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Disulfiram

Pronunciation

Pronunciation

(dye SUL fi ram)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Antabuse: 250 mg

Antabuse: 500 mg [scored]

Generic: 250 mg, 500 mg

Brand Names: U.S.

  • Antabuse

Pharmacologic Category

  • Aldehyde Dehydrogenase Inhibitor

Pharmacology

Disulfiram is a thiuram derivative which blocks the oxidation of alcohol at the acetaldehyde stage. When taken concomitantly with alcohol, there is an increase in serum acetaldehyde levels. High acetaldehyde causes uncomfortable symptoms including flushing, throbbing in head and neck, nausea, vomiting, diaphoresis, thirst, palpitations, chest pain, dyspnea, hyperventilation, tachycardia, syncope, weakness, blurred vision, confusion, vertigo, and hypotension. This reaction is the basis for disulfiram use in post-withdrawal long-term care of alcoholism.

Absorption

Slow

Metabolism

Reduction of disulfide linkage to diethyldithiocarbamic acid, then further metabolized via glucuronidation, non-enzymatic degradation, methylation and oxidation (Eneanya 1981)

Excretion

Feces (20% unchanged) and exhaled gases (as metabolites), urine (50% metabolites). (Eneanya 1981)

Onset of Action

Full effect: 12 hours

Duration of Action

~1 to 2 weeks after last dose

Use: Labeled Indications

Alcoholism: Management of chronic alcoholism

Contraindications

Hypersensitivity to disulfiram or any component of the formulation or to other thiuram derivatives used in pesticides and rubber vulcanization; patients receiving or using alcohol, metronidazole, paraldehyde, or alcohol-containing preparations (eg, cough syrup, tonics); psychosis; severe myocardial disease or coronary occlusion.

Dosing: Adult

Alcoholism: Oral: Note: Do not administer until the patient has abstained from alcohol for at least 12 hours.

Initial: Up to 500 mg once daily for 1 to 2 weeks (maximum: 500 mg/day)

Average maintenance dose: 250 mg once daily (range: 125 to 500 mg/day; maximum: 500 mg/day).

Dosing: Geriatric

Refer to adult dosing; use with caution, starting at low end of dosing range.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use with extreme caution in chronic and acute nephritis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use with extreme caution in hepatic cirrhosis or insufficiency.

Administration

Administration of any medications containing alcohol, including topicals, is contraindicated. Do not administer disulfiram if alcohol has been consumed within the prior 12 hours. Morning administration is preferred, but may be given at bedtime if sedation is experienced. Tablets may be crushed and mixed with liquids.

Dietary Considerations

Do not administer disulfiram if alcohol has been consumed within the prior 12 hours.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Alcohol (Ethyl): Disulfiram may enhance the adverse/toxic effect of Alcohol (Ethyl). A disulfiram-like reaction may occur. Avoid combination

Atazanavir: May diminish the therapeutic effect of Disulfiram. Monitor therapy

Carbocisteine: Disulfiram may enhance the adverse/toxic effect of Carbocisteine. Specifically, disulfiram may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Avoid combination

ChlordiazePOXIDE: Disulfiram may increase the serum concentration of ChlordiazePOXIDE. Monitor therapy

Chlorzoxazone: Disulfiram may decrease the metabolism of Chlorzoxazone. Monitor therapy

CYP2E1 Substrates: CYP2E1 Inhibitors (Strong) may decrease the metabolism of CYP2E1 Substrates. Consider therapy modification

DiazePAM: Disulfiram may increase the serum concentration of DiazePAM. Monitor therapy

Flunitrazepam: Disulfiram may increase the serum concentration of Flunitrazepam. Monitor therapy

Fosphenytoin: Disulfiram may increase the serum concentration of Fosphenytoin. Management: Avoid concomitant use of disulfiram and phenytoin when possible. Phenytoin dose adjustment will likely be necessary when starting and/or stopping concurrent disulfiram. Monitor phenytoin response and concentrations closely. Consider therapy modification

Isoniazid: Disulfiram may enhance the adverse/toxic effect of Isoniazid. Disulfiram may increase the serum concentration of Isoniazid. Monitor therapy

Lopinavir: May enhance the adverse/toxic effect of Disulfiram. Specifically, the combination of lopinavir/ritonavir solution, which contains 42% alcohol, may result in a disulfiram-alcohol reaction if combined. Avoid combination

MetroNIDAZOLE (Systemic): Disulfiram may enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Avoid combination

