Daraprim 25mg Tablets

Pyrimethamine 25.0 mg

For excipients see 6.1.

Tablet

Each tablet is white and round with the markingGS A3A.

Malaria prophylaxis

Daraprim is indicated for chemoprophylaxis of malaria due to susceptible strains of Plasmodia. However, since resistance to pyrimethamine is increasing worldwide, Daraprim can only be considered suitable for use in individuals who are resident in areas where pyrimethamine is acknowledged to be effective. It is not suitable as a prophylactic for travellers.

Toxoplasmosis

Treatment is not normally required for asymtomatic or mild toxoplasma infection. Daraprim, in conjunction with a sulphonamide, is effective in the treatment of the following conditions associated with toxoplasma infections:

Toxoplasmic encephalitis and other manifestations in immune deficient individuals including those with AIDS.

Ocular infections where there is considered to be a risk of visual damage.

Proven foetal infection following maternal infection during pregnancy.

For the treatment of toxoplasmosis, Daraprim should not be used as monotherapy. It must be combined with a synergistic agent, normally an orally administered sulphonamide as recommended in section 4.2, Posology and Method of Administration.

Malaria Prophylaxis:

Adults: 1 tablet regularly each week.

Children: Over 10 years: 1 tablet regularly each week.

 5 to 10 years: ½ tablet regularly each week.

Under 5 years: Formulation not applicable.

Daraprim is rapidly absorbed and therefore prophylactic cover can be expected shortly after the first dose. Prophylaxis should commence before arrival in an endemic area and be continued once weekly. On returning to a non-malarious area dosage should be maintained for a further four weeks.

Toxoplasmosis treatment:

Daraprim should be given concurrently with sulphadiazine or another appropriate sulphonamide. Data on the extent to which other combinations might be better than pyrimethamine alone are limited. For patients who are intolerant of sulphonamides however, consideration should be given to substituting the sulphonamide for another agent such as clindamycin.

In the treatment of toxoplasmosis, all patients receiving Daraprim should be given a folate supplement to reduce the risk of bone marrow depression. Whenever possible calcium folinate should be administered. Folic acid is likely to be less effective than calcium folinate.

Daraprim treatment should generally be given for 3 to 6 weeks and not less than three weeks in immunosuppressed patients. If further therapy is indicated, a period of two weeks should elapse between treatments.

There have been no dose response studies of pyrimethamine in the treatment of toxoplasmosis. The following recommendations are therefore for guidance only.

Dosage for Toxoplasmic encephalitis and other manifestations in immune-deficient patients (adults and children over 5 years)

Daraprim

A loading dose of 100 mg – 200 mg daily should be given for the first 2 - 3 days of treatment.

The optimal dose subsequently for the treatment of toxoplasmic encephalitis in AIDS patients is not fully established but is generally in the range 25mg-75mg/day. Doses up to 100mg/day have been used successfully. The duration of treatment of the acute infection will depend on the clinical response and tolerability, but should normally be not less than three to six weeks.

Maintenance treatment is required indefinitely in immunocompromised patients if relapses are to be avoided. There is insufficient evidence to establish the optimal dose regimen, but doses of 25-100mg daily have been employed successfully.

Sulphadiazine 2 - 6 g per day in divided doses.

Dosage for treatment of ocular infections (adults and children over 5 years)

Daraprim

A loading dose of 100mg for 1-2 days followed by maintenance doses of 25-50mg daily. The optimal maintenance dose has not been clearly established.

Sulphadiazine 2-4g daily in divided doses.

•Dosage for treatment of foetal toxoplasmosis during pregnancy

See Section 4.4 Special Warnings and Precautions for Use and Section 4.6 Pregnancy and Lactation

Children under 5 years

There is insufficient data to provide specific dose recommendations in children. This formulation is not suitable for children under 5 years.

