Atovaquone

Atovaquone is a structural analogue of the universal mitochondrial electron carrier ubiquinone (coenzyme Q). By occupying the ubiquinol-oxidising (Qo) site on the cytochrome bc1 complex of apicomplexan parasites and Pneumocystis, it brings the parasite’s mitochondrial electron transport chain — and the multiple anabolic pathways that depend on it — to a halt. The selectivity comes from structural differences between mammalian and parasite/fungal cytochrome b at the Qo site; mammalian mitochondria are largely unaffected at therapeutic concentrations.

Mechanism of Action

• Cytochrome bc1 (complex III) inhibition: atovaquone binds the Qo (ubiquinol-binding) site on parasite cytochrome b, blocking electron flow from ubiquinol to cytochrome c. This collapses the mitochondrial membrane potential (ΔΨm).
• Downstream consequences: many parasite metabolic enzymes are coupled to mitochondrial electron transport via ubiquinone — most notably dihydroorotate dehydrogenase (DHODH), the essential enzyme for de novo pyrimidine biosynthesis in Plasmodium and Pneumocystis (which lack salvage pathways). Atovaquone therefore indirectly halts pyrimidine synthesis, ATP synthesis, and nucleic acid synthesis.
• Synergy with proguanil in malaria: proguanil is metabolised to cycloguanil, a dihydrofolate reductase inhibitor, but proguanil itself also collapses the parasite mitochondrial membrane potential at concentrations that potentiate atovaquone. The combination is therefore synergistic and substantially reduces the rate of atovaquone resistance.
• Resistance: in Plasmodium, point mutations in the cytochrome b gene (notably Y268S, Y268N, Y268C) confer high-level atovaquone resistance — the principal mechanism of treatment failure. Resistance mutations have also been described in Pneumocystis cytochrome b after long-term low-dose exposure.

Pharmacokinetics

• Absorption: low and variable oral bioavailability — highly dependent on formulation and on co-administration with fat. Oral suspension bioavailability ~47% with a fatty meal vs. ~23% in the fasted state; administration with food (especially fat-containing food) is mandatory for adequate exposure.
• Volume of distribution: 0.60 ± 0.17 L/kg.
• Protein binding: 99.9% — extensive, predominantly albumin.
• Metabolism: minimal — no identified metabolites of clinical relevance.
• Half-life: 2.2–3.2 days, attributed to extensive enterohepatic recirculation and slow faecal elimination of unchanged drug.
• Excretion: primarily faecal (essentially complete recovery of unchanged drug); urinary excretion is negligible (<0.6%).
• Clearance: ~10 mL/min (very low) on IV administration in HIV patients.
• No clinically significant induction of CYP enzymes; atovaquone is a weak inhibitor of CYP2C9.

Atovaquone Monotherapy (Mepron)

• Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents ≥13 years:
  • Acute treatment of mild-to-moderate PCP in patients who are intolerant of trimethoprim-sulfamethoxazole (TMP-SMX).
  • Prevention of PCP in patients who are intolerant of TMP-SMX.

Off-label: prophylaxis and treatment of Toxoplasma gondii reactivation in patients with advanced HIV infection (typically with sulphadiazine or pyrimethamine).

Atovaquone + Proguanil (Malarone)

• Prevention of Plasmodium falciparum malaria in adults and paediatric patients (weight bands defined; ≥5 kg in many regions).
• Treatment of acute, uncomplicated Plasmodium falciparum malaria in adults and paediatric patients.

Atovaquone/proguanil is the preferred adult traveller prophylaxis for short trips in many regions because of its excellent tolerance, daily dosing, and short pre/post-travel coverage requirements (start 1–2 days before entry; stop 7 days after exit).

• Hypersensitivity to atovaquone, proguanil (in the combination), or any of the excipients.
• Atovaquone/proguanil (Malarone): prophylaxis is contraindicated in severe renal impairment (creatinine clearance <30 mL/min) due to proguanil accumulation; treatment use in this group requires careful risk–benefit evaluation.

Monotherapy (Mepron suspension) — common (≥1/100 to <1/10): rash, pruritus, nausea, vomiting, diarrhoea, abdominal pain, fever, headache, insomnia.

Atovaquone/proguanil (Malarone) — common: abdominal pain, nausea, vomiting, diarrhoea, headache, cough, dizziness, transaminase elevations, rash.

