacy of dextromethorphan may be reduced if these drugs are administered concurrently. (Moderate) Chlorpheniramine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of chlorpheniramine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like sedating H1-blockers and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Oxybutynin: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and oxybutynin use. Concomitant use may result in additive anticholinergic adverse effects.
Oxycodone: (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.
Oxymorphone: (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.
Ozanimod: (Contraindicated) Coadministration of ozanimod with dextromethorphan is contraindicated. Allow at least 14 days between discontinuation of ozanimod and initiation of dextromethorphan. Consider if an alternative to dextromethorphan would be appropriate. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for serious and possibly fatal drug interactions with dextromethorphan, including serotonin syndrome.
Paliperidone: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Panobinostat: (Major) Avoid coadministrating panobinostat with sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
Paromomycin: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Paroxetine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Pazopanib: (Moderate) Use of dextromethorphan with pazopanib may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Coadministration of dextromethorphan and pazopanib resulted in an increase of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine, indicating reduced CYP2D6 metabolism to the dextrorphan metabolite.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to chlorpheniramine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while chlorpheniramine is a CYP2D6 substrate. (Minor) Monitor for adverse effects associated with increased exposure to dextromethorphan if peginterferon alfa-2b is coadministered. Peginterferon alfa -2b is a CYP2D6 inhibitor, while dextromethorphan is a CYP2D6 substrate.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
Pentobarbital: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
Perphenazine: (Moderate) Additive anticholinergic and sedative effects may be seen when perphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Perphenazine; Amitriptyline: (Moderate) Additive anticholinergic and sedative effects may be seen when perphenazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Pertuzumab; Trastuzumab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Phenelzine: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites.
Phenobarbital: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and scopolamine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including sedating antihistamines. Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with pimozide. Additive drowsiness or other CNS effects may occur.
Pitolisant: (Major) Avoid coadministration of pitolisant with chlorpheniramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like chlorpheniramine, may reduce pitolisant efficacy.
Plazomicin: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as acetaminophen, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
Posaconazole: (Moderate) Posaconazole and acetaminophen should be coadministered with caution due to an increased potential for acetaminophen-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of acetaminophen. These drugs used in combination may result in elevated acetaminophen plasma concentrations, causing an increased risk for acetaminophen-related adverse events.
Pramipexole: (Moderate) Concomitant use of pramipexole with other CNS depressants, such as sedating H1-blockers, can potentiate the sedation effects of pramipexole.
Pramlintide: (Minor) Because pramlintide has the potential to delay the absorption of concomitantly administered medications, medications should be administered at least 1 hour before or 2 hours after pramlintide injection when the rapid onset of a concomitantly administered oral medication is a critical determinant of effectiveness (i.e., analgesics).
Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of chlorpheniramine and pregabalin. Concurrent use may result in additive CNS depression.
Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Chlorpheniramine may potentiate the arrhythmogenic effects of epinephrine. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Primidone: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Procarbazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with procarbazine, an antineoplastic agent with monoamine oxidase inhibitor (MAOI) activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Use procarbazine and sedating H1-blockers together with caution; additive central nervous system depression may occur.
Prochlorperazine: (Moderate) Additive anticholinergic and sedative effects may be seen when prochlorperazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Promethazine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Promethazine; Dextromethorphan: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Promethazine; Phenylephrine: (Moderate) Additive anticholinergic and sedative effects may be seen when promethazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Propafenone: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
Propantheline: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and propantheline use. Concomitant use may result in additive anticholinergic adverse effects.
Propofol: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
Quetiapine: (Moderate) Somnolence is a commonly reported adverse effect of quetiapine. Co-administration of quetiapine with sedating H1-blockers may result in additive effects. Additive drowsiness or other CNS effects may occur.
Quinidine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of quinidine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and quinidine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Quinine: (Moderate) Although clinical drug interaction studies have not been performed, antimalarial doses of quinine (greater than or equal to 600 mg/day in adults) may inhibit the metabolism of CYP2D6 substrates such as dextromethorphan and may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Ramelteon: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as ramelteon.
Rasagiline: (Contraindicated) Dextromethorphan prescription products are contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping dextromethorphan before starting an MAOI, including rasagiline. Brief episodes of psychosis or bizarre behavior have also been reported with this combination. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotoninergic agents, a sufficient amount of time must be allowed for clearance of the serotoninergic agent and its active metabolites. (Moderate) Concurrent use of monoamine oxidase inhibitors (MAOIs) and sedating H1-blockers (sedating antihistamines) may result in additive sedation, anticholinergic effects, or hypotensive reactions. Rasagiline may be less likely to produce these interactions than other MAOIs, due to MAO-B selectivity. However, consider alternatives therapy to antihistamines where possible. If alternative combinations are not available, these medications may be used together with close monitoring. Many non-prescription products for coughs, colds, allergy, hay fever or insomnia contain sedating antihistamines. Patients receiving rasagiline should be counseled that it is essential to consult their healthcare provider or pharmacist prior to the use of any non-prescription products. Patients should also be advised against driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Remifentanil: (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.
Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Rifampin: (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution is advisable when risperidone is given with other centrally acting medications including sedating H1-blockers such as chlorpheniramine. Patients should be informed of the risk of driving or performing other tasks requiring mental alertness until the effects of these medicines are known.
Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Rituximab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Rivastigmine: (Moderate) Concurrent use of sedating H1-blockers and rivastigmine should be avoided if possible. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of rivastigmine.
Rolapitant: (Major) Use caution if products containing chlorpheniramine and rolapitant are used concurrently, and monitor for chlorpheniramine-related adverse effects. Consider if another antihistamine would be a better choice for treatment. Chlorpheniramine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Moderate) Rolapitant increases exposure to dextromethorphan. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Rolapitant is a moderate CYP2D6 inhibitor with a prolonged effect; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. During drug interaction studies, exposure (AUC) to dextromethorphan following a single dose of rolapitant increased close to 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan exposure (AUC), the last time point measured.
Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants, such as sedating H1-blockers, can potentiate the sedation effects of ropinirole.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Safinamide: (Contraindicated) Dextromethorphan prescription products are contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping dextromethorphan before starting an MAOI, including safinamide. Brief episodes of psychosis or bizarre behavior have also been reported with this combination. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotoninergic agents, a sufficient amount of time must be allowed for clearance of the serotoninergic agent and its active metabolites. (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of other sedating medications, such as sedating H1-blockers.
Scopolamine: (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and scopolamine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Secobarbital: (Moderate) Additive CNS depression may occur if barbiturates are co-used with sedating antihistamines, such as chlorpheniramine. Monitor for additive CNS and respiratory effects, and warn about the potential effects to driving and other activities. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Selegiline: (Contraindicated) Dextromethorphan products are contraindicated in patients taking selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor) or in patients who have taken an selegiline within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of selegiline. Patients should read nonprescription product labels carefully. Before initiating selegiline after using dextromethorphan, a sufficient amount of time is advisable for clearance of dextromethorphan. (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and chlorpheniramine. Concurrent use may result in additive CNS depression.
Serotonin-Receptor Agonists: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant dextromethorphan and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Sertraline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with sertraline. 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. In addition, sertraline inhibits CYP2D6 and may increase systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent medications, including H1-blockers. False study results are possible; thorough patient history is important in the interpretation of procedure results.
Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Sodium Iodide: (Moderate) Antihistamines may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administration. In addition, medications that decrease salivation increase the time of radiation exposure to salivary glands. Consider discontinuing sedating H1-blockers prior to sodium iodide I-131 administration.
Solifenacin: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with other antimuscarinics, such as sedating H1 blockers.
St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and chlorpheniramine. CNS depressants can potentiate the effects of stiripentol.
Streptomycin: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Sufentanil: (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.
Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of suvorexant and sedating antihistamines (H1-blockers). Dosage adjustments of suvorexant and sedating H1-blockers may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants. Patients should generally avoid nonprescription antihistamine products that are marketed as sleep-aids concurrently with suvorexant.
Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as chlorpheniramine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Tapentadol: (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.
Tasimelteon: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as tasimelteon.
Tedizolid: (Minor) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tedizolid. Tedizolid is an antibiotic that is also a weak, reversible, non-selective MAO inhibitor in vitro. In theory, tedizolid has potential to interact with serotonergic agents, but interactions are thought to be unlikely. In clinical interaction studies with a related antibiotic (linezolid), interactions with dextromethorphan were studied, but serotonin syndrome or adverse effects were not reported. No drug-drug interaction precautions with dextromethorphan are specifically mentioned in the tedizolid label. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Terbinafine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of terbinafine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and terbinafine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Thalidomide: (Major) Avoid the concomitant use of thalidomide with opiate agonists; antihistamines; antipsychotics; anxiolytics, sedatives, and hypnotics; and other central nervous system depressants due to the potential for additive sedative effects.
Thioridazine: (Moderate) Additive anticholinergic and sedative effects may be seen when thioridazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Thiothixene: (Moderate) Additive anticholinergic effects may be seen when antipsychotics, such as thiothixene, are used concomitantly with other drugs such as sedating H1-blockers. Additive drowsiness or other CNS effects may also occur.
Tipranavir: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of tipranavir is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
Tobramycin: (Minor) Chlorpheniramine may effectively mask vestibular symptoms (e.g., dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
Tocilizumab: (Minor) Concomitant use of tocilizumab and dextromethorphan may lead to a decrease in the efficacy of dextromethorphan; clinical significance of this interaction is not known or established. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 5% decrease in dextromethorphan exposure and a 29% decrease in its metabolite, dextrorphan was noted 1 week after a single tocilizumab infusion. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dextromethorphan is a CYP2D6 substrate.
Tolcapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. 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. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tramadol: (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.
Tramadol; Acetaminophen: (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.
Tranylcypromine: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites.
Trastuzumab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Trazodone: (Moderate) Antihistamines that may cause sedation, such as chlorpheniramine, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects.
Tricyclic antidepressants: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trifluoperazine: (Moderate) Additive anticholinergic and sedative effects may be seen when trifluoperazine is used with first generation antihistamines, such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Trihexyphenidyl: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant sedating H1-blocker and trihexyphenidyl use. Concomitant use may result in additive anticholinergic adverse effects.
Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the sedating h1-blockers, may potentiate the effects of either trimethobenzamide or the sedating h1-blocker.
Trospium: (Moderate) Additive anticholinergic effects may be seen when trospium is used concomitantly with drugs that are known to possess relatively significant antimuscarinic properties, including sedating H1-blockers. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy. (Moderate) Concomitant use of vemurafenib and chlorpheniramine may result in increased chlorpheniramine concentrations. Chlorpheniramine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity. (Minor) Use of dextromethorphan with vemurafenib increases dextromethorphan exposure. Vemurafenib is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Coadministration of vemurafenib and dextromethorphan increased the AUC of dextromethorphan by 47% and the dextromethorphan Cmax by 36%.
Venlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with venlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
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 sedating H1-blockers.
Vilazodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with vilazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics. Also, Cyproheptadine is an antagonist of serotonin in the CNS, a property which may oppose some of the pharmacologic effects of vilazodone. Cyproheptadine has been used for the management of orgasm dysfunction caused by the serotonergic antidepressants and for the adjunctive treatment of serotonin syndrome; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the antidepressant. Clinically, cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine, but more data are needed to confirm a direct drug-drug interaction.
Viloxazine: (Moderate) Monitor for an increase in dextromethorphan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase dextromethorphan exposure; viloxazine is a weak CYP2D6 inhibitor and dextromethorphan is a CYP2D6 substrate.
Vortioxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with vortioxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Warfarin: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Zaleplon: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Ziconotide: (Moderate) Sedating H1-blockers are CNS depressant medications that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Ziprasidone: (Moderate) Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur with ziprasidone.
Zolmitriptan: (Minor) Zolmitriptan can delay the Tmax of acetaminophen by one hour. A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its active metabolite. The interaction between zolmitriptan and acetaminophen is not likely to be clinically significant.
Zolpidem: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of sedating H1-blockers and zolpidem due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Limit the dose of Intermezzo sublingual tablets to 1.75 mg/day.

