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ALVOGEN INC
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47781033331

dapsone 25 mg tablet

Generic
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Uses

Leprosy

Dapsone is used in conjunction with other anti-infectives in multidrug therapy (MDT) for treatment of multibacillary and paucibacillary leprosy (Hansen's disease).

Dapsone was used alone for treatment of leprosy until the early 1980s; however, because the drug is slow acting and only weakly bactericidal against Mycobacterium leprae, prolonged or life-long dapsone monotherapy was necessary and led to poor patient compliance and emergence of dapsone-resistant strains. The World Health Organization (WHO) and US National Hansen's Disease Program (NHDP) recommend that MDT regimens that also include rifampin be used for the treatment of all forms of leprosy. MDT can rapidly kill M. leprae, render patients noninfectious after only a few days of treatment, delay or prevent emergence of resistant M. leprae, and reduce the risk of relapse after treatment is discontinued. MDT does not enhance the rate of clearance of dead M. leprae from the body; such clearance may take years and depends largely on the individual's immune response, which may be defective in leprosy patients. Reactive episodes reported in leprosy patients receiving treatment appear to be due to destruction of the bacilli and immune responses to released bacterial antigens.(See Cautions: Leprosy Reactional States.) MDT regimens recommended by NHDP for US patients differ from those recommended by WHO.

For treatment of multibacillary leprosy (i.e., 6 or more lesions or skin smear positive) in adults, WHO recommends a 12-month MDT regimen of dapsone (once daily), rifampin (once monthly), and clofazimine (once daily and once monthly). For treatment of paucibacillary leprosy (i.e., 1-5 lesions) in adults, WHO recommends a 6-month MDT regimen of dapsone (once daily) and rifampin (once monthly). Because of reports of relapse of leprosy in patients who were treated with dapsone monotherapy (''burnt-out cases''), WHO states that patients who previously received only dapsone should be retreated with a currently recommended MDT regimen, even if the disease appears bacteriologically and clinically inactive. Since 1995, WHO has provided MDT regimens at no cost for treatment of leprosy. Although there are some countries where leprosy is still highly endemic, most countries where leprosy was previously highly endemic have achieved elimination of the disease at the national level and are intensifying efforts at regional and district levels.

For US patients, NHDP recommends more prolonged treatment. NHDP recommends that adults with multibacillary leprosy (i.e., those who are skin smear positive and/or have a biopsy indicating more advanced disease) receive a 24-month MDT regimen of dapsone (once daily), rifampin (once daily), and clofazimine (once daily), and that adults with paucibacillary leprosy (i.e., those who are skin smear negative without evidence of more advanced disease on biopsy) receive a 12-month MDT regimen of dapsone (once daily) and rifampin (once daily). Clofazimine is no longer commercially available in the US, but may be obtained from NHDP under an investigational new drug (IND) protocol for treatment of leprosy. NHDP can provide MDT regimens at no cost for treatment of US leprosy patients. Data indicate that leprosy is rare in the US (total of approximately 6500 living patients, about 3300 requiring active medical management), although about 150-200 new cases are reported each year.

Treatment of leprosy is complicated and should be undertaken in consultation with a specialist familiar with the disease. In the US, clinicians should contact NHDP at 800-642-2477 on weekdays from 9:00 a.m. to 5:30 p.m. Eastern Standard Time or via email at nhdped@hrsa.gov for assistance with diagnosis or treatment of leprosy or assistance obtaining clofazimine for treatment of leprosy.

Dermatitis Herpetiformis

Dapsone is used for treatment of dermatitis herpetiformis. A gluten-free diet is recommended for all patients with dermatitis herpetiformis, and strict adherence to such a diet can result in slow resolution of skin lesions (may take months to years) and improvement in GI symptoms. Dapsone is used as an adjunct to a gluten-free diet; in responsive patients, initiation of the drug usually results in a prompt decrease in pruritus and resolution of dermatitis herpetiformis skin lesions. Dapsone alone has no effect on the GI component of dermatitis herpetiformis. After several months when skin manifestations have responded to dapsone, some patients who adhere to a strict gluten-free diet may be able to decrease dosage or discontinue the drug; dapsone may then be reinitiated for brief periods as needed to control flares.

Pneumocystis jirovecii Pneumonia

Dapsone is used as an alternative for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) and prevention of P. jirovecii infections. Dapsone is designated an orphan drug by the US Food and Drug Administration (FDA) for treatment and prevention of PCP.

Treatment of Pneumocystis jirovecii Pneumonia

Dapsone is used in conjunction with trimethoprim as an alternative for treatment of mild to moderate PCP, including mild to moderate PCP in adults, adolescents, and children with human immunodeficiency virus (HIV) infection.

Co-trimoxazole is the drug of choice for treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.

The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that alternative regimens for treatment of mild to moderate PCP in HIV-infected adults and adolescents are dapsone in conjunction with trimethoprim, primaquine in conjunction with clindamycin, or atovaquone alone. These experts state that dapsone in conjunction with trimethoprim may be as effective as co-trimoxazole for treatment of mild to moderate PCP and has fewer adverse effects, but is less convenient because of higher pill burden. Although efficacy and safety data are limited regarding use of dapsone in conjunction with trimethoprim for treatment of PCP in children, some clinicians also recommend the regimen as an alternative for treatment of mild to moderate PCP in children when co-trimoxazole cannot be used. The dapsone and trimethoprim regimen is not included in CDC, NIH, IDSA, and AAP recommendations for treatment of severe PCP.

