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  • CLASSES

    Non-Opioid Antitussives

    DEA CLASS

    OTC

    DESCRIPTION

    Oral non-opioid antitussive with no expectorant activity
    Used to treat cough; generally regarded as useful in suppressing cough due to chronic bronchitis and COPD; less evidence of its efficacy in treating cough due to upper respiratory illness
    As an antagonist of N-methyl-D-aspartate (NMDA) receptors, it has been studied in the treatment of cancer, postoperative, and neuropathic pain but the high doses required often cause intolerable side effects

    COMMON BRAND NAMES

    Buckley's Cough Suppressant, Buckley's DM, Buckley's Mixture, Cough DM, Cough Suppressant, Delsym, Delsym Children's, Delsym Children's Cough Relief, ElixSure Cough DM, Giltuss DM, Health Mart Cough DM, Robafen Cough, Robitussin Children's Cough, Robitussin Cough, Robitussin Lingering Cold, Robitussin Lingering Cold Long-Acting Cough, Scot-Tussin CF, Triaminic Long Acting Cough, Vicks DayQuil Cough

    HOW SUPPLIED

    Buckley's Cough Suppressant/Buckley's DM/Buckley's Mixture Oral Susp: 5mL, 12.5mg
    Cough DM/Delsym/Delsym Children's/Delsym Children's Cough Relief/Dextromethorphan/Dextromethorphan Polistirex/Health Mart Cough DM/Robitussin Children's Cough/Robitussin Cough Oral Susp ER: 5mL, 30mg
    Cough Suppressant/Dextromethorphan/Dextromethorphan Hydrobromide/ElixSure Cough DM/Giltuss DM/Robitussin Lingering Cold Long-Acting Cough/Scot-Tussin CF/Triaminic Long Acting Cough/Vicks DayQuil Cough Oral Sol: 5mL, 7.5mg, 10mL, 10mg, 15mg, 15mL, 30mg
    Dextromethorphan/Dextromethorphan Hydrobromide/Robafen Cough/Robitussin Cough/Robitussin Lingering Cold/Robitussin Lingering Cold Long-Acting Cough Oral Cap: 15mg

    DOSAGE & INDICATIONS

    For temporary relief of cough; especially useful for non-productive cough due to minor throat and bronchial irritation associated with the common cold, inhaled irritants, or chronic bronchitis.
    Oral dosage (immediate-release oral films, capsules, solutions, suspensions and syrups)
    Adults, Adolescents, and Children 12 years and older

    Usual dose range: 10 to 20 mg PO every 4 hours as needed; or 30 mg PO every 6 to 8 hours as needed. Maximum: 120 mg/day PO.

    Children 6 to 11 years

    Usual dose range: 5 mg to 10 mg PO every 4 hours as needed; or 15 mg PO every 6 to 8 hours as needed. Maximum: 60 mg/day PO.

    Children 4 to 5 years

    Usual dose range: 2.5 mg to 5 mg PO every 4 hours as needed; or 7.5 mg PO every 6 to 8 hours as needed. Maximum: 30 mg/day PO.

    Children 2 to 3 years

    Usual dose range: 2.5 mg to 5 mg PO every 4 hours as needed; or 7.5 mg PO every 6 to 8 hours as needed. Maximum: 30 mg/day PO. Use with caution. Serious adverse events, including death, have been associated with the misuse of these medications.

    Oral dosage (extended-release oral suspension containing dextromethorphan 30 mg per 5 mL)
    Adults, Adolescents, and Children 12 years and older

    60 mg (10 mL) PO every 12 hours as needed. Maximum: 120 mg/day PO.

    Children 6 to 11 years

    30 mg (5 mL) PO every 12 hours as needed. Maximum: 60 mg/day PO.

    Children 4 to 5 years

    15 mg (2.5 mL) PO every 12 hours as needed. Maximum: 30 mg/day PO.

