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  • CLASSES

    Agents Used In Alcohol Dependence

    DEA CLASS

    Rx

    DESCRIPTION

    Used in management of ethanol abuse. Not a cure for alcoholism but deterrent to ethanol consumption. Use only in highly motivated individuals who are receiving psychotherapy. Purpose is to aid patient in maintaining abstinence until adequate self-motivation established.

    COMMON BRAND NAMES

    Antabuse

    HOW SUPPLIED

    Antabuse/Disulfiram Oral Tab: 250mg, 500mg

    DOSAGE & INDICATIONS

    For the maintenance treatment of alcohol dependence.
    Oral dosage
    Adults

    Initially, 500 mg PO once daily every morning for 1 to 2 weeks, then reduce to 250 mg PO once daily. The dose may be taken in the evening if drowsiness occurs. Recommended maintenance dosage range: 125 mg to 500 mg PO once daily. Max: 500 mg/day PO. Required duration of treatment ranges from months to years, and is dependent on the patient's ability to abstain from ingesting alcohol. Pharmacotherapy should be used as a part of a comprehensive management program that includes psychosocial support and treatment.

    MAXIMUM DOSAGE

    Adults

    500 mg/day PO.

    Elderly

    500 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; the manufacturer warns that disulfiram should be used with extreme caution in patients with hepatic cirrhosis or insufficiency. Disulfiram has been reported to cause hepatic impairment and failure resulting in transplantation or death in some cases.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    WARNING: Disulfiram should never be administered to a patient with ethanol intoxication, and should never be administered to a patient without their knowledge. Relatives of patients receiving the drug should be instructed as to the precautions and risks associated with its use.
    NOTE: It is important to check the alcohol content of other medications the patient is receiving prior to disulfiram therapy. Do not administer disulfiram within 12 hours of alcohol-containing preparations.

    Oral Administration
    Oral Solid Formulations

    Tablets may be crushed and mixed with fluids prior to administration.

    STORAGE

    Antabuse:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Disulfiram is contraindicated for use in individuals who have disulfiram hypersensitivity or are allergic to other thiuram-related compounds (i.e., those used in pesticides or rubber vulcanization). Therefore, patients with rubber contact dermatitis should be evaluated for hypersensitivity to disulfiram.

    Ethanol ingestion, ethanol intoxication

    WARNING: Disulfiram should never be administered to patients with ethanol intoxication and should never be administered to patients without their knowledge. Relatives of patients receiving the drug should be instructed about the precautions and risks associated with its use. Patients should carry identification cards describing the symptoms of a reaction and the persons to notify in case of an emergency. Patients should be warned to avoid any ethanol ingestion including ethanol-containing foods or medications (e.g., vinegar, cough syrup, and sauces) while receiving disulfiram because a disulfiram-ethanol reaction can occur. The application of alcohol-containing linaments or lotions also may precipitate this reaction, and patients should be warned that reactions can occur up to 14 days following cessation of therapy. Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. The intensity of the reaction varies with each individual, but is generally proportional to the amounts of disulfiram and alcohol ingested. Mild reactions may occur in the sensitive individual when the blood alcohol concentration is increased to as little as 5 to 10 mg/100 mL. Symptoms are fully developed at 50 mg/100 mL, and unconsciousness usually results when the blood alcohol level reaches 125 to 150 mg per 100 mL. The duration of the reaction varies from 30 to 60 minutes, to several hours in the more severe cases, or as long as there is alcohol in the blood.

    Pregnancy

    The safe use of disulfiram in pregnancy has not been established. Therefore, disulfiram should be used during pregnancy only when, in the judgement of the physician, the probable benefits outweigh the possible risks. There are no well-controlled human studies of the effects of disulfiram during pregnancy. It is not known if disulfiram crosses the placenta, but the molecular weight of the drug suggests that placental transfer is likely. Various abnormalities (e.g., club feet, Pierre-Robin sequence, VACTERL association with radial aplasia, cleft soft palate, microcephaly, phocomelia) have been documented in infants of women treated with disulfiram during pregnancy. In some cases, disulfiram exposure in utero has not resulted in adverse neonatal outcomes. In a surveillance study, one major birth defect (cardiovascular) was observed (one expected) among 25 newborns who had been exposed to disulfiram during the first trimester. Pregnancy outcomes reported following disulfiram administration may be complicated by maternal use of ethanol or other substances of abuse, making it difficult to determine the exact role of disulfiram in causing birth defects. The adverse effects of ethanol abuse during pregnancy are well-documented. If supportive ethanol prevention measures are ineffective, the risks to the fetus of continued ethanol abuse by the mother should be weighed against the potential for fetal drug exposure when determining whether to use disulfiram during pregnancy. The effects of disulfiram during labor and delivery are unknown.

    Breast-feeding

    According to the manufacturer, it is not known if disulfiram is excreted into human milk, and disulfiram should not be given to  mothers who are breast-feeding. If the nursing infant is exposed to any medications or other items containing alcohol, the infant may potentially experience a "disulfiram reaction", which could be serious. Alcohol is excreted in the breast milk, for example. If supportive measures are ineffective to deter alcohol abuse, the risks to the nursing infant of ethanol exposure in the breast milk due to continued ethanol abuse by the mother should be weighed against the potential for adverse disulfiram effects when determining whether to use disulfiram during breast-feeding. Consider if alternative feeding methods or adjusted times of administration of disulfiram in relation to nursing are appropriate in these cases.