There is evidence that a combination regimen of dapsone (100 mg once daily) and trimethoprim (20 mg/kg daily in 4 divided doses) given for 21 days is effective for treatment of initial episodes of mild to moderate PCP in patients with acquired immunodeficiency syndrome (AIDS), achieving a clinical response in 93% of patients in one study. Most patients exhibited clinical improvement within 6 days, and the regimen generally was well tolerated. Dapsone alone appears to be less effective than co-trimoxazole or the combination regimen of dapsone and trimethoprim for treatment of initial episodes of PCP in patients with AIDS.

Prevention of Pneumocystis jirovecii Infections

Dapsone is used alone or in conjunction with pyrimethamine (and leucovorin) as an alternative for prevention of P. jirovecii infections in HIV-infected adults, adolescents, and children who cannot tolerate co-trimoxazole.

Prevention of Initial Episode (Primary Prophylaxis)

CDC, NIH, and IDSA recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected adults and adolescents with CD4 T-cell counts less than 200/mm or a history of oropharyngeal candidiasis. These experts state that primary PCP prophylaxis should be considered in HIV-infected adults and adolescents with CD4 T-cell percentages less than 14% or a history of an AIDS-defining illness who would not otherwise qualify for prophylaxis and also should be considered in those with CD4 T-cell counts greater than 200 but less than 250/mm if frequent monitoring of CD4 T-cell counts (e.g., every 3 months) is not possible.

CDC, NIH, and IDSA state that primary PCP prophylaxis should be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4 T-cell counts that have remained greater than 200/mm for longer than 3 months. Discontinuance of primary PCP prophylaxis is recommended in these individuals since it appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, cost, and potential for drug toxicity, drug interactions, and selection of drug-resistant pathogens. Primary PCP prophylaxis should be reinitiated if CD4 T-cell counts decrease to less than 200/mm.

Co-trimoxazole is the drug of choice for primary PCP prophylaxis in HIV-infected adults and adolescents. CDC, NIH, and IDSA recommend that co-trimoxazole prophylaxis be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole prophylaxis should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.

Alternative regimens recommended by CDC, NIH, and IDSA for primary PCP prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole are dapsone alone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, atovaquone alone, or atovaquone in conjunction with pyrimethamine (and leucovorin). In HIV-infected adults or adolescents who cannot tolerate co-trimoxazole and are seropositive for Toxoplasma gondii, dapsone with pyrimethamine (and leucovorin), atovaquone alone, or atovaquone with pyrimethamine (and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.

Prevention of Recurrence (Secondary Prophylaxis)

CDC, NIH, and IDSA recommend that HIV-infected adults and adolescents who have a history of PCP receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence.

Secondary PCP prophylaxis generally is administered for life, unless immune recovery occurs as a result of antiretroviral therapy. CDC, NIH, and IDSA state that secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4 T-cell counts that have remained greater than 200/mm for longer than 3 months, but should be reinitiated if CD4 T-cell counts decrease to less than 200/mm. In addition, these experts state that it may be prudent to continue secondary PCP prophylaxis for life (regardless of CD4 T-cell count) if PCP occurred or recurred when CD4 T-cell counts were greater than 200/mm.

Co-trimoxazole is the drug of choice for secondary PCP prophylaxis in HIV-infected adults and adolescents. CDC, NIH, and IDSA recommend that co-trimoxazole prophylaxis be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole prophylaxis should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.

Alternative regimens recommended by CDC, NIH, and IDSA for secondary PCP prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole are the same as those recommended for primary prophylaxis and include dapsone alone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, atovaquone alone, or atovaquone in conjunction with pyrimethamine (and leucovorin). In HIV-infected adults or adolescents who cannot tolerate co-trimoxazole and are seropositive for T. gondii, dapsone with pyrimethamine (and leucovorin), atovaquone alone, or atovaquone with pyrimethamine (and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.

Primary and Secondary Prophylaxis in Children

CDC, NIH, IDSA, and American Academy of Pediatrics (AAP) recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected children 1 to less than 6 years of age with CD4 T-cell counts less than 500/mm or CD4 T-cell percentages less than 15% and in HIV-infected children 6-12 years of age with CD4 T-cell counts less than 200/mm or CD4 T-cell percentages less than 15%. These experts recommend that all HIV-infected infants younger than 1 year of age (regardless of CD4 T-cell count or percentage) receive primary PCP prophylaxis. In addition, infants born to HIV-infected mothers should be considered for primary PCP prophylaxis beginning at 4-6 weeks of age and those with indeterminate HIV status should continue to receive prophylaxis until they are determined to be non-HIV-infected or presumptively non-HIV-infected. Those found to be HIV-infected should receive primary PCP prophylaxis throughout the first year of life; at 1 year of age, the need for continued PCP prophylaxis should be reassessed based on age-specific CD4 T-cell thresholds.

HIV-infected children who have a history of PCP should receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence.

CDC, NIH, IDSA, and AAP state that, in HIV-infected children who have received at least 6 months of antiretroviral therapy, discontinuance of primary or secondary PCP prophylaxis should be considered in those 1 to less than 6 years of age if CD4 T-cell counts have remained at 500/mm or greater or CD4 T-cell percentages have remained at 15% or greater for more than 3 consecutive months and in those 6-12 years of age if CD4 T-cell counts have remained at 200/mm or greater or CD4 T-cell percentages have remained at 15% or greater for more than 3 consecutive months. If primary or secondary PCP prophylaxis is discontinued in HIV-infected children, CD4 T-cell counts and CD4 T-cell percentages should be assessed every 3 months and PCP prophylaxis reinitiated if indicated based on age-specific CD4 T-cell thresholds.

