Disulfiram (Systemic)

VA CLASSIFICATION
Primary: AD100^{17}

Commonly used brand name(s): Antabuse.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Alcohol-abuse deterrent—

Indications

Accepted

Alcoholism (treatment)—Disulfiram is used to help maintain sobriety in the treatment of chronic alcoholism in conjunction with supportive and psychotherapeutic measures. ^{{01} {19}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    296.52 ^{17}

Mechanism of action/Effect:

Produces irreversible inhibition of the enzyme responsible for oxidation of the ethanol metabolite acetaldehyde. ^{{01} {28}} The resultant accumulation of acetaldehyde may be responsible for most of the signs and symptoms occurring after ethanol ingestion in disulfiram-treated patients. ^{{01} {28}} The hypotensive response may be due to inhibition of norepinephrine synthesis by the major disulfiram metabolite diethyldithiocarbamate.

Absorption:

Slow. ^{{01} {19} {28}} 80 to 90% of an oral dose is absorbed. ^{40}

Biotransformation:

Hepatic.

Onset of action:

A single dose of disulfiram will begin to affect ethanol metabolism within 1 to 2 hours. ^{32}

Duration of action:

Disulfiram-alcohol reactions may occur up to 14 days following last dose of disulfiram. ^{{01} {28}}

Elimination:
    Primarily renal, as metabolites. ^{19} Some of the metabolites are also exhaled as carbon disulfide. ^{19} Up to 20% of a dose may remain in the body for 1 week or longer. ^{40} About 5 to 20% of a dose is eliminated unchanged in the feces. ^{19}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other thiuram derivatives (used in rubber, pesticides, or fungicides) may be sensitive to disulfiram also. ^{01}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done. However, there have been a few reports of congenital defects in infants whose mothers received disulfiram during pregnancy. ^{{19} {29} {31} {40}} Further study is needed to determine the relationship between disulfiram and congenital malformations. ^{29}

Disulfiram is reported to be embryotoxic in animals. ^{29}

Breast-feeding

Problems in humans have not been documented. ^{29}

Pediatrics

No information is available on the relationship of age to the effects of disulfiram in pediatric patients. Safety and efficacy have not been established.


Geriatrics


No information is available on the relationship of age to the effects of disulfiram in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving this medication. In addition, elderly patients with cardiac or cerebrovascular disease may not tolerate the hypotension that accompanies the disulfiram-alcohol reaction as well as younger patients. ^{33}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol^{01}{28}    (use of alcohol or alcohol-containing products within 14 days of disulfiram therapy will result in a disulfiram-alcohol reaction)


» Alfentanil    (chronic preoperative administration or perioperative use of hepatic enzyme inhibitors, such as disulfiram, may decrease plasma clearance and prolong the duration of action of alfentanil ^{13})


Amoxicillin and clavulanate combination^{11} or
Bacampicillin    (metabolism of bacampicillin produces low plasma concentrations of alcohol and acetaldehyde; although the risk of a disulfiram-alcohol interaction appears minimal, caution is recommended if concurrent use is unavoidable ^{12})

    (a similar reaction is thought to occur with amoxicillin and clavulanate combination ^{{15} {20} {21}})


» Anticoagulants,^{{01}{19}{28}{37}{40}} coumarin- or indandione-derivative    (anticoagulant effect may be increased during concurrent use with disulfiram because of inhibition of the enzymatic metabolism of the anticoagulant; also, disulfiram may act directly in the liver to increase the hypoprothrombinemia-inducing activity of coumarin derivatives; anticoagulant dosage adjustments based on prothrombin time determinations may be necessary during and following concurrent use)


» Anticonvulsants, hydantoin, especially phenytoin^{{01}{19}{28}{37}{40}}    (concurrent use with disulfiram may increase the serum concentrations of hydantoins, possibly leading to hydantoin toxicity; hydantoin serum concentrations should be obtained prior to and during concurrent therapy with disulfiram and dosage adjustments made accordingly)


Antidepressants, tricyclic,^{37}{40}{43} especially amitriptyline    (concurrent use with disulfiram may cause transient delirium)


Ascorbic acid    (may interfere with the disulfiram-alcohol reaction, especially with chronic use or high doses of ascorbic acid; although controversial, ^{{33} {37} {40}} this effect has been used beneficially by some clinicians ^{{01} {19} {33} {34}} in the management of disulfiram-alcohol reactions)


