Proguanil

Proguanil is one of the oldest synthetic antimalarials still in active use, with a dual mode of action that has become increasingly important as resistance has eroded the utility of single-mechanism antimalarials. After oral absorption, a fraction is converted by hepatic CYP2C19 (predominantly) and CYP3A4 to cycloguanil, a triazine that inhibits Plasmodium DHFR. The parent compound itself also exerts antimalarial activity by collapsing the parasite mitochondrial membrane potential — independent of cycloguanil formation — and this property underlies the synergy with atovaquone.

Mechanism of Action

• Activation to cycloguanil (DHFR pathway): proguanil is cyclised by hepatic CYP2C19 (and to a lesser extent CYP3A4) to cycloguanil, a dihydrotriazine. Cycloguanil binds Plasmodium dihydrofolate reductase (DHFR) with much higher affinity than the human enzyme, blocking the reduction of dihydrofolate to tetrahydrofolate.
• Downstream: depletion of tetrahydrofolate-dependent one-carbon donors stops parasite de novo purine and pyrimidine synthesis, halting DNA replication. The effect is manifested as failure of nuclear division at the schizont stage in liver and erythrocyte forms.
• Cycloguanil resistance: rapid resistance development in many regions (DHFR point mutations S108N, N51I, C59R, I164L confer increasing levels of cycloguanil and pyrimethamine resistance). This resistance limits proguanil monotherapy efficacy and is the reason it is rarely used alone.
• Cycloguanil-independent activity: proguanil itself (not via cycloguanil) collapses the parasite mitochondrial membrane potential at concentrations achieved in vivo. This action is synergistic with atovaquone — proguanil enhances atovaquone’s effect on the bc1 complex and depolarises the parasite mitochondrion, even in CYP2C19 poor metabolisers who generate little cycloguanil. This is the basis for the highly effective Malarone (atovaquone/proguanil) combination.
• CYP2C19 poor metabolisers: 3–5% of Caucasians, 15–20% of East Asians, and ~4% of Black populations are CYP2C19 poor metabolisers; they generate little cycloguanil. For proguanil monotherapy this matters substantially; for Malarone it does not, because the cycloguanil-independent synergy with atovaquone preserves efficacy.

Pharmacokinetics

• Absorption: rapid and complete after oral doses of 50–500 mg; bioavailability is high but pharmacokinetic data are limited in absolute terms. Take with food or a milky drink to reduce gastrointestinal upset.
• Volume of distribution: extensive tissue distribution (not formally characterised).
• Protein binding: approximately 75%.
• Metabolism: CYP2C19-predominant (with CYP3A4) cyclisation to cycloguanil; minor de-isopropylation to 4-chlorophenylbiguanide.
• Half-life: proguanil parent ~20 hours; cycloguanil shorter (~12 hours).
• Excretion: predominantly renal — both parent and cycloguanil are excreted in urine. Proguanil accumulates significantly in severe renal impairment, raising toxicity risk — the basis for the renal contraindication in Malarone prophylaxis.

• Prevention of Plasmodium falciparum malaria in adults and children (in combination with atovaquone, as Malarone).
• Treatment of acute, uncomplicated Plasmodium falciparum malaria in adults and children (in combination with atovaquone, as Malarone).
• Historical/niche: prevention of chloroquine-sensitive Plasmodium malaria when used with chloroquine (regimen now rarely recommended due to declining chloroquine sensitivity and superior alternatives).

Proguanil also has activity against Plasmodium vivax and P. ovale liver stages, but is not the preferred agent for radical cure (primaquine or tafenoquine, combined with G6PD testing, are standard).

• Hypersensitivity to proguanil, atovaquone (in the combination), or any of the excipients.
• Severe renal impairment (creatinine clearance <30 mL/min): proguanil prophylaxis or Malarone prophylaxis is contraindicated due to proguanil and cycloguanil accumulation. Treatment use in severe renal impairment requires careful benefit-risk evaluation.

Proguanil monotherapy — common: mild gastrointestinal upset (nausea, vomiting, diarrhoea, abdominal pain), mouth ulcers, stomatitis, mild hair loss with prolonged use.

Malarone (atovaquone/proguanil) — common (≥1/100 to <1/10): headache, abdominal pain, nausea, vomiting, diarrhoea, dizziness, cough, transaminase elevations, rash, pruritus, vivid dreams.

Uncommon to rare: oral ulcers, alopecia, anaemia, neutropenia, severe cutaneous reactions (rare: erythema multiforme, Stevens-Johnson syndrome), cholestatic hepatitis, pancreatitis, anaphylaxis (very rare).

Pregnancy considerations: long clinical experience supports the safety of proguanil in pregnancy at standard antimalarial doses; folate supplementation (5 mg/day) is recommended when proguanil is used in pregnancy due to weak antifolate activity in the host.