Co-trimoxazole is the drug of choice for primary and secondary PCP prophylaxis in HIV-infected infants and children. CDC, NIH, IDSA, and AAP recommend that co-trimoxazole be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.

Alternative regimens recommended by CDC, NIH, IDSA, and AAP for primary and secondary PCP prophylaxis in HIV-infected infants and children who cannot tolerate co-trimoxazole are dapsone (1 month of age or older), atovaquone (1 month of age or older), or aerosolized pentamidine (5 years of age or older).

Toxoplasmosis

Dapsone is used in conjunction with pyrimethamine (and leucovorin) as an alternative for primary prophylaxis to prevent initial episodes of toxoplasmosis caused by Toxoplasma gondii in HIV-infected adults, adolescents, and children. Dapsone is designated an orphan drug by FDA for toxoplasmosis prophylaxis in severely immunocompromised individuals with CD4 T-cell counts less than 100/ mm.

Dapsone is not included in CDC, NIH, IDSA, and AAP recommendations for treatment of toxoplasmosis in HIV-infected individuals or for chronic maintenance therapy to prevent relapse of toxoplasmosis (secondary prophylaxis) in HIV-infected individuals.

Prevention of Toxoplasmosis

Prevention of Initial Episode (Primary Prophylaxis)

CDC, NIH, and IDSA recommend primary prophylaxis against T. gondii encephalitis in HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and have CD4 T-cell counts less than 100/mm.

CDC, NIH, and IDSA state that primary toxoplasmosis prophylaxis should be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4 T-cell counts that have remained greater than 200/mm for longer than 3 months. Discontinuance of primary toxoplasmosis prophylaxis is recommended in these individuals since it appears to add little benefit in terms of toxoplasmosis disease prevention and discontinuance reduces the medication burden, cost, and potential for toxicity, drug interactions, and selection of drug-resistant pathogens. Primary toxoplasmosis prophylaxis should be reinitiated in HIV-infected adults and adolescents if CD4 T-cell counts decrease to less than 100-200/mm.

Co-trimoxazole is the drug of choice for primary toxoplasmosis prophylaxis in HIV-infected adults and adolescents. Dapsone in conjunction with pyrimethamine (and leucovorin) is the preferred alternative for such prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole. CDC, NIH, and IDSA state that other alternatives for primary toxoplasmosis prophylaxis in those who cannot tolerate co-trimoxazole are atovaquone alone or atovaquone in conjunction with pyrimethamine (and leucovorin).

Primary Prophylaxis in Children

Although specific levels of immunosuppression that increase the risk for T. gondii encephalitis in HIV-infected children are less well defined than those for HIV-infected adults and adolescents, CDC, NIH, IDSA, and AAP recommend primary prophylaxis against T. gondii encephalitis in toxoplasma-seropositive HIV-infected children younger than 6 years of age who have CD4 T-cell percentages less than 15% and in toxoplasma-seropositive HIV-infected children 6 years of age or older who have CD4 T-cell counts less than 100/mm.

The safety of discontinuing primary toxoplasmosis prophylaxis in HIV-infected children whose immunologic status improves in response to antiretroviral therapy has not been extensively studied. CDC, NIH, IDSA, and AAP state that primary toxoplasmosis prophylaxis should not be discontinued in HIV-infected children younger than 1 year of age. However, based on data from adults, these experts state that discontinuance of primary toxoplasmosis prophylaxis can be considered in HIV-infected children 1 to less than 6 years of age who have received at least 6 months of antiretroviral therapy and have CD4 T-cell percentages that have remained at 15% or greater for longer than 3 months. In HIV-infected children 6 years of age or older who have received at least 6 months of antiretroviral therapy, primary toxoplasmosis prophylaxis can be discontinued if CD4 T-cell counts have remained greater than 200/mm for longer than 3 months. Primary toxoplasmosis prophylaxis should be reinitiated if CD4 T-cell percentages decrease to less than 15% in HIV-infected children younger than 6 years of age or if CD4 T-cell counts decrease to less than 100-200/mm in HIV-infected children 6 years of age or older.

For primary toxoplasmosis prophylaxis in HIV-infected infants and children, the drug of choice is co-trimoxazole. Dapsone in conjunction with pyrimethamine (and leucovorin) is the preferred alternative for such prophylaxis in those 1 month of age or older who cannot tolerate co-trimoxazole. CDC, NIH, IDSA, and AAP state that atovaquone alone is another alternative for primary toxoplasmosis prophylaxis in HIV-infected children and adolescents 1 month of age or older; those 4-24 months of age can receive atovaquone alone or in conjunction with pyrimethamine (and leucovorin).

Dosage and Administration

Administration

Dapsone is administered orally.

For administration to children, commercially available tablets of dapsone have been crushed and dissolved in strawberry syrup; however, studies evaluating bioavailability of the drug following administration of this preparation have not been published to date.

Dosage

Leprosy

Treatment of Multibacillary Leprosy

For treatment of multibacillary leprosy, the World Health Organization (WHO) recommends that adults receive dapsone in a dosage of 100 mg once daily in conjunction with rifampin (600 mg once monthly) and clofazimine (50 mg once daily and 300 mg once monthly) given for 12 months. WHO recommends that children 10-14 years of age with multibacillary leprosy receive dapsone in a dosage of 50 mg once daily in conjunction with rifampin (450 mg once monthly) and clofazimine (50 mg once every other day and 150 mg once monthly) given for 12 months. Children younger than 10 years of age should receive a 12-month regimen using appropriately adjusted dosage based on weight (e.g., dapsone 2 mg/kg once daily in conjunction with rifampin [10 mg/kg once monthly] and clofazimine [1 mg/kg once every other day]).