Coricidin HPB Flu Oral Tab: 500-2-15mg
Diabetic Tussin Cold and Flu Oral Cap: 325-4-15mg
Triaminic Multi-Symptom Fever/Vicks Formula 44/Vicks Nyquil Cold & Flu Oral Sol: 5mL, 15mL, 30mL, 160-1-7.5mg, 650-4-30mg
Tylenol Children's Cold + Cold + Runny Nose Oral Susp: 5mL, 160-1-5mg

Adults

3,250 mg/day PO acetaminophen; 20 mg/day PO chlorpheniramine; 100 mg/day PO dextromethorphan for tablets and 2,600 mg/day PO acetaminophen; 16 mg/day PO chlorpheniramine; 120 mg/day dextromethorphan for liquid.

Geriatric

3,250 mg/day PO acetaminophen; 20 mg/day PO chlorpheniramine; 100 mg/day PO dextromethorphan for tablets and 2,600 mg/day PO acetaminophen; 16 mg/day PO chlorpheniramine; 120 mg/day dextromethorphan for liquid.

Adolescents

3,250 mg/day PO acetaminophen; 20 mg/day PO chlorpheniramine; 100 mg/day PO dextromethorphan for tablets and 2,600 mg/day PO acetaminophen; 16 mg/day PO chlorpheniramine; 120 mg/day dextromethorphan for liquid.

