DARAPRIM (pyrimethamine) is an antiparasitic compound available in tablet form for oral administration. Each scored tablet contains 25 mg pyrimethamine and the inactive ingredients corn and potato starch, lactose, and magnesium stearate.

Pyrimethamine, known chemically as 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, has the following structural formula:

C₁₂H₁₃ClN₄
Mol. Wt 248.71

Last updated on RxList: 1/20/2009

Treatment of Toxoplasmosis: DARAPRIM is indicated for the treatment of toxoplasmosis when used conjointly with a sulfonamide, since synergism exists with this combination.

Treatment of Acute Malaria: DARAPRIM is also indicated for the treatment of acute malaria. It should not be used alone to treat acute malaria. Fast-acting schizonticides such as chloroquine or quinine are indicated and preferable for the treatment of acute malaria. However, conjoint use of DARAPRIM with a sulfonamide (e.g., sulfadoxine) will initiate transmission control and suppression of susceptible strains of plasmodia.

Chemoprophylaxis of Malaria: DARAPRIM is indicated for the chemoprophylaxis of malaria due to susceptible strains of plasmodia. However, resistance to pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent for travelers to most areas.

For Treatment of Toxoplasmosis: The dosage of DARAPRIM for the treatment of toxoplasmosis must be carefully adjusted so as to provide maximum therapeutic effect and a minimum of side effects. At the dosage required, there is a marked variation in the tolerance to the drug. Young patients may tolerate higher doses than older individuals. Concurrent administration of folinic acid is strongly recommended in all patients.

The adult starting dose is 50 to 75 mg of the drug daily, together with 1 to 4 g daily of a sulfonamide of the sulfapyrimidine type, e.g., sulfadoxine. This dosage is ordinarily continued for 1 to 3 weeks, depending on the response of the patient and tolerance to therapy. The dosage may then be reduced to about one half that previously given for each drug and continued for an additional 4 to 5 weeks.

The pediatric dosage of DARAPRIM is 1 mg/kg/day divided into 2 equal daily doses; after 2 to 4 days this dose may be reduced to one half and continued for approximately 1 month. The usual pediatric sulfonamide dosage is used in conjunction with DARAPRIM.

For Treatment of Acute Malaria: DARAPRIM is NOT recommended alone in the treatment of acute malaria. Fast-acting schizonticides, such as chloroquine or quinine, are indicated for treatment of acute malaria. However, DARAPRIM at a dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission control and suppression of non-falciparum malaria. DARAPRIM is only recommended for patients infected in areas where susceptible plasmodia exist. Should circumstances arise wherein DARAPRIM must be used alone in semi-immune persons, the adult dosage for acute malaria is 50 mg for 2 days; children 4 through 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 below for chemoprophylaxis. Regimens which include suppression should be extended through any characteristic periods of early recrudescence and late relapse, i.e., for at least 10 weeks in each case.

For Chemoprophylaxis of Malaria:

Adults and pediatric patients over 10 years — 25 mg (1 tablet) once weekly

Children 4 through 10 years — 12.5 mg (1/2 tablet) once weekly

Infants and children under 4 years — 6.25 mg (1/4 tablet) once weekly

White, scored tablets containing 25 mg pyrimethamine, imprinted with “DARAPRIM” and “A3A” in bottles of 100 (NDC 0173-0201-55).

Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light.

Manufactured by: DSM Pharmaceuticals, Inc. Greenville, NC 27834 for GlaxoSmithKline, Research Triangle Park, NC 27709. March 2003. FDA Rev date: 11/18/2003

Last updated on RxList: 1/20/2009

Hypersensitivity reactions, occasionally severe (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and hyperphenylalaninemia, can occur particularly when pyrimethamine is administered concomitantly with a sulfonamide.

Consult the complete prescribing information for the relevant sulfonamide for sulfonamide-associated adverse events. With doses of pyrimethamine used for the treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be minimized by giving the medication with meals; it usually disappears promptly upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm. Hematologic effects, however, may also occur at low doses in certain individuals (see PRECAUTIONS: General).

Pulmonary eosinophilia has been reported rarely.

Pyrimethamine may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. However, the concomitant use of other antifolic drugs or agents associated with myelosuppression including sulfonamides or trimethoprim-sulfamethoxazole combinations, proguanil, zidovudine, or cytostatic agents (e.g., methotrexate), while the patient is receiving pyrimethamine, may increase the risk of bone marrow suppression. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored (see WARNINGS). Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly.

Last updated on RxList: 1/20/2009

The dosage of pyrimethamine required for the treatment of toxoplasmosis is 10 to 20 times the recommended antimalaria dosage and approaches the toxic level. If signs of folate deficiency develop (see ADVERSE REACTIONS), reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid (leucovorin) should be administered in a dosage of 5 to 15 mg daily (orally, IV, or IM) until normal hematopoiesis is restored.