    Hematological disease, hepatic disease, hepatitis, jaundice

    Hypersensitivity and hematological disease have been reported during the administration of disulfiram. Hepatic disease or insufficiency may be exacerbated. Hepatic toxicity including hepatic failure resulting in transplantation or death have been reported. Severe and sometimes fatal hepatitis associated with disulfiram therapy may develop even after many months of therapy. Hepatic toxicity has occurred in patients with or without prior history of abnormal liver function. Patients should be advised to immediately notify their physician of any early symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, vomiting, jaundice or dark urine. Baseline and follow-up liver function tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may result with disulfiram therapy. In addition, a complete blood count and serum chemistries, including liver function tests, should be monitored.

    Diabetes mellitus, hypothyroidism, renal disease, seizure disorder

    Disulfiram therapy can exacerbate certain conditions, such as diabetes mellitus, hypothyroidism, seizure disorder, cerebral damage, abnormal EEGs, renal disease, and multiple drug dependence, so the drug should be used with caution, if at all, in patients with these conditions.

    Acute myocardial infarction, cardiac disease, psychosis

    Disulfiram is contraindicated for use in patients with severe cardiac disease (e.g., coronary occlusion that usually results in acute myocardial infarction) or psychosis.

    ADVERSE REACTIONS

    Severe

    heart failure / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known

    Moderate

    sinus tachycardia / Rapid / Incidence not known
    blurred vision / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    confusion / Early / Incidence not known
    palpitations / Early / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    neuritis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    psychosis / Early / Incidence not known