    For the treatment of painful diabetic neuropathy†.
    Oral dosage (immediate-release, compounded extemporaneous formulations)
    Adults

    A median dose of 400 mg/day PO, given in 4 divided doses, has been used in clinical trials. Doses are initiated at 30 mg PO 4 times daily, then titrated to effectiveness and maximal tolerance. Limited, small, randomized trials have suggested that high doses of dextromethorphan may produce moderate reductions of painful diabetic neuropathy (PDN); however, significant adverse effects occur. Max: 960 mg/day PO given in 4 divided doses. American Academy of Neurology guidelines consider dextromethorphan as probably effective in lessening pain and improving quality of life; moderate pain reductions of 16% to 24% are achieved; however, sedation approaches 58% and other substantial adverse effects (e.g., anorexia, constipation, ataxia, confusion) may occur. Because of the dosages used, commercially available products are not amenable for dosing; trials used extemporaneously compounded capsules for dosing.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    120 mg/day PO for extended- and immediate-release formulations as a cough suppressant ; off-label suggested maximum for diabetic neuropathy: 960 mg/day PO of immediate-release formulations.

    Geriatric

    120 mg/day PO for extended- and immediate-release formulations as a cough suppressant ; off-label suggested maximum for neuropathy: 960 mg/day PO of immediate-release formulations.

    Adolescents

    120 mg/day PO for extended- and immediate-release formulations.

    Children

    6 to 11 years: 60 mg/day PO for extended- and immediate-release formulations.
    4 to 5 years: 30 mg/day PO for extended- and immediate-release formulations.
    2 to 3 years: 30 mg/day PO for immediate-release formulations ONLY.
    Less than 2 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dextromethorphan is extensively metabolized by the liver and should be used cautiously in patients with hepatic impairment due to the potential for drug accumulation and resultant toxicity.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    It is not known whether dextromethorphan or its active metabolite are removed by hemodialysis; it appears that no supplemental dosage is needed following hemodialysis.

    ADMINISTRATION

     
    NOTE: Doses are expressed in terms of dextromethorphan hydrobromide.

    Oral Administration
    Oral Solid Formulations

    Chewable tablets: Instruct patient to chew well before swallowing.
    Lozenges: Patients should be instructed to suck, not chew the lozenges. Do not administer to children under 6 years of age.

    Oral Liquid Formulations

    Syrup: Administer using a calibrated measuring device. Since dextromethorphan is more soluble in ethanol than in water, avoid drinking fluids after each dose; this may reduce the drug solubility and bioavailability.
    Extended-release suspension: Shake well prior to administration. Administer using a calibrated measuring device.

    STORAGE

    AeroTuss:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    Buckley's Cough Suppressant :
    - Store at room temperature (between 59 to 86 degrees F)
    Buckley's DM:
    - Store at room temperature (between 59 to 86 degrees F)
    Buckley's Mixture:
    - Store at room temperature (between 59 to 86 degrees F)
    Cough DM:
    - Store between 68 to 77 degrees F
    Cough Suppressant :
    - Store at room temperature (between 59 to 86 degrees F)
    Delsym:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Delsym Children's:
    - Store between 68 to 77 degrees F
    Delsym Children's Cough Relief:
    - Store between 68 to 77 degrees F
    ElixSure Cough DM:
    - Store at room temperature (between 59 to 86 degrees F)
    Giltuss DM:
    - Store at room temperature (between 59 to 86 degrees F)
    Health Mart Cough DM:
    - Store between 68 to 77 degrees F
    PediaCare Children's Long Acting Cough:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until contents are used
    PediaCare Long-Acting Cough :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Robafen Cough:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from light
    - Store between 68 to 77 degrees F
    Robitussin:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Robitussin Children's Cough:
    - Store between 68 to 77 degrees F
    Robitussin Cough:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from light
    - Store between 68 to 77 degrees F
    Robitussin Lingering Cold:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from light
    - Store between 68 to 77 degrees F
    Robitussin Lingering Cold Long-Acting Cough:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from light
    - Store between 68 to 77 degrees F
    Robitussin Pediatric Cough:
    - Avoid exposure to heat
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    Scot-Tussin CF:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Silphen DM:
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Triaminic Long Acting Cough :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol Children's Simply Cough:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vicks DayQuil Cough:
    - Store at room temperature (between 59 to 86 degrees F)
    Vicks DayQuil Nature Fusion:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in carton
    Vicks Formula 44:
    - Store at room temperature (between 59 to 86 degrees F)
    Vicks Nature Fusion Cough:
    - Store at room temperature (between 59 to 86 degrees F)
    Zicam Concentrated Cough:
    - Store at room temperature (between 59 to 86 degrees F)
    Zicam Cough Max:
    - Store at room temperature (between 59 to 86 degrees F)
    Zicam Cough Nite:
    - Store at room temperature (between 59 to 86 degrees F)

