Action And Clinical Pharmacology: Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine does not destroy gametocytes, but arrests sporogony in the mosquito.
Peak plasma levels are found between 2 and 4 hours after oral administration of 100 mg of pyrimethamine. Plasma concentrations are maintained over a prolonged time with a plasma half-life of approximately 90 hours. Urinary excretion is extended over 30 days or longer. Twenty to 30% of a single 100 mg dose is excreted in the urine. Pyrimethamine is secreted in breast milk and may be of some value in the protection of breast fed infants from malaria.
Indications And Clinical Uses: The chemoprophylaxis of malaria due to susceptible strains of plasmodia. Fast acting schizonticides (chloroquine, amodiaquin, quinacrine or quinine) are indicated and preferable for the treatment of acute attacks. However, conjoint use of pyrimethamine will initiate transmission control and suppressive cure.
Pyrimethamine is also indicated for the treatment of toxoplasmosis. For this purpose the drug should be used conjointly with a sulfonamide since synergism exists with this combination.
Contra-Indications: Patients with a history of sensitivity to pyrimethamine.
Precautions: Pyrimethamine should be used with caution in patients with hepatic or renal disorders.
Pyrimethamine may exacerbate folate deficiency due to innate disease or malnutrition.
In areas of known or suspected resistance to pyrimethamine or related compounds, an alternative prophylactic should be used.
When a sulfonamide is given in combination, an adequate fluid intake should be ensured to minimize the risk of crystalluria.
The dosage of pyrimethamine required for the treatment of toxoplasmosis is 10 to 20 times the recommended antimalarial dosage and approaches the toxic level. If signs of folic acid deficiency develop (see Adverse Effects) reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid may be administered in a dosage of 5 to 15 mg orally, i.v. or im. daily for 3 days, or as required to produce a return of depressed platelet or white blood cell counts to safe levels.
Warn patients to keep pyrimethamine out of the reach of children since accidental ingestion has led to fatality.
Pregnancy: Pyrimethamine like other folic acid antagonists, may, in large doses produce teratogenic effects in laboratory animals.
Toxoplasmosis: The risks resulting from the administration of high doses of pyrimethamine must be balanced against the dangers of abortion or fetal malformation due to the infection. Toxoplasmosis is thought not to infect the fetus before the sixth week of pregnancy and only rarely during early placentation.
Treatment is indicated only for women whose serological tests become positive during pregnancy, and women who show rising titres of antibodies against Toxoplasma during pregnancy. Although the eyes are sometimes affected during an acute, acquired attack, most authorities consider that ocular toxoplasmosis is usually a late manifestation of congenital infection. Thus, in the majority of cases, ocular disease does not reflect a danger to the fetus. Pregnant women should be treated only in the presence of rising titres or if the eye lesion threatens maternal vision.
Concurrent administration of folinic acid is recommended when pyrimethamine is used for the treatment of toxoplasmosis during pregnancy.
The recommended dosage for malaria suppression should not be exceeded. In patients receiving high dosage, as for the treatment of toxoplasmosis, semi-weekly blood counts, including platelet counts, should be made. In patients with convulsive disorders a smaller “starting” dose (for toxoplasmosis) is recommended to avoid the potential nervous system toxicity of pyrimethamine.
Drug Interactions: The high protein binding exhibited by pyrimethamine may prevent protein binding by other compound. This will be of relevance when the level of unbound, concomitantly administered drug (e.g. quinine or warfarin) affects its efficacy or toxicity.
The concurrent administration of lorazepam and pyrimethamine may induce hepatotoxicity.
Pyrimethamine, by its mode of action, may further depress folate metabolism in patients receiving treatment with other folate inhibitors. Occasional reports suggest that individuals taking pyrimethamine as malaria prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anemia if cotrimoxazole is prescribed concurrently.
Pyrimethamine may cause exacerbation of the myelosuppressive effects of cytostatic agents, especially those of the antifolate, methotrexate. Convulsions have occurred after concurrent administration of methotrexate and pyrimethamine to children with central nervous system leukemia and cases of fatal bone marrow aplasia have been associated with the administration of daunorubicin, cytosine arabinoside and pyrimethamine to individuals suffering from acute myeloid leukemia.
Adverse Reactions: Malaria Prophylaxis: At the recommended dose, side effects are rare. Occasionally, rashes have been observed which disappeared when administration of pyrimethamine was stopped.
Malaria Treatment: Nausea, colic, vomiting and diarrhea are seldom recorded. However, the low frequency of reports may reflect the difficulties in distinguishing whether such symptoms are a result of the disease process or attributable to medication. Disorders of cardiac rhythm and hematuria occur infrequently at doses of 75 mg and may be associated to some extent with the nature of the infection.
Toxoplasmosis: Therapeutic doses of pyrimethamine have been shown to depress hematopoiesis in about 25% of patients. The likelihood of anemia or thrombocytopenia developing is reduced by concurrent administration of calcium folinate.