Children

12 years: 3,250 mg/day PO acetaminophen; 20 mg/day PO chlorpheniramine; 100 mg/day PO dextromethorphan for tablets and 2,600 mg/day PO acetaminophen; 16 mg/day PO chlorpheniramine; 120 mg/day dextromethorphan for liquid.
6 to 11 years: 1600 mg/day PO acetaminophen; 10 mg/day PO chlorpheniramine; 50 mg/day PO dextromethorphan for suspension. Safety and efficacy of tablets and liquid have not been established.
1 to 5 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Acetaminophen acts within the CNS to increase the pain threshold by inhibiting central cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Acetaminophen does not inhibit PG synthesis in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects. Chlorpheniramine is an H1-antagonist belonging to the alkylamine class of antihistamines. Antihistamines appear to compete with histamine for receptor sites on effector cells. Chlorpheniramine also has anticholinergic (drying) and sedative effects. Among the antihistaminic effects, it antagonizes the allergic response (vasodilatation, increased vascular permeability, increased mucus secretion) of nasal tissue. Dextromethorphan is a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors in the brain and spinal cord, and this activity is responsible for its therapeutic and toxic effects. As an antitussive, dextromethorphan acts centrally on the cough center in the medulla to raise the threshold for coughing by decreasing the excitability of the cough center. Dextromethorphan is about equal to codeine in depressing the cough reflex. It is the d-isomer of levorphanol but has none of the analgesic, respiratory depressive, or sedative effects associated with opioid agonists when used in usual antitussive dosages. In therapeutic dosage, dextromethorphan also does not inhibit ciliary activity.

Acetaminophen; chlorpheniramine; dextromethorphan is administered orally.    At therapeutic concentrations, acetaminophen protein binding is about 10% to 25%. Acetaminophen is widely distributed throughout most body tissues except fat; low protein binding and molecular weight allow blood-brain barrier penetration. Vd is approximately 1 L/kg in children and adults. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves 3 separate pathways: glucuronidation, sulfate conjugation, and cytochrome P450 (CYP450) oxidation. Glucuronidation and sulfate conjugation are the major routes of metabolism, while a small amount of drug undergoes oxidative metabolism via CYP2E1 producing the hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). At therapeutic doses, NAPQI is rapidly conjugated with glutathione to form inert cysteine and mercapturic acid metabolites. The P450 isoenzymes 1A2 and 3A4 appear to have a minor role in the metabolism of acetaminophen. Supratherapeutic or repeated therapeutic doses of acetaminophen, fasting, and alcoholism may deplete glutathione stores, leading to increased concentrations of NAPQI and hepatotoxicity. Acetaminophen is renally excreted primarily as the glucuronide conjugate (40% to 65%) and sulfate metabolite (25% to 35%). Mercapturic acid and cysteine metabolites account for 5% to 12% of the urinary metabolites; less than 5% is excreted as unchanged drug. The elimination half-life of acetaminophen is 2 to 3 hours in healthy adult patients. Chlorpheniramine is widely distributed throughout the tissues of the body, including the central nervous system. It has an apparent steady-state Vd of approximately 3.2 L/kg in adults and children and is about 70% bound to plasma proteins. Chlorpheniramine is rapidly and extensively metabolized via demethylation in the liver, forming mono-and didesmethyl derivatives. Oxidative metabolism of chlorpheniramine is catalyzed by CYP2D6. Chlorpheniramine and its metabolites are primarily excreted through the kidneys, with large individual variation. Urinary excretion depends on urine pH and flow rate. The mean plasma half-life of chlorpheniramine is approximately 21 to 24 hours. Dextromethorphan is rapidly absorbed from the gastrointestinal tract. It is metabolized primarily by liver enzymes undergoing O-demethylation, N-demethylation, and partial conjugation with glucuronic acid and sulfate. In humans, (+)-3-hydroxy-N-methyl-morphinan, (+)-3-hydroxymorphinan, and traces of unmetabolized drug were found in urine after oral administration.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP2E1
Although acetaminophen is primarily metabolized via glucuronidation and sulfate conjugation, it is also a substrate of CYP2E1. Drugs that induce CYP2E1 may increase the metabolism of acetaminophen to its toxic metabolite and therefore increase the risk of hepatotoxicity. Because CYP1A2 and CYP3A4 have negligible contribution to acetaminophen metabolism, the enzymes are unlikely to affect toxic metabolite formation. Chlorpheniramine is a CYP2D6 substrate. Dextromethorphan is primarily metabolized by the CYP2D6 isoenzyme and is a sensitive substrate.

