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FANSIDAR«
Roche
Sulfadoxine - Pyrimethamine
Antimalarial
 
Action And Clinical Pharmacology: Fansidar is a combination of sulfadoxine and pyrimethamine, which inhibits sequential steps involved in the biosynthesis of tetrahydrofolic acid. This depletes folic acid, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. Sulfadoxine is a structural analogue of para-aminobenzoic acid (PABA) and competitively inhibits the enzyme dihydropteroate synthetase. Pyrimethamine is a competitive inhibitor of the enzyme dihydrofolate reductase. The effect of the dual sequential action is to reduce the minimum effective dose of each agent (synergism). tag_IndicationsIndications

Indications And Clinical Uses: Treatment (Single Administration): For the treatment of patients with P. falciparum malaria when chloroquine resistance is suspected and oral treatment is appropriate.

Prophylaxis (Repeated Administration): Fansidar is not routinely recommended for malaria prophylaxis. Prophylaxis with Fansidar can only be considered for areas where P. falciparum malaria is endemic and sensitive to Fansidar, and when alternative drugs are not available or are contraindicated.

Strains of P. falciparum may be encountered which have developed resistance to Fansidar.

Contra-Indications: Treatment and Prophylaxis: Known hypersensitivity to sulfonamides or to pyrimethamine. If skin reactions are observed, Fansidar must be withdrawn immediately, as these may be indicative of a life-threatening reaction to the drug. Premature or newborn infants during the first 2 months of life, due to immaturity of the glucuronide-forming enzyme system. Patients with acute intermittent porphyria and variegate porphyria, because sulfonamides are reported to precipitate acute attacks of porphyria.

Prophylaxis (Repeated Administration): In the prophylactic treatment of: patients with severe renal insufficiency, marked liver parenchymal disease or blood dyscrasias; patients with megaloblastic anemia due to folate deficiency because of the antifolate action of the sulfonamide component; pregnant women at term because sulfonamides cross the placenta and may cause kernicterus (see Warnings); and women who are nursing because sulfonamides are excreted in breast milk and may cause kernicterus (see Warnings).

Manufacturers' Warnings In Clinical States: Fatalities associated with the administration of Fansidar have occurred due to severe hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Fansidar 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 Fansidar have occurred due to severe reactions including fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

Excessive exposure to the sun must be strictly avoided, since sulfonamides may induce photosensitivity reactions. Such exposure (especially when sunburn ensues), may also play a decisive role in the occurrence of severe cutaneous adverse reactions to Fansidar.

Leukopenia has been reported in patients treated with Fansidar.

Fansidar used prophylactically (repeated administration) has been associated with lower white blood cell counts and reduced serum folate concentrations. It should not be used in conjunction with other antifolate agents.

Hemolysis may occur in individuals administered Fansidar who are deficient in glucose-6-phosphate dehydrogenase.

An increased incidence of severe adverse reactions may occur in elderly patients receiving sulfonamides, particularly when complicating conditions exist; for example, impaired kidney and/or liver function or concomitant use of other drugs. Similar effects could be anticipated with Fansidar.

Compared with the general population, the incidence of side effects (rash, fever and leukopenia) with trimethoprim-sulfamethoxazole therapy in patients with Acquired Immunodeficiency Syndrome (AIDS) has been reported to be increased. AIDS patients treated with Fansidar may have a similar increased risk, especially if they have previously reacted to cotrimoxazole.

Pregnancy and Lactation (see also Contraindications): The safety of Fansidar (treatment or prophylaxis) during human pregnancy has not been established. It should not be used by pregnant women at term. The potential benefit of the use of Fansidar for malaria treatment or prophylaxis during earlier stages of pregnancy must be carefully weighed against the potential risk to the embryo or fetus. Both pyrimidine and sulfadoxine cross the placental barrier and pass into breast milk.

Malaria is associated with increased maternal and fetal mortality. Fansidar is teratogenic in rats at low multiples of the human dose and is embryolethal at higher doses. Women who are travelling to areas where malaria is endemic should be warned of the risks associated with malaria and with Fansidar during pregnancy.

Precautions: The changing patterns and degree of parasite resistance to antimalarial drugs in various parts of the world and the resultant changes in recommended antimalarial therapy should be reviewed prior to the prescription of Fansidar.

Fansidar should be given only with caution to patients with impaired renal or hepatic function, to those with severe allergy or bronchial asthma, and to those with possible folate deficiency. Subclinical folate deficiency may be anticipated if one or more of the following occur: improper nutrition, excessive alcohol intake, advanced age, pregnancy, and use of antifolate agents. When patients are administered Fansidar prophylactically, urinalysis with microscopic examination, renal function tests and complete blood counts should be performed periodically.

Travellers using Fansidar for prophylactic therapy should be cautioned that the appearance of skin rash, sore throat, fever, pallor, purpura, jaundice or glossitis may be early indications of serious disorders. They should be instructed to discontinue the use of the drug and seek medical advice immediately.

During treatment, adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.