Central nervous system (CNS) depression–producing medications (See Appendix II )^{24}    (concurrent use may enhance the CNS depressant effects of either these medications or disulfiram)


Ethylene dibromide^{19}{41}    (exposure to ethylene dibromide or its vapors concurrently with disulfiram treatment may result in a toxic reaction)


Hepatic enzyme inhibitors (See Appendix II )    (concurrent use of disulfiram with other hepatic enyzme inhibitors may potentiate the effect ^{24})


Hepatotoxic medication, other (See Appendix II )    (concurrent use of disulfiram with other hepatotoxic medications may increase the potential for hepatotoxicity ^{24})


» Isoniazid^{{01}{19}{28}{40}}    (concurrent use may result in increased incidence of CNS effects, such as dizziness, incoordination, irritability, or insomnia; a reduction of dosage or discontinuation of disulfiram may be necessary)


» Metronidazole^{01}{28}{37}    (concurrent use with disulfiram may result in confusion and psychotic reactions because of combined toxicity; metronidazole is not recommended concurrently with, and for 2 weeks following, disulfiram)


Midazolam    (concurrent use may decrease first-pass metabolism and elimination of midazolam in the liver, probably by competitive inhibition at the cytochrome P-450 binding sites, thereby increasing steady-state plasma concentrations of midazolam ^{07})


Neurotoxic medications (See Appendix II )    (concurrent use of disulfiram with other neurotoxic medications may increase the potential for neurotoxicity ^{24})


» Organic solvents^{19}{42}    (exposure to organic solvents, ingested or inhaled, which may contain alcohol, acetaldehyde, paraldehyde, or structural analogs, may result in a disulfiram-alcohol reaction)


» Paraldehyde^{01}{28}    (concurrent use with disulfiram is not recommended, because inhibition of acetaldehyde dehydrogenase may occur, resulting in decreased metabolism of paraldehyde and increased blood concentrations of paraldehyde and acetaldehyde)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Cholesterol concentrations, serum    (may be increased with doses of 500 mg a day)


Vanillylmandelic acid (VMA) concentrations, urine    (may be decreased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Allergic eczematous contact dermatitis^{01}{28}    (may be exacerbated)


Cardiovascular disorders^{{01}{19}{28}{37}{40}}    (disulfiram-alcohol reaction may exacerbate condition)


Depression^{34}{37}{40}    (behavioral toxicity may be precipitated)


Diabetes mellitus^{{01}{19}{28}{32}}    (disulfiram-alcohol reaction may exacerbate condition)


Epilepsy^{01}{19}{28} or other seizure disorder, or history of    (disulfiram-alcohol reaction may exacerbate condition)


Hepatic function impairment or cirrhosis^{{01}{04}{05}{06}{19}{28}{37}{40}}    (increased potential for hepatotoxicity)


Hypothyroidism^{01}{19}{28}    (disulfiram-alcohol reaction may exacerbate condition)


Psychoses^{{01}{19}{28}{34}{37}{40}}    (behavioral toxicity may be precipitated)


Pulmonary insufficiency, severe^{32}{37}{40}    (disulfiram-alcohol reaction may exacerbate condition)


Renal function impairment^{{01}{19}{28}{37}{40}}    (disulfiram elimination may be inhibited)


Sensitivity to disulfiram, rubber, pesticides, or fungicides^{01}{19}{28}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts and
Blood chemistry profiles    (recommended at 6-month intervals during therapy ^{{01} {19} {28}})


Hepatic function determinations^{01}{19}    (baseline studies are recommended, followed by transaminase tests after 10 to 14 days of therapy; ^{{01} {09} {28}} additional liver function tests may also be required at periodic intervals during therapy)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Neurotoxicity, including optic neuritis (eye pain or tenderness or any change in vision)^{01}{19}{28}
    
peripheral neuritis ^{{01} {19} {28} {40}} or polyneuritis ^{{01} {19} {28}} (numbness, pain, tingling, or weakness in hands or feet)
    
psychotic reaction ^{01}{19}{32}(mood or mental changes)

Note: Neurotoxicity is usually reversible if disulfiram is discontinued. ^{38}


Incidence rare
    
Encephalopathy (mental changes)^{{32}{34}{35}{36}{37}}
    
hepatitis (yellow eyes or skin ; darkening of urine; light gray–colored stools; severe stomach pain)^{{01}{04}{05}{06}{19}{28}{32}{40}}