For US patients, the National Hansen's Disease Program (NHDP) recommends that adults with multibacillary leprosy receive dapsone in a dosage of 100 mg once daily in conjunction with rifampin (600 mg once daily) and clofazimine (50 mg once daily) given for 24 months. These experts recommend that children with multibacillary leprosy receive dapsone in a dosage of 1 mg/kg once daily in conjunction with rifampin (10-20 mg/kg [up to 600 mg] once daily) and clofazimine (1 mg/kg once daily or 2 mg/kg once every other day) given for 24 months.

Treatment of Paucibacillary Leprosy

For treatment of paucibacillary leprosy, WHO recommends that adults receive dapsone in a dosage of 100 mg once daily in conjunction with rifampin (600 mg once monthly) given for 6 months. WHO recommends that children 10-14 years of age with paucibacillary leprosy receive dapsone in a dosage of 50 mg once daily in conjunction with rifampin (450 mg once monthly) given for 6 months. Children younger than 10 years of age should receive a 6-month regimen using appropriately adjusted dosage based on weight (e.g., dapsone 2 mg/kg once daily in conjunction with rifampin [10 mg/kg once monthly]).

For US patients, NHDP recommends that adults with paucibacillary leprosy receive dapsone in a dosage of 100 mg once daily in conjunction with rifampin (600 mg once daily) given for 12 months. These experts recommend that children with paucibacillary leprosy receive dapsone in a dosage of 1 mg/kg once daily in conjunction with rifampin (10-20 mg/kg [up to 600 mg] once daily) given for 12 months.

Dermatitis Herpetiformis

For treatment of dermatitis herpetiformis, dapsone dosage should be individually titrated to find the daily dosage that most effectively controls pruritus and lesions; daily dosage should then be reduced to a minimum maintenance dosage as soon as possible.

The manufacturer recommends that adults receive an initial dapsone dosage of 50 mg daily for treatment of dermatitis herpetiformis and, if full control is not achieved within the range of 50-300 mg daily, higher dosage may be tried. For treatment of dermatitis herpetiformis in children, the manufacturer recommends correspondingly smaller doses of dapsone.

Some clinicians state that dapsone dosages of 25-100 mg daily usually control symptoms of dermatitis herpetiformis.

Occasional new lesions (3 or 4 per week) may occur during dapsone maintenance therapy and are not generally an indication to alter maintenance dosage of the drug. Maintenance dosage of dapsone often can be reduced or the drug discontinued after several months in patients who adhere to a gluten-free diet. The manufacturer states that the average time for dapsone dosage reduction is 8 months (range 4 months to 2.5 years) and the average time before discontinuance of the drug is 29 months (range 6 months to 9 years).

Pneumocystis jirovecii Pneumonia

Treatment of Pneumocystis jirovecii Pneumonia

When used as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) in adults and adolescents 13 years of age or older, including those with human immunodeficiency virus (HIV) infection, dapsone is given in a dosage of 100 mg once daily for 21 days in conjunction with oral trimethoprim (5 mg/kg 3 times daily for 21 days).

Although efficacy and safety data are limited in children, some clinicians state that dapsone may be given in a dosage of 2 mg/kg (up to 100 mg) once daily for 21 days in conjunction with oral trimethoprim (5 mg/kg 3 times daily for 21 days) as an alternative for treatment of mild to moderate PCP in children younger than 13 years of age.

Prevention of Initial Episode (Primary Prophylaxis)

When dapsone monotherapy is used as an alternative for prevention of initial episodes (primary prophylaxis) of PCP in adults and adolescents 13 years of age or older, including HIV-infected individuals, the usual dosage is 100 mg once daily or 50 mg twice daily. Alternatively, dapsone can be given in a dosage of 50 mg once daily in conjunction with oral pyrimethamine (50 mg once weekly) and oral leucovorin (25 mg once weekly) or, alternatively, in a dosage of 200 mg once weekly in conjunction with oral pyrimethamine (75 mg once weekly) and oral leucovorin (25 mg once weekly). The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that primary PCP prophylaxis should be discontinued in HIV-infected adults and adolescents if CD4 T-cell counts have remained greater than 200/mm for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4 T-cell counts decrease to less than 200/mm.(See Prevention of Initial Episode [Primary Prophylaxis] under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)

When dapsone monotherapy is used as an alternative for primary PCP prophylaxis in HIV-infected children and infants 1 month of age or older, CDC, NIH, IDSA, American Academy of Pediatrics (AAP), and others recommend a dosage of 2 mg/kg (up to 100 mg) once daily or 4 mg/kg (up to 200 mg) once weekly. In HIV-infected children 1 year of age or older who have received at least 6 months of antiretroviral therapy, CDC, NIH, IDSA, and AAP state that discontinuance of primary PCP prophylaxis should be considered based on age-related CD4 T-cell counts or CD4 T-cell percentages, but should be reinitiated if these parameters decrease below the age-related thresholds.(See Primary and Secondary Prophylaxis in Children under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)

Prevention of Recurrence (Secondary Prophylaxis)