Data in 2 humans indicate that pyrimethamine may be carcinogenic: a 51-year-old female who developed chronic granulocytic leukemia after taking pyrimethamine for 2 years for toxoplasmosis,³ and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of pyrimethamine for toxoplasmosis.⁴

Pyrimethamine has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg.⁵

DARAPRIM should be kept out of the reach of infants and children as they are extremely susceptible to adverse effects from an overdose. Deaths in pediatric patients have been reported after accidental ingestion.

General

The recommended dosage for chemoprophylaxis of malaria should not be exceeded. A small “starting” dose for toxoplasmosis is recommended in patients with convulsive disorders to avoid the potential nervous system toxicity of pyrimethamine. DARAPRIM should be used with caution in patients with impaired renal or hepatic function or in patients with possible folate deficiency, such as individuals with malabsorption syndrome, alcoholism, or pregnancy, and those receiving therapy, such as phenytoin, affecting folate levels (see Pregnancy subsection).

Laboratory Tests

In patients receiving high dosage, as for the treatment of toxoplasmosis, semiweekly blood counts, including platelet counts, should be performed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section for information on carcinogenesis.

Mutagenesis: Pyrimethamine has been shown to be nonmutagenic in the following in vitro assays: the Ames point mutation assay, the Rec assay, and the E. coli WP2 assay. It was positive in the L5178Y/TK +/- mouse lymphoma assay in the absence of exogenous metabolic activation.⁶ Human blood lymphocytes cultured in vitro had structural chromosome aberrations induced by pyrimethamine.

In vivo, chromosomes analyzed from the bone marrow of rats dosed with pyrimethamine showed an increased number of structural and numerical aberrations.

Pregnancy

Teratogenic Effects: Pregnancy Category C. Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis.

There are no adequate and well-controlled studies in pregnant women. DARAPRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis during pregnancy.

Nursing Mothers

Pyrimethamine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pyrimethamine and from concurrent use of a sulfonamide with DARAPRIM for treatment of some patients with toxoplasmosis, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS and PRECAUTIONS: Pregnancy ).

Pediatric Use

See DOSAGE AND ADMINISTRATION section.

Geriatric Use

Clinical studies of DARAPRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

REFERENCES

3. Jim RTS, Elizaga FV. Development of chronic granulocytic leukemia in a patient treated with pyrimethamine. Hawaii Med J. 1977;36:173-176.

4. Sadoff L. Antimalarial drugs and Burkitt's lymphoma. Lancet. 1973;2:1262-1263.

5. Bahna L. Pyrimethamine. LARC Monogr Eval Carcinog Risk Chem. 1977;13:233-242.

6. Clive D, Johnson KO, Spector JKS, et al. Validation and characterization of the L5178Y/TK +/- mouse lymphoma mutagen assay system. Mut Res. 1979;59:61-108.

Last updated on RxList: 1/20/2009

Following the ingestion of 300 mg or more of pyrimethamine, gastrointestinal and/or central nervous system signs may be present, including convulsions. The initial symptoms are usually gastrointestinal and may include abdominal pain, nausea, severe and repeated vomiting, possibly including hematemesis. Central nervous system toxicity may be manifest by initial excitability, generalized and prolonged convulsions which may be followed by respiratory depression, circulatory collapse, and death within a few hours. Neurological symptoms appear rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross overdosage pyrimethamine has a direct toxic effect on the central nervous system.

The fatal dose is variable, with the smallest reported fatal single dose being 375 mg. There are, however, reports of pediatric patients who have recovered after taking 375 to 625 mg.

There is no specific antidote to acute pyrimethamine poisoning. In the event of overdosage, symptomatic and supportive measures should be employed. Gastric lavage is recommended and is effective if carried out very soon after drug ingestion. Parenteral diazepam may be used to control convulsions. Folinic acid should also be administered within 2 hours of drug ingestion to be most effective in counteracting the effects on the hematopoietic system (see WARNINGS). Due to the long half-life of pyrimethamine, daily monitoring of peripheral blood counts is recommended for up to several weeks after the overdose until normal hematologic values are restored.

Use of DARAPRIM is contraindicated in patients with known hypersensitivity to pyrimethamine or to any component of the formulation. Use of the drug is also contraindicated in patients with documented megaloblastic anemia due to folate deficiency.

Last updated on RxList: 1/20/2009

Pyrimethamine is well absorbed with peak levels occurring between 2 to 6 hours following administration. It is eliminated slowly and has a plasma half-life of approximately 96 hours. Pyrimethamine is 87% bound to human plasma proteins.

Microbiology

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 possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito.