Note: Fulminant hepatic necrosis occurs rarely. Although it cannot be predicted which patients will develop this potentially fatal hepatitis, published experience suggests that the chance of survival is markedly improved if disulfiram is stopped as soon as jaundice is detected. Careful clinical monitoring with discontinuation of disulfiram and laboratory (bilirubin and hepatic enzyme) determinations is recommended when hepatitis is suspected. ^{38}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Drowsiness ^{{01}{19}{28}{40}}

Incidence less frequent or rare
    
Headache ^{01}{19}{28}
    
impotence (decreased sexual ability in males)^{{01}{16}{19}{28}}
    
metallic or garlic-like taste in mouth ^{01}{19}{28}
    
skin rash ^{01}{19}{28}
    
unusual tiredness ^{{01}{19}{28}{40}}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Disulfiram (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to disulfiram, rubber, pesticides, or fungicides
Other medications, especially alcohol; alfentanil; coumarin- or indandione-derivative anticoagulants; hydantoin anticonvulsants, especially phenytoin; isoniazid; metronidazole; organic solvents; or paraldehyde

Proper use of this medication
» Not taking this medication within 12 hours of using any alcohol-containing preparation or medication, or if the blood alcohol level is not zero

» Compliance with therapy

» Proper dosing

» Proper storage

Precautions while using this medication
» Not drinking or using any alcohol-containing products or medications while taking this medication and for 14 days after discontinuing this medication ^{{01} {28}}

Symptoms of disulfiram-alcohol reaction ^{{01} {28} {37} {40}}
Blurred vision
Chest pain
Confusion
Dizziness or fainting
Fast or pounding heartbeat
Flushing or redness of face
Increased sweating
Nausea and vomiting
Throbbing headache
Troubled breathing
Weakness, severe
Rarely, seizures, heart attack, unconsciousness, or death if reaction is severeCarrying medical identification card during therapy ^{{01} {28}}

Regular visits to physician to check progress during long-term therapy

» Checking all liquid medications for presence of alcohol

» Caution if drowsiness occurs

» Checking with physician before using other CNS depressants


Side/adverse effects
Signs of potential side effects, especially optic neuritis, peripheral neuritis, polyneuritis, or psychotic reaction


General Dosing Information
The patient should be made fully aware of the nature of this medicine and the disulfiram-alcohol reaction and its consequences. ^{{01} {28}}

Disulfiram should not be administered until the patient has abstained from alcohol for at least 12 hours ^{01} and the blood alcohol level is zero. ^{39}

The duration of the disulfiram-alcohol reaction is dependent upon the dose of disulfiram and on the quantity of alcohol ingested; it may persist from 30 minutes to several hours. ^{{01} {28}}

Reactions to alcohol may occur for up to 2 weeks following withdrawal of disulfiram therapy. ^{{01} {28}}

For treatment of disulfiram-alcohol reaction ^{01}
In severe reactions, supportive measures to restore blood pressure and treat shock should be instituted. ^{{01} {19}} Other recommendations include:

   • Administration of supplemental oxygen. ^{{01} {19} {30}}
   • Monitoring of serum potassium levels. ^{{01} {19} {30}}
   • Monitoring of ECG tracings. ^{30}
Although controversial, ^{{33} {37} {40}} administration of intravenous ascorbic acid ^{{01} {19} {33} {34}} or intravenous antihistamines ^{{01} {19} {34}} has been advocated by some clinicians. Phenothiazines should not be used as they may exacerbate hypotension. ^{30}


Oral Dosage Forms

DISULFIRAM TABLETS USP

Usual adult and adolescent dose
Alcohol-abuse deterrent
Initial: Oral, up to 500 mg once a day for one or two weeks. ^{{01} {19}}

Maintenance: Oral, 125 to 500 mg (average of 250 mg) once a day. ^{{01} {19}}

Note: Some clinicians recommend the dose be administered at bedtime to reduce daytime drowsiness. ^{40}



Usual pediatric dose
Safety and efficacy have not been established.

Usual geriatric dose
See Usual adult and adolescent dose.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Strength(s) usually available
U.S.—


250 mg (Rx) [Antabuse (scored)][Generic]


500 mg (Rx) [Antabuse (scored)][Generic]

Canada—


250 mg (Rx) [Antabuse (scored)]


500 mg (Rx) [Antabuse (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container.

Note: Patient identification cards may be available from the manufacturer.