• Warfarin and other coumarin anticoagulants: proguanil may enhance the anticoagulant effect — monitor INR closely.
• Cimetidine: reduces proguanil metabolism to cycloguanil (CYP inhibition).
• Co-trimoxazole, pyrimethamine, sulphonamides: additive antifolate effect — generally avoid combination for prolonged periods.
• Magnesium- and aluminium-containing antacids, kaolin: reduce proguanil absorption; separate by ≥1 hour.
• Strong CYP2C19 inhibitors (esomeprazole, fluvoxamine, fluconazole, voriconazole): reduce cycloguanil formation — clinically relevant for proguanil monotherapy; less important for Malarone given the cycloguanil-independent synergy.
• Strong CYP2C19 inducers (rifampicin): increase cycloguanil formation but may also reduce overall proguanil exposure unpredictably.
• Oral live typhoid vaccine (Ty21a / Vivotif): proguanil generally does not abolish the response, but product labelling may advise short separation; atovaquone/proguanil and Ty21a can be co-administered per current WHO travel-medicine guidance.
• Food: take with food or a fat-containing milky drink to reduce gastrointestinal upset and (when combined with atovaquone) to optimise atovaquone absorption.

Tablets are swallowed whole with food or a milky drink. Atovaquone/proguanil should always be taken at the same time each day to maintain steady absorption of the atovaquone component.

Proguanil Monotherapy (Paludrine)

• Adult prophylaxis: 200 mg (2 × 100 mg tablets) once daily, starting 1 week before entry to the malaria area and continuing for 4 weeks after leaving.
• Paediatric prophylaxis: weight-based dosing per current product labelling.
• Combined with chloroquine (historical regimen): proguanil 200 mg daily + chloroquine 300 mg base weekly.

Atovaquone/Proguanil (Malarone) — Prophylaxis

Adult tablets contain 250 mg atovaquone + 100 mg proguanil. Take with food once daily.

• Adults and paediatric patients ≥40 kg: 1 adult tablet once daily.
• Paediatric weight bands using paediatric strength (62.5 mg / 25 mg) tablets:
  • 11–20 kg: 1 paediatric tablet once daily.
  • 21–30 kg: 2 paediatric tablets once daily.
  • 31–40 kg: 3 paediatric tablets once daily.
• Schedule: start 1–2 days before entering the malaria area; continue daily during stay; continue for 7 days after leaving the malaria area.

Atovaquone/Proguanil (Malarone) — Treatment of Acute Uncomplicated P. falciparum Malaria

• Adults and paediatric patients ≥40 kg: 4 adult tablets once daily for 3 consecutive days.
• Paediatric weight bands: per weight, using either adult or paediatric tablets; refer to current labelling.

Renal Impairment

• CrCl ≥30 mL/min: standard dosing.
• CrCl <30 mL/min: Malarone prophylaxis contraindicated. Treatment use requires careful benefit-risk evaluation and dose adjustment per current guidance — proguanil and cycloguanil both accumulate.
• Haemodialysis: limited data; specialist input required.

Hepatic Impairment

Use with caution; clinical data are limited.

Missed Dose

Take as soon as remembered with food; if close to the next dose, skip the missed dose. Adherence is particularly important for malaria prophylaxis — even single missed doses on a short Malarone regimen substantially compromise protection.

Folate Supplementation in Pregnancy

Proguanil weakly inhibits human DHFR and may, with prolonged use, contribute to functional folate insufficiency. In pregnant women taking proguanil-containing antimalarial regimens, co-prescribe folic acid 5 mg/day during the period of vulnerability (typically the first trimester and through delivery for ongoing exposure).

Hypersensitivity

Discontinue if rash develops, especially blistering or mucosal involvement. Rare severe cutaneous reactions have been reported.

Resistance and Adherence

Strict daily adherence is essential for Malarone prophylaxis efficacy. Failure of prophylaxis or treatment with atovaquone/proguanil should prompt evaluation for atovaquone resistance (Plasmodium cytochrome b Y268S/Y268N/Y268C mutations) and consideration of alternative agents.

Vomiting

If vomiting occurs within 1 hour of a dose, repeat the dose. Persistent vomiting compromises absorption; switch to a parenteral antimalarial if treatment-indication and severe.

Pregnancy and Lactation

• Pregnancy: long human experience supports the safety of proguanil at standard doses; folate supplementation (5 mg/day) is recommended. Atovaquone/proguanil (Malarone) data in pregnancy are less extensive — many guidelines suggest alternative regimens (mefloquine for areas without chloroquine resistance, or chloroquine for sensitive areas) in the first trimester, with Malarone considered in later trimesters when alternatives are unsuitable.
• Breastfeeding: small amounts of proguanil and cycloguanil are excreted in milk; insufficient to provide infant protection but generally considered safe for the breastfed infant.

Paediatric Use

Atovaquone/proguanil (Malarone) is widely used in children from approximately 5 kg upward with weight-banded paediatric tablets. Proguanil monotherapy is rarely used in modern paediatric travel medicine.

Elderly

No specific dose adjustment; ensure renal function is reasonable before prescribing for prophylaxis.

Effect on Driving

Dizziness has been reported with atovaquone/proguanil; affected patients should avoid driving.

Store below 25–30 °C in the original packaging to protect from moisture.

Typically 3 years for unopened blister packs. Do not use after the expiry date.

Prescription required (Rx). Frequently dispensed through travel medicine clinics for malaria prophylaxis. Proguanil monotherapy (Paludrine) is now uncommon in clinical practice; the fixed-dose combination with atovaquone (Malarone) accounts for nearly all current proguanil use in travel medicine.