概述

双硫仑, 戒酒硫（安塔布司片）

Antabuse   (Disulfiram Tablets),

英文药名: Antabuse(Disulfiram Tablets)

中文药名: 双硫仑, 戒酒硫（安塔布司片）

双硫仑口服用片剂，在含250或500毫克每双硫仑，以及辅助部件的封装20部分：聚氧乙烯40硬脂酸酯，硬脂酸，微晶纤维素，羟丙基纤维素，淀粉，硬脂酸钠，钙二磷酸;

双硫仑片植入物在含各100毫克硫仑10的玻璃瓶碎片的使用。 助剂凸出药物氯化钠，甘露糖醇，双硫仑（disulfiram）是一种戒酒药物，服用该药后即使饮用少量的酒，身体也会产生严重不适，而达到戒酒的目的。

中文名称：双硫仑

中文别名：戒酒硫；双(二乙硫代氨基甲酰)二硫化物；双硫伦；二硫化四乙基秋兰姆；促进剂TETD；双硫伦；双硫醒

英文名称：Disulfiram

英文别名：Disulfiram; N1,N1,N3,N3-tetraethyl-2-dithioperoxy-1,3-dithiodicarbonic diamide; Tetraethylthiuram Disulfide; tetraethylthioperoxydicarbonic diamide ([[(C2H5)2N]C(S)]2S2); tetraethylthiuram disulfide

CAS号：97-77-8

分子式：C10H20N2S4

分子量：296.53900

精确质量：296.05100

PSA：121.26000

LogP：3.62120

物化性质

外观与性状：黄色-白色晶体或灰色粉末

密度：1.27g/cm3

熔点：69-71 °C(lit.)

沸点：117°C

闪点：117°C/17mm

折射率：1.6126 (84ºC)

水溶解性：0.02 g/100 mL

储存条件：密封，干燥阴凉处保存[1]。

用于酒精依赖的治疗，适用于50岁以下愿意合作的酗酒者。

患者停用含酒精饮料至少12小时后才能服用双硫仑。据国外报道，在治疗初期，一天最大剂量为500mg，持续1～2周；以后的维持剂量为125～500mg/d，取决于患者对不良反应的耐受性。另一种用法为，第一天剂量为800mg，以后200mg/d，维持量100～200mg/d。均为早晨一次服用。

双硫仑单独应用无明显毒性，作为解酒药其本身对酒精代谢也无明显影响。乙醇在体内被酒精脱氢酶氧化成乙醛，乙醛很快再被乙醛脱氢酶氧化。双硫仑的某些代谢产物不可逆地抑制胞质内和线粒体内的乙醛脱氢酶，使饮酒者血中乙醛浓度升高5～10倍，产生强烈的不适感，让嗜酒者转而对饮酒产生厌恶和恐惧心理，从而放弃酗酒而达到戒酒目的。用药者再饮酒后15～20min，有剧烈头痛、潮红、焦虑、心动过速及胸前区痛；再过15～20min可有恶心、呕吐、眩晕、无力、出汗、视物模糊、血压下降及呼吸困难，可持续2～6h。以上反应，个体差异较大，少数严重者可意识丧失及惊厥，血压可降至休克水平，极个别可引起死亡。故治疗开始必须住院密切观察，并应警告患者，一旦开始服用双硫仑，任何形式的酒精摄入均可引起其不适甚至危及生命。

药物相互作用

双硫仑可抑制肝药酶，因此可干扰苯妥英、氯氮卓及巴比妥类等药物的代谢。

药代动力学

口服双硫仑主要在胃肠道吸收，随后很快被红细胞中谷胱甘肽还原成其单体二乙二硫氨甲酯，肝脏中也同时进行此反应。其单体在肝中代谢成为葡糖苷酯或甲酯、二硫化碳、二乙胺及硫酸根离子，大多数代谢产物从尿中排出，而二硫化碳由呼吸系统排出。

