Fansidar is an antimalarial agent, each tablet containing 500 mg N¹-(5,6-dimethoxy-4-pyrimidinyl) sulfanilamide (sulfadoxine) and 25 mg 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (pyrimethamine). Each tablet also contains cornstarch, gelatin, lactose, magnesium stearate and talc.

Last updated on RxList: 10/10/2008

Treatment of Acute Malaria

Fansidar is indicated for the treatment of acute, uncomplicated P. falciparum malaria for those patients in whom chloroquine resistance is suspected. However, strains of P. falciparum (see CLINICAL PHARMACOLOGY: Microbiology) may be encountered which have developed resistance to Fansidar, in which case alternative treatment should be administered.

Prevention of Malaria

Malaria prophylaxis with Fansidar is not routinely recommended and should only be considered for travelers to areas where chloroquine-resistant P. falciparum malaria is endemic and sensitive to Fansidar, and when alternative drugs are not available or are contraindicated (see CONTRAINDICATIONS). However, strains of P. falciparum may be encountered which have developed resistance to Fansidar.

(See INDICATIONS AND USAGE)

The dosage should be swallowed whole, and not chewed, with plenty of fluids after a meal.

Treatment of Acute Malaria

Prevention of Malaria

The malaria risk must be carefully weighed against the risk of serious adverse drug reactions (see INDICATIONS AND USAGE). If Fansidar is prescribed for prophylaxis, it is important that the physician inquires about sulfonamide intolerance and points out the risk and the need for immediate drug withdrawal if skin reactions do occur.

The first dose of Fansidar should be taken 1 or 2 days before arrival in an endemic area; administration should be continued during the stay and for 4 to 6 weeks after return.

Prophylaxis with Fansidar should not be continued for more than two years, since no experience of more prolonged administration is available to date.

Scored tablets, containing 500 mg sulfadoxine and 25 mg pyrimethamine — unit dose packages of 25 (NDC-0004-0161-03). Imprint on tablets: FANSIDAR ((ROCHE LOGO)) ROCHE.

Manufactured by: F. Hoffmann-La Roche Ltd. Basel, Switzerland. Distributed by: Roche Laboratories Inc., 340 Kingsland Street, Nutley, New Jersey, NJ 07110-1199. Revised: August 2004. FDA revision date: 2/26/2004

Last updated on RxList: 10/10/2008

For completeness, all major reactions to sulfonamides and to pyrimethamine are included below, even though they may not have been reported with Fansidar (see WARNINGS and PRECAUTIONS: Information For The Patient).

Hematological Changes

Agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, and eosinophilia.

Skin and Miscellaneous Sites Allergic Reactions

Erythema multiforme, Stevens-Johnson syndrome, generalized skin eruptions, toxic epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis, anaphylactoid reactions, periorbital edema, conjunctival and scleral injection, photosensitization, arthralgia, allergic myocarditis, slight hair loss, Lyell's syndrome,

Gastrointestinal Reactions

Glossitis, stomatitis, nausea, emesis, abdominal pains, hepatitis, hepatocellular necrosis, diarrhea, pancreatitis, feeling of fullness, and transient rise of liver enzymes.

Central Nervous System Reactions

Headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo, insomnia, apathy, fatigue, muscle weakness, nervousness, and polyneuritis.

Respiratory Reactions

Pulmonary infiltrates resembling eosinophilic or allergic alveolitis.

Genitourinary

Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria.

Miscellaneous Reactions

Drug fever, chills, periarteritis nodosa and LE phenomenon have occurred.

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides, and long-term administration has produced thyroid malignancies in the species.

There have been reports which may indicate an increase in incidence and severity of adverse reactions when chloroquine is used with Fansidar as compared to the use of Fansidar alone. Fansidar is compatible with quinine and with antibiotics. However, antifolic drugs such as sulfonamides, trimethoprim, or trimethoprim-sulfamethoxazole combinations should not be used while the patient is receiving Fansidar for antimalarial prophylaxis. Fansidar has not been reported to interfere with antidiabetic agents.

If signs of folic acid deficiency develop, Fansidar should be discontinued. When recovery of depressed platelets or white blood cell counts in patients with drug-induced folic acid deficiency is too slow, folinic acid (leucovorin) may be administered in doses of 5 to 15 mg intramuscularly daily for 3 days or longer.

Last updated on RxList: 10/10/2008

Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Fansidar prophylactic regimen has been reported to cause leukopenia during a treatment of 2 months or longer. This leukopenia is generally mild and reversible.