MetroNIDAZOLE (Topical): May enhance the adverse/toxic effect of Disulfiram. Management: Warn patients and monitor for the development of serious CNS toxicity if topical metronidazole is used in a patient taking disulfiram. Some manufacturers of vaginal metronidazole products list disulfiram use within 2 weeks as a contraindication. Consider therapy modification

Paraldehyde: Disulfiram may increase the serum concentration of Paraldehyde. Avoid combination

Phenytoin: Disulfiram may increase the serum concentration of Phenytoin. Management: Avoid concomitant use of disulfiram and phenytoin when possible. Phenytoin dose adjustment will likely be necessary when starting and/or stopping concurrent disulfiram. Monitor phenytoin response and concentrations closely. Consider therapy modification

Ritonavir: May enhance the adverse/toxic effect of Disulfiram. Specifically, the combination of ritonavir oral solution, which contains 43% alcohol, may result in a disulfiram-alcohol reaction if combined. Avoid combination

Sertraline: Disulfiram may enhance the adverse/toxic effect of Sertraline. This is specifically related to sertraline oral concentrate due to its alcohol content (12%). Management: Sertraline Oral Concentrate contains 12% alcohol, and its use should be avoided with disulfiram. Avoid combination

Theophylline Derivatives: Disulfiram may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Tinidazole: May enhance the adverse/toxic effect of Disulfiram. Avoid combination

Tipranavir: Disulfiram may enhance the adverse/toxic effect of Tipranavir. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Disulfiram may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

Frequency not defined.

Central nervous system: Aftertaste (metallic or garlic-like), drowsiness, fatigue, headache, peripheral neuritis, peripheral neuropathy, polyneuropathy, psychosis

Dermatologic: Acneiform eruption, allergic dermatitis, skin rash

Genitourinary: Impotence

Hepatic: Cholestatic hepatitis, fulminant hepatitis, hepatic failure (multiple case reports)

Ophthalmic: Optic neuritis

ALERT: U.S. Boxed Warning

Alcohol intoxication:

Disulfiram should never be administered to a patient when he is in a state of alcohol intoxication, or without his full knowledge. The physician should instruct relatives accordingly.

Warnings/Precautions

Concerns related to adverse effects:

• Disulfiram-reaction: Ingesting alcohol, even in small amounts, during treatment with disulfiram may result in flushing, throbbing in head and neck, nausea, copious vomiting, respiratory difficulty, diaphoresis, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision and confusion. Severe reactions may involve respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, seizure and death. The intensity of the reaction is generally proportional to the amounts of disulfiram and alcohol ingested. The reaction can last from 30 minutes to several hours in more severe cases, or as long as it takes the alcohol to be metabolized.

• Hepatotoxicity: Severe (sometimes fatal) hepatitis and/or hepatic failure resulting in transplantation have been associated with use; may occur in patients with or without prior history of abnormal hepatic function. Monitor for hepatotoxicity and educate patients about signs and symptoms.

Disease-related concerns:

• Cerebral damage: Use with extreme caution in patients with cerebral damage.

• Contact dermatitis: Evaluate patients with a history of rubber contact dermatitis for hypersensitivity to thiuram derivatives before administering disulfiram.

• Diabetes: Use with extreme caution in patients with diabetes mellitus.

• Hepatic impairment: Use with extreme caution in patients with hepatic cirrhosis or impairment.

• Hypothyroidism: Use with extreme caution in patients with hypothyroidism.

• Nephritis: Use with extreme caution in patients with acute or chronic nephritis.

• Seizures: Use with extreme caution in patients with a history of seizure disorder.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Alcohol intoxication: [US Boxed Warning]: Should never be administered to a patient when he/she is in a state of alcohol intoxication, or without his/her knowledge. The physician should instruct relatives accordingly.

• Patient information: Patients must receive appropriate counseling, including information on the disulfiram reaction, “disguised” forms of alcohol (eg, tonics, mouthwashes, cough mixtures, sauces, vinegars, aftershave lotions, back rubs) and the duration of the drug's activity (up to 14 days).

Monitoring Parameters

Liver function tests (baseline and after 10 to 14 days of treatment), CBC, serum chemistries

Pregnancy Considerations

Safety in pregnancy has not been established; there is limited data on maternal use during pregnancy (Reitnauer,1997).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, loss of strength and energy, sexual dysfunction, acne, headache, or change in taste. Have patient report immediately to prescriber vision changes, burning or numbness feeling, mood changes, behavioral changes, or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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