CONTRAINDICATIONS / PRECAUTIONS
Asthma, emphysema, tobacco smoking
Dextromethorphan is contraindicated in the treatment of chronic cough, especially when associated with excessive bronchial secretion. This includes cough related to asthma, tobacco smoking, and emphysema. Dextromethorphan has no expectorant action and acts only to suppress the cough reflex. A recurrent or persistent cough (lasting for more than one week), or a cough accompanied by fever, nausea/vomiting, rash, or persistent headache may be signs of a more serious condition and should be evaluated by a physician.
Hepatic disease
Dextromethorphan is extensively metabolized by the liver and should be used with caution in patients with hepatic disease because of possible accumulation of the drug and resultant toxicity.
Children, infants
In January 2007, the CDC warned caregivers and healthcare providers of the risk for serious injury or fatal overdose from the administration of cough and cold products to children and infants less than 2 years of age. This warning followed an investigation of the deaths of three (3) infants less than 6 months of age that were attributed to the inadvertent inappropriate use of these products. The symptoms preceding these deaths have not been clearly defined, and there is a lack of conclusive data describing the exact cause of death. The report estimated that 1519 children less than 2 years of age were treated in emergency departments during 2004—2005 for adverse events related to cough and cold medications. In October 2007, the FDA Nonprescription Drug Advisory Committee and the Pediatric Advisory Committee recommended that nonprescription cough and cold products containing pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, brompheniramine, phenylephrine, clemastine, or guaifenesin not be used in children less than 6 years of age. In January 2008, the FDA issued a Public Health Advisory recommending that OTC cough and cold products not be used in infants and children less than 2 years. An official ruling regarding the use of these products in children greater than 2 years has not yet been announced. The FDA recommends that if parents and caregivers use cough and cold products in children greater than 2 years, labels should be read carefully, caution should be used when administering multiple products, and only measuring devices specifically designed for use with medications should be used. While some combination cough/cold products containing these ingredients are available by prescription only and are not necessarily under scrutiny by the FDA, clinicians should thoroughly assess each patient's use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose.
Pregnancy
There are no adequate and well-controlled studies of dextromethorphan in pregnant women. Dextromethorphan is available without a prescription, and because it 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 one 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.
Breast-feeding
Limited data are available regarding the use of dextromethorphan by breast-feeding women. It is not known whether dextromethorphan is excreted into human breast milk; however, based on dextromethorphan's relatively low molecular weight, some transfer into breast milk is expected. Despite the lack of published data, dextromethorphan is often considered to be compatible with breast-feeding when usual antitussive doses are taken by the mother, due to the lack of expected harm in the breast-fed infant. Some dextromethorphan cough products contain alcohol and these products should be avoided while breast-feeding.
Driving or operating machinery
Dextromethorphan may cause dizziness or confusion. Patients should be warned against driving or operating machinery, or doing anything that needs mental alertness until they know how dextromethorphan affects them.
MAOI therapy
Dextromethorphan should be used cautiously, if at all, in patients receiving MAOI therapy; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranycypromine, phenelzine).
Geriatric
There are no particular precautions for the use of dextromethorphan in the ambulatory, non-debilitated geriatric patient compared to use in younger adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities. According to the OBRA guidelines, cough, cold, and allergy medications should be used only for a limited duration (less than 14 days) unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected.
DRUG INTERACTIONS
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; 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.
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.
Artemether; Lumefantrine: (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.
Aspirin, ASA; Butalbital; Caffeine; 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.
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.
Atazanavir; Cobicistat: (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; 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.
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.
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.
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.
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.
Butalbital; Acetaminophen; Caffeine; 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.
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.
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) 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.
Cobicistat: (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.
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.
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.
Codeine; Phenylephrine; Promethazine: (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.
Codeine; Promethazine: (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.
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.
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) 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) 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.
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.
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.
Donepezil; 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.
Dronedarone: (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.
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.
Eliglustat: (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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (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) 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.
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.
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) 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.
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.
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.
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.
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.
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.
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.
Isocarboxazid: (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.
Lasmiditan: (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.
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.
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.
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.
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.
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.
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.
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.
Mirabegron: (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.
Monoamine oxidase inhibitors: (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.
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.
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.
Oliceridine: (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.
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.
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.
Panobinostat: (Major) Avoid coadministrating panobinostatwith 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.
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.
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: (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.
Phenelzine: (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.
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.
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.
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.
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.
Rolapitant: (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.
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.
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.
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.
Sibutramine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with sibutramine. 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.
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.
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.
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.
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.
Tranylcypromine: (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.
Tricyclic antidepressants: (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.
Vemurafenib: (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.
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.
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.