    Mild

    flushing / Rapid / Incidence not known
    weakness / Early / Incidence not known
    nausea / Early / Incidence not known
    vertigo / Early / Incidence not known
    syncope / Early / Incidence not known
    headache / Early / Incidence not known
    vomiting / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    fatigue / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Caffeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Severe) Dichloralphenazone is metabolized to chloral hydrate. A mutual inhibition of metabolism exists between ethanol and chloral hydrate. In rare instances, a disulfiram-like effect, characterized by tachycardia, palpitations, facial flushing, and dysphoria, has occurred with concomitant use of ethanol and chloral hydrate. Disulfiram should be avoided in patients receiving chloral hydrate.
    Alprazolam: (Moderate) Disulfiram can decrease the hepatic oxidative metabolism of alprazolam if administered concomitantly. Patients receiving alprazolam therapy should be monitored for signs of altered benzodiazepine response when disulfiram is initiated or discontinued.
    Amitriptyline: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Amitriptyline; Chlordiazepoxide: (Moderate) Disulfiram competes for the binding sites on hepatic cytochrome P-450 with benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide, thereby slowing the metabolism of benzodiazepines and increasing their steady-state plasma concentrations. (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Amoxapine: (Moderate) Limited data suggest that the combination of cyclic antidepressants with disulfiram can produce transient delirium. Disulfiram is known to inhibit some of the hepatic cytochrome P450 isoenzymes involved in cyclic antidepressant metabolism.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor patients to determine if it is necessary to adjust the dose of disulfiram when taken concomitantly with omeprazole. In a single patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on 2 separate challenges when omeprazole was added to disulfiram therapy.
    Amprenavir: (Severe) Due to the high concentrations of propylene glycol, amprenavir oral solution is contraindicated in patients receiving disulfiram concurrently. Patients should avoid ethanol-containing products or beverages while taking amprenavir oral solution.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if disulfiram and aprepitant, fosaprepitant are used concurrently and monitor for an increase in disulfiram-related adverse effects, including for several days after administration of a multi-day aprepitant regimen. Disulfiram is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of disulfiram. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-foldy, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Ascorbic Acid, Vitamin C: (Moderate) As ascorbic acid, vitamin C has on occasion been used as a specific antidote for symptoms resulting from interaction between ethanol and disulfiram, it may be expected that the administration of large doses of vitamin C may interfere with the effectiveness of disulfiram given to patients to encourage abstinence from alcohol.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Aspirin, ASA; Omeprazole: (Moderate) Monitor patients to determine if it is necessary to adjust the dose of disulfiram when taken concomitantly with omeprazole. In a single patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on 2 separate challenges when omeprazole was added to disulfiram therapy.
    Atazanavir: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate. (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Benznidazole: (Severe) Coadministration of benznidazole with disulfiram or in patients who have taken disulfiram within the last 2 weeks is contraindicated. Although not reported with benznidazole, psychotic reactions have been reported in patients concurrently taking disulfiram and other nitroimidazole agents, of which benznidazole is structurally similar to.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Severe) The combination of systemic metronidazole and disulfiram is contraindicated. Do not administer systemic metronidazole concomitantly or within 2 weeks after the administration of disulfiram because additive CNS toxic effects can occur. Case reports have described the development of CNS toxicity after metronidazole was coadministered with disulfiram, resulting in psychosis and confusion. This toxicity is believed to occur because of combined inhibition of aldehyde dehydrogenase. When metronidazole and disulfiram are combined, symptoms may become evident within 10 to 14 days, and symptoms may remain for 2 to 3 days after the drugs are discontinued.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Severe) The combination of systemic metronidazole and disulfiram is contraindicated. Do not administer systemic metronidazole concomitantly or within 2 weeks after the administration of disulfiram because additive CNS toxic effects can occur. Case reports have described the development of CNS toxicity after metronidazole was coadministered with disulfiram, resulting in psychosis and confusion. This toxicity is believed to occur because of combined inhibition of aldehyde dehydrogenase. When metronidazole and disulfiram are combined, symptoms may become evident within 10 to 14 days, and symptoms may remain for 2 to 3 days after the drugs are discontinued.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering disulfiram with boceprevir due to an increased potential for disulfiram-related adverse events. If disulfiram dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of disulfiram. Disulfiram is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated disulfiram plasma concentrations.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like disulfiram; the risk of peripheral neuropathy may be additive.
    Bosentan: (Moderate) Disulfiram inhibits CYP2C9 and may theoretically lead to elevated plasma concentrations of bosentan when coadministered. Monitor for potential adverse effects of bosentan during coadministration; excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and disulfiram may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; disulfiram inhibits CYP1A2.
    Bupropion; Naltrexone: (Major) The safety and efficacy of concomitant use of naltrexone and disulfiram is unknown. There is the possibility of additive hepatotoxicity and concurrent use of these agents is not recommended. If concomitant use of naltrexone and disulfiram is required, liver function tests should be performed prior to beginning combination therapy, then they should be repeated every 2 weeks for 1 to 2 months. Continue monitoring LFTs monthly after the third month of combined use.
    Caffeine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease. (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study; however, the decrease could be significant in some patients, including some patients with cardiovascular disease.
    Caffeine; Ergotamine: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
    Chloral Hydrate: (Severe) The central nervous system-depressant effects of chloral hydrate can be potentiated by ethanol. In addition, a mutual inhibition of metabolism exists between ethanol and chloral hydrate. In rare instances, a disulfiram-like effect, characterized by tachycardia, palpitations, facial flushing, and dysphoria, has resulted from concomitant use of ethanol and chloral hydrate. Disulfiram should be avoided in patients receiving chloral hydrate.