When dapsone monotherapy is used as an alternative for prevention of recurrence (secondary prophylaxis) of PCP in adults and adolescents 13 years of age or older, including HIV-infected individuals, the usual dosage is 100 mg once daily or 50 mg twice daily. Alternatively, dapsone can be given in a dosage of 50 mg once daily in conjunction with oral pyrimethamine (50 mg once weekly) and oral leucovorin (25 mg once weekly) or, alternatively, in a dosage of 200 mg once weekly in conjunction with oral pyrimethamine (75 mg once weekly) and oral leucovorin (25 mg once weekly). CDC, NIH, and IDSA state that secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents if CD4 T-cell counts have remained greater than 200/mm for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4 T-cell counts decrease to less than 200/mm. However, secondary prophylaxis probably should be continued for life (regardless of CD4 T-cell count) if PCP occurred or recurred when CD4 T-cell counts were greater than 200/mm.(See Prevention of Recurrence [Secondary Prophylaxis] under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)

When dapsone monotherapy is used as an alternative for secondary prophylaxis of PCP in HIV-infected children and infants 1 month of age or older, CDC, NIH, IDSA, AAP, and others recommend a dosage of 2 mg/kg (up to 100 mg) once daily or 4 mg/kg (up to 200 mg) once weekly. In HIV-infected children 1 year of age or older who have received at least 6 months of antiretroviral therapy, CDC, NIH, IDSA, and AAP state that discontinuance of secondary PCP prophylaxis should be considered based on age-related CD4 T-cell counts or CD4 T-cell percentages, but should be reinitiated if these parameters decrease below the age-related thresholds.(See Primary and Secondary Prophylaxis in Children under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)

Toxoplasmosis

Prevention of Initial Episode (Primary Prophylaxis)

When used as an alternative for primary prophylaxis of toxoplasmosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend that dapsone be given in a dosage of 50 mg once daily in conjunction with pyrimethamine (50 mg once weekly) and oral leucovorin (25 mg once weekly). Alternatively, HIV-infected adults and adolescents can receive a dapsone dosage of 200 mg once weekly in conjunction with pyrimethamine (75 mg once weekly) and oral leucovorin (25 mg once weekly).

When used as an alternative for primary prophylaxis of toxoplasmosis in HIV-infected children and infants 1 month of age or older, CDC, NIH, IDSA, and AAP recommend a dapsone dosage of 2 mg/kg or 15 mg/m (up to 25 mg) once daily in conjunction with pyrimethamine (1 mg/kg [up to 25 mg] once daily) and oral leucovorin (5 mg once every 3 days).

CDC, NIH, and IDSA state that primary prophylaxis against toxoplasmosis should be discontinued in HIV-infected adults and adolescents who have CD4 T-cell counts that have remained greater than 200/mm for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4 T-cell counts decrease to less than 100-200/mm. The safety of discontinuing primary prophylaxis against toxoplasmosis in HIV-infected children whose immunologic status improves in response to antiretroviral therapy has not been extensively studied.(See Prevention of Toxoplasmosis under Uses: Toxoplasmosis.)

Cautions

Hematologic Effects

The most frequent adverse effects of dapsone are dose-related hemolytic anemia and methemoglobinemia. Hemolysis occurs in most patients receiving 200 mg or more of dapsone daily; however, symptomatic anemia occurs only occasionally. The manufacturer states that the hemoglobin level is generally decreased by 1-2 g/dL, the reticulocyte count is increased 2-12%, erythrocyte life span is shortened, and methemoglobinemia occurs in most patients receiving dapsone. Heinz body formation also occurs frequently. Unless severe, hemolysis or methemoglobinemia does not generally require discontinuance of dapsone therapy. These adverse hematologic effects occur in patients with or without glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, but are most severe in patients with G-6-PD deficiency. Hemolysis and Heinz body formation may be exaggerated in patients with G-6-PD deficiency, methemoglobin reductase deficiency, or hemoglobin M. Hemolysis and methemoglobinemia may be poorly tolerated by patients with severe cardiopulmonary disease. In addition, dapsone-induced adverse hematologic effects may be poorly tolerated by some patients with acquired immunodeficiency syndrome (AIDS) receiving the drug for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia, since such patients may have preexisting anemia and/or hypoxemia. Generally, however, dapsone is well tolerated in AIDS patients, although asymptomatic methemoglobinemia has been reported in two-thirds of such patients receiving 100 mg of dapsone daily concomitantly with trimethoprim 20 mg/kg daily.(See Drug Interactions: Trimethoprim.) Methemoglobinemia has been reported substantially less frequently in AIDS patients receiving dapsone alone.

Cyanosis, which is usually associated with mild methemoglobinemia, may occur during dapsone therapy. Acute methemoglobinemia occurs rarely, but may result in anemia, vascular collapse, and death. Unless the patient has G-6-PD deficiency, acute methemoglobinemia should be treated with IV methylene blue. (See Acute Toxicity: Treatment.) Prophylactic administration of ascorbic acid, folate, and iron reportedly may prevent some of the adverse hematologic effects of dapsone.

Leukopenia has been reported occasionally during therapy with dapsone, and potentially fatal agranulocytosis and aplastic anemia have been reported rarely.

Leprosy Reactional States

Effective treatment of leprosy with dapsone or other antileprosy agents generally results in abrupt changes in the clinical and immune status of the patient and many patients have reactive episodes (reactions) that may be mild to severe. Leprosy reactive episodes can occur before, during, or after treatment is completed and apparently result from destruction of Mycobacterium leprae and immune responses to released bacterial antigens. Reactive episodes are classified into 2 main types: reversal reactions (type 1) and erythema nodosum leprosum (ENL) reactions (type 2). Other reactions (e.g., neuritis or silent neuropathies, iridocyclitis, orchitis) also can occur independently of reactive episodes.

