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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dapsone 50 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg dapsone.

Each tablet also contains 8.81 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

Dapsone 50 mg Tablets are white, circular, biconvex tablets, debossed with ‘50’ on one side and with a score line between ‘D’ & ‘P’ on the other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

1)    As part of a multi-drug regimen in the treatment of all forms of leprosy.

2)    Treatment of dermatitis herpetiformis and other dermatoses.

3)    Prophylaxis of malaria in combination with pyrimethamine.

4)    Prophylaxis of Pneumocystis carinii pneumonia in immunodeficient subjects,

especially AIDS patients.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

Adults and children over 12 years:

■    Multibacillary leprosy (3-drug regimen): 100mg daily for at least two years.

■    Paucibacillary leprosy (2-drug regimen): 100mg daily for at least six months.

■    Malaria prophylaxis: 100mg weekly with 12.5mg pyrimethamine.

■    Dermatitis herpetiformis: Initially 50mg daily, gradually increased to 300mg daily if required. Once lesions have begun to subside, the dose should be reduced to a minimum as soon as possible, usually 25-50mg daily, which may be continued for a number of years. Maintenance dosage can often be reduced in patients receiving a gluten-free diet.

■    Pneumocystis carinii pneumonia: In combination with trimethoprim, 50-100mg daily; 100mg twice weekly or 200mg once weekly.

Children 6-12 years:

■    Multibacillary leprosy (3-drug regimen): 50mg daily for at least two years.

■    Paucibacillary leprosy (2-drug regimen): 50mg daily for at least six months.

Elderly:

Dosage should be reduced in the elderly where there is an impairment of hepatic function.

Method of Administration

For oral administration.

4.3 Contraindications

Known hypersensitivity to sulphonamides, sulphones, or any of the excipients; severe anaemia; porphyria; severe glucose-6-phosphate dehydrogenase deficiency.

Special warnings and precautions for use

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

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.

Dapsone should be used with caution in anaemia. Severe anaemia should be treated before starting Dapsone.

Dapsone tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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

4.6 Fertility, Pregnancy and lactation

Pregnancy

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.

Lactation

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.

Fertility

There are insufficient fertility data available to indicate whether dapsone has any effect of fertility.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

The table below lists the undesirable effects according to the MedDRA system organ classes (MedDRA SOCs). The frequency category of the undesirable effects listed in the table is “not known (cannot be estimated from the available data)” as it is not possible to reliably estimate the frequency of these reactions.

MedDRA System Organ Class	Undesirable effect(s)
Immune system disorders	Severe lepra reactions. Dapsone should be discontinued or reduced in dosage if severe lepra reactions affecting the eyes or nerve trunks occur.
Blood and lymphatic system disorders	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, haemolytic anaemia and agranulocytosis. Agranulocytosis has been reported rarely with dapsone when used alone and reports have been more common when dapsone has been used with other agents in the prophylaxis of malaria.
Metabolism and nutrition disorders	Anorexia may occur infrequently.
Psychiatric disorders	Insomnia and psychosis may occur infrequently.

Nervous system disorders	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.
	Headache may occur infrequently.
Cardiac disorders	Tachycardia may occur infrequently.
Gastrointestinal disorders	Nausea and vomiting may occur infrequently.
Hepatobiliary disorders	Hepatitis, jaundice and changes in liver function tests may occur infrequently.
Skin and subcutaneous tissue disorders	Serious cutaneous hypersensitivity reactions occur rarely and include maculopapular rash, exfoliative dermatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
	"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.
	Rash, photosensitivity, pruritis and fixed drug eruptions may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Tel: Freephone 0808 100 3352 or Website: www.mhra.gov.uk/yellowcard).

4.9 Overdose

Symptoms are hypoxia, methaemoglobinaemia and haemolytic anaemia. In severe overdosage the stomach should be emptied by gastric lavage. Administration of activated charcoal by mouth has been shown to enhance the elimination of dapsone and its monoacetyl metabolite. Methaemoglobinaemia has been treated with slow IV injections of methylene blue 1-2mg/kg bodyweight, repeated after one hour if necessary. Methylene blue should not be administered to patients with glucose-6-phosphate dehydrogenase deficiency since it will not be effective. Haemolysis has been treated by infusion of concentrated human red blood cells to replace the damaged cells.

Supportive therapy includes oxygen to alleviate hypoxia, and administration of fluids to maintain renal flow and promote the elimination of dapsone.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of lepra Therapeutic classification: JO4B A02

Dapsone is a sulphone active against a wide range of bacteria.

Dapsones mechanism of action is probably similar to that of the sulphonamides which involves inhibition of folic acid synthesis in susceptible organisms. It is usually considered to be bacteriostatic against M leprae although it may also possess weak bactericidal activity. It is also active against Plasmodium and Pneumocystis carinii. As with sulphonamides, antibacterial activity is inhibited by p-aminobenzoic acid.

5.2 Pharmacokinetic properties

Dapsone is almost completely absorbed from the GI tract with peak plasma concentrations occurring about 2-8 hours after a dose. Steady-state concentrations are not obtained until after at least 8 days of daily administration; doses of 100mg daily provide trough concentrations of 0.5 micrograms/ml. About 50-80% of dapsone in the circulation is bound to plasma proteins and nearly 100% of its monoacetylated metabolite is bound. Dapsone undergoes enterohepatic recycling. It is widely distributed; is present in saliva, breast milk and crosses the placenta. The half-life ranges from 10-80 hours. Dapsone is acetylated to monoacetyldapsone, the major metabolite, and other mono and diacetyl derivatives. Acetylation exhibits genetic polymorphism. Hydroxylation is the other major metabolic pathway resulting in hydroxylamine dapsone which may be responsible for dapsone-associated methaemoglobinaemia and haemolysis. Dapsone is mainly excreted in the urine, only 20% of a dose as unchanged drug.

Preclinical safety data

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Pregelatinised maize starch Maize starch Sodium lauryl sulfate Stearic acid Magnesium stearate

6.2 Incompatibilities

None applicable.

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store in the original package in order to protect from light.

6.5 Nature and contents of container

PVC/aluminium blisters. Pack size of 28 tablets.