    Chlordiazepoxide: (Moderate) Disulfiram competes for the binding sites on hepatic cytochrome P-450 with benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide, thereby slowing the metabolism of benzodiazepines and increasing their steady-state plasma concentrations.
    Chlordiazepoxide; Clidinium: (Moderate) Disulfiram competes for the binding sites on hepatic cytochrome P-450 with benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide, thereby slowing the metabolism of benzodiazepines and increasing their steady-state plasma concentrations.
    Chlorhexidine: (Minor) Some chlorhexidine oral rinses contain ethanol in significant percentages. Although chlorhexidine is poorly absorbed from the GI tract and the products are intended for oral topical rinse and not for systemic ingestion, there is a potential for interaction with disulfiram when such products are swallowed.
    Chlorzoxazone: (Minor) Chlorzoxazone is a known substrate for the cytochrome P450 isozyme CYP2E1. Disulfiram inhibits CYP2E1 and has been shown to interfere with the clearance of chlorzoxazone.
    Ciprofloxacin: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with ciprofloxacin. Clinical monitoring for adverse effects is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Clomipramine: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Clonazepam: (Moderate) Disulfiram can decrease the hepatic oxidative metabolism of clonazepam if administered concomitantly. Patients receiving clonazepam should be monitored for signs of an exaggerated response if disulfiram is used concomitantly.
    Clorazepate: (Moderate) Disulfiram can decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving clorazepate should be monitored for signs of an exaggerated response if any of the above drugs are used concomitantly.
    Clozapine: (Moderate) Caution is advisable during concurrent use of disulfiram and clozapine. Disulfiram is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Cocaine: (Major) Avoid concomitant use of cocaine and disulfiram. Consider using other local anesthetic agents. Disulfiram increased the Cmax and the AUC of cocaine by 2- to 3-fold and 3- to 6-fold, respectively, in a study of volunteers with cocaine-abuse histories who received intranasal cocaine after disulfiram. Disulfiram increased the heart rate response to cocaine compared to placebo. After administration of 2 mg/kg cocaine intranasally, disulfiram-treated patients also experienced increased diastolic and systolic blood pressures.
    Cyclosporine: (Major) Cyclosporine parenteral and oral solutions contain ethanol; liquid-filled capsules contain ethanol in lower percentages. Administration of ethanol-containing formulations of cyclosporine to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Darunavir: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate. (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate. (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Desipramine: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Diazepam: (Moderate) Disulfiram may compete for the binding sites on hepatic cytochrome P-450 (CYP) with benzodiazepines that undergo oxidative metabolism such as diazepam, thereby slowing the metabolism of diazepam and increasing its steady-state plasma concentrations.
    Doxepin: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like disulfiram, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Dronabinol: (Major) The use of disulfiram-containing products within 14 days of beginning therapy with dronabinol oral solution is contraindicated; use caution if coadministration with dronabinol capsules is necessary. Do not administer disulfiram-containing products within 7 days of completing therapy with the oral solution. Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5% (w/w) propylene glycol, which can produce disulfiram-like reactions (e.g., abdominal cramps, nausea/vomiting, headaches, and flushing) with disulfiram or other drugs that produce this reaction. Ethanol competitively inhibits the metabolism of propylene gycol; however, the contribution of propylene glycol to these reactions is unknown. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations (e.g., dronabinol oral capsules). Additionally, a reversible hypomanic reaction was reported in a 28 year old male who smoked marijuana while taking disulfiram. This reaction was confirmed by dechallenge and rechallenge. Because dronabinol, THC is a synthetic analog of a naturally occurring substance found in marijuana, this interaction may also occur with dronabinol (oral solution and capsules).
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Disulfiram is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Duloxetine: (Moderate) Co-administration of duloxetine and potent inhibitors of CYP1A2 should be avoided. Duloxetine is partially metabolized by CYP1A2. One study involving a potent CYP1A2 inhibitor in concomitant use with duloxetine showed that duloxetine exposure was significantly increased. Concurrent use of duloxetine and disulfiram, a CYP1A2 inhibitor, may result in excessive serotonin activity. Careful monitoring is recommended if concurrent therapy is considered necessary.
    Dyphylline: (Major) The ingestion of alcohol by patients receiving disulfiram causes an extremely unpleasant reaction that can last from 30 minutes to several hours. Some dyphylline containing oral solutions contain a high percentage of alcohol (17%) and should not be co-administered with disulfiram. A disulfiram-like reaction is not expected with formulations of dyphylline that do not contain alcohol.
    Dyphylline; Guaifenesin: (Major) The ingestion of alcohol by patients receiving disulfiram causes an extremely unpleasant reaction that can last from 30 minutes to several hours. Some dyphylline containing oral solutions contain a high percentage of alcohol (17%) and should not be co-administered with disulfiram. A disulfiram-like reaction is not expected with formulations of dyphylline that do not contain alcohol.
    Efavirenz: (Moderate) The pathway to disulfiram activation is mediated by CYP3A4/5 (major), CYP1A2, CYP2B6, and CYP2E1.Efavirenz is an in vivo inducer of CYP3A4 and CY2B6. Increased disulfiram activation may occur if these drugs are administred together.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) The pathway to disulfiram activation is mediated by CYP3A4/5 (major), CYP1A2, CYP2B6, and CYP2E1.Efavirenz is an in vivo inducer of CYP3A4 and CY2B6. Increased disulfiram activation may occur if these drugs are administred together.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) The pathway to disulfiram activation is mediated by CYP3A4/5 (major), CYP1A2, CYP2B6, and CYP2E1.Efavirenz is an in vivo inducer of CYP3A4 and CY2B6. Increased disulfiram activation may occur if these drugs are administred together.
    Elbasvir; Grazoprevir: (Moderate) Administering disulfiram with elbasvir; grazoprevir may result in elevated disulfiram plasma concentrations. Disulfiram is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Estazolam: (Moderate) Disulfiram can decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving estazolam therapy should be monitored for signs of altered benzodiazepine response when disulfiram is initiated or discontinued.