Use in the elderly

There is no definitive information on the effect of Daraprim on elderly individuals. It is theoretically possible that elderly patients might be more susceptible to folate depression associated with the daily administration of Daraprim in the treatment of toxoplasmosis, and folate supplements are therefore essential (See Special Warnings and Precautions for Use).

Daraprim should not be given to patients with a history of pyrimethamine sensitivity.

Daraprim should not be used during the first trimester of pregnancy. (See Section 4.6 Pregnancy and Lactation).

Breast-feeding should be avoided during toxoplasmosis treatment. (See Section 4.6 Pregnancy and Lactation).

During pregnancy and in other conditions predisposing to folate deficiency, a folate supplement should be given. The co-administration of a folate supplement is necessary for treatment of toxoplasmosis (see Dosage & Method of Administration). Full blood counts should be carried out weekly during therapy and for a further two weeks after treatment is stopped. In immunosuppressed patients, full blood counts should be carried out twice weekly. Should signs of folate deficiency develop, treatment must be discontinued and high doses of calcium folinate administered. Calcium folinate should be used because folic acid does not correct folate deficiency due to dihydrofolate reductase inhibitors.

Daraprim may exacerbate folate deficiency in subjects predisposed to this condition through disease or malnutrition. Accordingly, a calcium folinate supplement should be given to such individuals. In patients with megaloblastic anaemia due to folate deficiency the risks versus benefits of administering Daraprim require careful consideration.

Caution should be exercised in administering Daraprim to patients with a history of seizures; large loading doses should be avoided in such patients (see Undesirable Effects).

When a sulphonamide is given an adequate fluid intake should be ensured to minimise the risk of crystalluria.

Since pyrimethamine is administered with a sulphonamide for the conditions indicated the general precautions applicable to sulphonamides should be observed.

Occasional reports suggest that individuals taking pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia if co-trimoxazole is prescribed concurrently.

Use in renal impairment

The kidney is not the major route of excretion of pyrimethamine and excretion is not significantly altered in patients with renal failure. There are, however, no substantial data on the use of Daraprim in renally impaired subjects. Due to lack of data on the theoretical possibility of active metabolites with prolonged treatment, caution should be exercised in renally impaired patients. It is not known if Daraprim is dialyzable. Since Daraprim is co-administered with a sulphonamide, care should be taken to avoid accumulation of the sulphonamide in renally impaired patients.

Use in hepatic impairment

The liver is the main route for metabolism of pyrimethamine. Data on the use of pyrimethamine in patients with liver disease are limited. Daraprim in combination with sulphonamides has been used effectively to treat toxoplasmosis in a patient with mild hepatic disease. There are no general recommendations for dosage reductions for liver-impaired states but consideration should be given to dose adjustment for individual cases.

Daraprim, by its mode of action, may further depress folate metabolism in patients receiving treatment with other folate inhibitors, or agents associated with myelosuppression, including co-trimoxazole, trimethoprim, proguanil, zidovudine, or cytostatic agents (eg. methotrexate). Cases of fatal bone marrow aplasia have been associated with the administration of daunorubicin, cytosine arabinoside and pyrimethamine to individuals suffering from acute myeloid leukaemia. Megaloblastic anaemia has been reported occasionally in individuals who took pyrimethamine in excess of 25 mg weekly concurrently with a trimethoprim/sulphonamide combination.

Convulsions have occurred after concurrent administration of methotrexate and pyrimethamine to children with central nervous system leukaemia. Also, seizures have occasionally been reported when pyrimethamine was used in combination with other antimalarial drugs.

The concurrent administration of lorazepam and Daraprim may induce hepatotoxicity.

In vitro data suggest that antacid salts and the anti-diarrhoeal agent kaolin reduce the absorption of pyrimethamine.

The high protein binding exhibited by pyrimethamine may prevent protein binding by other compounds (eg. quinine or warfarin). This could affect the efficacy or toxicity of the concomitant drug depending on the levels of unbound drug.