Oral Route

Immediate-release acetaminophen is rapidly and almost completely absorbed from the gastrointestinal (GI) tract, primarily the small intestine. Bioavailability ranges from 85% to 98%. Peak plasma concentrations occur within 30 to 60 minutes and range from 7.7 to 17.6 mcg/mL after a single 1,000 mg dose and 7.9 to 27 mcg/mL at steady-state after 1,000 mg every 6 hours in adult patients. In a study of febrile children 2 to 7 years of age, acetaminophen 12 mg/kg achieved maximum concentration (14.6 +/- 2.6 mcg/mL) within 0.55 +/- 0.08 hours. Maximum concentrations of acetaminophen are delayed with concurrent food administration, however the extent of absorption is not affected. Chlorpheniramine mean peak plasma concentration of 58.4 ng/mL occurred at 6.3 hours after multiple dosing. The onset of antitussive action occurs in 15 to 30 minutes after dextromethorphan administration, and the duration of action is approximately 3 to 6 hours.

Pregnancy

Published epidemiological studies have not reported a clear association with acetaminophen use during pregnancy and birth defects, miscarriage, or adverse maternal or fetal outcomes. Large observational studies of newborns exposed to oral acetaminophen during the first trimester have not shown an increased risk for congenital malformations or major birth defects; however, these studies cannot definitely establish the absence of risk because of methodological limitations. Acetaminophen does cross the placenta and should be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus or infant. No overall increase in fetal mortality, determined by pregnancy outcomes of mothers that overdosed on various amounts of oral acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions were subsequent to first trimester exposure. First-trimester use of antihistamines is not recommended. In general, sedating antihistamines are not recommended for use in the last 2 weeks of pregnancy due to a possible association between these drugs and retrolental fibroplasia in premature neonates. Non-pharmacologic methods (e.g., fluids, and rest) are recommended to be tried first for symptomatic relief of colds or allergies during pregnancy. Consider alternatives to first generation sedating antihistamines if drug therapy is necessary. Guidelines consider loratadine an acceptable alternative in pregnancy, preferably after the first trimester, when first generation antihistamines are not tolerated. The majority of studies examining the use of chlorpheniramine in human pregnancy did not find an association with an increased risk of congenital anomalies. In the few studies reporting an association, there was no consistent pattern of malformations noted. Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryolethal at a dose approximately 9 times the maximum recommended human dose (MRHD) and decreased postnatal survival when dosing was continued after parturition. Chlorpheniramine administered by the oral route to male and female rats prior to mating produced embryolethality at a dose approximately 9 times the MRHD. Because dextromethorphan acts as a low affinity antagonist to the glutamate receptor subtype N-methyl-D-aspartate (NMDA) in the CNS, there has been some concern about its safe use during pregnancy. Dextromethorphan exhibited adverse developmental effects in avian embryos; however, the avian study data have limited applicability to human gestation. Human surveillance data and retrospective studies have shown dextromethorphan to be relatively safe during the first trimester; a human epidemiologic study and a smaller controlled study have not demonstrated elevated risks of congenital malformations. In a controlled study, there were no cases of neural tube defects, and no differences in number of live births, spontaneous or elective abortions, stillbirths, or major or minor malformations among infants exposed to dextromethorphan during the first trimester and those who were not. The results suggested that use during pregnancy does not pose a risk to the fetus; however, due to the small sample size, an increased risk of rare malformations could not be ruled out.

Limited published studies report acetaminophen passes rapidly into human milk with similar concentrations in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral dose of 1,000 mg. There is a well-documented report of rash occurring in a breast-fed infant that resolved with drug discontinuation and recurred with resumption.[42289] According to previous recommendations from the American Academy of Pediatrics (AAP), acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast-feeding. The AAP and other experts regard acetaminophen as a maternal medicine that is usually compatible with breast-feeding.[27500] Chlorpheniramine is present in human milk. Chlorpheniramine has not been reported to cause effects on the breast-feeding infant. The published literature suggests that chlorpheniramine may decrease milk production based on its anticholinergic effects. Antihistamines can lower basal prolactin secretion and may interfere with the establishment of lactation.  It is not known whether dextromethorphan is excreted in human milk. There are no data on the effects of dextromethorphan on the breast-fed infant or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for dextromethorphan and any potential adverse effects on the breast-fed infant from dextromethorphan or the underlying maternal condition.