Sulfadoxine and Pyrimethamine (Systemic)


VA CLASSIFICATION
Primary: AP101

Commonly used brand name(s): Fansidar.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiprotozoal—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Malaria (prophylaxis)—Sulfadoxine and pyrimethamine combination is indicated as a secondary agent in the prophylaxis of chloroquine-resistant Plasmodium falciparum malaria {01} {02}. However, because of its potentially life-threatening toxicity, it is not recommended for weekly use in the prophylaxis of chloroquine-resistant P. falciparum malaria in travelers to areas where chloroquine-resistant malaria is endemic. It is indicated only in persons at high risk for chloroquine-resistant malaria in remote areas who are unable to take alternative medication {01} {02} {06} {11}.

Malaria (treatment)—Sulfadoxine and pyrimethamine combination is indicated in combination with quinine as a primary agent in the treatment of chloroquine-resistant P. falciparum malaria. It is also indicated in the presumptive treatment of chloroquine-resistant P. falciparum malaria for self-treatment of febrile illness when medical care is not immediately available (within 24 hours) {01} {02} {05} {06}.

[Isosporiasis (prophylaxis) ]1—Sulfadoxine is used with pyrimethamine in the prophylaxis of isosporiasis caused by Isospora belli in patients with acquired immunodeficiency disease {04} {13}.

—Some strains of P. falciparum have developed resistance to sulfadoxine and pyrimethamine combination {01} {02}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Sulfadoxine: 310.34
    Pyrimethamine: 248.72

Mechanism of action/Effect:


Sulfadoxine:

Bacteriostatic; structural analog of aminobenzoic acid (PABA); competitively inhibits a bacterial enzyme, dihydropteroate synthetase, which is responsible for incorporation of PABA into dihydrofolic acid. This blocks the synthesis of dihydrofolic acid and decreases the amount of metabolically active tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA.

Susceptible bacteria are those that must synthesize folic acid. The action of sulfonamides is antagonized by PABA and its derivatives (e.g., procaine and tetracaine) and by the presence of pus or tissue breakdown products, which provide the necessary components for bacterial growth {01}.



Pyrimethamine:

Binds to and reversibly inhibits the protozoal enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. Protozoal dihydrofolate reductase is many times more tightly bound by pyrimethamine than is the corresponding mammalian enzyme.

Pyrimethamine exerts its effect in the folate biosynthesis at a step immediately subsequent to the one at which sulfonamides exert their effect. When pyrimethamine is administered concurrently with sulfonamides, synergism occurs, which is attributed to inhibition of tetrahydrofolate production at two sequential steps in its biosynthesis.

Pyrimethamine is active against asexual erythrocytic forms and, to a lesser degree, tissue forms of Plasmodium falciparum malaria. It does not destroy gametocytes, but arrests sporogony in the mosquito {01}.


Absorption:

Well absorbed following oral administration {01} {09} {10}.

Distribution:

Pyrimethamine—Widely distributed; mainly concentrated in red and white blood cells, kidneys, lungs, liver, and spleen. Crosses into the cerebrospinal fluid (CSF), with concentrations ranging from 13 to 26% of the corresponding serum concentrations {07}.

Sulfadoxine and pyrimethamine both cross the placenta and are distributed into breast milk.

Protein binding:

Pyrimethamine—High (87%) {03}.

Sulfadoxine—High (> 90%) {10}.

Biotransformation:

Pyrimethamine—Hepatic.

Half-life:


Elimination:

Sulfadoxine: Approximately 100 to 230 hours (mean, approximately 169 hours) {01} {10}.

Pyrimethamine: Approximately 54 to 148 hours (mean, approximately 111 hours) {01} {09}.


Time to peak plasma concentration

Sulfadoxine—2.5 to 6 hours {01} {10}.

Pyrimethamine—Approximately 3 hours (range, 2 to 6 hours) {01} {09}.

Peak plasma concentration

Sulfadoxine—Approximately 50 to 75 mcg per mL, 2.5 to 6 hours following a single oral dose of 500 mg of sulfadoxine and 25 mg of pyrimethamine {01}.

Pyrimethamine—Approximately 0.13 to 0.4 mcg per mL, 1.5 to 8 hours following a single oral dose of 500 mg of sulfadoxine and 25 mg of pyrimethamine {01}.

Elimination:


Sulfadoxine—
        Renal: Excreted primarily unchanged by the kidneys {10}.



