商品名称： 氨苯砜片

  英文名称： Dapsone Tablets

别名        二氨基二苯砜

【主要成份】  本品主要成分为4,4'-磺酰基双苯胺。

主要适用症     抑菌作用

【性 状】   本品为白色或类白色片。

【适应症/功能主治】  

本品与其他抑制麻风药联合用于由麻风分枝杆菌引起的各种类型麻风和疱疹样皮炎的治疗，也用于脓疱性皮肤病、聚会性痤疮、银屑病、带状疱疹的治疗等。

【规格型号】

0.1g*100s

【用法用量】

口服给药： 1．抑制麻风 与一种或多种其他抗麻风药合用。 （1）成人，一次50～100mg，一日1次；或按体重一次0.9～1.4mg/kg，一日1次，最高剂量每日200mg。开始可每日口服12.5～25mg，以后逐渐加量到一日100mg。 （2）小儿按体重一次0.9～1.4mg/kg，一日1次。 由于本品有蓄积作用，故每服药6日停药1日，每服药10周停药2周。 2．治疗疱疹样皮炎 （1）成人起始一日50mg，如症状未完全抑制，每日剂量可增加至300mg，成人最高剂量每日500mg，待病情控制后减至最低有效维持量。 （2）小儿开始按体重一次2mg/kg，一日1次，如症状未完全控制，可逐渐增加剂量，待病情控制后减至最小有效量。 3．预防疟疾，本品100mg与乙胺嘧啶12.5mg联合，1次顿服，每7日服药1次。

【不良反应】 1．发生率较高者有：背、腿痛，胃痛，食欲减退；皮肤苍白、发热、溶血性贫血；皮疹；异常乏力或软弱；变性血红蛋白血症。 2．发生率较低者有：皮肤瘙痒、剥脱性皮炎、精神紊乱、周围神经炎；咽痛、粒细胞减低或缺乏；砜类综合征或肝脏损害等。 3．下列症状如持续存在需引起注意：眩晕、头痛、恶心、呕吐。

【禁 忌】对本品及磺胺类药物过敏者、严重肝功能损害和精神障碍者禁用。

【注意事项】 1．下列情况应慎用本品：严重贫血、葡萄糖-6-磷酸脱氢酶(G-6PD)缺乏、变性血红蛋白还原酶缺乏症、肝、肾功能减退、胃与十二指肠溃疡及有精神病史者。 2．交叉过敏：砜类药物之间存在交叉过敏现象。此外，对磺胺类、呋噻米类、噻嗪类、磺酰脲类以及碳酸酐酶抑制药过敏的患者亦可能对本品发生过敏。 3．随访检查 (1)血常规计数，用药前和治疗第一月中每周一次，以后每月一次，连续6个月，以后每半年一次。 (2)G-6PD测定，如为G-6PD缺乏者则本品应慎用。 (3)肝功能试验(如尿胆红素和门冬氨酸氨基转移酶测定)，治疗中患者发生食欲减退、恶心或呕吐时应作测定，如有肝脏损害，应停用本品。 (4)肾功能测定，有肾功能减退者在治疗中应定期测定肾功能，适当调整剂量。 4．原发性和继发性耐氨苯砜麻风杆菌菌株日渐增多，本品不宜单独用于治疗麻风，应与利福平、氯法齐明、乙硫异烟胺、丙硫异烟胺、氧氟沙星、米诺环素、克拉霉素等联合应用。 5．皮损查菌阴性者疗程6个月，阳性者至少2年或用药至细菌转阴。对未定型和结核样麻风的治疗需持续3年，二型麻风需2～10年，瘤型麻风需终身服药。 6．快乙酰化型患者本品的血药浓度可能很低，需调整剂量。慢乙酰化型患者本品的血药浓度可能较高，亦需调整剂量。 7．肾功能减退患者用药时需减量，如肌酐清除率低于4ml/分时需测定血药浓度，无尿患者应停用本品。 8．用药过程中如出现新的或中毒性皮肤发应，应迅速停用本品。但出现麻风反应状态时不需停药。 9．治疗中如出现严重"可逆性"反应(I型)或神经炎时，应合用大剂量肾上皮质激素。 10．G-6PD缺乏患者应用本品时需减量。 11．治疗庖疹样皮炎时，应服用无麸质饮食，连续6个月，氨苯砜的剂量可减少50%或停用本品。