    Ethanol: (Severe) Disulfiram is contraindicated for use in patients who are receiving or have recently received alcohol or alcohol-containing preparations. Disulfiram should never be administered until the patient has abstained from alcohol for at least 12 hours. The ingestion of ethanol by patients receiving disulfiram causes an extremely unpleasant reaction ('Antabuse Reaction') that can last from 30 minutes to several hours; however, the intensity and duration are generally dependent upon the disulfiram dosage. Disulfiram administration causes ethanol intolerance by interfering with the hepatic oxidation of acetaldehyde, leading to increased acetaldehyde concentrations. The unpleasant reaction that occurs in patients who ingest ethanol while receiving disulfiram includes a throbbing headache, dyspnea, throbbing in the neck, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, tachycardia, hypotension, blurred vision, vertigo, weakness, anxiety, syncope, and confusion. Typically, the reaction is followed by a deep sleep, but severe reactions include arrhythmias, cardiovascular collapse, esophageal rupture, polyneuritis, or respiratory depression. Fatalities have been reported rarely and usually are associated with administration of larger doses (> 500 mg daily) of disulfiram and ingestion of three or more alcoholic beverages. Certain medications contain a high percentage of ethanol and should not be co-administered with disulfiram and include, but may not be limited to: cyclosporine (parenteral and oral solutions; liquid-filled capsules contain ethanol in lower percentages), oral solutions of ritonavir , Kaletra (lopinavir; ritonavir), oral solutions of Zoloft (sertraline), and Taxol (paclitaxel) injection. Mild reactions have been associated with topical products containing ethanol. However, in other cases, no reactions have occurred from concomitant administration of disulfiram with ear drops, nebulizer solutions, or with small sips of wine.
    Ethotoin: (Major) Disulfiram can interfere with the metabolism of hydantoin anticonvulsants, particularly phenytoin, resulting in increased serum concentrations and possible phenytoin toxicity (i.e., ataxia, hyperreflexia, nystagmus, tremor). The mechanism is most likely due to inhibition of CYP2C9 by disulfiram. Phenytoin serum concentrations should be performed prior to and during disulfiram administration, and dosages of either agent should be adjusted accordingly. This interaction may not occur if disulfiram therapy is initiated prior to beginning phenytoin, but, in this scenario, if disulfiram therapy is discontinued, subtherapeutic phenytoin concentrations can ensue. A similar interaction may occur with fosphenytoin or ethotoin.
    Flurazepam: (Moderate) Disulfiram may compete with flurazepam for hepatic CYP450 binding sites, thereby slowing the metabolism of flurazepam and increasing the steady-state plasma concentrations. This may increase the risk for benzodiazepine-related side effects such as dizziness, sedation, low blood pressure, or other flurazepam-related adverse effects.
    Fosphenytoin: (Major) Disulfiram can interfere with the metabolism of hydantoin anticonvulsants, particularly phenytoin, resulting in increased serum concentrations and possible phenytoin toxicity (i.e., ataxia, hyperreflexia, nystagmus, tremor). The mechanism is most likely due to inhibition of CYP2C9 by disulfiram. Phenytoin serum concentrations should be performed prior to and during disulfiram administration, and dosages of either agent should be adjusted accordingly. This interaction may not occur if disulfiram therapy is initiated prior to beginning phenytoin, but, in this scenario, if disulfiram therapy is discontinued, subtherapeutic phenytoin concentrations can ensue. A similar interaction may occur with fosphenytoin or ethotoin.
    Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like disulfiram. Monitor serum glucose concentrations if glimepiride is coadministered with disulfiram. Dosage adjustments may be necessary.
    Glimepiride; Pioglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like disulfiram. Monitor serum glucose concentrations if glimepiride is coadministered with disulfiram. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like disulfiram. Monitor serum glucose concentrations if glimepiride is coadministered with disulfiram. Dosage adjustments may be necessary.
    Green Tea: (Minor) Disulfiram has been shown to inhibit caffeine elimination. During concomitant disulfiram therapy, it may be prudent to limit caffeine-containing medications, foods including chocolate, dietary supplements such as green tea.
    Hydantoins: (Major) Disulfiram can interfere with the metabolism of hydantoin anticonvulsants, particularly phenytoin, resulting in increased serum concentrations and possible phenytoin toxicity (i.e., ataxia, hyperreflexia, nystagmus, tremor). The mechanism is most likely due to inhibition of CYP2C9 by disulfiram. Phenytoin serum concentrations should be performed prior to and during disulfiram administration, and dosages of either agent should be adjusted accordingly. This interaction may not occur if disulfiram therapy is initiated prior to beginning phenytoin, but, in this scenario, if disulfiram therapy is discontinued, subtherapeutic phenytoin concentrations can ensue. A similar interaction may occur with fosphenytoin or ethotoin.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with disulfiram, a CYP3A substrate, as disulfiram toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imipenem; Cilastatin: (Moderate) Disulfiram is potentially neurotoxic. Additive effects can occur if it is administered concomitantly with other neurotoxic medications including imipenem; cilastatin.
    Imipenem; Cilastatin; Relebactam: (Moderate) Disulfiram is potentially neurotoxic. Additive effects can occur if it is administered concomitantly with other neurotoxic medications including imipenem; cilastatin.
    Imipramine: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with disulfiram may result in increased serum concentrations of disulfiram. Disulfiram is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Minor) Concomitant administration of isoniazid, INH and disulfiram has resulted in adverse CNS effects, including psychosis and coordination difficulties, in a limited number of patients. Data appears to be limited to one report; the incidence of the interaction is uncertain, but apparently quite small. Two-thirds of the group in this report did not experience an interaction, and in another report, 200 additional patients did not experience an interaction. Concurrent use need not be avoided, although patient response should be monitored and, if necessary, the disulfiram dose reduced, or treatment withdrawn.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Concomitant administration of isoniazid, INH and disulfiram has resulted in adverse CNS effects, including psychosis and coordination difficulties, in a limited number of patients. Data appears to be limited to one report; the incidence of the interaction is uncertain, but apparently quite small. Two-thirds of the group in this report did not experience an interaction, and in another report, 200 additional patients did not experience an interaction. Concurrent use need not be avoided, although patient response should be monitored and, if necessary, the disulfiram dose reduced, or treatment withdrawn.
    Isoniazid, INH; Rifampin: (Minor) Concomitant administration of isoniazid, INH and disulfiram has resulted in adverse CNS effects, including psychosis and coordination difficulties, in a limited number of patients. Data appears to be limited to one report; the incidence of the interaction is uncertain, but apparently quite small. Two-thirds of the group in this report did not experience an interaction, and in another report, 200 additional patients did not experience an interaction. Concurrent use need not be avoided, although patient response should be monitored and, if necessary, the disulfiram dose reduced, or treatment withdrawn.