Pyrimethamine—
        Renal: Primary route; 20 to 30% excreted unchanged in urine. Urinary excretion may persist for 30 days or longer.
        In dialysis: The serum concentration of pyrimethamine was decreased by approximately 47% after peritoneal dialysis in one patient {07}.



Precautions to Consider

Cross-sensitivity and/or related problems

For sulfadoxine—Patients allergic to one sulfonamide may be allergic to other sulfonamides also. Patients allergic to furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors may be allergic to sulfonamides also {01}.

Carcinogenicity/Tumorigenicity

For sulfadoxine—Long-term administration of sulfonamides in rats has been shown to result in thyroid malignancies {01}.

For pyrimethamine—Pyrimethamine has not been shown to be carcinogenic in female mice or in male or female rats {01}.

Mutagenicity

For pyrimethamine—Pyrimethamine has been shown to be mutagenic in laboratory animals and in human bone marrow following three or four consecutive daily doses totaling 200 to 300 mg. However, pyrimethamine has not been shown to be mutagenic in the Ames test {01}.

Pregnancy/Reproduction
Fertility—
Studies in rats given sulfadoxine and pyrimethamine combination in doses of 105 mg per kg of body weight (mg/kg) daily or pyrimethamine alone in doses of 15 mg/kg daily have shown that both regimens cause testicular changes.

The fertility of male rats and the ability of male or female rats to mate has not been shown to be adversely affected when sulfadoxine and pyrimethamine combination was given in doses of up to 210 mg/kg daily.

The pregnancy rate of female rats was significantly reduced when the rats were given doses of 31.5 mg/kg daily (approximately 30 times the weekly prophylactic dose) or higher, but was not adversely affected at doses of 10.5 mg/kg daily {01}.

Pregnancy—
Sulfonamides and pyrimethamine cross the placenta. Adequate and well-controlled studies in humans have not been done {01}. Sulfadoxine and pyrimethamine combination may interfere with folic acid metabolism in the fetus and is generally not recommended for use during pregnancy. However, malaria in pregnant women may be more severe than in nonpregnant women and may result in maternal death. The risk of adverse pregnancy outcomes, including premature births, stillbirths, and abortion, may be increased. These risks should be weighed against the risks and benefits of sulfadoxine and pyrimethamine combination use during pregnancy. Women of childbearing potential who travel to areas where chloroquine-resistant malaria is endemic should be warned not to become pregnant {01}.

Studies in rats given weekly doses approximately 12 times the weekly prophylactic dose have shown that sulfadoxine and pyrimethamine combination is teratogenic. Studies in rats given sulfadoxine and pyrimethamine (20:1) have shown that the minimum oral teratogenic dose is approximately 18 mg of sulfadoxine and 0.9 mg of pyrimethamine per kg of body weight. However, studies in rabbits given doses as high as 400 mg of sulfadoxine and 20 mg of pyrimethamine per kg of body weight have not shown that sulfadoxine and pyrimethamine combination is teratogenic {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

Sulfadoxine and pyrimethamine are distributed into breast milk. Use is not recommended in nursing women since sulfonamides may cause kernicterus in nursing infants. In addition, pyrimethamine may interfere with folic acid metabolism in nursing infants, especially when given in large doses to nursing women {01}.

Pediatrics

Sulfadoxine and pyrimethamine combination is contraindicated in infants younger than 2 months of age since sulfonamides may cause kernicterus in neonates {01}.


Geriatrics


No information is available on the relationship of age to the effects of sulfadoxine and pyrimethamine combination in geriatric patients.


Dental

Sulfadoxine and pyrimethamine combination may cause a change in or loss of the sense of taste; soreness, redness, swelling, burning, or stinging of the tongue; sore throat or difficulty in swallowing; and ulcers, sores, or white spots in the mouth.

The leukopenic and thrombocytopenic effects of sulfadoxine and pyrimethamine combination may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anticoagulants, coumarin- or indandione-derivative or
Anticonvulsants, hydantoin or
Antidiabetic agents, oral    (these medications may be displaced from protein-binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy {08})


» Bone marrow depressants (see Appendix II )    (concurrent use of these medications with sulfadoxine and pyrimethamine combination may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered, especially when sulfadoxine and pyrimethamine combination is used in high doses {08})


Chloroquine    (concurrent use may increase the incidence and severity of side effects {01})


Folate antagonists, other (see Appendix II )    (concurrent use of other folate antagonists with pyrimethamine or use of pyrimethamine between courses of other folate antagonists is not recommended because of the possibility of megaloblastic anemia {01})