【儿童用药】儿童用量酌减，一般对儿童的生长发育无明显影响。

【老年患者用药】老年患者肝肾功能有所减退，用药量应酌减。

【孕妇及哺乳期妇女用药】本品可在乳汁中达有效浓度，对新生儿具预防作用。但砜类药物在G-6PD缺乏的新生儿中可能引起溶血性贫血。孕妇及哺乳期妇女用药前应充分权衡利弊后决定是否采用，如确有应用指征者应在严密观察下应用。

【药物相互作用】 1．与丙磺舒合用可减少肾小管分泌砜类，使砜类药物血浓度高而持久，易发生毒性反应。因此在应用丙磺舒的同时或以后需调整砜类的剂量。 2．利福平可刺激肝微粒体酶的活性，使本品血药浓度降低1/7～1/10，故服用利福平的同时或以后应用氨苯砜时需调整后者的剂量。 3．本品不宜与骨髓抑制药物合用，因可加重白细胞和血小板减少的程度，必须合用时应密切观察对骨髓的毒性。 4．本品与其他溶血药物合用时可加剧溶血反应。 5．与甲氧苄啶合用时，两者的血药浓度均可增高，其机制可能为： (1)抑制氨苯砜在肝脏的代谢。(2)两者竞争在肾脏中的排泄，本品血药浓度增高可加重其不良反应。 6．与去羟肌苷合用时可减少本品的吸收，因为口服去羟肌苷需同时服用缓冲液以中和胃酸，而本品则需在酸性环境中增加吸收，因此如两者必须同用时应至少间隔2小时。

【药物过量】 过量服用本品主要导致高铁血红蛋白血症、溶血、肝肾功能损害和精神障碍。过量的处理： 1．洗胃，给予活性炭30g，同时给予泻药每6小时1次，至少持续24～48小时。 2．紧急情况下，对正常及变性血红蛋白还原酶缺乏的患者用亚甲蓝1～2mg/kg缓慢静脉注射，如变性血红蛋白重新出现，可重复注射。 3．非紧急情况时，用亚甲蓝3～5mg/kg，每4～6小时口服1次，但G-6PD缺乏患者不能使用。亦可用活性炭，即使在使用本品数小时后仍可应用。

【药理毒理】本品为砜类抑菌剂，对麻风杆菌有较强的抑菌作用，大剂量时显示杀菌作用。其作用机制与磺胺类药物相似，作用于细菌的二氢叶酸合成酶，干扰叶酸的合成。两者的抗菌谱相似，均可为对氨基苯甲酸所拮抗。本品亦可作为二氢叶酸还原酶抑制剂。此外，本品尚具免疫抑制作用，可能与抑制疱疹样皮炎的作用有关。如长期单用，麻风杆菌易对本品产生耐药。

【药代动力学】本品口服后吸收迅速而完全。蛋白结合率为50%～90%。吸收后广泛分布于全身组织和体液中，以肝、肾的浓度为高，病损皮肤的浓度比正常皮肤高10倍。本品在肝内经N-乙酰转移酶代谢。患者可分为氨苯砜慢乙酰化型和快乙酰化型，前者服药后其血药峰浓度(Cmax)亦较高，易产生不良反应，尤其血液系统的不良反应，但临床疗效未见增加。快乙酰化型患者用药时可能需要调整剂量。口服后数分钟即可在血液中测得本品，达峰时间(tmax)为2～6小时，有时为4～8小时，本品存在肝胆循环，所以排泄缓慢，血消除半衰期(t1/2β)为10～50小时(平均为28小时)。停药后本品在血液中仍可持续存在达数周之久。约70%～85%的给药量以原型和代谢产物自尿中排出，少量经粪便、汗液、唾液、痰液和乳汁排泄。

【贮 藏】密封。

【包 装】0.1g*100s/瓶。

Dosage Form: tablet

Rx Only
DESCRIPTION

Dapsone-USP, 4,4'-diaminodiphenylsulfone (DDS), is a primary treatment for Dermatitis herpetiformis. It is an antibacterial drug for susceptible cases of leprosy. It is a white, odorless crystalline powder, practically in-soluble in water and insoluble in fixed and vegetable oils.