General

Oral Fansidar has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema or renal failure. Patients with severe malaria are not candidates for oral therapy. In the event of recrudescent P. falciparum infections after treatment with Fansidar or failure of chemoprophylaxis with Fansidar, patients should be treated with a different blood schizonticide.

Fansidar should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency and to those with severe allergy or bronchial asthma. As with some sulfonamide drugs, in glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. Urinalysis with microscopic examination and renal function tests should be performed during therapy of those patients who have impaired renal function. Excessive sun exposure should be avoided.

Laboratory Tests

Regularly scheduled complete blood counts, liver enzyme tests and analysis of urine for crystalluria should be performed whenever Fansidar is administered for more than three months.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pyrimethamine was not found carcinogenic in female mice or in male and female rats. The carcinogenic potential of pyrimethamine in male mice could not be assessed from the study because of markedly reduced life-span. Pyrimethamine was found to be mutagenic in laboratory animals and also in human bone marrow following 3 or 4 consecutive daily doses totaling 200 mg to 300 mg. Pyrimethamine was not found mutagenic in the Ames test. Testicular changes have been observed in rats treated with 105 mg/kg/day of Fansidar and with 15 mg/kg/day of pyrimethamine alone. Fertility of male rats and the ability of male or female rats to mate were not adversely affected at dosages of up to 210 mg/kg/day of Fansidar. The pregnancy rate of female rats was not affected following their treatment with 10.5 mg/kg/day, but was significantly reduced at dosages of 31.5 mg/kg/day or higher, a dosage approximately 30 times the weekly human prophylactic dose or higher.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Fansidar has been shown to be teratogenic in rats when given in weekly doses approximately 12 times the weekly human prophylactic dose. Teratology studies with pyrimethamine plus sulfadoxine (1:20) in rats showed the minimum oral teratogenic dose to be approximately 0.9 mg/kg pyrimethamine plus 18 mg/kg sulfadoxine. In rabbits, no teratogenic effects were noted at oral doses as high as 20 mg/kg pyrimethamine plus 400 mg/kg sulfadoxine.

There are no adequate and well-controlled studies in pregnant women. However, due to the teratogenic effect shown in animals and because pyrimethamine plus sulfadoxine may interfere with folic acid metabolism, Fansidar therapy should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing potential who are traveling to areas where malaria is endemic should be warned against becoming pregnant, and should be advised to practice contraception during prophylaxis with Fansidar and for three months after the last dose.

Nonteratogenic Effects

See CONTRAINDICATIONS.

Nursing Mothers

See CONTRAINDICATIONS.

Pediatric Use

Fansidar should not be given to infants less than 2 months of age because of inadequate development of the glucuronide-forming enzyme system.

Geriatric Use

Clinical studies of Fansidar 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Last updated on RxList: 10/10/2008

Acute intoxication may be manifested by headache, nausea, anorexia, vomiting and central nervous system stimulation (including convulsions), followed by megaloblastic anemia, leukopenia, thrombocytopenia, glossitis and crystalluria. In acute intoxication, emesis and gastric lavage followed by purges may be of benefit. The patient should be adequately hydrated to prevent renal damage. The renal, hepatic, and hematopoietic systems should be monitored for at least 1 month after an overdosage. If the patient is having convulsions, the use of parenteral diazepam or a barbiturate is indicated. For depressed platelet or white blood cell counts, folinic acid (leucovorin) should be administered in a dosage of 5 mg to 15 mg intramuscularly daily for 3 days or longer.

• Repeated prophylactic (prolonged) use of Fansidar is contraindicated in patients with renal or hepatic failure or with blood dyscrasias;
• Hypersensitivity to pyrimethamine, sulfonamides, or any other ingredient of Fansidar;
• Patients with documented megaloblastic anemia due to folate deficiency;
• Infants less than 2 months of age;
• Prophylactic use of Fansidar in pregnancy at term and during the nursing period.

Last updated on RxList: 10/10/2008

Microbiology

Mechanism of Action

Sulfadoxine and pyrimethamine, the constituents of Fansidar, are folic acid antagonists. Sulfadoxine inhibits the activity of dihydropteroate synthase whereas pyrimethamine inhibits dihydrofolate reductase.

Activity in vitro

Sulfadoxine and pyrimethamine are active against the asexual erythrocytic stages of Plasmodium falciparum. Fansidar may also be effective against strains of P. falciparum resistant to chloroquine.