Severe orthostatic hypotension has been associated with the administration of a single 3 tablet dose of Fansidar for the treatment of malaria. Orthostatic hypotension is also a common and prominent clinical feature of malaria, and may be exacerbated by the administration of Fansidar. Patients should be advised that they may become faint following the ingestion of Fansidar for the treatment of malaria.

Drug Interactions: Limited data exist regarding potential interactions between Fansidar and other antimalarial drugs. The concurrent or sequential use of Fansidar and quinine is not known to produce increased adverse drug reactions or interactions.

There have been reports which may indicate an increase in incidence and severity of adverse reactions when chloroquine is used with Fansidar.

Fansidar should not be taken with antibiotics having antifolic acid activity.

Folic acid supplements (folinic acid; leucovorin) may antagonize the action of Fansidar. Consequently, the effectiveness of Fansidar may be reduced by the concomitant administration of folic acid.

The combined use of Fansidar with other drugs having antifolate activity may produce megaloblastic anemia. Thus, pyrimethamine, trimethoprim, sulfonamides or trimethoprim-sulfamethoxazole combinations should not be used while the patient is receiving Fansidar prophylactically.

If signs of folic acid deficiency develop, discontinue the administration of Fansidar. The administration of folic acid supplements (folinic acid; leucovorin) may be considered for cases in which depressed platelets or white blood cell counts may be due to drug induced folate deficiency.

Plasma protein binding displacement and/or inhibition of hepatic metabolism may account for a number of interactions between sulfonamides and other drugs (e.g. phenylbutazone, oxyphenbutazone, salicylates and sulfinpyrazone). Sulfonamides have been reported to increase the half-life and inhibit the hepatic metabolism of phenytoin.

The sulfonamide in Fansidar may displace orally administered anticoagulants from their carrier proteins which may result in an increased anticoagulant effect.

Diuresis and hypoglycemia have occurred in patients receiving sulfonamides. Similar effects could be anticipated with Fansidar. Since the sulfonamide component bears chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents, the possibility of an interaction exists. The blood glucose-lowering effect of sulfonamides should be borne in mind when prescribing Fansidar to patients with diabetes.

Para-aminobenzoic acid (PABA) or its derivatives antagonize the action of sulfonamides. It has been reported that the percutaneous absorption of PABA from sunscreen preparations is 1.6 to 9.6% of the applied dose. Therefore, the possibility of an interaction between PABA and the sulfadoxine component of Fansidar should be considered in patients using sunscreens concomitantly with this drug.

Mutagenicity, Carcinogenicity and Impairment of Fertility: The significance to humans of the following laboratory observations has not been determined. Pyrimethamine was found to be mutagenic to mouse and human bone marrow cells in addition to rat embryo. A carcinogenicity study in mouse suggested a dose related increase in pulmonary tumors but was inconclusive due to reduced survival. Although the fertility of male rats was unaffected, a delay in sperm maturation was noted. Fertility was, however, significantly affected in female rats and teratogenic effects were observed.

Adverse Reactions: Fansidar use has been associated with severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis). The incidence of such reactions during prophylactic use in U.S. patients administered concomitant chloroquine has been estimated as 1:5 000 to 1:8 000 with a risk of fatality of 1:11 000 to 1:25 000. Similar incidences of severe cutaneous reactions (1:10 000) and fatalities (1:35 000) following Fansidar monoprophylaxis have been reported in Sweden. Amongst Swiss travellers, however, the estimated incidence of reactions is lower (1:150 000), with no fatalities reported.

For completeness, major reactions to sulfonamides or to pyrimethamine are included below. Most of these reactions have been reported with Fansidar.

Allergic: erythema multiforme, Stevens-Johnson syndrome, generalized skin eruptions, toxic epidermal necrolysis, urticaria, SÚzary syndrome-like erythroderma, angioedema, serum sickness, pruritus, exfoliative dermatitis, bruising, petechia, anaphylactoid reactions, periorbital edema, conjunctival and scleral injection, photosensitization, photodermatitis, arthralgia, myalgia, allergic myocarditis, drug fever, vasculitis, allergic pericarditis. Pulmonary hypersensitivity reactions and a fatal reaction involving the skin (toxic epidermal necrolysis), liver and kidneys have also been reported.

Blood Dyscrasias: agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, and eosinophilia.

Gastrointestinal: glossitis, stomatitis, gastritis, dyspepsia, dry mouth, black tongue, gastroenteritis, anorexia, nausea, vomiting, abdominal pains, diarrhea, pancreatitis, and pseudomembranous enterocolitis.

Mild, transient gastrointestinal reactions (nausea,vomiting, abdominal pain, diarrhea) occurred in 30% of 50 male patients with symptomatic falciparum malaria administered a 3-tablet treatment dose of Fansidar.

Hepatic: abnormal liver function test results (e.g. elevated serum ALT, AST, alkaline phosphatase and bilirubin concentrations), jaundice, hepatitis, hepatocellular necrosis and hepatic granulomas.

CNS: headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo, dizziness, insomnia, apathy, fatigue, muscle weakness and nervousness.