Pregnancy

Pyrimethamine in combination with sulphonamide has been used for many years in the treatment of toxoplasmosis during pregnancy. This infection carries a high risk to the foetus. Pyrimethamine crosses the placenta and, although there is a theoretical risk of foetal abnormalities from all folate inhibitors given during pregnancy, there have been no reports that have shown with any certainty that pyrimethamine is associated with human teratogenicity. Nevertheless, caution should be exercised in the administration of pyrimethamine.A folate supplement should be given to pregnant women receiving Daraprim.

Consideration should be given to the treatment of all suspected cases of acquired toxoplasmosis in pregnancy. The risks associated with the administration of Daraprim must be balanced against the dangers of abortion or foetal malformation due to the infection.

Treatment with pyrimethamine and sulfadiazine during pregnancy is indicated in the presence of confirmed placental or foetal infection or when the mother is at risk of serious sequelae. However, in view of the theoretical risk of foetal abnormality arising from the use of Daraprim in early pregnancy, its use in combination therapy should be restricted to the second and third trimesters.Alternative therapy is therefore advised in the first trimester of pregnancy and until diagnosis has been confirmed.

Lactation

Pyrimethamine enters human breast milk. It has been estimated that over a 9-day period an average weight infant would receive about 45% of the dose ingested by the mother. In view of the high doses of pyrimethamine and concurrent sulphonamides needed in toxoplasmosis treatment, breast feeding should be avoided for the duration of treatment.

Not known.

At the recommended dose for malaria prophylaxis, side-effects are rare. Occasionally, rashes have been observed. At the doses required for treatment of toxoplasmosis, pyrimethamine may produce myleosuppression with anaemia, leucopenia and thrombocytopenia.

Precipitation of a grand mal attack in one patient predisposed to epilepsy has been reported but the clinical significance has not been defined.

Since a concurrent sulphonamide is to be taken with pyrimethamine for the indications listed the relevant sulphonamide data sheet/SPC or published literature should be consulted for sulphonamide associated adverse events.

Symptoms and signs:-

Vomiting and convulsions occur in cases of severe, acute overdoses. Ataxia, tremor and respiratory depression can also occur. There have been isolated cases with fatal outcomes following acute overdose of pyrimethamine.

Chronic excess doses can result in bone marrow depression (eg. megaloblastic anaemia, leucopenia, thrombocytopenia) resulting from folic acid deficiency.

Management:-

Routine supportive treatment, including maintenance of a clear airway and control of convulsions.

Adequate fluids should be given to ensure optimal diuresis.

Gastric lavage may be of value only if instituted within two hours of ingestion in view of the rapid absorption of Daraprim.

To counteract possible folate deficiency, calcium folinate should be given until signs of toxicity have subsided. There may a delay of 7 to 10 days before the full leucopenic side effects become evident, therefore calcium folinate therapy should be continued for the period at risk.

Pyrimethamine is an antiparasitic agent.

Group: diaminopyrimidines

ATC code:- P01B D01

Mode of Action:-

The antiparasitic action of pyrimethamine is due to its specific activity on folic acid metabolism in the Plasmodium and Toxoplasma parasites. In this respect it competitively inhibits the dihydrofolate reductase enzyme with an affinity far greater for the protozoal than for the human enzyme.

Absorption:-

Pyrimethamine is rapidly absorbed from the gastrointestinal tract after administration. Time to peak plasma concentration is 2 to 4 hours in healthy volunteers. Peak plasma concentrations vary widely between individuals and can range from 260 to 1411ng/ml after daily doses of 25mg. A similar degree of inter-patient variability in serum levels has been noted in patients with AIDS.

Distribution:-

The volume of distribution for pyrimethamine is approximately 2L/kg. In patients with HIV infection, population pharmacokinetic analysis has indicated that the mean volume of distribution (corrected for bioavailability) is 246+/-64L.