» Hemolytics, other (see Appendix II )    (concurrent use with sulfonamides may increase the potential for toxic side effects)


» Hepatotoxic medications, other (see Appendix II )    (concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored)


Methotrexate or
Phenylbutazone or
Sulfinpyrazone    (the effects of these medications may be potentiated during concurrent use with some sulfonamides because of displacement from plasma protein-binding sites {08})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergy to sulfonamides, pyrimethamine, furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors
Risk-benefit should be considered when the following medical problems exist
» Anemia or
» Bone marrow depression    (pyrimethamine may cause folic acid deficiency, resulting in megaloblastic anemia; sulfonamides and pyrimethamine may cause blood dyscrasias, including agranulocytosis and thrombocytopenia {01})


Hepatic function impairment    (sulfonamides and pyrimethamine are metabolized in the liver; may cause fulminant hepatic necrosis {01})


» Porphyria    (sulfonamides may precipitate an acute attack of porphyria)


» Renal function impairment{01}    (pyrimethamine and sulfadoxine are eliminated primarily through the kidneys)


Seizure disorders    (pyrimethamine may cause central nervous system [CNS] toxicity when used in high doses)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood counts (CBCs)    (may be required prior to and monthly or less frequently during treatment to detect blood dyscrasias in patients on prolonged therapy; therapy should be discontinued if a significant decrease in the count of any formed blood elements occurs {01})


Urinalyses    (may be required prior to and periodically during treatment to detect crystalluria and/or urinary calculi formation in patients on long-term or high-dose therapy and in patients with impaired renal function {01})




Side/Adverse Effects

Note: Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. These toxicities were associated with multiple dosing regimens. Therapy should be discontinued at the first appearance of skin rash or if symptoms of folic acid deficiency occur {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Glossitis (irritation or soreness of tongue)
    
hypersensitivity (fever; skin rash)
    
photosensitivity (increased sensitivity of skin to sunlight)

Incidence less frequent
    
Agranulocytosis, leukopenia, or thrombocytopenia (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)
    
anemia (unusual tiredness or weakness)
    
erythema multiforme and/or Stevens-Johnson syndrome (bleeding or crusting sores on lips; chest pain; fever with or without chills; muscle cramps or pain; redness, blistering, peeling, or loosening of skin; sores, ulcers, and/or white spots in mouth; sore throat; unusual tiredness or weakness)
    
hepatitis (loss of appetite; nausea; swelling in upper abdominal area; vomiting; yellow eyes and/or skin)
    
stomatitis (sores in mouth and on lips)

Incidence rare
    
Anaphylaxis or anaphylactoid reaction (changes in facial skin color; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash and/or itching)
    
crystalluria or hematuria (blood in urine; lower back pain; pain or burning while urinating)
    
goiter or thyroid function disturbance (swelling of front part of neck)
    
pancreatitis (abdominal or stomach pain; constipation; nausea; vomiting)
    
toxic epidermal necrolysis [Lyell's syndrome] (redness, tenderness, itching, burning, or peeling of skin; sore throat; fever with or without chills)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
CNS effects (anxiety; drowsiness; fatigue; headache; nervousness)
    
gastrointestinal disturbances (abdominal pain; diarrhea; nausea or vomiting)

Incidence less frequent
    
Arthralgia (pain in joints)





Overdose
For specific information on the agents used in the management of sulfadoxine and pyrimethamine overdose, see:
   • Barbiturates (Systemic) monograph;
   • Benzodiazepines (Systemic) monograph; and/or
   • Leucovorin (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute—In order of occurrence:
    
Gastrointestinal toxicity (anorexia [loss of appetite]; severe vomiting)
    
glossitis (irritation or soreness of tongue)
    
CNS toxicity (ataxia [clumsiness or unsteadiness]; trembling; seizures)
    
blood dyscrasias, specifically leukopenia (fever and sore throat), megaloblastic anemia (unusual tiredness or weakness), or thrombocytopenia (unusual bleeding or bruising){01}


Treatment of overdose
Recommended treatment includes: {01}


To decrease absorption:
Gastric emptying by emesis or lavage.



Specific treatment:
Control of CNS stimulation, including seizures, by parenteral administration of benzodiazepines or short-acting barbiturates.

Administration of leucovorin, 5 to 15 mg a day intramuscularly for 3 days or longer, to counteract the effects of folic acid antagonism (e.g., reduced white blood cell counts) induced by the pyrimethamine component.

Adequate hydration to prevent renal damage.



Monitoring:
Monitoring of renal and hematopoietic status for at least 1 month following overdose.



