MALARONE PEDIATRIC
Clinical safety rating
cautionComprehensive clinical and safety monograph for MALARONE PEDIATRIC (MALARONE PEDIATRIC).
MALARONE PEDIATRIC is a fixed-dose combination of atovaquone and proguanil. Atovaquone selectively inhibits the mitochondrial electron transport chain of Plasmodium species at the cytochrome bc1 complex, collapsing mitochondrial membrane potential and disrupting pyrimidine synthesis. Proguanil is a prodrug converted to cycloguanil, which inhibits dihydrofolate reductase in the parasite, blocking DNA synthesis. The combination synergistically kills blood-stage schizonts and inhibits liver-stage hypnozoites of P. falciparum.
| Metabolism | Atovaquone undergoes minimal metabolism, with glucuronidation as a minor pathway, and is primarily excreted unchanged in feces. Proguanil is hepatically metabolized via CYP2C19 to its active metabolite cycloguanil, and to a lesser extent by CYP3A4. |
| Excretion | Atovaquone: >90% excreted unchanged in feces via biliary elimination; <1% renal. Proguanil: ~40-60% excreted renally as unchanged drug and active metabolite cycloguanil; ~30% fecal. |
| Half-life | Atovaquone: terminal half-life 1.5-3 days (range 2-3 days in adults, longer in children). Proguanil: terminal half-life 12-21 hours (parent drug) and 14-23 hours (cycloguanil). Clinically, atovaquone's long half-life supports single daily dosing. |
| Protein binding | Atovaquone: >99% bound to plasma proteins. Proguanil: ~75% bound to plasma proteins. |
| Volume of Distribution | Atovaquone: Vd ~0.6-1.0 L/kg (extensive tissue distribution). Proguanil: Vd ~0.2-0.5 L/kg. |
| Bioavailability | Atovaquone: Oral bioavailability highly variable (range 10-50%) but improved with fatty food; ~23% in fasted state, increased ~2-fold with high-fat meal. Proguanil: Oral bioavailability ~70-90%. |
| Onset of Action | Oral: Parasite clearance begins within 24-48 hours; clinical improvement typically observed within 24-72 hours. |
| Duration of Action | Oral: Prophylactic effect persists for 7 days after last dose due to atovaquone's long half-life. Treatment course is 3 consecutive days; repeat courses may be needed if vomiting occurs within 1 hour. |
| Molecular Weight | 366.84 |
Adults: 250 mg atovaquone/100 mg proguanil orally once daily for 3 consecutive days for treatment; for prophylaxis, 250 mg/100 mg orally once daily starting 1-2 days before travel and continued for 7 days after leaving endemic area.
| Dosage form | TABLET |
| Renal impairment | For prophylaxis: If CrCl 30-50 mL/min, reduce dose to half the standard adult dose; if CrCl <30 mL/min, use alternative agent. For treatment: If CrCl 30-50 mL/min, reduce dose to half the standard adult dose; if CrCl <30 mL/min, use alternative agent. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). For severe hepatic impairment (Child-Pugh C), use with caution due to limited data; no specific dose recommendation available. |
| Pediatric use | Children ≥5 kg: For treatment, 20 mg/kg atovaquone/8 mg/kg proguanil orally once daily for 3 days. For prophylaxis, 20 mg/kg atovaquone/8 mg/kg proguanil orally once daily. Dosing based on weight: 5-8 kg: pediatric tablet (62.5 mg/25 mg) daily; 9-10 kg: 1.5 pediatric tablets daily; 11-20 kg: 2 pediatric tablets daily; 21-30 kg: 3 pediatric tablets daily; 31-40 kg: 4 pediatric tablets daily; >40 kg: adult tablet (250 mg/100 mg) daily. |
| Geriatric use | No specific dose adjustment required based on age alone; use standard adult dosing, but consider renal function as older adults may have reduced creatinine clearance. Monitor for adverse effects, particularly gastrointestinal. |
| 1st trimester | Use only if benefit outweighs risk; associated with increased risk of first-trimester pregnancy loss in animal studies. |
| 2nd trimester | Limited human data; no known increased risk of major malformations; monitor for maternal anemia and infection. |
| 3rd trimester | Avoid near term due to theoretical risk of kernicterus from sulfadoxine; can be used if no safer alternative. |
Clinical note
Comprehensive clinical and safety monograph for MALARONE PEDIATRIC (MALARONE PEDIATRIC).
| Placental transfer | Both atovaquone and proguanil cross the placenta; proguanil reaches fetal concentrations similar to maternal; atovaquone transfer is lower. |
| Breastfeeding | Excreted in breast milk in low concentrations; not expected to cause adverse effects in breastfed infants; caution in infants with G6PD deficiency due to dapsone component (not in Malarone). |
| Lactation Rating | L2 (Probably Compatible) |
| Teratogenic Risk | MALARONE PEDIATRIC contains atovaquone and proguanil. Atovaquone is not teratogenic in animals, but proguanil is associated with increased risk of neural tube defects and other congenital anomalies if used in the first trimester. Data in humans are limited; it should only be used if benefit outweighs risk. Pregnancy category C. |
| Fetal Monitoring | Monitor for hemolysis in neonates with G6PD deficiency if maternal use late in pregnancy. No specific fetal monitoring required, but assess for congenital anomalies if first-trimester exposure. Monitor maternal liver function and blood counts periodically. |
| Fertility Effects | No evidence of impaired fertility in animal studies. No human data on effects on fertility. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to atovaquone, proguanil, or any componentSevere renal impairment (CrCl <30 mL/min) as prophylaxis
| Precautions | Not recommended for severe malaria or cerebral malaria, May cause hypersensitivity reactions, including angioedema and anaphylaxis, Avoid in patients with severe renal impairment (CrCl <30 mL/min) due to risk of accumulation of proguanil, May cause hepatotoxicity; monitor liver function in prolonged use, May cause gastrointestinal disturbances; administer with food, Parasite resistance may develop; monitor for clinical failure |
| Food/Dietary | Take with food or milk to increase atovaquone absorption. Avoid high-fat meals immediately before or after dosing as they may slightly delay absorption but overall increase bioavailability. No known significant food-drug interactions with proguanil. |
| Clinical Pearls | Malarone Pediatric (atovaquone/proguanil) is indicated for prophylaxis and treatment of acute, uncomplicated P. falciparum malaria. Prophylaxis should start 1-2 days before travel, continued during stay, and for 7 days after leaving endemic area. Administer with food or milk to enhance absorption. Not recommended for children <5 kg. Avoid use for malaria treatment in patients with severe renal impairment (CrCl <30 mL/min). Monitor for signs of hepatotoxicity, especially in patients with pre-existing liver disease. |
| Patient Advice | Take this medication exactly as prescribed, with food or milk to improve absorption and reduce stomach upset. · For prevention: start 1-2 days before entering malarious area, continue while there, and for 7 days after leaving. · Complete full course even if feeling better; do not skip doses. · Use additional protective measures like insect repellent and bed nets. · Contact doctor immediately if signs of malaria (fever, chills, headache) occur during or after travel. · Report any rash, mouth ulcers, easy bruising/bleeding, or yellowing of eyes/skin. · Keep out of reach of children; overdose can be fatal. |
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