Dapsone

Excretion of dapsone is reduced and plasma concentrations are increased by concurrent administration of probenecid.

Rifampicin has been reported to increase the plasma clearance of dapsone.

Dapsone should be used with caution in patients with cardiac or pulmonary disease.

Increased dapsone and trimethoprim concentrations have been reported following concurrent administration in AIDs patients.

It is recommended that regular blood counts be performed during treatment with dapsone. Patients deficient in glucose-6-phosphate dehydrogenase, or methaemoglobin reductase, or with haemoglobin M are more susceptible to the haemolytic effects of dapsone.

Oral administration

It is now generally considered that the benefits of dapsone in the treatment of leprosy outweigh any potential risk to the pregnant patient. Some leprologists recommend 5mg folic acid daily for leprosy patients receiving dapsone during pregnancy.

Topical application

Risk Summary

There are no available data on dapsone gel, 7.5%, use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. The systemic absorption of ACZONE in humans following topical application is low relative to oral dapsone administration. In animal reproduction studies, oral doses of dapsone administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 400 times the systemic exposure at the maximum recommended human dose (MRHD) of dapsone gel, 7.5%, resulted in embryocidal effects. When orally administered to rats from the onset of organogenesis through the end of lactation at systemic exposures approximately 500 times the exposure at the MRHD, dapsone resulted in increased stillbirths and decreased pup weight [see Data].

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Dapsone has been shown to have an embryocidal effect in rats and rabbits when administered orally daily to females during organogenesis at dosages of 75 mg/kg/day and 150 mg/kg/day, respectively. These dosages resulted in systemic exposures that represented approximately 1407 times [rats] and 425 times [rabbits] the systemic exposure observed in human females as a result of use of the MRHD of dapsone gel, 7.5%, based on AUC comparisons. These effects were probably secondary to maternal toxicity.

Dapsone was assessed for effects on perinatal/postnatal pup development and postnatal maternal behavior and function in a study in which dapsone was orally administered to female rats daily beginning on the seventh day of gestation and continuing until the twenty-seventh day postpartum. Maternal toxicity (decreased body weight and food consumption) and developmental effects (increase in stillborn pups and decreased pup weight) were seen at a dapsone dose of 30 mg/kg/day (approximately 563 times the systemic exposure that is associated with the MRHD of dapsone gel, 7.5%, based on AUC comparisons). No effects were observed on the viability, physical development, behavior, learning ability, or reproductive function of surviving pups.

Oral administration

Dapsone diffuses into breast milk and there has been a report of haemolytic anaemia in a breast fed infant. While some feel that dapsone should not be used in lactating mothers, in general treatment for leprosy is continued in such patients.

Topical application

Risk Summary

There is no information regarding the presence of topical dapsone in breastmilk, the effects on the breastfed infant or the effects on milk production. Orally administered dapsone appears in human milk and could result in hemolytic anemia and hyperbilirubinemia especially in infants with G6PD deficiency. Systemic absorption of dapsone following topical application is low relative to oral dapsone administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dapsone gel, 7.5% and any potential adverse effects on the breastfed child from dapsone gel, 7.5% or from the underlying maternal condition.

None known.

Oral administration

Dapsone should be discontinued or reduced in dosage if severe lepra reactions affecting the eyes or nerve trunks occur.

Varying degrees of dose-related haemolysis and methaemoglobinaemia are the most frequently reported adverse effects of dapsone and occur in most subjects given more than 200mg daily; doses of up to 100mg daily do not cause significant haemolysis but subjects deficient in glucose-6-phosphate dehydrogenase are affected by doses above about 50mg daily. Hypoalbuminaemia and haemolytic anaemia has also been reported.

Although agranulocytosis has been reported rarely with dapsone when used alone, reports have been more common when dapsone has been used with other agents in the prophylaxis of malaria.

Rash, photosensitivity and pruritis may develop. Serious cutaneous hypersensitivity reactions occur rarely and include maculopapular rash, exfoliative dermatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Fixed drug eruptions have occurred.

A “dapsone syndrome” may occur after 3-6 weeks therapy; symptoms include rash, which is always present, fever, and eosinophilia. If dapsone is not stopped immediately, the syndrome may progress to exfoliative dermatitis, hepatitis, albuminuria and psychosis. Deaths have been recorded. Most patients require steroid therapy for several weeks, possibly due to the prolonged elimination time of the drug.

Peripheral neuropathy with motor loss has been reported in patients on dapsone for dermatological conditions. Peripheral neuropathy may occur as part of leprosy reaction states and it is not an indication to discontinue dapsone. Other adverse effects occur infrequently and include anorexia, headache, hepatitis, jaundice, changes in liver function tests, insomnia, nausea, psychosis, tachycardia and vomiting.

Topical application

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2161 subjects were treated with dapsone gel, 7.5%, for 12 weeks in 2 controlled clinical trials. The population ranged in age from 12 to 63 years, was 56% female, and 58% Caucasian. Adverse drug reactions that were reported in at least 0.9% of subjects treated with dapsone gel, 7.5% appear in Table 1 below.

Table 1. Adverse Reactions Occurring in at Least 0.9% of Subjects with Acne Vulgaris in 12-week Controlled Clinical Trials:

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post-approval use of topical dapsone: methemoglobinemia, rash (including erythematous rash, application site rash) and swelling of face (including lip swelling, eye swelling).