Revised: 07/20/1994

References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

1. Antabuse package insert (Ayerst—US), Rev 6/22/90, Rec 10/90.
   

2. Guidelines for Antabuse users, Ayerst, Rev 1981, Rec 5/86.
   

3. Disulfiram package insert (Sidmak—US), Rev 11/83, Rec 3/84.
   

4. Disulfiram-hepatotoxicity, Clin-Alert, 7/26/85.
   

5. Disulfiram-hepatotoxicity, Reactions, 3/23/85: 7.
   

6. Disulfiram-induced hepatotoxicity, Reactions, 4/20/85: 3.
   

7. Midazolam drug interaction change sheet, GC, 5/1/86.
   

8. Reviewer to leaflets, 9/86.
   

9. Disulfiram: Hepatotoxicity-Death Legal Action, Clin-Alert, 5/16/86.
   

10. McEvoy GK, editor. AHFS Drug information 77. Bethesda, MD: American Society of Hospital Pharmacists, 1977: 713.
    

11. Augmentin-disulfiram warning, F&C Drug Newsletter 1985: 27.
    

12. Rationale for bacampicillin-disulfiram drug interaction, letter from Pfizer, 1/9/85.
    

13. Alfentanil drug interaction change sheet, EK, 5/22/87.
    

14. Alfentanil not needed in Advice.
    

15. Reviewers' consensus on monograph revision of 8/87.
    

16. Drugs that cause sexual dysfunction. Med Let 1987; 65-73.
    

17. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 224-5.
    

18. Red Book 1987, many generics listed.
    

19. Antabuse product monograph (Ayerst—Canada), Rev 5/86.
    

20. Augmentin (Beecham). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 689.
    

21. McEvoy GK, editor. AHFS Drug information 87. Bethesda, MD: American Society of Hospital Pharmacists, 1987: 255.
    

22. The United States pharmacopeia. The national formulary. USP 21st revision (January 1, 1985). NF 16th ed (January 1, 1985). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1985: 2981.
    

23. Not used.
    

24. Addendum No 1 in Memo.
    

25. McNichol RW, Ewing JA, Faiman MD. Disulfiram (Antabuse): a unique medical aid to sobriety. Springfield, IL: Thomas, 1987.
    

26. McNichol RW, Sowell JM, Logsdon SA, Delgado MH, McNichol J. Disulfiram: a guide to clinical use in alcoholism treatment. Am Fam Physician 1991; 44: 481-4.
    

27. CA Beach, et al. Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics. Clin Pharmacol Ther 1986; 39: 265-70.
    

28. Disulfiram package insert (Danbury Pharmacal—US), Rev 4/87, Rec 1/89.
    

29. Briggs GG, Freeman RK, Yaffe SJ. A reference guide to fetal and neonatal risk. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams & Wilkins, 1990: 219.
    

30. Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier, 1988: 422-31.
    

31. Nora AH, Nora JJ, Blu J. Limb-reduction anomalies in infants born to disulfiram-treated alcoholic mothers [letter]. Lancet 1977; 2: 664.
    

32. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Med 1990; 88: 647-55.
    

33. Panel comment, 9/91.
    

34. Panel comment, 9/91.
    

35. Hotson JH, Langston JW. Disulfiram-induced encephalopathy. Arch Neurol 1976; 33: 141-2.
    

36. Borrett D, Ashby P, Bilbao J, Carlen P. Reversible, late-onset disulfiram-induced neuropathy and encephalopathy. Ann Neurol 1985; 17: 396-9.
    

37. Peachey JE, Naranjo CA. The role of drugs in the treatment of alcoholism. Drugs 1984; 27: 171-82.
    

38. Panel comment, 9/91.
    

39. Panel comment, 9/91.
    

40. Sellers EM, Naranjo CA, Peachey JE. Drugs to decrease alcohol consumption. N Engl J Med 1981; 305: 1255-62.
    

41. NIOSH current intelligence bulletin #23—Ethylene dibromide (EDB) and disulfiram: Toxic interaction. MMWR 1985; 30: 40S.
    

42. Scott GE, Little FW. Disulfiram reaction to organic solvents other than ethanol [letter]. N Engl J Med 1985; 312: 790.
    

43. Ciraulo DA, Barnhill J, Boxenbaum H. Pharmacokinetic interaction of disulfiram and antidepressants. Am J Psych 1985; 142: 1373-4.