Reversal reactions (type 1) occur mainly in borderline tuberculoid, mid-borderline, and borderline lepromatous leprosy patients. Reversal reactions are usually evidenced by edema and erythema of pre-existing lesions. These reactions presumably occur because the patient is able to mount an enhanced delayed hypersensitivity response to the residual infection and this leads to swelling (reversal) of existing skin and nerve lesions. Existing lesions become erythematous and edematous and may ulcerate; fever and an increased leukocyte count frequently occur, and acute neuritis and loss of nerve function may develop.

ENL reactions (type 2) are recurrent immunologically mediated reactions that occur principally in patients with multibacillary leprosy (borderline lepromatous and lepromatous leprosy). While ENL reactions have been reported to occur in 10-50% of lepromatous leprosy patients and 25-30% of borderline lepromatous patients, these reactions have been reported less frequently in patients receiving currently recommended multidrug therapy (MDT) regimens that include clofazimine than in patients who received dapsone monotherapy. ENL reactions usually manifest with fever and painful erythematous nodules, but peripheral neuritis, orchitis, lymphadenitis, iridocyclitis, nephritis, periostitis, arthralgia, malaise, albuminuria, epistaxis, or depression may also occur. These reactions are considered to be a manifestation of the disease rather than an adverse reaction to antileprosy regimens.

Treatment of leprosy reactional states depends on the severity of manifestations; severe reactions may require hospitalization. In general, the usual antileprosy regimen is continued despite the occurrence of a leprosy reactional state and, if nerve injury or skin ulceration is threatened, corticosteroids are administered.

Reversal reactions that include neuritis or ulceration always require treatment with corticosteroids (e.g., prednisone 1 mg/kg daily); although only a short course of corticosteroid treatment may be needed if the patient has only minimally active disease and no neuritis, prolonged treatment (4-6 months) may be required in those with neuritis. Mild ENL reactions may require no treatment or only symptomatic measures (e.g., analgesics); treatment with corticosteroids generally is effective and is always indicated in those with acute neuritis since this may prevent permanent nerve injury. Thalidomide and clofazimine also are effective for treatment of ENL reactions. For additional information on treatment on ENL, and .

Early diagnosis and treatment of leprosy reactional states is important since these reactions are associated with considerable morbidity, especially if chronic, recurrent ENL occurs.

Therapy for leprosy and leprosy reactional states should be undertaken in consultation with an expert in the treatment of leprosy. In the US, clinicians should contact the National Hansen's Disease Program (NHDP) at 800-642-2477 on weekdays from 9:00 a.m. to 5:30 p.m. Eastern Standard Time or via email at nhdped@hrsa.gov for information on management of leprosy reactional states.

Dermatologic Reactions

Adverse cutaneous effects, which usually result from sensitization to dapsone, occur rarely during therapy with the drug. Cutaneous reactions include exfoliative dermatitis, toxic erythema, erythema multiforme, toxic epidermal necrolysis, morbilliform and scarlatiniform eruptions, urticaria, and erythema nodosum. If a new or toxic dermatologic reaction occurs during therapy with dapsone, the drug should be discontinued and appropriate therapy initiated. Rash reportedly occurs in about 30-40% of AIDS patients receiving dapsone concomitantly with trimethoprim, but less frequently in those receiving dapsone alone.

Nervous System Effects

Peripheral neuropathy with motor loss has been reported rarely in patients receiving high dosage of dapsone (200-500 mg daily). If muscle weakness occurs during therapy with dapsone, the drug should be discontinued; complete recovery may occur if the drug is withdrawn, but may take many months to several years. The mechanism of recovery is reportedly by axonal regeneration, and some recovered patients have tolerated retreatment with dapsone using a lower dosage of the drug. Although peripheral neuropathy has not been reported to date in patients with leprosy receiving dapsone, presumably because lower dosage is used, this adverse effect may be difficult to distinguish from a leprosy reactional state.

Insomnia, headache, nervousness, vertigo, and psychosis have also been reported with dapsone.

GI Effects

Adverse GI effects including anorexia, abdominal pain, nausea, and vomiting have occurred in patients receiving dapsone.

Hepatic Effects

Toxic hepatitis and cholestatic jaundice have been reported with dapsone. Cholestatic jaundice may be a hypersensitivity reaction, and generally appears to be reversible following discontinuance of the drug. Adverse hepatic effects have occurred shortly after initiation of dapsone therapy and may be manifested by increased serum concentrations of alkaline phosphatase, AST, bilirubin, and LDH. Liver function test abnormalities reportedly occur more frequently during combined dapsone and trimethoprim therapy than during dapsone alone. Hyperbilirubinemia has also occurred during dapsone therapy and may occur more often in patients with G-6-PD deficiency.

Renal and Electrolyte Effects

Albuminuria, nephrotic syndrome, and renal papillary necrosis have occurred rarely during dapsone therapy. Mild, generally asymptomatic hyperkalemia has been reported frequently in patients receiving combined dapsone and trimethoprim therapy, but serum potassium concentrations generally returned to normal during continued therapy.

Other Adverse Effects

Blurred vision, tinnitus, fever, phototoxicity, hyperpigmented macules, hypoalbuminemia without proteinuria, drug-induced lupus erythematosus, and an infectious mononucleosis-like syndrome have been reported with dapsone. Tachycardia has also occurred with dapsone, particularly with excessive dosage of the drug.

Precautions and Contraindications

Dapsone is contraindicated in patients who are hypersensitive to the drug or dapsone derivatives.