    Ixabepilone: (Severe) The supplied diluent that must be used for reconstitution of ixabepilone has a high concentration of dehydrated alcohol (39.8% w/v). Administration of ixabepilone to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and disulfiram may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; disulfiram inhibits CYP1A2.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and disulfiram may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; disulfiram inhibits CYP1A2.
    Lithium: (Major) Because lithium has the potential to impair cognitive and motor skills, it is advisable to avoid ethanol ingestion during treatment with lithium. In addition, some formulations of lithium solution contain alcohol; therefore, disulfiram should be avoided in patients receiving these products.
    Lopinavir; Ritonavir: (Major) Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. (Major) The ingestion of ethanol by patients receiving disulfiram causes an extremely unpleasant reaction ('Antabuse Reaction') that can last from 30 minutes to several hours; however, the intensity and duration are dependent upon the disulfiram dosage. Oral solutions of lopinavir; ritonavir contain ethanol. Administration of lopinavir; ritonavir oral solution to patients receiving or who have recently received disulfiram may result in antabuse reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of disulfiram by decreasing its systemic exposure. If used together, monitor patients closely for loss of disulfiram efficacy; a disulfiram dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Disulfiram is primarily metabolized by CYP3A4 and is also a substrate of CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of disulfiram by decreasing its systemic exposure. If used together, monitor patients closely for loss of disulfiram efficacy; a disulfiram dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Disulfiram is primarily metabolized by CYP3A4 and is also a substrate of CYP2B6. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may induce CYP2B6.
    Maprotiline: (Moderate) The combination of cyclic antidepressants with disulfiram can produce transient delirium. Pharmacokinetic interactions have been noted between disulfiram and tricyclic antidepressants, but the clinical significance is uncertain. Disulfiram is known to inhibit some of the hepatic cytochrome P450 isoenzymes involved in cyclic antidepressant metabolism.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with disulfiram is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and disulfiram is a weak CYP2C9 inhibitor.
    Mesoridazine: (Major) Mesoridazine oral concentrate contains 0.61% alcohol and should not be administered to patients receiving disulfiram.
    Metronidazole: (Severe) The combination of systemic metronidazole and disulfiram is contraindicated. Do not administer systemic metronidazole concomitantly or within 2 weeks after the administration of disulfiram because additive CNS toxic effects can occur. Case reports have described the development of CNS toxicity after metronidazole was coadministered with disulfiram, resulting in psychosis and confusion. This toxicity is believed to occur because of combined inhibition of aldehyde dehydrogenase. When metronidazole and disulfiram are combined, symptoms may become evident within 10 to 14 days, and symptoms may remain for 2 to 3 days after the drugs are discontinued.
    Midazolam: (Moderate) Disulfiram may decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving midazolam should be monitored for signs of altered benzodiazepine response when midazolam is coadministered.
    Mitotane: (Moderate) Use caution if mitotane and disulfiram are used concomitantly, and monitor for decreased efficacy of disulfiram and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and disulfiram is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of disulfiram.
    Nabilone: (Minor) A reversible hypomanic reaction was reported in a 28 year old male who smoked marijuana while taking disulfiram. This reaction was confirmed by dechallenge and rechallenge. Because nabilone is a synthetic analog similar to a naturally occurring substance found in marijuana, this interaction may also occur with nabilone.
    Naltrexone: (Major) The safety and efficacy of concomitant use of naltrexone and disulfiram is unknown. There is the possibility of additive hepatotoxicity and concurrent use of these agents is not recommended. If concomitant use of naltrexone and disulfiram is required, liver function tests should be performed prior to beginning combination therapy, then they should be repeated every 2 weeks for 1 to 2 months. Continue monitoring LFTs monthly after the third month of combined use.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as disulfiram. The plasma concentrations of disulfiram can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nortriptyline: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Omeprazole: (Moderate) Monitor patients to determine if it is necessary to adjust the dose of disulfiram when taken concomitantly with omeprazole. In a single patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on 2 separate challenges when omeprazole was added to disulfiram therapy.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor patients to determine if it is necessary to adjust the dose of disulfiram when taken concomitantly with omeprazole. In a single patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on 2 separate challenges when omeprazole was added to disulfiram therapy.
    Omeprazole; Sodium Bicarbonate: (Moderate) Monitor patients to determine if it is necessary to adjust the dose of disulfiram when taken concomitantly with omeprazole. In a single patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on 2 separate challenges when omeprazole was added to disulfiram therapy.
    Oritavancin: (Minor) Disulfiram is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of disulfiram may be reduced if these drugs are administered concurrently.
    Paclitaxel: (Major) Some formulations of paclitaxel injection contain a high level of ethanol. Administration to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and disulfiram, a CYP3A4 substrate, may cause an increase in systemic concentrations of disulfiram. Use caution when administering these drugs concomitantly.
    Perphenazine; Amitriptyline: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with disulfiram. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Phenytoin: (Major) Disulfiram can interfere with the metabolism of hydantoin anticonvulsants, particularly phenytoin, resulting in increased serum concentrations and possible phenytoin toxicity (i.e., ataxia, hyperreflexia, nystagmus, tremor). The mechanism is most likely due to inhibition of CYP2C9 by disulfiram. Phenytoin serum concentrations should be performed prior to and during disulfiram administration, and dosages of either agent should be adjusted accordingly. This interaction may not occur if disulfiram therapy is initiated prior to beginning phenytoin, but, in this scenario, if disulfiram therapy is discontinued, subtherapeutic phenytoin concentrations can ensue. A similar interaction may occur with fosphenytoin or ethotoin.
    Pimozide: (Major) Concurrent use of pimozide with CYP1A2 inhibitors such as disulfiram should be avoided if possible. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide concentrations occurring through inhibition of CYP3A4, CYP2D6, and/or CYP1A2 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pirfenidone: (Major) Discontinue disulfiram prior to beginning pirfenidone because it may increase exposure to pirfenidone. Disulfiram is a moderate inhibitor of CYP1A2 and a potent inhibitor of CYP2E1. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