    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.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    coma / Early / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    respiratory depression / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    nystagmus / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    confusion / Early / Incidence not known

    Mild

    fatigue / Early / Incidence not known
    dizziness / Early / Incidence not known
    drowsiness / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    vomiting / Early / Incidence not known
    nausea / Early / Incidence not known
    irritability / Delayed / Incidence not known
    restlessness / Early / Incidence not known

    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.
    Amiodarone: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amlodipine; Celecoxib: (Moderate) Use of dextromethorphan with celecoxib may result in increased dextromethorphan exposure. Celecoxib inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine 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.
    Buprenorphine; Naloxone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering buprenorphine 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.
    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.
    Celecoxib: (Moderate) Use of dextromethorphan with celecoxib may result in increased dextromethorphan exposure. Celecoxib inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Celecoxib; Tramadol: (Moderate) Use of dextromethorphan with celecoxib may result in increased dextromethorphan exposure. Celecoxib inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    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.
    Cinacalcet: (Moderate) Use of dextromethorphan with cinacalcet may result in increased dextromethorphan exposure. Cinacalcet inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    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) Use of dextromethorphan with dacomitinib results in increased dextromethorphan exposure. Dacomitinib is a potent inhibitor of CYP2D6 and dextromethorphan is a sensitive CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. The Cmax and AUC of dextromethorphan were increased by approximately 10-fold when coadminstered with a single dose of dacomitinib.
    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.
    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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. 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, fluoxetine inhibits CYP2D6 and may increase systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. 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, fluoxetine inhibits CYP2D6 and may increase systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with paroxetine. 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, paroxetine inhibits CYP2D6 and may increase systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    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.
    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), due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with serotonin-receptor agonists ("triptans"). 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.
    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) Use of dextromethorphan with systemic terbinafine may result in increased dextromethorphan exposure. Terbinafine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    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.

    PREGNANCY AND LACTATION

    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.

    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.

    MECHANISM OF ACTION

    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. The NMDA receptor complex is a ligand-gated ion channel capable of allowing intracellular entry of calcium ions, which, in turn, stimulates second and third messenger signaling pathways. The NMDA receptor is found throughout the nervous system and is involved in processes such as development, learning, and memory. The NMDA receptor is also thought to sensitize interneurons following repetitive activation of nociceptors. Sustained activation of the NMDA receptor is believed to be involved in allodynia, hyperalgesia, and reduced efficacy of opioids. Activation of NMDA receptors by glutamate and aspartate may play a role in the "wind-up" phenomenon or secondary pain. Secondary pain occurs due to C-fiber stimulation of nociceptors. As compared to A-fibers, the afferent C-fibers are small and have slow conduction, resulting in delayed sensation of dull, persistent, poorly localized pain. The overactivity of these receptors has been shown to produce neurotoxicity that may lead to nerve death. NMDA antagonists, such as dextromethorphan, can block these actions and, in theory, may be neuroprotective. NMDA antagonists can also potentiate opioids and reduce the development of tolerance to opiates, which may be helpful in treating neuropathic pain.
     
    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 opiate agonists when used in usual antitussive dosages. In therapeutic dosage dextromethorphan also does not inhibit ciliary activity. Naloxone, an opiate-antagonist, does not block the antitussive effects of dextromethorphan.

    PHARMACOKINETICS

    Dextromethorphan is administered orally. Dextromethorphan is approximately 60% to 70% protein bound. Dextromethorphan is primarily metabolized in the liver by CYP2D6. When dextromethorphan is administered to extensive CYP2D6 metabolizers (normal metabolizers), the drug undergoes rapid and extensive hepatic metabolism to demethylated metabolites. Excretion of dextromethorphan is primarily by renal elimination of metabolites. In humans, (+)-3-hydroxy-N-methylmorphinan, (+)-3-hydroxy-morphinan, and traces of unmetabolized drug were found in urine after oral administration.
    Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6
    Dextromethorphan is primarily metabolized by the CYP2D6 isoenzyme and is a senstive substrate.

    Oral Route

    Dextromethorphan is rapidly absorbed from the GI tract, with antitussive activity appearing within 15 to 30 minutes. Food does not affect absorption. Antitussive activity can last for 3 to 6 hours.