Dapsone should not be administered to patients with severe anemia; the anemia should be treated prior to initiation of dapsone therapy. Dapsone should be used with caution in patients with G-6-PD deficiency, methemoglobin reductase deficiency, or hemoglobin M. Dapsone should also be used with caution in patients who are exposed to other drugs or agents that are capable of inducing hemolysis (see Drug Interactions) and in patients with conditions associated with hemolysis (e.g., certain infections, diabetic ketosis). Some clinicians recommend that screening for G-6-PD deficiency be performed prior to initiating dapsone therapy in human immunodeficiency virus (HIV)-infected patients, and that hemoglobin and methemoglobin concentrations and hematocrit be monitored periodically in such patients, particularly those receiving the drug concomitantly with trimethoprim.(See Drug Interactions: Trimethoprim.)

Complete blood cell counts (CBCs) should be performed frequently during dapsone therapy. Some clinicians recommend that CBCs be performed weekly during the first month of therapy, monthly for the next 6 months, and every 6 months thereafter. If a substantial reduction in leukocytes, platelets, or hematopoiesis is evident, dapsone should be discontinued and the patient closely monitored.

Because toxic hepatitis and cholestatic jaundice have been reported with dapsone, liver function should be monitored, when feasible, before and during therapy with the drug. If any abnormality in liver function is evident, the drug should be discontinued until the source of the abnormality is established. Patients should be instructed to report to their clinician the presence of sore throat, fever, pallor, purpura, or jaundice during dapsone therapy.

Leprosy patients should be informed about the signs and symptoms of neuritis and cautioned about the importance of immediately reporting such signs and symptoms to a clinician.(See Cautions: Leprosy Reactional States.)

Pediatric Precautions

Dapsone is labeled for treatment of leprosy and for treatment of dermatitis herpetiformis in children. The drug is generally considered to have no effect on growth, development, and functional development of children.

Although data are limited regarding efficacy and safety in children, some experts recommend a regimen of dapsone in conjunction with trimethoprim as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) in children and recommend dapsone monotherapy as an alternative for primary and secondary prophylaxis of PCP in HIV-infected children 1 month of age or older(see Uses: Pneumocystis jirovecii Pneumonia). In addition, dapsone in conjunction with pyrimethamine (and leucovorin) is recommended as an alternative for primary prophylaxis of toxoplasmosis in HIV-infected children 1 month of age or older(see Uses: Toxoplasmosis).

Mutagenicity and Carcinogenicity

Dapsone was not mutagenic in microbial tests using Salmonella typhimurium, with or without microsomal activation.

Dapsone has been found to be carcinogenic in animal studies. The drug has caused mesenchymal tumors in the spleen and peritoneum of male rats and female mice and thyroid carcinoma in female rats.

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with dapsone. Although dapsone has been used in pregnant women without evidence of fetal abnormalities, the drug should be used during pregnancy only when clearly needed.

In patients with leprosy, some clinicians recommend maintaining dapsone treatment during pregnancy. In addition, dapsone has been important for the management of dermatitis herpetiformis in some pregnant women.

Fertility

Infertility has been reported in males receiving dapsone; in 2 patients, fertility was restored following discontinuance of the drug.

Lactation

Because dapsone is distributed into milk and because of the tumorigenic potential demonstrated in animal studies, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Drugs Associated with Adverse Hematologic Effects

Because the drugs have similar adverse hematologic effects, concurrent use of a folic acid antagonist (e.g., pyrimethamine) and dapsone may result in an increased risk of these adverse effects. Agranulocytosis has developed during the second and third months of therapy in patients receiving concomitant treatment with weekly pyrimethamine and dapsone. If pyrimethamine is used concomitantly with dapsone, the patient should be monitored more frequently than usual for adverse hematologic effects.

Because effects may be additive, dapsone should be used with caution in patients with G-6-PD deficiency receiving or exposed to other drugs or agents which are capable of inducing hemolysis in these individuals (e.g., nitrite, aniline, phenylhydrazine, naphthalene, niridazole, nitrofurantoin, primaquine).

Clofazimine

Results of several studies indicate that concomitant clofazimine does not affect the pharmacokinetics of dapsone, although a transient increase in urinary excretion of dapsone reportedly occurred in a few patients receiving concomitant therapy with the drugs. In a study in lepromatous leprosy patients receiving dapsone (100 mg daily) and rifampin (600 mg daily), concomitant administration of clofazimine (100 mg daily) did not affect plasma dapsone concentrations or the plasma half-life or urinary elimination of dapsone.

There is some evidence that dapsone may decrease or nullify some of the anti-inflammatory effects of clofazimine. In vitro, clofazimine and dapsone have opposing effects on neutrophil motility and lymphocyte transformation. Some clinicians suggest that this theoretically could adversely affect the efficacy of clofazimine in patients with erythema nodosum leprosum (ENL) reactions. Several borderline leprosy and lepromatous leprosy patients with severe, recurrent ENL reactions reportedly required higher clofazimine dosage to control these reactions when dapsone therapy was given concomitantly than when clofazimine was given alone. The manufacturer of clofazimine, however, suggests that further study is needed to confirm this interaction and states that it is advisable to continue treatment with both clofazimine and dapsone in patients who develop leprosy-associated inflammatory reactions, including ENL, during concomitant therapy with the drugs. There is no evidence to date that dapsone and clofazimine interfere with the antimycobacterial activity of each other.