The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides. This was demonstrated by Eyles and Coleman¹ in the treatment of experimental toxoplasmosis in the mouse. Jacobs et al² demonstrated that combination of the 2 drugs effectively prevented the development of severe uveitis in most rabbits following the inoculation of the anterior chamber of the eye with toxoplasma.

REFERENCES

1. Eyles DE, Coleman N. Synergistic effect of sulfadiazine and Daraprim against experimental toxoplasmosis in the mouse. Antibiot Chemother. 1953;3:483-490.

2. Jacobs L, Melton ML, Kaufman HE. Treatment of experimental ocular toxoplasmosis. Arch Ophthalmol. 1964;71:111-118.

Last updated on RxList: 1/20/2009

Patients should be warned that at the first appearance of a skin rash they should stop use of DARAPRIM and seek medical attention immediately. Patients should also be warned that the appearance of sore throat, pallor, purpura, or glossitis may be early indications of serious disorders which require treatment with DARAPRIM to be stopped and medical treatment to be sought.

Women of childbearing potential who are taking DARAPRIM should be warned against becoming pregnant. Patients should be warned to keep DARAPRIM out of the reach of children. Patients should be advised not to exceed recommended doses. Patients should be warned that if anorexia and vomiting occur, they may be minimized by taking the drug with meals.

Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis in all patients.

Last updated on RxList: 1/20/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PYRIMETHAMINE - ORAL

(pir-ih-METH-uh-meen)

COMMON BRAND NAME(S): Daraprim

USES: This medication is usually used with other medications to treat a certain parasite infection of the body, brain, or eye (toxoplasmosis). Usually, pyrimethamine is no longer recommended for prevention or treatment of malaria. Pyrimethamine belongs to a class of drugs known as antiparasitics. It works by killing the parasites.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used with other medications for the prevention and treatment of Pneumocystis pneumonia in AIDS patients. It is also used to treat an intestine infection with Isospora.

HOW TO USE: Take this medication by mouth with or without food, exactly as prescribed by your doctor. Pyrimethamine is usually taken once daily depending on the type of infection. If this medication causes nausea or stomach upset, take it with food.

Dosage is based on the type of infection, your age, your response to treatment. The length of time you will take this medication depends on your infection but is usually 4 to 8 weeks. Your doctor may prescribe another medication (folinic acid) to decrease the side effects.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug and other antiparasitic drugs at evenly spaced intervals, exactly as prescribed by your doctor. To help you remember, take it at the same time each day.

Do not take more or less of this drug than prescribed. Do not stop taking it before completing this prescription unless directed to do so by your doctor, even if you feel better. Skipping or changing your dose without approval from your doctor may cause the amount of parasite to increase, make the infection more difficult to treat (resistant), or worsen side effects.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: See also Overdose section.

Nausea, vomiting, and loss of appetite may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication may develop serious side effects, especially at higher doses. This risk can be reduced with the use of folinic acid and frequent visits to your doctor.

Tell your doctor immediately if any of these unlikely but serious side effects occur: signs of serious infection (e.g., high fever, severe chills, persistent sore throat), easy bruising/bleeding, severe tiredness, pale lips/nails/skin, fast heartbeat/breathing with usual activities, flattening of taste buds of the tongue.

Tell your doctor immediately if any of these rare but very serious side effects occur: bloody/pink urine, dry cough, wheezing, chest pain, irregular heartbeat.

A very serious allergic reaction to this drug is rare. However, stop this medication immediately and seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking pyrimethamine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain type of low red blood cells (megaloblastic anemia due to low blood folate).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: seizures, kidney problems, liver problems, decreased blood folate from other conditions (e.g., problems with absorption of food, alcoholism), low red/white blood cell counts, low blood-clotting cell (platelet) count.

Caution is advised when using this drug in the elderly because they may be more sensitive to its effects, especially blood cell problems.

During pregnancy, this medication should be used only when clearly needed. Your blood folate levels may be lower if you are pregnant, making drug side effects more likely to occur. Discuss the risks and benefits with your doctor.

This drug passes into breast milk. Due to the possibility of severe side effects in your nursing infant, avoid breastfeeding while taking pyrimethamine. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medication because very serious interactions may occur: penicillamine.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting pyrimethamine.

Before using pyrimethamine, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of drugs that may cause a decrease in white blood cells: sulfa drugs (e.g., sulfamethoxazole), trimethoprim, proguanil, zidovudine, chemotherapy drugs (e.g., methotrexate).

Also tell your doctor or pharmacist if you are taking lorazepam or drugs that may lower blood folate levels (e.g., phenytoin).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: abdominal pain, persistent nausea, severe and repeated vomiting, vomiting blood, seizures, fainting, very slow breathing, inability to wake up.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood cell counts, platelet count, liver blood tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-77 degrees F (15-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.