Uncommon to rare: oral and stomatitic ulcers, alopecia, neutropenia, anaemia, hyponatraemia, hepatotoxicity (including cholestatic hepatitis), pancreatitis, severe cutaneous reactions (very rare: Stevens-Johnson syndrome).

Methemoglobinemia has been reported after overdose, particularly when co-administered with dapsone.

• Rifampicin / rifabutin: substantially reduce atovaquone plasma concentrations (~50%) — combination should be avoided where possible.
• Tetracycline: reduces atovaquone exposure ~40% — monitor for efficacy if combination is unavoidable.
• Metoclopramide: reduces atovaquone bioavailability; use an alternative antiemetic where possible.
• Efavirenz, lopinavir/ritonavir, atazanavir/ritonavir: reduce atovaquone exposure modestly; clinical relevance varies and may warrant dose monitoring in PCP prophylaxis.
• Indinavir: atovaquone reduces indinavir trough concentrations.
• Warfarin: atovaquone may increase the anticoagulant effect via CYP2C9 inhibition — monitor INR.
• Zidovudine: atovaquone increases zidovudine exposure modestly; routine dose adjustment not required.
• Food: fat-containing meals increase atovaquone bioavailability 2- to 4-fold — administration with food is required, not a precaution.
• Tetracycline antibiotics, anti-acid drugs reducing bile flow: may reduce absorption.

For the atovaquone/proguanil combination, additional interactions apply to proguanil (e.g., warfarin enhancement, antifolate interactions).

Mepron (Atovaquone Monotherapy Suspension) — for PCP

• Treatment of mild-to-moderate PCP (adults and adolescents ≥13 years): 750 mg (5 mL) twice daily with food for 21 days.
• Prevention of PCP (adults and adolescents ≥13 years): 1,500 mg (10 mL) once daily with food, or 750 mg (5 mL) twice daily with food.

The suspension must be shaken vigorously immediately before each dose. Take with food, ideally a fat-containing meal.

Malarone (Atovaquone/Proguanil) — for Malaria Prophylaxis

Adult tablets contain 250 mg atovaquone + 100 mg proguanil. Take with food or a milky drink.

• 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.

Malarone — for 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

• Mepron: no specific dose adjustment.
• Malarone: prophylaxis contraindicated in CrCl <30 mL/min; treatment in this group requires careful benefit-risk evaluation.

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. Particular attention is needed for malaria prophylaxis — missing doses substantially compromises protection.

Administration with Food

Fat-containing food increases atovaquone bioavailability 2- to 4-fold. Patients unable to tolerate food (e.g., severe nausea, vomiting, diarrhoea, AIDS-related gastrointestinal disease) may have insufficient exposure on the suspension; consider alternative therapy or escalation.

Resistance in Malaria

Atovaquone monotherapy is never used for malaria — high-level resistance develops rapidly with single-agent use. The fixed combination with proguanil substantially mitigates this risk. Failure of prophylaxis or treatment with atovaquone/proguanil should prompt evaluation for resistance.

Hypersensitivity

Discontinue if a rash develops, especially blistering or mucosal involvement. Severe cutaneous reactions are rare but require immediate discontinuation.

Pregnancy and Lactation

• Atovaquone monotherapy: limited human data; animal data do not show teratogenicity. Use in pregnancy only when clearly needed.
• Atovaquone/proguanil for malaria prophylaxis in pregnancy: limited data — many travel-medicine guidelines recommend alternative agents in the first trimester; later pregnancy use is reasonable when benefits outweigh risks (e.g., travel to chloroquine-resistant areas where mefloquine is contraindicated).
• Breastfeeding: atovaquone is excreted in animal milk in concentrations approaching maternal plasma levels; benefit-risk assessment required. Proguanil and its metabolites are excreted in human milk in small amounts.

Paediatric Use

Mepron suspension is not indicated below age 13 in many regions. Malarone is widely used in children from 5 kg upward with weight-banded dosing.

Elderly

No specific dose adjustment.

Effect on Driving

Dizziness has been reported with the combination product; affected patients should avoid driving.

Store the suspension below 25 °C; do not freeze. Shake well before each use. Tablets should be stored below 25–30 °C in the original packaging, protected from moisture.

Typically 2–3 years from manufacture for unopened bottles or blister packs. Use the suspension within the labelled expiry once opened; do not use beyond the printed expiry date.

Prescription required (Rx). Frequently dispensed through travel medicine clinics and HIV care services depending on indication.