Dapsone is issued on prescription in tablets of 25 and 100 mg for oral use.

Inactive Ingredients: Colloidal silicone dioxide, magnesium stearate, microcrystalline cellulose and corn starch.

Dapsone - Clinical Pharmacology

Actions

The mechanism of action in Dermatitis herpetiformis has not been established. By the kinetic method in mice, Dapsone is bactericidal as well as bacteriostatic against Mycobacterium leprae.

Absorption and Excretion

Dapsone, when given orally, is rapidly and almost completely absorbed. About 85 percent of the daily intake is recoverable from the urine mainly in the form of water-soluble metabolites. Excretion of the drug is slow and a constant blood level can be maintained with the usual dosage.

Blood Levels

Detected a few minutes after ingestion, the drug reaches peak concentration in 4 to 8 hours. Daily administration for at least eight days is necessary to achieve a plateau level. With doses of 200 mg daily, this level averaged 2.3 mcg/mL with a range of 0.1 to 7.0 mcg/mL The half-life in the plasma in different individuals varies from ten hours to fifty hours and averages twenty-eight hours. Repeat tests in the same individual are constant. Daily administration (50 to 100 mg) in leprosy patients will provide blood levels in excess of the usual minimum inhibitory concentration even for patients with a short Dapsone half-life.

Indications and Usage for Dapsone

Dermatitis herpetiformis: (D.H.)

Leprosy: All forms of leprosy except for cases of proven Dapsone resistance.

CONTRAINDICATION

Hypersensitivity to Dapsone and/or its derivatives.

Warnings

The patient should be warned to respond to the presence of clinical signs such as sore throat, fever, pallor, purpura or jaundice. Deaths associated with the administration of Dapsone have been reported from agranulocytosis, aplastic anemia and other blood dyscrasias. Complete blood counts should be done frequently in patients receiving Dapsone. The FDA Dermatology Advisory Committee recommended that, when feasible, counts should be done weekly for the first month, monthly for six months and semi-annually thereafter. If a significant reduction in leucocytes, platelets or hemopoiesis is noted, Dapsone should be discontinued and the patients followed intensively. Folic acid antagonists have similar effects and may increase the incidence of hematologic reactions; if co-administered with Dapsone the patient should be monitored more frequently. Patients on weekly pyrimethamine and Dapsone have developed agranulocytosis during the second and third month of therapy.

Severe anemia should be treated prior to initiation of therapy and hemoglobin monitored. Hemolysis and methemoglobin may be poorly tolerated by patients with severe cardiopulmonary disease.

Cutaneous reactions, especially bullous, include exfoliative dermatitis and are probably one of the most serious, though rare, complications of sulfone therapy. They are directly due to drug sensitization. Such reactions include toxic erythema, erythema multiforme, toxic epidermal necrolysis, morbilliform and scarlatiniform reactions, urticaria and erythema nodosum. If new or toxic dermatologic reactions occur, sulfone therapy must be promptly discontinued and appropriate therapy instituted. Leprosy reactional states, including cutaneous, are not hypersensitivity reactions to Dapsone and do not require discontinuation. See special section.

Precautions

General

Hemolysis and Heinz body formation may be exaggerated in individuals with a glucose-6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin reductase deficiency, or hemoglobin M. This reaction is frequently dose-related. Dapsone should be given with caution to these patients or if the patient is exposed to other agents or conditions such as infection or diabetic ketosis capable of producing hemolysis. Drugs or chemicals which have produced significant hemolysis in G6PD or methemoglobin reductase deficient patients include Dapsone, sulfanilamide, nitrite, aniline, phenylhydrazine, naphthalene, niridazole, nitro-furantoin and 8-amino-antimalarials such as primaquine.

