Sulphadoxine + Pyrimethamine

Approved Indications:

• Treatment of Uncomplicated Falciparum Malaria:
  Indicated for the treatment of Plasmodium falciparum malaria, particularly in regions where the parasite is sensitive to this drug combination.
• Intermittent Preventive Treatment in Pregnancy (IPTp):
  Recommended for the prevention of P. falciparum malaria in pregnant women residing in high-transmission areas.
• Intermittent Preventive Treatment in Infants (IPTi):
  Used in malaria-endemic zones for periodic prophylaxis against P. falciparum in infants as per national malaria programs.
• Intermittent Preventive Treatment in Children (IPTc):
  Used in seasonal malaria chemoprevention programs targeting children aged 3–59 months in areas with seasonal transmission.

Important Off-label or Regionally Approved Uses:

• Prophylaxis in Travelers:
  Occasionally used for short-term malaria prevention in travelers where chloroquine-resistant P. falciparum is prevalent, although rarely preferred due to resistance concerns.

Route: Oral

Adults (including non-pregnant women):

• Treatment of malaria:
  Single dose of Sulphadoxine 1500 mg + Pyrimethamine 75 mg orally.

Pregnant Women (IPTp):

• Prophylaxis regimen:
  Sulphadoxine 1500 mg + Pyrimethamine 75 mg orally at each antenatal visit, starting after the first trimester (from 13 weeks), with at least 1 month between doses, up to delivery.

Infants (IPTi):

• Prophylaxis schedule:
  Sulphadoxine 250 mg + Pyrimethamine 12.5 mg given at routine immunization visits (e.g., 10 weeks, 14 weeks, 9 months).

Children (IPTc):

• Ages 3–59 months:
  Sulphadoxine 500 mg + Pyrimethamine 25 mg monthly during the malaria season, for up to 4 doses per year.

Renal/Hepatic Impairment:

• Use with caution due to prolonged half-life. Dose adjustment not well established; monitor closely for toxicity.

Administration Tips:

• Administer with food to minimize gastrointestinal upset.
• Ensure adequate hydration.
• Do not repeat within 30 days due to risk of accumulation and toxicity.

Sulphadoxine and Pyrimethamine act synergistically by sequentially inhibiting folate metabolism in Plasmodium species. Sulphadoxine, a long-acting sulfonamide, competitively inhibits dihydropteroate synthase, thereby blocking the conversion of para-aminobenzoic acid (PABA) to dihydropteroate. Pyrimethamine inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate. This sequential blockade depletes folate derivatives essential for DNA synthesis and cell multiplication in the parasite, leading to its death.

• Absorption: Well absorbed orally; bioavailability >90%.
• Distribution: Widely distributed; crosses placenta; found in breast milk.
• Protein Binding:
• Sulphadoxine: ~90%
• Pyrimethamine: ~85–90%
• Metabolism:
• Sulphadoxine: Partial hepatic metabolism via acetylation.
• Pyrimethamine: Hepatic metabolism primarily via CYP2C9.
• Elimination:
• Sulphadoxine: Renal excretion, mostly unchanged.
• Pyrimethamine: Renal and fecal excretion.
• Half-life:
• Sulphadoxine: ~7–9 days
• Pyrimethamine: ~3–6 days
• Onset of Action: Within hours of administration.
• Peak Plasma Concentration: 2–8 hours post-dose.

• Pregnancy:
  Classified as FDA Pregnancy Category C (old system).
  Safe for intermittent use after the first trimester (i.e., from 13 weeks) for malaria prevention in endemic areas. Avoid during the first trimester due to theoretical teratogenicity.
• Lactation:
  Excreted in breast milk in small amounts. Generally considered safe during breastfeeding when used for IPTp or treatment. Monitor infant for rash or GI symptoms.
• Caution: Folic acid antagonism may be a concern in folate-deficient populations; supplement with folic acid (≤5 mg/day) if needed.

• Primary Class: Antimalarial
• Sub-Class: Antifolate Combination (Dihydropteroate Synthase and Dihydrofolate Reductase Inhibitors)

• Known hypersensitivity to sulfonamides, pyrimethamine, or any excipient.
• Severe renal or hepatic impairment.
• Megaloblastic anemia due to folate deficiency.
• Infants under 2 months of age.
• Concurrent use of methotrexate or other antifolate drugs.

• Severe skin reactions (e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis) may occur; discontinue immediately if rash appears.
• Hematologic effects: Risk of agranulocytosis, thrombocytopenia, and megaloblastic anemia; monitor CBC periodically during prolonged use.
• G6PD deficiency: Increased risk of hemolysis.
• Folic acid supplementation: High doses (>5 mg/day) may reduce antimalarial efficacy.
• Avoid repeat dosing within 28 days due to long half-life and risk of toxicity.
• Monitor renal and hepatic function during use, especially in high-risk groups.

Common (≥1%):

• Gastrointestinal: Nausea, vomiting, anorexia, abdominal pain.
• Skin: Mild rash, photosensitivity.
• CNS: Headache, dizziness.

Uncommon to Rare:

• Severe Cutaneous: Stevens-Johnson syndrome, toxic epidermal necrolysis.
• Hematologic: Anemia, leukopenia, thrombocytopenia, agranulocytosis.
• Hepatic: Elevated liver enzymes, hepatitis (rare).
• Renal: Crystalluria, nephritis (rare).
• Allergic Reactions: Urticaria, anaphylaxis (very rare).

Onset & Severity:

• Serious side effects may occur 1–2 weeks after dosing due to long half-lives.
• Dose-related hematologic toxicity may develop with repeated dosing.

• Folic Acid >5 mg/day: May reduce efficacy by bypassing antifolate action.
• Methotrexate/Trimethoprim: Increased risk of additive antifolate toxicity.
• Sulfonylureas: Increased risk of hypoglycemia due to sulphonamide interactions.
• Phenytoin: May increase phenytoin levels and toxicity.
• Rifampicin or CYP inducers: May reduce pyrimethamine efficacy.
• Warfarin: Potentiation of anticoagulant effect possible; monitor INR.

• WHO Malaria Guidelines (2022):
  Reaffirms the use of Sulphadoxine + Pyrimethamine for IPTp and seasonal malaria chemoprevention (SMC) in children in Africa.
• Resistance Consideration:
  Increasing resistance to this combination in parts of Southeast Asia and sub-Saharan Africa has led to changes in treatment policies in certain regions.
• IPTp in Pregnancy:
  Three or more doses during pregnancy significantly reduce maternal anemia and low birth weight.

• Temperature: Store below 25°C. Do not freeze.
• Humidity: Store in a dry place, protected from excessive moisture.
• Light: Protect from direct sunlight.
• Packaging: Keep in original blister pack or tightly closed container.
• Handling: Keep out of reach of children. Do not use if tablets are discolored or chipped.