About 87% of the drug is bound to plasma proteins. Pyrimethamine has been shown to reach the cerebrospinal fluid of patients with AIDS given daily doses,achieving concentrations approximately one fifth of those in serum.

Metabolism and elimination:-

Pyrimethamine is predominantly eliminated by metabolism, with up to 30% recovered in the urine as parent compound over a period of several weeks. The mean elimination half-life is 85 hours (ranging from 35 to 175 hours). In AIDS patients, the total clearance is 1.28+/-0.41L/h resulting in an elimination half life of 139+/-34h . Data are lacking on the nature of the metabolites of pyrimethamine, their route/rate of formation and elimination in man and any pharmacological activity, particularly after prolonged daily dosing.

Multiple dose studies indicate that steady state is achieved in 12 to 20 days with daily dosing. It is theoretically possible that metabolic pathways might be saturable, leading to excessive accumulation of the drug in some patients. However, it has been demonstrated that plasma levels are approximately proportional to dose at steady state so this appears unlikely. Genetic variation in the exposure to pyrimethamine has been reported but these data are unsubstantiated.

Some studies in patients with AIDS have indicated shorter half lives than those noted above: these are very likely to be a consequence of inappropriate sampling and analytical techniques. However, if there are patients in whom the half-life is particularly short, steady state therapeutic levels might be inadequate.

Mutagenicity:-

In microbial tests, pyrimethamine was found to be non-mutagenic in the Ames Salmonella assay whereas DNA damage was seen in the Escherichia coli repair assay.

Further in vitro data indicate that pyrimethamine induces mutagenic activity in mouse lymphoma cells in the absence, but not in the presence of metabolic activation.

Pyrimethamine also showed clastogenic activity in mammalian lymphocytes in the absence of metabolic activation.

Following intraperitoneal administration, pyrimethamine has been shown to induce chromosomal damage in male rodent germ cells although studies in somatic cells (micronucleus tests) are either negative or inconclusive. Studies following oral administration of pyrimethamine in rodents showed negative results in female germ cells and in male and female bone marrow/peripheral blood cells.

Carcinogenicity

A study in mice (dosed with either 500 or 1000 ppm pyrimethamine in the diet for 5 days per week, for 78 weeks) showed no evidence of carcinogenicity in females. Survival in the male mice did not allow for an assessment of carcinogenicity in this sex.

A similar study in rats dosed at 200 or 400 ppm pyrimethamine showed no evidence of carcinogenicity.

Teratogenicity

No changes in early development were seen in embryos from 15 mice given a single intra-gastric dose of pyrimethamine (50mg/kg bodyweight) on the first day of gestation. However development of mouse and rat embryos in culture was severely hindered by pyrimethamine in a dose-dependent manner.

Pyrimethamine was teratogenic in rodents and in the Gottingen minipig in a dose-dependent manner.

Other studies in rats dosed at either 1mg/kg or 10mg/kg bodyweight showed some inhibition of developmental processes but no teratological effects.

Pyrimethamine was not teratogenic in rabbits at dose levels up to 100mg/kg bodyweight/day administered on days 6 to 18 of pregnancy. Pyrimethamine markedly reduced early stage cell division in rabbit embryos but implantation and foetal development were normal.

Fertility

A study in rats dosed with 5mg/kg bodyweight/day for 6 weeks resulted in reduced sperm concentrations and testis weights, but there were no effects on fertility. Reversible arrest of spermatogenesis was shown in a study on mice dosed with 200mg/kg/day for 50 days. However, this dose is far in excess of human therapeutic doses.

Lactose Monohydrate

Maize Starch

Hydrolysed Starch

Docusate sodium

Magnesium stearate

Not applicable

5 years

Do not store above 30°C.

Store in the original container.

Vinyl - lacquered aluminium foil strip-packs.

Pack size: 30 tablets

Not applicable

PL 00003/5026R

21 December 2005

21 December 2005