Toxic hepatitis and cholestatic jaundice have been reported early in therapy. Hyperbilirubinemia may occur more often in G6PD deficient patients. When feasible, baseline and subsequent monitoring of liver function is recommended; if abnormal, Dapsone should be discontinued until the source of the abnormality is established.

Drug Interactions

Rifampin lowers Dapsone levels 7 to 10-fold by accelerating plasma clearance; in leprosy this reduction has not required a change in dosage. Folic acid antagonists such as pyrimethamine may increase the likelihood of hematologic reactions.

A modest interaction has been reported for patients receiving 100 mg Dapsone daily in combination with trimethoprim 5 mg/kg q6h. On Day 7, serum Dapsone levels averaged 2.1 ± 1.0 mcg/mL in comparison to 1.5 ± 0.5 mcg/mL for Dapsone alone. On Day 7, trimethoprim levels averaged 18.4 ± 5.2 mcg/mL in comparison to 12.4 ± 4.5 mcg/mL for patients not receiving Dapsone. Thus, there is a mutual interaction between Dapsone and trimethoprim in which each raises the level of the other about 1.5 times.

A crossover study1 designed to assess the potential of a drug interaction between Dapsone, 100 mg/day and trimethoprim, 200 mg every 12 hours, in eight asymptomatic HIV positive volunteers (average CD4 count 524 cells/mm3) demonstrated that there was not a significant drug interaction between Dapsone and trimethoprim. However, an earlier report2 also by Lee et al, in 78 HIV infected patients with acute Pneumocystis carinii pneumonia, receiving Dapsone, 100 mg/day and higher trimethoprim dose, 20 mg/kg/day, demonstrated that the serum levels of Dapsone were increased by 40% and trimethoprim levels were increased by 48% when the drugs were administered concurrently.

Carcinogenesis, mutagenesis

Dapsone has been found carcinogenic (sarcomagenic) for male rats and female mice causing mesenchymal tumors in the spleen and peritoneum, and thyroid carcinoma in female rats. Dapsone is not mutagenic with or without microsomal activation in S. typhimurium tester strains 1535, 1537, 1538, 98, or 100.

Pregnancy

Teratogenic Effects 

Pregnancy Category C

Animal reproduction studies have not been conducted with Dapsone. Extensive, but uncontrolled experience and two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can affect reproduction capacity. Because of the lack of animal studies or controlled human experience, Dapsone should be given to a pregnant woman only if clearly needed. In general, for leprosy, USPHS at Carville recommends maintenance of Dapsone. Dapsone has been important for the management of some pregnant D.H. patients.

Nursing Mothers

Dapsone is excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. See section on hemolysis. Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of drug to the mother.

Pediatric Use

Pediatric patients are treated on the same schedule as adults but with correspondingly smaller doses. Dapsone is generally not considered to have an effect on the later growth, development and functional development of the pediatric patient.

Adverse Reactions

In addition to the warnings listed above, the following syndromes and serious reactions have been reported in patients on Dapsone.

Hematologic Effects

Dose-related hemolysis is the most common adverse effect and is seen in patients with or without G6PD deficiency. Almost all patients demonstrate the inter-related changes of a loss or 1 to 2g of hemoglobin, an increase in the reticulocytes (2 to 12%), a shortened red cell life span and a rise in methemoglobin. G6PD deficient patients have greater responses.

Nervous System Effects

Peripheral neuropathy is a definite but unusual complication of Dapsone therapy in non-leprosy patients. Motor loss is predominant. If muscle weakness appears, Dapsone should be withdrawn. Recovery on withdrawal is usually substantially complete. The mechanism of recovery is reported by axonal regeneration. Some recovered patients have tolerated retreatment at reduced dosage. In leprosy this complication may be difficult to distinguish from a leprosy reactional state.

