DISULFIRAM
* WARNING *
* 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. *
* *
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CHEMICAL NAME: bis(diethylthiocarbamoyl) disulfide.
Disulfiram occurs as a white to off-white, odorless, and almost tasteless powder,
soluble in water to the extent of about 20 mg in 100 mL, and in alcohol to the
extent of about 3.8 g in 100 mL.
Disulfiram contains these inactive ingredients: magnesium aluminum silicate;
magnesium stearate, NF; povidone, USP; starch, NF.
ACTIONS/CLINICAL PHARMACOLOGY:
Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant
reaction when the patient under treatment ingests even small amounts of alcohol.
Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage. During
alcohol metabolism following Disulfiram intake, the concentration of acetaldehyde
occurring in the blood may be 5- to 10-times higher than that found during
metabolism of the same amount of alcohol alone.
Accumulation of acetaldehyde in the blood produces a complex of highly
unpleasant symptoms referred to hereinafter as the Disulfiram-alcohol reaction.
This reaction, which is proportional to the dosage of both Disulfiram and alcohol,
will persist as long as alcohol is being metabolized. Disulfiram does not appear
to influence the rate of alcohol elimination from the body.
Disulfiram is absorbed slowly from the gastrointestinal tract and eliminated
slowly from the body. One (or even two) weeks after a patient has taken his last
dose of Disulfiram, ingestion of alcohol may produce unpleasant symptoms.
Prolonged administration of Disulfiram does not produce tolerance; the longer a
patient remains on therapy, the more exquisitely sensitive he becomes to
alcohol.
INDICATIONS AND USAGE:
Disulfiram is an aid in the management of selected chronic alcoholic patients who
Want to remain in a state of enforced sobriety so that supportive and
psychotherapeutic treatment may be applied to best advantage.
Disulfiram is not a cure for alcoholism. When used alone, without proper
motivation and supportive therapy, it is unlikely that it will have any
substantive effect on the drinking pattern of the chronic alcoholic.
CONTRAINDICATIONS:
Patients who are receiving or have recently received metronidazole, paraldehyde,
alcohol, or alcohol-containing preparations, e.g., cough syrups, tonics and the
like, should not be given Disulfiram.
Disulfiram is contraindicated in the presence of severe myocardial disease or
coronary occlusion, psychoses, and hypersensitivity to disulfiram or to other
thiuram derivatives used in pesticides and rubber vulcanization.
WARNINGS:
*************************************************
* *
* WARNING *
* 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. *
* *
*************************************************
The patient must be fully informed of the Disulfiram-alcohol reaction. He must be
strongly cautioned against surreptitious drinking while taking the drug, and he
must be fully aware of possible consequences. He should be warned to avoid
alcohol in disguised form, i.e., in sauces, vinegars, cough mixtures, and even
aftershave lotions and back rubs. He should also be warned that reactions may
occur with alcohol up to 14 days after ingesting Disulfiram.
THE DISULFIRAM-ALCOHOL REACTION:
Disulfiram plus alcohol, even small amounts, produces 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 per 100 mL. Symptoms are fully developed at
50 mg per 100 mL, and unconsciousness usually results when the blood alcohol
level reaches 125 to 150 mg.
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.
DRUG INTERACTIONS
Disulfiram appears to decrease the rate at which certain drugs are metabolized
and therefore may increase the blood levels and the possibility of clinical
toxicity of drugs given concomitantly.
DISULFIRAM INHIBITS HEPATIC ENZYMES AND MAY INTERFERE WITH THE METABOLISM OF OTHER DRUGS TAKEN AT THE SAME TIME. IT ENHANCES THE EFFECTS OF PHENYTOIN AND COUMARIN ANTICOAGULANTS. IT INHIBITS THE METABOLISM AND EXCRETION OF RIFAMPICIN, PETHIDINE, MORPHINE, AND AMPHETAMINES. CONCURRENT USE WITH ISONIAZID OR METRONIDAZOLE CAN CAUSE TOXIC REACTIONS.
DISULFIRAM SHOULD BE USED WITH CAUTION IN THOSE PATIENTS RECEIVING PHENYTOIN AND
ITS CONGENERS, SINCE THE CONCOMITANT ADMINISTRATION OF THESE TWO DRUGS CAN LEAD
TO PHENYTOIN INTOXICATION. PRIOR TO ADMINISTERING DISULFIRAM TO A PATIENT ON
PHENYTOIN THERAPY, A BASELINE PHENYTOIN SERUM LEVEL SHOULD BE OBTAINED.