Drug Resistance

Strains of P. falciparum with decreased susceptibility to sulfadoxine and/or pyrimethamine can be selected in vitro or in vivo. P. falciparum malaria that is clinically resistant to Fansidar occurs frequently in parts of Southeast Asia and South America, and is also prevalent in East and Central Africa. Therefore, Fansidar should be used with caution in these areas. Likewise, Fansidar may not be effective for treatment of recrudescent malaria that develops after prior therapy (or prophylaxis) with Fansidar.

Pharmacokinetics

Absorption

After administration of 1 tablet, peak plasma levels for pyrimethamine (approximately 0.2 mg/L) and for sulfadoxine (approximately 60 mg/L) are reached after about 4 hours.

Distribution

The volume of distribution for sulfadoxine and pyrimethamine is 0.14 L/kg and 2.3 L/kg, respectively.

Patients taking 1 tablet a week (recommended adult dose for malaria prophylaxis) can be expected to have mean steady state plasma concentrations of about 0.15 mg/L for pyrimethamine after about four weeks and about 98 mg/L for sulfadoxine after about seven weeks. Plasma protein binding is about 90% for both pyrimethamine and sulfadoxine. Both pyrimethamine and sulfadoxine cross the placental barrier and pass into breast milk.

Metabolism

About 5% of sulfadoxine appears in the plasma as acetylated metabolite, about 2 to 3% as the glucuronide. Pyrimethamine is transformed to several unidentified metabolites.

Elimination

A relatively long elimination half-life is characteristic of both components. The mean values are about 100 hours for pyrimethamine and about 200 hours for sulfadoxine. Both pyrimethamine and sulfadoxine are eliminated mainly via the kidneys.

Characteristics in Patients

In malaria patients, single pharmacokinetic parameters may differ from those in healthy subjects, depending on the population concerned. In patients with renal insufficiency, delayed elimination of the components of Fansidar must be anticipated.

Last updated on RxList: 10/10/2008

Patients should be warned that at the first appearance of a skin rash, they should stop use of Fansidar and seek medical attention immediately. Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.

Patients should also be warned that the appearance of sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura, jaundice or glossitis may be early indications of serious disorders which require prophylactic treatment to be stopped and medical treatment to be sought.

Females should be cautioned against becoming pregnant and should not breastfeed their infants during Fansidar therapy or prophylactic treatment.

Patients should be warned to keep Fansidar out of reach of children.

Patients also should be advised:

• that malaria can be a life-threatening infection;
• that Fansidar is being prescribed to help prevent or treat this serious infection;
• that no chemoprophylactic regimen is 100% effective, and protective clothing, insect repellents, and bednets are important components of malaria prophylaxis;
• to seek medical attention for any febrile illness that occurs after return from a malarious area and inform their physician that they may have been exposed to malaria;
• that in a small percentage of cases, patients are unable to take this medication because of side effects, and it may be necessary to change medications;
• that when used as prophylaxis, the first dose of Fansidar should be taken 1 or 2 days prior to arrival in an endemic area;
• that if the patient experiences any symptom that may affect the ability to take this drug as prescribed, the physician should be contacted and alternative antimalarial medication should be considered.

Last updated on RxList: 10/10/2008

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.

SULFADOXINE/PYRIMETHAMINE - ORAL

(sull-fuh-DOX-een/pir-ih-METH-uh-meen)

COMMON BRAND NAME(S): Fansidar

WARNING: Sulfadoxine/pyrimethamine has caused sometimes severe, fatal allergic reactions. These severe reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) usually start with a skin rash. You should stop taking sulfadoxine/pyrimethamine at the first sign of a rash and seek immediate medical attention.

Sulfadoxine/pyrimethamine has also caused severe decreases in white blood cells. This can result in severe, sometimes fatal infections. If you experience symptoms of a severe infection (e.g., high fever, severe chills, muscle aches, persistent sore throat), stop this medication and seek immediate medical attention.

USES: This medication contains 2 medicines, sulfadoxine and pyrimethamine. It is used to treat a serious, possibly fatal, parasite infection of the red blood cells (malaria caused by Plasmodium falciparum) when other medications cannot be used. It is used if the infection is suspected of being resistant to other malaria medications (e.g., chloroquine). Sulfadoxine/pyrimethamine belongs to a class of drugs known as antimalarials. It works by killing the form of the malaria parasite that infects the red blood cells. This medication does not treat a return of the same malaria infection (relapse). Other medications should be used for this purpose.

Due to the possibility of severe side effects, this medication should not be used for the prevention of malaria unless other medications cannot be taken.