Nausea, colic, vomiting and diarrhea are common during early treatment. They seldom necessitate withholding treatment.
Less common side effects are headache, giddiness, dryness of mouth or throat, fever, malaise, dermatitis, abnormal skin pigmentation and depression.
Hyperphenylalaninemia has occurred in 3 neonates treated for congenital toxoplasmosis. Circulatory collapse and buccal ulceration have been reported in association with pyrimethamine but only in patients treated with doses higher than those recommended. Precipitation of a grand mal attack in one patient predisposed to epilepsy has been reported, but the clinical significance has not been defined.
Symptoms And Treatment Of Overdose: Symptoms: Symptoms reported have included vomiting, cyanosis, respiratory distress, convulsions and tachycardia. tag_Treatment
Treatment: Routine supportive treatment, including maintenance of a clear airway and control of convulsions should be given. Adequate fluids should be given to ensure optimal diuresis. Gastric lavage may be of value only if instituted within 2 hours of ingestion, in view of the rapid absorption of pyrimethamine. Fresh blood transfusions to counteract blood dyscrasias should be available.
To counteract possible folate deficiency, calcium folinate 9 to 15 mg daily should be given until the signs of toxicity have subsided. There may be a delay of 7 to 10 days before the leukopenic side effects become evident; therefore, calcium folinate therapy should be continued for the period at risk.
Dosage And Administration: Chemoprophylaxis of Malaria: Adults and children over 10 years, 25 mg once weekly; children 5 through 10 years, 12.5 mg once weekly; infants and children under 5 years, 6.25 mg once weekly. Prophylaxis should begin 1 week prior to arrival in endemic area and be continued once weekly. On returning to a nonmalarious area, dosage should be maintained for a further 4 weeks.
Regimens planned to include suppressive cure should be extended through any characteristic periods of early recrudescence and late relapses for at least 10 weeks in each case.
Treatment of acute attacks: Use pyrimethamine in areas where only susceptible plasmodia exist. The drug is not recommended alone in the treatment of acute attacks of malaria in nonimmune persons. Fast acting schizonticides (chloroquine, amodiaquin, quinacrine or quinine) are indicated for treatment of acute attacks. However, conjoint pyrimethamine dosage of 25 mg daily for 2 days will initiate transmission control and suppressive cure.
Should circumstances arise wherein pyrimethamine must be used alone in semi-immune persons, the adult dosage for an acute attack is 50 mg daily for 2 days; children 4 to 10 years old may be given 25 mg daily for 2 days. In any event, clinical cure should be followed by the once-weekly regimen described above.
Pyrimethamine should be given concurrently with sulfalene or sulfadoxine as a single dose. Adults and children over 14 years, 50 to 75 mg pyrimethamine with 1 to 1.5 g sulfalene or sulfadoxine; children 9 to 14 years, 50 mg pyrimethamine with 1 g sulfalene or sulfadoxine; children 4 to 8 years, 25 mg pyrimethamine with 500 mg sulfalene or sulfadoxine; children under 4 years, 12.5 mg pyrimethamine with 250 mg sulfalene or sulfadoxine. A single dose is sufficient to eliminate asexual parasites from the blood of the majority of patients.
Toxoplasmosis: Pyrimethamine should be given concurrently with sulfadiazine or another sulfonamide. Adults and children over 6 years, an initial dose of 50 mg pyrimethamine followed by 25 mg pyrimethamine daily given with 150 mg/kg (maximum 4 g) sulfadiazine daily in 4 divided doses; children 2 to 6 years, an initial dose of 25 mg pyrimethamine followed by 12.5 mg pyrimethamine daily given with 150 mg/kg (maximum 2 g) sulfadiazine daily in 4 divided doses; children 10 months to 2 years, 12.5 mg pyrimethamine daily given with 150 mg/kg (maximum 1.5 g) sulfadiazine daily in 4 divided doses; infants 3 to 9 months: 6.25 mg pyrimethamine daily given with 100 mg/kg (maximum 1 g) sulfadiazine daily in 4 divided doses; infants under 3 months, 6.25 mg pyrimethamine on alternate days given with 100 mg/kg (maximum 750 mg) sulfadiazine given in 4 divided doses on alternate days.
Warning: The risk of administering sulfadiazine or other sulfonamides to neonates should be weighed against their therapeutic benefit.
Treatment: Treatment should be continued for 3 to 6 weeks. If further therapy is indicated a period of 2 weeks should elapse between treatments.
Availability And Storage: Each white, biconvex tablet, with code number DARAPRIM A3A on same side as score mark, contains: pyrimethamine USP 25 mg. Also contains cornstarch, lactose and potato starch. Bottles of 50. Store between 15 to 30°C and keep dry. (Shown in Product Recognition Section)
DARAPRIM® Glaxo Wellcome Pyrimethamine Antimalarial