双硫仑的表观半衰期为7.3。给药剂量为250mg时，双硫仑及其代谢产物平均达峰时间为8～10h。但是双硫仑及其代谢产物血浆浓度个体间差异较大，这种差异可能由于双硫仑的强脂溶性、与血浆蛋白的结合力各不相同及肝肠循环造成的。

对于严重酗酒者大多数实验研究表明双硫仑可减少患者的依赖性，但也有少数持不同意见，还有人建议使用纳曲酮替代双硫仑，消除双硫仑-酒精的剧烈反应，让患者达到逐步戒酒的目的。

剂型与规格

片剂：100mg，200mg。

单独应用双硫仑，不良反应较轻，可能引起痤疮样皮疹，荨麻疹，疲乏，震颤，不安，头痛，眩晕，口中有大蒜味或金属味，轻度胃肠不适[2]。

由于药物自体内排出缓慢，故应警告患者服药期间甚至在停药后1～2周内饮用含有酒精的饮料均可出现上述反应，因此此药适用于有强烈戒酒愿望的自觉戒酒者。双硫仑不能连续使用超过3个月，以避免蓄积作用。

少数人可有低血压及阳萎。周围神经炎、精神病和酮血症也见有报道[3]。

心肌病、冠心病、精神病及对双硫仑过敏者禁用。

密封，干燥阴凉处保存

Antabuse

Generic Name: disulfiram
Dosage Form: tablet

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.

Disulfiram, USP is an alcohol antagonist drug.

CHEMICAL NAME

bis(diethylthiocarbamoyl) disulfide.

STRUCTURAL FORMULA

C10H20N2S4 M.W. 296.54

Disulfiram, USP 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.

Each tablet for oral administration contains 250 mg or 500 mg disulfiram, USP. Tablets also contain colloidal silicon dioxide, lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid.

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 is 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.

Disulfiram Tablets USP are an aid in the management of selected chronic alcohol patients who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage.

Disulfiram Tablets USP are 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.

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.

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 the possible consequences. He should be warned to avoid alcohol in disguised forms, i.e., in sauces, vinegars, cough mixtures, and even in aftershave lotions and back rubs. He should also be warned that reactions may occur with alcohol up to 14 days after ingesting disulfiram.

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 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.

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.

Patients with a history of rubber contact dermatitis should be evaluated for hypersensitivity to thiuram derivatives before receiving disulfiram (see CONTRAINDICATIONS).

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.

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.

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.

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 rat’s diet did not lead to such tumors. The relevance of this finding to humans is not known at this time.

The safe use of this drug 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.

Safety and effectiveness in pediatric patients have not been established.

It is not known whether this drug is excreted in human milk. Since many drugs are so excreted, disulfiram should not be given to nursing mothers.

A determination has not been made whether controlled clinical studies of disulfiram included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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, as well as hepatic failure resulting in transplantation or death, have been reported 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, acneform 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.

No specific information is available on the treatment of overdosage with disulfiram. It is recommended that the physician contact the local Poison Control Center.

Disulfiram tablets should never be administered until the patient has abstained from alcohol for at least 12 hours.

In the first phase of treatment, a maximum of 500 mg 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.

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.

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.

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.

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.

Disulfiram Tablets USP are available as follows:

250 mg - white, round, unscored, biconvex tablets, debossed with OP over 706 on one side and plain on the other side, in bottles of 100 tablets (NDC 51285-523-02).

500 mg - white, round, scored tablets, debossed with OP over 707 on one side and scored on the other side, in bottles of 100 tablets (NDC 51285-524-02).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Manufactured In Croatia By:

PLIVA HRVATSKA d.o.o.

Zagreb, Croatia

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. B 9/2015

NDC 51285-523-02

Antabuse®

(disulfiram

tablets USP)

250 mg

See Side Panel for Warnings

Rx only

100 TABLETS

TEVA

NDC 51285-524-02

Antabuse®

(disulfiram

tablets USP)

500 mg

See Side Panel for Warnings

Rx only

100 TABLETS

TEVA

Revised: 05/2017

Teva Women's Health, Inc