SUBSEQUENT TO INITIATION OF DISULFIRAM THERAPY, SERUM LEVELS OF PHENYTOIN SHOULD
BE DETERMINED ON DIFFERENT DAYS FOR EVIDENCE OF AN INCREASE OR FOR A CONTINUING
RISE IN LEVELS. INCREASED PHENYTOIN LEVELS SHOULD BE TREATED WITH APPROPRIATE
DOSAGE ADJUSTMENT.
It may be necessary to adjust the dosage of oral anticoagulants upon beginning
or stopping disulfiram, since disulfiram may prolong prothrombin time.
Patients taking isoniazid when disulfiram is given should be observed for the
appearance of unsteady gait or marked changes in mental status; the disulfiram
should be discontinued if such signs appear.
In rats, simultaneous ingestion of disulfiram and nitrite in the diet for 78
weeks has been reported to cause tumors, and it has been suggested that
disulfiram may react with nitrites in the rat stomach to form a nitrosamine,
which is tumorigenic. Disulfiram alone in the rats' diet did not lead to such
tumors. The relevance of this finding to humans is not known at this time.
CONCOMITANT CONDITIONS
Because of the possibility of an accidental Disulfiram-alcohol reaction, Disulfiram
should be used with extreme caution in patients with any of the following
conditions: diabetes mellitus, hypothyroidism, epilepsy, cerebral damage,
chronic and acute nephritis, hepatic cirrhosis or insufficiency.
USAGE IN PREGNANCY
The safe use of this drug in pregnancy has not been established. Therefore,
Disulfiram should be used during pregnancy only when, in the judgment of the
physician, the probable benefits outweigh the possible risks.
PRECAUTIONS:
Patients with a history of rubber contact dermatitis should be evaluated for
hypersensitivity to thiuram derivatives before receiving Disulfiram (see
"Contraindications").
It is suggested that every patient under treatment carry an Identification Card,
stating that he is receiving Disulfiram and describing the symptoms most likely to
occur as a result of the Disulfiram-alcohol reaction. In addition, this card
should indicate the physician or institution to be contacted in an emergency.
(Cards may be obtained from Wyeth-Ayerst Laboratories upon request.)
Alcoholism may accompany or be followed by dependence on narcotics or sedatives.
Barbiturates and Disulfiram have been administered concurrently without untoward
effects; the possibility of initiating a new abuse should be considered.
Baseline and follow-up transaminase 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 a sequential multiple analysis-12 (SMA-12)
test should be made every six months.
Patients taking Disulfiram Tablets should not be exposed to ethylene dibromide or
its vapors. This precaution is based on preliminary results of animal research
currently in progress that suggest a toxic interaction between inhaled ethylene
dibromide and ingested disulfiram resulting in a higher incidence of tumors and
mortality in rats. A correlation between this finding and humans, however, has
not been demonstrated.
DRUG INTERACTIONS:
Disulfiram appears to decrease the rate at which certain drugs are metabolized
and therefore may increase the blood levels and the possibility of clinical
toxicity of drugs given concomitantly.
DISULFIRAM SHOULD BE USED WITH CAUTION IN THOSE PATIENTS RECEIVING PHENYTOIN AND
ITS CONGENERS, SINCE THE CONCOMITANT ADMINISTRATION OF THESE TWO DRUGS CAN LEAD
TO PHENYTOIN INTOXICATION. PRIOR TO ADMINISTERING DISULFIRAM TO A PATIENT ON
PHENYTOIN THERAPY, A BASELINE PHENYTOIN SERUM LEVEL SHOULD BE OBTAINED.
SUBSEQUENT TO INITIATION OF DISULFIRAM THERAPY, SERUM LEVELS OF PHENYTOIN SHOULD
BE DETERMINED ON DIFFERENT DAYS FOR EVIDENCE OF AN INCREASE OR FOR A CONTINUING
RISE IN LEVELS. INCREASED PHENYTOIN LEVELS SHOULD BE TREATED WITH APPROPRIATE
DOSAGE ADJUSTMENT.
It may be necessary to adjust the dosage of oral anticoagulants upon beginning
or stopping disulfiram, since disulfiram may prolong prothrombin time.
