Prescription Drugs

CLINICAL PHARMACOLOGY Microbiology Mechanism of Action Sulfadoxine and pyrimethamine, the constituents of Fansidar (sulfadoxine and pyrimethamine) , 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 (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) occurs frequently in parts of Southeast Asia and South America, and is also prevalent in East and Central Africa. Therefore, Fansidar (sulfadoxine and pyrimethamine) should be used with caution in these areas. Likewise, Fansidar (sulfadoxine and pyrimethamine) may not be effective for treatment of recrudescent malaria that develops after prior therapy (or prophylaxis) with Fansidar (sulfadoxine and pyrimethamine) . 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 (sulfadoxine and pyrimethamine) must be anticipated.

Fansidar® (sulfadoxine and pyrimethamine) Tablets WARNING FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF FANSIDAR (sulfadoxine and pyrimethamine) HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. FANSIDAR (sulfadoxine and pyrimethamine) PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH, IF A SIGNIFICANT REDUCTION IN THE COUNT OF ANY FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE OCCURRENCE OF ACTIVE BACTERIAL OR FUNGAL INFECTIONS. DESCRIPTION Fansidar (sulfadoxine and pyrimethamine) 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.

INDICATIONS Treatment of Acute Malaria Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) , in which case alternative treatment should be administered. Prevention of Malaria Malaria prophylaxis with Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) , 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 (sulfadoxine and pyrimethamine) . DOSAGE AND ADMINISTRATION (See INDICATIONS AND USAGE) The dosage should be swallowed whole, and not chewed, with plenty of fluids after a meal. Treatment of Acute Malaria Adults 2 to 3 tablets taken as a single dose. Pediatric patients (>2 months to 18 years) The dosage for treatment of malaria in children is based upon body weight: Weight (kg) Number of Tablets Taken as a Single Dose >45 3 31 to 45 2 21 to 30 1 ½ 11 to 20 1 5 to 10 ½ Prevention of Malaria The malaria risk must be carefully weighed against the risk of serious adverse drug reactions (see INDICATIONS AND USAGE). If Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) 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. Once Weekly Once Every 2 Weeks Adults 1 tablet 2 tablets Pediatric patients (>2 months to 18 years) The dosage for prevention of malaria in children is based upon body weight: Weight (kg) Number of Tablets Taken Once Weekly >45 1½ 31 to 45 1 21 to 30 ¾ 11 to 20 ½ 5 to 10 ¼ Prophylaxis with Fansidar (sulfadoxine and pyrimethamine) should not be continued for more than two years, since no experience of more prolonged administration is available to date. HOW SUPPLIED Scored tablets, containing 500 mg sulfadoxine and 25 mg pyrimethamine — unit dose packages of 25 (NDC-0004-0161-03). Imprint on tablets: FANSIDAR (sulfadoxine and pyrimethamine) ((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

SIDE EFFECTS 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. DRUG INTERACTIONS There have been reports which may indicate an increase in incidence and severity of adverse reactions when chloroquine is used with Fansidar (sulfadoxine and pyrimethamine) as compared to the use of Fansidar (sulfadoxine and pyrimethamine) alone. Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) for antimalarial prophylaxis. Fansidar (sulfadoxine and pyrimethamine) has not been reported to interfere with antidiabetic agents. If signs of folic acid deficiency develop, Fansidar (sulfadoxine and pyrimethamine) 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.

WARNINGS FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF FANSIDAR (sulfadoxine and pyrimethamine) HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. FANSIDAR (sulfadoxine and pyrimethamine) PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH, IF A SIGNIFICANT REDUCTION IN THE COUNT OF ANY FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE OCCURRENCE OF ACTIVE BACTERIAL OR FUNGAL INFECTIONS. 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 (sulfadoxine and pyrimethamine) prophylactic regimen has been reported to cause leukopenia during a treatment of 2 months or longer. This leukopenia is generally mild and reversible. PRECAUTIONS General Oral Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) or failure of chemoprophylaxis with Fansidar (sulfadoxine and pyrimethamine) , patients should be treated with a different blood schizonticide. Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) . 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 (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) and for three months after the last dose. Nonteratogenic Effects See CONTRAINDICATIONS. Nursing Mothers See CONTRAINDICATIONS. Pediatric Use Fansidar (sulfadoxine and pyrimethamine) 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 (sulfadoxine and pyrimethamine) 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.