    Posaconazole: (Moderate) Posaconazole and disulfiram should be coadministered with caution due to an increased potential for disulfiram-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of disulfiram. These drugs used in combination may result in elevated disulfiram plasma concentrations, causing an increased risk for disulfiram-related adverse events.
    Protriptyline: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Quazepam: (Moderate) Disulfiram can decrease the hepatic metabolism of quazepam if administered concomitantly. Patients receiving quazepam should be monitored for signs of an exaggerated response if disulfiram is used concomitantly.
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP2C9, such as disulfiram, may lead to increases in the serum concentrations of ramelteon.
    Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and disulfiram. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; disulfiram is a weak CYP1A2 inhibitor. When administered with a strong CYP1A2 inhibitor, the AUC of rasagiline was increased by 83%.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and disulfarim. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ritonavir: (Major) Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Sertraline: (Major) The ingestion of ethanol by patients receiving disulfiram causes an extremely unpleasant reaction that can last from 30 minutes to several hours. Oral sertraline solution contains a high percentage of alcohol (12%) and should not be co-administered with disulfiram. A disulfiram-like reaction is not expected with formulations of sertraline that do not contain alcohol.
    Sevoflurane: (Moderate) Disulfiram decreases the activity of cytochrome P450 2E1 isoenzyme and may inhibit sevoflurane metabolism.
    Simeprevir: (Minor) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of disulfiram, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of disulfiram.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) The ingestion of ethanol by patients receiving disulfiram causes an extremely unpleasant reaction that can last from 30 minutes to several hours. Intravenous sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole contains ethanol and should not be co-administered with disulfiram. This reaction would not be expected to occur with oral sulfamethoxazole; trimethoprim.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering disulfiram with telaprevir due to an increased potential for disulfiram-related adverse events. If disulfiram dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of disulfiram. disulfiram is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated disulfiram plasma concentrations.
    Telithromycin: (Minor) Concentrations of disulfiram may be increased with concomitant use of telithromycin. Disulfiram is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and disulfiram is necessary, as the systemic exposure of disulfiram may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of disulfiram; consider increasing the dose of disulfiram if necessary. Disulfiram is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering disulfiram. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2; disulfiram is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Thalidomide: (Moderate) Thalidomide and other agents that cause peripheral neuropathy such as disulfiram should be used cautiously due to the potential for additive effects.
    Theophylline, Aminophylline: (Major) Aminophylline is a prodrug of theophylline. Disulfiram inhibits the hepatic hydroxylation and demethylation of theophylline, thereby increasing the serum levels of theophylline and increasing the risk for theophylline toxicity. Patients should be monitored for theophylline toxicity if disulfiram is added to aminophylline therapy. If aminophylline is added after disulfiram is begun and disulfiram is later discontinued, subtherapeutic theophylline serum concentrations can result. In addition, some preparations of aminophylline elixir may contain significant amounts of ethanol, which can cause reactions with disulfiram; read labels carefully. (Major) Disulfiram inhibits the hepatic hydroxylation and demethylation of theophylline, thereby increasing the serum levels of theophylline and increasing the risk for theophylline toxicity. Patients should be monitored for theophylline toxicity if disulfiram is added to theophylline therapy. If theophylline is added after disulfiram is begun and disulfiram is later discontinued, subtherapeutic theophylline serum concentrations can result. In addition, some preparations of theophylline elixir contain significant amounts of ethanol, which can cause reactions with disulfiram; read labels carefully.
    Tinidazole: (Major) Do not use tinidazole in patients who have taken disulfiram within the last 2 weeks. Psychotic reactions have been reported in patients with alcoholism using another nitroimidazole and disulfiram concurrently.
    Tipranavir: (Major) The Aptivus brand of tipranavir capsules contain alcohol. Administration of Aptivus capsules to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
    Tranylcypromine: (Major) The combination of tranylcypromine and disulfiram should be avoided if possible. If they must be used together, closely monitor the patient for changes in mental status. A single, limited case report describes a potential interaction between tranylcypromine and disulfiram. Severe CNS adverse effects, including acute delirium, hallucinations, agitation and disorientation occurred after the patient received two different monoamine oxidase inhibitors (MAOI) in combination with disulfiram. For a depressive episode the patient first received moclobemide which had no therapeutic effect. Moclobemide was stopped and tranylcypromine was started at 10 mg twice a day. Within 48 hours, the patient patient developed acute delirium, which resolved within 24 hours of stopping the MAOI.
    Triazolam: (Moderate) Disulfiram may decrease the hepatic oxidative metabolism of benzodiazepines if administered concomitantly. Patients receiving triazolam should be monitored for signs of altered benzodiazepine response when triazolam is coadministered.
    Tricyclic antidepressants: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Trimipramine: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Vemurafenib: (Minor) Concomitant use of vemurafenib and disulfiram may result in altered concentrations of disulfiram. Vemurafenib is an inhibitor of CYP1A2 and an inducer of CYP3A4. Disulfiram is a substrate of CYP1A2 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Voriconazole: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9, such as disulfiram, may theoretically lead to elevated plasma levels of voriconazole when coadministered.
    Warfarin: (Moderate) Disulfiram can interfere with the metabolism of oral anticoagulants, increasing their serum concentrations and effects. In addition, disulfiram can act directly on the liver to enhance the hypoprothrombinemia precipitated by anticoagulant therapy. Prothrombin time should be performed prior to and during disulfiram administration and anticoagulant dosages adjusted accordingly.
    Zalcitabine, ddC: (Moderate) Coadministration of zalcitabine, ddC with drugs associated with peripheral neuropathy, such as disulfiram, should be avoided when possible.

