Protogen

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.

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.

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

Protogene contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

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

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

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

None known.

Protogene 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 Protogene 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 Protogene when used alone, reports have been more common when Protogene 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 "Protogene syndrome" may occur after 3-6 weeks therapy; symptoms include rash, which is always present, fever, and eosinophilia. If Protogene 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 Protogene for dermatological conditions. Peripheral neuropathy may occur as part of leprosy reaction states and it is not an indication to discontinue Protogene. Other adverse effects occur infrequently and include anorexia, headache, hepatitis, jaundice, changes in liver function tests, insomnia, nausea, psychosis, tachycardia and vomiting.

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; website: www.mhra.gov.uk/yellowcard

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 Protogene 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 Protogene.

Protogene is a sulfone active against a wide range of bacteria.

Protogene's mechanism of action is probably similar to that of the sulfonamides 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 sulfonamides, antibacterial activity is inhibited by p-aminobenzoic acid.

Protogene 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 Protogene in the circulation is bound to plasma proteins and nearly 100% of its monoacetylated metabolite is bound. Protogene 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. Protogene is acetylated to monoacetylProtogene, the major metabolite, and other mono and diacetyl derivatives. Acetylation exhibits genetic polymorphism. Hydroxylation is the other major metabolite pathway resulting in hydroxylamine Protogene which may be responsible for Protogene-associated methaemoglobinaemia and haemolysis. Protogene is mainly excreted in the urine, only 20% of a dose as unchanged drug.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

None known.

Not applicable.