HOW TO USE: To treat a malaria infection, take this medication by mouth after a meal as a single dose, exactly as prescribed by your doctor. Do not crush or chew the tablets. Take this drug with at least a full glass of fluid (8 ounces or 240 milliliters). Drink lots of fluids (6 to 8 glasses a day) for the next 7 to 10 days.

For prevention of malaria, take this medication by mouth, usually once weekly or once every 2 weeks, or as directed by your doctor. Start this medication 1 to 2 days before you enter the malaria area, and continue for 4 to 6 weeks after leaving it. Drink lots of fluids (6 to 8 glasses a day, each glass 8 ounces/240 milliliters) for the entire time that you are taking this medication and for at least 7 to 10 days after your last dose.

Dosage is based on your weight, medical condition, and response to treatment.

If you are taking this medication for prevention, it is very important to continue taking it exactly as prescribed by your doctor. This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it at the same time each day for the prescribed time period.

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 well or better from a malaria attack. Skipping or changing your dose without approval from your doctor may cause prevention treatment to be ineffective, cause the amount of parasite to increase during treatment of a malaria attack, make the infection more difficult to treat (resistant), or worsen side effects.

No drug treatment is completely effective in preventing malaria, and it is still possible to get malaria, no matter what prevention treatment is used. Seek immediate medical attention if you develop symptoms of malaria (e.g., fever, chills, headache, other flu-like symptoms) while traveling or after return, especially for 2 months after completing this prescription.

It is important to take measures to reduce contact with mosquitoes (e.g., using appropriate insect repellents, wearing clothes that cover most of the body, remaining in air-conditioned or well-screened areas, using mosquito nets, using insect sprays). Obtain insect repellent before traveling. The most effective insect repellents contain diethyltoluamide (DEET). Ask your doctor or pharmacist to recommend an appropriate strength of mosquito repellent for you or your children.

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, and loss of appetite may occur. This product may make you more sensitive to the sun and sunburn (see also Precautions section). Less common side effects may include headache, lightheadedness, trouble sleeping, tiredness, or irritability. 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 do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mouth sores, diarrhea, increased sensitivity to touch, tingling/numbness/pain, mental/mood changes (e.g., depression, hallucinations, nervousness), ringing in the ears, muscle weakness, severe dizziness.

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, signs of low red blood cells (e.g., severe tiredness, pale lips/nails/skin, fast heartbeat, rapid breathing at rest), flattening of taste buds of the tongue, lower abdominal/back pain, bloody/pink urine, decreased urination, dry cough, wheezing, chest pain, irregular heartbeat, signs of severe liver problems (e.g., severe tiredness, persistent nausea/vomiting, yellowing skin/eyes, abdominal pain, dark urine).

A very serious allergic reaction to this drug is rare. However, 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: See also Warning section.

Before taking sulfadoxine/pyrimethamine, tell your doctor or pharmacist if you are allergic to either sulfadoxine or pyrimethamine; or to other "sulfa" drugs (e.g., sulfamethoxazole, sulfisoxazole); or if you have any other allergies.

This medication should not be used to prevent malaria for longer than 2 years if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: kidney problems, liver problems, low white blood cell count, low platelet count.

This medication should not be used for any reason if you have: a certain type of low red blood cells (megaloblastic anemia due to low blood folate), a certain enzyme problem (glucose-6-phosphate dehydrogenase deficiency-G6PD), a certain blood/liver problem (porphyria).

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 cells (platelets).

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

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

This medication should not be used if possible in children younger than 2 months because it contains a sulfa drug, which can cause a serious (possibly fatal) brain condition in some infants. Consult your doctor for more details.

This medication should not be used during the last 3 months of pregnancy. During the first 6 months of pregnancy, this medication should be used only when clearly needed. 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 breast-feeding while taking sulfadoxine/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 medications because very serious interactions may occur: other sulfa drugs (e.g., sulfamethoxazole, sulfisoxazole), trimethoprim, chloroquine, penicillamine, methenamine.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting sulfadoxine/pyrimethamine.

Before using this medication, 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 (e.g., trimethoprim, proguanil, zidovudine, chemotherapy drugs such as methotrexate), lorazepam, warfarin, cyclosporine, PABA (para-aminobenzoic acid), 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, dangerously slowed breathing, inability to wake up.

NOTES: Do not share this medication with others.

If you are taking this medication for longer than 3 months, laboratory and/or medical tests (e.g., blood cell counts, liver tests, urine test) 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 77 degrees F (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.