Patients taking isoniazid when disulfiram is given should be observed for the
appearance of unsteady gait or marked changes in mental status; the disulfiram
should be discontinued if such signs appear.
In rats, simultaneous ingestion of disulfiram and nitrite in the diet for 78
weeks has been reported to cause tumors, and it has been suggested that
disulfiram may react with nitrites in the rat stomach to form a nitrosamine,
which is tumorigenic. Disulfiram alone in the rats' diet did not lead to such
tumors. The relevance of this finding to humans is not known at this time.
(See Also WARNINGS)
ADVERSE REACTIONS:
(See "Contraindications"," Warnings," and "Precautions.")
OPTIC NEURITIS, PERIPHERAL NEURITIS, POLYNEURITIS, AND PERIPHERAL NEUROPATHY MAY
OCCUR FOLLOWING ADMINISTRATION OF DISULFIRAM.
Multiple cases of hepatitis, including both cholestatic and fulminant hepatitis,
have been reported to be associated with administration of Disulfiram.
Occasional skin eruptions are, as a rule, readily controlled by concomitant
administration of an antihistaminic drug.
In a small number of patients, a transient mild drowsiness, fatigability,
impotence, headache, acneiform eruptions, allergic dermatitis, or a metallic or
garlic-like aftertaste may be experienced during the first two weeks of therapy.
These complaints usually disappear spontaneously with the continuation of
therapy, or with reduced dosage.
Psychotic reactions have been noted, attributable in most cases to high dosage,
combined toxicity (with metronidazole or isoniazid), or to the unmasking of
underlying psychoses in patients stressed by the withdrawal of alcohol.
DOSAGE AND ADMINISTRATION:
Disulfiram should never be administered until the patient has abstained from
alcohol for at least 12 hours.
INITIAL DOSAGE SCHEDULE
In the first phase of treatment, a Maximum of 500mg daily is given in a single
dose for one to two weeks. Although usually taken in the morning, Disulfiram may
be taken on retiring by patients who experience a sedative effect.
Alternatively, to minimize, or eliminate, the sedative effect, dosage may be
adjusted downward.
MAINTENANCE REGIMEN
The average maintenance dose is 250 mg daily (range, 125 to 500 mg); it should
not exceed 500 mg daily.
Note: Occasionally patients, while seemingly on adequate maintenance doses of
Disulfiram, report that they are able to drink alcoholic beverages with impunity
and without any symptomatology. All appearances to the contrary, such patients
must be presumed to be disposing of their tablets in some manner without
actually taking them. Until such patients have been observed reliably taking
their daily Disulfiram tablets (preferably crushed and well mixed with liquid), it
cannot be concluded that Disulfiram is ineffective.
DURATION OF THERAPY
The daily, uninterrupted administration of Disulfiram must be continued until the
patient is fully recovered socially and a basis for permanent self-control is
established. Depending on the individual patient, maintenance therapy may be
required for months, or even years.
TRIAL WITH ALCOHOL
During early experience with Disulfiram, it was thought advisable for each patient
to have at least one supervised alcohol-drug reaction. More recently, the test
reaction has been largely abandoned. Furthermore, such a test reaction should
never be administered to a patient over 50 years of age. A clear, detailed, and
convincing description of the reaction is felt to be sufficient in most cases.
However, where a test reaction is deemed necessary, the suggested procedure is
as follows:
After the first one to two weeks' therapy with 500 mg daily, a drink of 15 mL
(1/2 oz) of 100 proof whiskey, or equivalent, is taken slowly. This test dose of
alcoholic beverage may be repeated once only, so that the total dose does not
exceed 30 mL (1 oz) of whiskey. Once a reaction develops, no more alcohol should
be consumed. Such tests should be carried out only when the patient is
hospitalized, or comparable supervision and facilities, including oxygen, are
available.
MANAGEMENT OF DISULFIRAM-ALCOHOL REACTION:
In severe reactions, whether caused by an excessive test dose or by the
patient's unsupervised ingestion of alcohol, supportive measures to restore
blood pressure and treat shock should be instituted. Other recommendations
include: oxygen, carbogen (95% oxygen and 5% carbon dioxide), vitamin C
intravenously in massive doses (1 g), and ephedrine sulfate. Antihistamines have
also been used intravenously. Potassium levels should be monitored, particularly
in patients on digitalis, since hypokalemia has been reported.
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