Didanosine

Failure of dapsone to prevent Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) was reported in about 40% of patients with human immunodeficiency virus (HIV) infection who were receiving didanosine concomitantly. This failure rate was substantially higher than that reported in other studies in which dapsone was not administered with didanosine or that were observed when didanosine was used in patients receiving co-trimoxazole or aerosolized pentamidine for prevention of PCP. Although the possibility of a pharmacokinetic interaction was not evaluated in these patients, it was suggested that the buffers present in the didanosine preparation, which provides a pH of 7-8 to facilitate GI absorption of the antiretroviral agent, may interfere with GI absorption of dapsone. Dapsone is insoluble at neutral pH, while solubility is facilitated at acidic pH. However, in a study in 6 healthy adults and 6 HIV-infected adults, the pharmacokinetics of dapsone was not affected when 100 mg of the drug was administered 5 minutes after a 200-mg dose of didanosine given as chewable/dispersible, buffered tablets (no longer commercially available in the US) in the patients, or 5 minutes after administration of placebo tablets containing the aluminum and magnesium buffer without didanosine, in the healthy individuals. It has been suggested that dapsone be administered at least 2 hours before didanosine, although some clinicians have observed prophylactic failure of dapsone despite such separation of dosing and therefore recommend that the drugs not be used concomitantly.

Concomitant use of dapsone (single 100-mg dose) and buffered didanosine (200 mg every 12 hours for 14 days) did not have a clinically important effect on peak plasma concentrations or area under the plasma concentration-time curve (AUC) of dapsone.

Rifamycins

Concomitant use of rifabutin (300 mg daily) and dapsone (50 mg daily) in HIV-infected individuals decreased the AUC of dapsone by about 27-40%.

Rifampin may accelerate metabolism of dapsone; decreased serum dapsone concentrations (7-10 times lower) and increased urinary excretion of dapsone have been reported. Dosage adjustments may be necessary when rifampin and dapsone are used concomitantly; however, dosage adjustments are not required when rifampin and dapsone are used concomitantly for treatment of leprosy.

Rifapentine may accelerate metabolism of dapsone; dosage adjustments may be necessary if rifapentine and dapsone are used concomitantly.

Trimethoprim

Concomitant use of dapsone and trimethoprim may increase serum dapsone concentrations and potentially increase the risk of adverse effects associated with dapsone. In a study in adults with acquired immunodeficiency syndrome (AIDS) who received oral dapsone (100 mg once daily) alone or in conjunction with oral trimethoprim (20 mg/kg daily) for treatment of PCP, plasma dapsone concentrations were 40% higher with the combined regimen than with dapsone alone and methemoglobinemia occurred more frequently with the combined regimen (67%) than with dapsone alone (11%). There also is some evidence that dapsone may increase plasma trimethoprim concentrations, but an increased risk of trimethoprim-associated adverse effects was not identified in this study.

Periodic monitoring for potential toxicity (e.g., methemoglobinemia) is recommended in patients receiving dapsone in conjunction with trimethoprim.

Pharmacokinetics

Absorption

Following oral administration, dapsone is rapidly and almost completely absorbed from the GI tract and peak serum concentrations of the drug are attained within 4-8 hours. When a dosage of 200 mg daily is used, steady-state serum concentrations of the drug range from 0.1-7 mcg/mL and average 2.3 mcg/mL after 8 days of therapy. Following oral administration of a single 100-mg oral dose of dapsone, serum concentrations of the drug range from 0.4-1.2 mcg/mL 24 hours after the dose. Trace amounts of dapsone may be found in serum for 8-12 days after oral administration of a single 200-mg dose of the drug or for as long as 35 days after discontinuance of repeated doses of the drug. Dapsone and its monoacetyl metabolite (MADDS) appear to undergo enterohepatic circulation.

Distribution

The volume of distribution of dapsone is reportedly 1.5-2.5 L/kg in adults.

Dapsone is distributed into most body tissues. Dapsone is reportedly retained in skin, muscle, kidneys, and liver; trace concentrations of the drug may be present in these tissues up to 3 weeks after discontinuance of dapsone therapy. Dapsone is also distributed into sweat, saliva, sputum, and tears. The drug is also distributed into bile.

Although in one study using radiolabeled dapsone in patients with leprosy, higher concentrations of radioactivity were attained in diseased than in presumably healthy skin, other studies indicate little or no difference in sulfone content of healthy and diseased skin in patients with leprosy. Dapsone may not penetrate ocular tissue well, since eye lesions may develop or progress during therapy of leprosy even though the disease may be controlled or eliminated in other tissues.

Dapsone crosses the placenta. Dapsone is distributed into milk. In a woman receiving dapsone in a dosage of 50 mg daily, dapsone concentrations in milk were 1.1 mcg/mL; concurrent maternal serum concentrations of the drug were 1.6 mcg/mL.

Dapsone is 50-90% bound to plasma proteins. The major metabolite of dapsone, monoacetyldapsone, is almost completely bound to plasma proteins.

Elimination

There are large interindividual variations in the plasma half-life of dapsone. The plasma half-life of dapsone may range from 10-83 hours and averages 20-30 hours.

Dapsone is acetylated in the liver to monoacetyl and diacetyl derivatives. The major metabolite of dapsone is monoacetyldapsone (MADDS). The rate of acetylation of dapsone is genetically determined and is subject to interindividual variation, although the rate is usually constant for each individual. The drug also is hydroxylated in the liver to hydroxylamine dapsone (NOH-DDS). NOH-DDS appears to be responsible for methemoglobinemia and hemolysis induced by the drug.

Approximately 20% of each dose of dapsone is excreted in urine as unchanged drug, 70-85% is excreted in urine as water-soluble metabolites, and a small amount is excreted in feces. Dapsone is excreted in urine as acid-labile mono-N-glucuronide and mono-N-sulfamate derivatives in addition to some unidentified metabolites.

Orally administered activated charcoal has been shown to substantially enhance the elimination of dapsone and its monoacetyl derivative in healthy adults and in several cases of acute dapsone overdosage. Hemodialysis also reportedly enhances the elimination of dapsone and its monoacetyl derivative.

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