Supportive care:
Mechanical assistance of respiration, if necessary. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sulfadoxine and Pyrimethamine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors, or pyrimethamine

Pregnancy—Pyrimethamine and sulfadoxine cross the placenta. Use not recommended because of possible interference with folic acid metabolism in fetus





Breast-feeding—Pyrimethamine and sulfadoxine are distributed into breast milk. Use not recommended because of possible kernicterus in the infant





Use in children—Use is not recommended in children younger than 2 months of age because of possible kernicterus






Dental—High doses may cause atrophic glossitis, leukopenia, or thrombocytopenia
Other medications, especially bone marrow depressants, other hemolytics, or other hepatotoxic medications
Other medical problems, especially anemia, bone marrow depression, porphyria, or renal function impairment

Proper use of this medication
» Not giving to infants younger than 2 months of age; keeping medication out of reach of children

» Maintaining adequate fluid intake; taking with meals or a snack if gastric irritation occurs

» Proper storage

For prevention of malaria
Starting medication 1 to 2 weeks before entering malarious area to ascertain patient response and allow time to substitute another medication if reactions occur

» Continuing medication while staying in area and for 4 weeks after leaving area; checking with physician immediately if fever develops while traveling or within 2 months after departure from endemic area

» Importance of not missing doses and of taking medication on a regular schedule

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

For treatment of malaria
» Compliance with therapy

For self-treatment of presumptive malaria
» After taking this medication, continuing to take an alternative effective malaria medication once a week

Precautions while using this medication
» Stopping medication immediately and reporting promptly to physician signs of skin rash, itching, redness, mouth or genital lesions, or sore throat

Mosquito-control measures to reduce the chance of getting malaria
Sleeping under mosquito netting

Wearing long-sleeved shirts or blouses and long trousers to protect arms and legs when mosquitoes are out

Applying mosquito repellant to uncovered areas of skin when mosquitoes are out

For prevention of malaria
» Regular visits to physician to check blood counts

Importance of taking leucovorin concurrently if anemia occurs

Using caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

» Possible photosensitivity reactions

For self-treatment of presumptive malaria
Checking with physician as soon as possible, especially if no improvement within 48 hours


Side/adverse effects
Signs of potential side effects, especially glossitis; hypersensitivity; photosensitivity; agranulocytosis, leukopenia, or thrombocytopenia; anemia; erythema multiforme and/or Stevens-Johnson syndrome; hepatitis; stomatitis; anaphylaxis or anaphylactoid reaction; crystalluria or hematuria; goiter or thyroid function disturbance; pancreatitis; and toxic epidermal necrolysis (Lyell's syndrome)


General Dosing Information
Sulfadoxine and pyrimethamine combination may be administered alone for the presumptive treatment, or sequentially with quinine in the treatment of acute attacks, of documented Plasmodium falciparum malaria {01}.

Fluid intake should be sufficient to maintain urine output of at least 1200 to 1500 mL per day in adults.

Sulfadoxine and pyrimethamine combination may cause gastric irritation, sometimes resulting in vomiting, when given in high doses. If this occurs, the medication may be taken with meals or a snack or the dosage may be reduced.

Therapy with sulfadoxine and pyrimethamine combination should be discontinued if skin rash or symptoms of folic acid deficiency occur {01} {02}. However, to prevent folic acid deficiency, leucovorin (folinic acid) may be administered to restore normal hematopoiesis. Leucovorin does not interfere with the antiprotozoal activity of the pyrimethamine component. In addition, since malarial parasites are unable to utilize preformed folic acid, the antimalarial effect of pyrimethamine should not be affected {08}. In adults, 5 to 15 mg of leucovorin may be given orally, intramuscularly, or intravenously once a day for 3 days or as required. Alternatively, adults may be given 9 mg of leucovorin two or three times a week. Infants may be given 1 mg of leucovorin once a day.

Because of its potentially life-threatening toxicity, sulfadoxine and pyrimethamine combination is no longer recommended for weekly use as a prophylactic agent except in persons at high risk for chloroquine-resistant malaria, in remote areas, who are unable to take alternative medications. If this combination is used, prophylaxis should be started 1 week before the patient enters a malarious area and should be continued for 4 weeks after the patient leaves the area. Starting the medication before the patient enters the malarious area will help to determine the patient's tolerance to the medication and allow time to substitute other antimalarials if the patient develops allergies to the medication or experiences other adverse effects.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

SULFADOXINE AND PYRIMETHAMINE TABLETS USP

Usual adult and adolescent dose
Malaria
Treatment: Chloroquine-resistant Plasmodium falciparum malaria—Oral, 3 tablets as a single dose {05} {10} on day three of quinine therapy.