Body As A Whole

In addition to the warnings and adverse effects reported above, additional adverse reactions include: nausea, vomiting, abdominal pains, pancreatitis, vertigo, blurred vision, tinnitus, insomnia, fever, headache, psychosis, phototoxicity, pulmonary eosinophilia, tachycardia, albuminuria, the nephrotic syndrome, hypoalbuminemia without proteinuria, renal papillary necrosis, male infertility, drug induced Lupus erythematosus and an infectious mononucleosis like syndrome. In general, with the exception of the complications of severe anoxia from overdosage (retinal and optic nerve damage, etc.) these adverse reactions have regressed off drug.

Overdosage

Nausea, vomiting, hyperexcitability can appear a few minutes up to 24 hours after ingestion of an overdosage. Methemoglobin induced depression, convulsions or severe cyanosis requires prompt treatment. In normal and methemoglobin reductase deficient patients, methylene blue, 1 to 2 mg/kg of body weight, given slowly intravenously, is the treatment of choice. The effect is complete in 30 minutes, but may have to be repeated if methemoglobin reaccumulates. For non-emergencies, if treatment is needed, methylene blue may be given orally in doses of 3 to 5 mg/kg every 4 to 6 hours. Methylene blue reduction depends on G6PD and should not be given to fully expressed G6PD deficient patients.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dapsone Dosage and Administration

Dermatitis herpetiformis

The dosage should be individually titrated starting in adults with 50 mg daily and correspondingly smaller doses in children. If full control is not achieved within the range of 50 to 300 mg daily, higher doses may be tried. Dosage should be reduced to a minimum maintenance level as soon as possible. In responsive patients there is a prompt reduction in pruritus followed by clearance of skin lesions. There is no effect on the gastrointestinal component of the disease. Dapsone levels are influenced by acetylation rates. Patients with high acetylation rates, or who are receiving treatment affecting acetylation may require an adjustment in dosage.

A strict gluten free diet is an option for the patient to elect, permitting many to reduce or eliminate the need for Dapsone; the average time for dosage reduction is 8 months with a range of 4 months to 2 ½ years and for dosage elimination 29 months with a range of 6 months to 9 years.

Leprosy

In order to reduce secondary Dapsone resistance, the WHO Expert Committee on Leprosy and the USPHS at Carville, LA, recommended that Dapsone should be commenced in combination with one or more anti-leprosy drugs. In the multidrug program Dapsone should be maintained at the full dosage of 100 mg daily without interruption (with corresponding smaller doses for children) and provided to all patients who have sensitive organisms with new or recrudescent disease or who have not yet completed a two year course of Dapsone monotherapy. For advice and other drugs, the USPHS at Carville, LA (1-800-642-2477) should be contacted. Before using other drugs consult appropriate product labeling.

In bacteriologically negative tuberculoid and indeterminate disease, the recommendation is the coadministration of Dapsone 100 mg daily with six months of Rifampin 600 mg daily. Under WHO, daily Rifampin may be replaced by 600 mg Rifampin monthly, if supervised. The Dapsone is continued until all signs of clinical activity are controlled - usually after an additional six months. Then Dapsone should be continued for an additional three years for tuberculoid and indeterminate patients and for five years for borderline tuberculoid patients.

In lepromatous and borderline lepromatous patients, the recommendation is the co-administration of Dapsone 100 mg daily with two years of Rifampin 600 mg daily. Under WHO daily Rifampin may be replaced by 600 mg Rifampin monthly, if supervised. One may elect the concurrent administration of a third anti-leprosy drug, usually either Clofazimine 50 to 100 mg daily or Ethionamide 250 to 500 mg daily. Dapsone 100 mg daily is continued 3 to 10 years until all signs of clinical activity are controlled with skin scrapings and biopsies are negative for one year. Dapsone should then be continued for an additional 10 years for borderline patients and for life for lepromatous patients.

Secondary Dapsone resistance should be suspected whenever a lepromatous or borderline lepromatous patient receiving Dapsone treatment relapses clinically and bacteriologically, solid staining bacilli being found in the smears taken from the new active lesions. If such cases show no response to regular and supervised Dapsone therapy within three to six months or good compliance for the past 3 to 6 months can be assured, Dapsone resistance should be considered confirmed clinically. Determination of drug sensitivity using the mouse footpad method is recommended and, after prior arrangement, is available without charge from the USPHS, Carville, LA. Patients with proven Dapsone resistance should be treated with other drugs.

