Dapsone

INDICATIONS AND USAGE Dermatitis herpetiformis: (D.H.) Leprosy: All forms of leprosy except for cases of proven Dapsone resistance.

Mfd. by: Taro Pharmaceutical Industries, Ltd. Haifa Bay, Israel 2624761 Dist. by: Taro Pharmaceuticals U.S.A., Inc. Hawthorne, NY 10532 Revised: December 2018 20991-1218-2

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 1⁄2 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 …

CONTRAINDICATIONS Hypersensitivity to Dapsone and/or its derivatives.

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 of 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. Falsely Reduced HbA1c : Falsely reduced HbA1c measurements have been reported with dapsone use. Alternate measures of glycemic control (e.g., fructosamine and/or more frequent blood glucose monitoring) are recommended when a discordance between HbA1c and blood glucose concentrations are observed or suspected. Falsely reduced HbA1c may occur without overt evidence of hemolysis or anemia. 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. To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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, the 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 study 1 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/mm 3 ) demonstrated that there was not a significant drug intreraction between Dapsone and trimethoprim. However, an earlier report 2 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.

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.

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 or creamy white crystalline powder, insoluble in water, sparingly soluble in alcohol, freely soluble in acetone and in dilute mineral acids. Dapsone is issued on prescription in tablets of 25 mg and 100 mg for oral use. Each dapsone tablet, USP contains 25 mg and 100 mg of dapsone and contains following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose. FDA approved dissolution test specifications differ from USP. dapsone Structure

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 mg/kg 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 mg/kg to 5 mg/kg every 4 hours to 6 hours. Methylene blue reduction depends on G6PD and should not be given to fully expressed G6PD deficient patients.

HOW SUPPLIED Dapsone Tablets USP, 25 mg are available as white, round tablet. One side scored and engraved with "DAP" above and "25" below the score and the other side is plain in a Unit of Use carton of 30 tablets (2 × 15). The blisters are light and child-resistant. NDC 51672-4197-2. Dapsone Tablets USP, 25 mg are available as white, round tablet. One side scored and engraved with "DAP" above and "25" below the score and the other side is plain in a light and child resistant bottle of 30 tablets. NDC 51672-4197-6. Dapsone Tablets USP, 100 mg are available as white, round tablet. One side scored and engraved with "DAP" above and "100" below the score and the other side is plain in a Unit of Use carton of 30 tablets (2 × 15). The blisters are light and child-resistant. NDC 51672-4198-2. Dapsone Tablets USP, 100 mg are available as white, round tablet. One side scored and engraved with "DAP" above and "100" below the score and the other side is plain in a light and child-resistant bottle of 30 tablets. NDC 51672-4198-6. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Keep this and all drugs out of the reach of children.