Presumptive treatment: Oral, 3 tablets as a single dose for self-treatment of febrile illness when medical care is not immediately available {05} {12}.

Chemoprophylaxis: Oral, 1 tablet once every seven days; or 2 tablets once every fourteen days {01} {02}.

[Isosporiasis (prophylaxis)]1
Oral, 1 tablet once every seven days {04} {13}.


Usual pediatric dose
Malaria


Treatment:


Chloroquine-resistant P. falciparum malaria {05} {10}



Children up to 2 months of age—
Use is contraindicated since sulfonamides may cause kernicterus in neonates {01} {02}.



Children 2 months of age and older—
Oral, 1.25 mg per kg of body weight of pyrimethamine in combination with 25 mg per kg of body weight of sulfadoxine as a single dose on day three of quinine therapy {01} {02}.




Presumptive treatment, for self-treatment of febrile illness when medical care is not immediately available {05} {12}:


Children up to 2 months of age—
Use is contraindicated since sulfonamides may cause kernicterus in neonates {01} {02}.



Children 2 months of age and older—
Children 5 to 10 kg of body weight: Oral, 1/2 tablet as a single dose {01} {02}.

Children 11 to 20 kg of body weight: Oral, 1 tablet as a single dose {01} {02}.

Children 21 to 30 kg of body weight: Oral, 11/2 tablets as a single dose {01} {02}.

Children 31 to 45 kg of body weight: Oral, 2 tablets as a single dose {01} {02}.

Children more than 45 kg of body weight: Oral, 3 tablets as a single dose {01} {02}.




Chemoprophylaxis:


Infants up to 2 months of age—
Use is contraindicated since sulfonamides may cause kernicterus in neonates {01} {02}.



Infants and children 2 months to 4 years of age—
Oral, 1/4 tablet once every seven days; or 1/2 tablet once every fourteen days {01} {02}.



Children 4 to 8 years of age—
Oral, 1/2 tablet once every seven days; or 1 tablet once every fourteen days {01} {02}.



Children 9 to 14 years of age—
Oral, 3/4 tablet once every seven days; or 11/2 tablets once every fourteen days {01} {02}.



Children older than 14 years of age—
See Usual adult and adolescent dose {01} {02}.




Strength(s) usually available
U.S.—


500 mg of sulfadoxine and 25 mg of pyrimethamine (Rx) [Fansidar]{01}

Canada—


500 mg of sulfadoxine and 25 mg of pyrimethamine (Rx) [Fansidar]{02}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • Take with a full glass of water.
   • Avoid too much sun or use of sunlamp or tanning bed or booth.
   • Continue medicine for full time of treatment (chemoprophylaxis).
   • Keep out of reach of children.

Note: Explain potential danger of accidental overdose in children.
Consider dispensing in unit-dose packaging in child-resistant containers (“double-barrier” packaging).




Revised: 05/18/1999



References
  1. Fansidar package insert (Roche—US), Rev 07/96, Rec 02/99.
  1. Fansidar (Roche). In: Gillis MC, editor. CPS compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 606-7.
  1. Daraprim package insert (GlaxoWellcome—US), Rev 04/98, Rec 02/99.
  1. Pape JW, Verdier RI, Johnson WD. Treatment and prophylaxis of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989; 320: 1044-7.
  1. Drugs for parasitic infections. Medical Letter 1990; 32(814): 23-32.
  1. Keystone JS. Prevention of malaria. Drugs 1990; 39(3): 337-54.
  1. Weiss LM, et al. Pyrimethamine concentrations in serum and cerebrospinal fluid during treatment of acute toxoplasma encephalitis in patients with AIDS. J Infect Dis 1988; 157(3): 580-3.
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea and Febiger; 1989. p. 106, 146, 171, 239.
  1. White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokinet 1985; 10: 187-215.
  1. Panisko DM, Keystone JS. Treatment of malaria–1990. Drugs 1990; 39(2): 160-89.
  1. Mandell GL, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. 3rd ed. NY: Churchill Livingstone; 1990. p. 412, 2065.
  1. Centers for Disease Control and Prevention (CDC). Recommendations for the prevention of malaria among travelers. MMWR Morb Mortal Wkly Rep 1990; 39(RR-3): 1-10.
  1. DeHovitz JA, et al. Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 1986; 315(2): 87-90.
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