LEPROSY REACTIONAL STATES

Abrupt changes in clinical activity occur in leprosy with any effective treatment and are known as reactional states. The majority can be classified into two groups. The "Reversal" reaction (Type 1) may occur in borderline or tuberculoid leprosy patients often soon after chemotherapy is started. The mechanism is presumed to result from a reduction in the antigenic load: the patient is able to mount an enhanced delayed hypersensitivity response to residual infection leading to swelling ("Reversal") of existing skin and nerve lesions. If severe, or if neuritis is present, large doses of steroids should always be used. If severe, the patient should be hospitalized. In general anti-leprosy treatment is continued and therapy to suppress the reaction is indicated such as analgesics, steroids, or surgical decompression of swollen nerve trunks. USPHS at Carville, LA should be contacted for advice in management.

Erythema nodosum leprosum (ENL) (lepromatous reaction) (Type 2 reaction) occurs mainly in lepromatous patients and small numbers of borderline patients. Approximately 50% of treated patients show this reaction in the first year. The principal clinical features are fever and tender erythematous skin nodules sometimes associated with malaise, neuritis, orchitis, albuminuria, joint swelling, iritis, epistaxis or depression. Skin lesions can become pustular and/or ulcerate. Histologically there is a vasculitis with an intense polymorphonuclear infiltrate. Elevated circulating immune complexes are considered to be the mechanism of reaction. If severe, patients should be hospitalized. In general, anti-leprosy treatment is continued. Analgesics, steroids, and other agents available from USPHS, Carville, LA, are used to suppress the reaction.

How is Dapsone Supplied

Dapsone Tablets USP, 25 mg are available as round white to off-white scored tablets, debossed "25" above and "102" below the score and on the obverse "NCP" in bottles of 90 tablets. NDC 42291-298-90.

Dapsone Tablets USP, 100 mg are available as round white to off-white scored tablets, debossed "100" above and "101" below the score and on the obverse "NCP" in bottles of 90 tablets. NDC 42291-299-90.

Store at 20°to 25° C (68°to 77°F). [see USP Controlled Room Temperature]. Protect from light.

Keep this and all medication out of the reach of children.

REFERENCES

1. Lee, B., et al., Zidovudine, Trimethoprim, and Dapsone Pharmacokinetic Interactions in Patients with HIV Infection. Antimicrobial Agents and Chemotherapy, May 1996; 1231-1236.

2. Lee, B., et al., Dapsone, Trimethoprim, and Sulfamethoxazole Plasma Levels During Treatment of Pneumocystis Carinii Pneumonia in Patients with AIDS, Annals of Internal Medicine, 1989; 110:606-611.

Rx only

Manufactured for:
AvKARE, Inc.
Pulaski, TN 38478

Mfg. Rev. 03/16
AV 05/17 (P)

PRINCIPAL DISPLAY PANEL - 25 mg Tablet Bottle Label

AvKARE   
NDC 42291-298-90
Dapsone Tablets, USP
25 mg
90 Tablets
Rx Only              

Each tablet contains:
25 mg Dapsone, USP.
Usual Dosage: Read accompanying literature.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.                      

Keep out of the reach of children.
Manufactured for:
AvKARE, Inc.
Pulaski, TN 38478

Mfg. Rev. 03/16
AV 05/17 (P)

N3 4229129890 3

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label

AvKARE
NDC 42291-299-90
Dapsone Tablets, USP
100 mg
90 Tablets
Rx Only
                 

Each tablet contains:
100 mg Dapsone, USP
Usual Dosage: Read accompanying literature.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.

Keep out of the reach of children.
Manufactured for:
AvKARE, Inc.
Pulaski, TN 38478

Mfg. Rev. 03/16
AV 05/17 (P)

N3 4229129990 0

Revised: 05/2017