    PREGNANCY AND LACTATION

    Pregnancy

    The safe use of disulfiram in pregnancy has not been established. Therefore, disulfiram should be used during pregnancy only when, in the judgement of the physician, the probable benefits outweigh the possible risks. There are no well-controlled human studies of the effects of disulfiram during pregnancy. It is not known if disulfiram crosses the placenta, but the molecular weight of the drug suggests that placental transfer is likely. Various abnormalities (e.g., club feet, Pierre-Robin sequence, VACTERL association with radial aplasia, cleft soft palate, microcephaly, phocomelia) have been documented in infants of women treated with disulfiram during pregnancy. In some cases, disulfiram exposure in utero has not resulted in adverse neonatal outcomes. In a surveillance study, one major birth defect (cardiovascular) was observed (one expected) among 25 newborns who had been exposed to disulfiram during the first trimester. Pregnancy outcomes reported following disulfiram administration may be complicated by maternal use of ethanol or other substances of abuse, making it difficult to determine the exact role of disulfiram in causing birth defects. The adverse effects of ethanol abuse during pregnancy are well-documented. If supportive ethanol prevention measures are ineffective, the risks to the fetus of continued ethanol abuse by the mother should be weighed against the potential for fetal drug exposure when determining whether to use disulfiram during pregnancy. The effects of disulfiram during labor and delivery are unknown.

    According to the manufacturer, it is not known if disulfiram is excreted into human milk, and disulfiram should not be given to  mothers who are breast-feeding. If the nursing infant is exposed to any medications or other items containing alcohol, the infant may potentially experience a "disulfiram reaction", which could be serious. Alcohol is excreted in the breast milk, for example. If supportive measures are ineffective to deter alcohol abuse, the risks to the nursing infant of ethanol exposure in the breast milk due to continued ethanol abuse by the mother should be weighed against the potential for adverse disulfiram effects when determining whether to use disulfiram during breast-feeding. Consider if alternative feeding methods or adjusted times of administration of disulfiram in relation to nursing are appropriate in these cases.

    MECHANISM OF ACTION

    Disulfiram interferes with the hepatic oxidation of acetaldehyde. This enzymatic inhibition results from the drug's ability to compete with nicotinamide adenine dinucleotide (NAD) for binding sites on aldehyde dehydrogenase. Ethanol is initially metabolized to acetaldehyde by alcohol dehydrogenase. Disulfiram does not alter the rate of elimination of ethanol. Instead, ingestion of small amounts of ethanol in individuals receiving disulfiram results in serum acetaldehyde concentrations 5—10 times higher than those in patients not receiving the drug. The unpleasant reaction that occurs in patients is believed to be related to the increased serum concentrations of acetaldehyde. Patients can experience a throbbing headache, dyspnea, throbbing in the neck, nausea, copious vomiting, diaphoresis, thirst, chest pain, palpitation, tachycardia, hypotension, blurred vision, vertigo, weakness, anxiety, syncope, and confusion. This reaction can occur after consuming as little as 15 mL of 100 proof ethanol. Typically, this reaction is followed by a deep sleep, but more severe reactions have occurred including respiratory depression, arrhythmias, and cardiovascular collapse.
     
    Deaths have also been reported following the administration of lower dosages of disulfiram and the ingestion of a single alcoholic drink. Tolerance to the drug has not been reported to date. By itself, disulfiram is relatively nontoxic, but due to its ability to inhibit hepatic enzymes, disulfiram interacts with many drugs that are hepatically metabolized, resulting in increased serum levels and corresponding adverse effects.

    PHARMACOKINETICS

    Disulfiram is administered orally. It undergoes slow hepatic metabolism to diethyldithiocarbamate (a dopamine hydroxylase inhibitor), diethylamine, and carbon disulfide. A portion of a dose is excreted by the lungs as carbon disulfide. One-fifth of a dose may remain in the body for a week or longer, and the risk of drug accumulation should be considered. Ingestion of alcohol up to 2 weeks after cessation of drug therapy can still cause the unpleasant disulfiram-alcohol reaction.
     
    Affected cytochrome P450 isoenzymes: CYP2E1, CYP1A2, CYP3A4/5, CYP2B6
    The relative selectivity of disulfiram for specific CYP isoforms may be duration of therapy dependent. Single-dose administration is reported to selectively inhibit CYP2E1 while chronic use has been shown to inhibit CYP2E1 and CYP1A2 metabolism by 95% and 34%, respectively. The pathway to disulfiram activation is mediated by CYP3A4/5 (major), CYP1A2, CYP2B6, and CYP2E1, thus several drugs may inhibit or induce the metabolism of disulfiram.
     

    Oral Route

    Although it is absorbed rapidly across the GI tract, 3—12 hours may pass before the effects of the drug are evident. Approximately 5—20% of an oral dose of the drug is excreted unchanged in the feces, with the rest excreted primarily in the urine as metabolites.