Mild, transient dizziness and tinnitus occurred in 6% of 50 male patients.

Respiratory: pulmonary infiltrates, pneumonitis, dyspnea.

Miscellaneous: chills, alopecia, epistaxis, toxic nephrosis with oliguria, anuria, dysuria, crystalluria, hematuria, bloody stool, jaundice, renal failure. Orthostatic hypotension and sinus bradycardia. Orthostatic hypotension and sinus bradycardia occurred in 20% and 32% respectively, of 50 male patients with symptomatic falciparum malaria administered a 3-tablet treatment dose of Fansidar. Four of the patients with sinus bradycardia had abnormal heartbeat prior to treatment. Periarteritis nodosa and lupus erythematosus and Jarisch-Herxheimer-like phenomenon have also occurred.

Canadian data provided by physicians or their patients who received Fansidar alone or in combination with chloroquine for prophylactic use were analyzed retrospectively. Out of a total of 5 089 individuals, 1 632 or 32% of these patients experienced approximately 3 840 adverse reactions (2.4/individual), judged to be possibly drug related. The reaction(s) reported for 33 patients were rated as serious. Seventeen of these 33 patients, 15 of whom received concomitant chloroquine, reported skin reactions, including one case of a Stevens-Johnson-like syndrome. One case of disseminated intravascular coagulation and a severe hematological reaction were also reported in 2 elderly women. The 96 individuals who received Fansidar alone reported 180 possible adverse reactions. The most frequently occurring reactions were those of the gastrointestinal tract (n=68) and CNS (n=31). Effects observed included diarrhea (n=23), stomach/abdominal pain or discomfort (n=23), nausea (n=10), headache (n=13), depression, anxiety, nervousness (n=8), tiredness, fatigue, drowsiness (n=6) and dizziness and fainting (n=3). Other reactions included: skin rash (n=7), sensitivity to sunlight (n=7), itchiness (n=4), sore throat (n=4), itchy or sore eyes, visual disturbances (n=7), fever (n=10), nonspecific malaise (n=4), and flu-like symptoms (n=3).

Symptoms And Treatment Of Overdose: Symptoms: Symptoms of overdosage may include anorexia, vomiting and CNS stimulation, including convulsions. These symptoms may be followed by megaloblastic anemia, leukopenia, thrombocytopenia, glossitis and crystalluria. tag_Treatment

Treatment: The treatment of overdosage should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis and gastric lavage may be of benefit. If the drug has passed through the stomach, the administration of mineral oil may promote fecal elimination.

Because of the possibility of crystalluria and stone formation, the patient should be adequately hydrated to prevent renal damage. Since Fansidar is excreted from the body over a prolonged period of time (t 1/2: sulfadoxine=184 hours; pyrimethamine=95 hours), urine should be checked regularly for crystalluria; renal and hepatic function as well as hematopoietic systems should also be monitored for at least 1 month after an overdosage. For depressed platelet or white blood cell counts, folinic acid (leucovorin) should be administered.

If the patient experiences convulsions, appropriate anticonvulsive measures should be taken.

Dosage And Administration: Fansidar should be taken with water and, when appropriate, with food.

Treatment (Single Administration): Adults:>45 kg, a single dose of 3 tablets. Children (Fansidar should not be administered to infants less than 2 months of age): 30 to 45 kg, a single dose of 2 tablets; 11 to 29 kg, a single dose of 1 tablet; 5 to 10 kg, a single dose of 1/2 tablet.

If aparasitemia and clearance of symptoms are not achieved within 2 to 4 days, the patient should be re-evaluated.

In cases of severe infection requiring rapid emergency measures, the use of faster acting antimalarial agents may be required.

Prophylaxis (Repeated Administration): The malaria risk must be carefully weighed against the risk of serious adverse drug reactions. If Fansidar is prescribed for prophylaxis, it is important that the physician inquires about any history of sulfonamide intolerance and points out the risk and the need for immediate drug withdrawal if skin reactions occur. The first dose of Fansidar should be taken 2 weeks prior to arrival at an endemic area. Treatment should be continued on a weekly basis throughout the stay in the malarious region, and for 6 weeks subsequent to leaving the area.

Adults: >45 kg, 1 tablet once weekly. Children (Fansidar should not be administered to infants less than 2 months of age): 30 to 45 kg, 3/4 tablet once weekly; 11 to 29 kg, 1/2 tablet once weekly; 5 to 10 kg, 1/4 tablet once weekly.

Prophylaxis with Fansidar should not be continued for more than 2 years since no experience of more prolonged administration is currently available.

Impaired Renal and Hepatic Function: At the present time there is insufficient data to recommend a special dosage regimen (see Precautions).



Availability And Storage: Each white tablet, cross-scored on one face, "ROCHE" and hexagon imprint on the other face, contains sulfadoxine 500 mg and pyrimethamine 25 mg. Also contains: starch, gelatin, lactose, magnesium stearate and talc. Energy: 2.8 kJ (0.7 kcal). Packages of 3. Stable for 5 years from the date of manufacture when stored at 15 to 30░C. (Shown in Product Recognition Section)