Dosing and uses of Malarone (atovaquone-proguanil)
Adult dosage forms and strengths
atovaquone/proguaniL
tablet
- 250mg/100mg
Malaria
Prophylaxis
- 250 mg/100 mg (1 tablet) PO daily, beginning 1-2 days before travel to malaria-endemic area and continued until 7 days after return
Treatment
- 1 g/400 mg (4 tablets) PO daily for 3 days
Dosing considerations
- In event of vomiting within 1 hour of dose, repeat dose
- In geriatric patients, cautious dose selection is necessary because of decreased hepatic/renal/cardiac function and increased systemic exposure to cycloguanil
Dosing Modifications
CrCl <30 mL/min: Prophylactic use not recommended; only use for treatment if benefits of therapy greatly outweigh risks
CrCl 30-80 mL/min: No dosage adjustments necessary
Administration
Take at same time daily with food or milky drink
For children with difficulty swallowing, may be crushed and mixed with condensed milk just before administration
Pediatric dosage forms and strengths
atovaquone/proguaniL
tablet
- 62.5mg/25mg
Malaria
Prophylaxis
- <11 kg: Safety and efficacy not established
- 11-20 kg: 62.5 mg/25 mg (1 pediatric tablet) PO daily
- 21-30 kg: 125 mg/50 mg (2 pediatric tablets) PO daily
- 31-40 kg: 187.5 mg/75 mg (3 pediatric tablets) PO daily
- >40 kg: 250 mg/100 mg (1 adult tablet) PO daily, beginning 1-2 days before travel to malaria-endemic area and continued until 7 days after return
Treatment
- <5 kg: Safety and efficacy not established
- 5-8 kg: 125 mg/50 mg (2 pediatric tablets) PO daily for 3 days
- 9-10 kg: 187.5 mg/75 mg (3 pediatric tablets) PO daily for 3 days
- 11-20 kg: 250 mg/100 mg (1 adult tablet) PO daily for 3 days
- 21-30 kg: 500 mg/200 mg (2 adult tablets) PO daily for 3 days
- 31-40 kg: 750 mg/300 mg (3 adult tablets) PO daily for 3 days
- >40 kg: 1 g/400 mg (4 adult tablets) PO daily for 3 days
Dosing considerations
- In event of vomiting within 1 hour of dose, repeat dose
Malarone (atovaquone-proguanil) adverse (side) effects
>10%
Abdominal pain (3-31%)
Transaminase increases (17-27%)
Headache (3-14%)
Vomiting (1-13%)
Nausea (12%)
1-10%
Asthenia (8%)
Diarrhea (1-8%)
Pruritus (6%)
Anorexia (5%)
Dizziness (5%)
Dyspepsia (1-4%)
Gastritis (0-3%)
<1%
Fever
Cough
Postmarketing Reports
Hematologic/lymphatic: Neutropenia, anemia (rarely), pancytopenia (patients with severe renal impairment treated with proguanil)
Immunologic: Allergic reactions, including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis
Neurologic: Rare cases of seizures and psychotic events (eg, hallucinations)
GI: Stomatitis
Hepatic: Elevated liver function tests (LFTs), rare cases of hepatitis, cholestasis
Skin: Photosensitivity, rash, and rare cases of erythema multiforme and Stevens-Johnson syndrome
Warnings
Contraindications
Hypersensitivity
Not to be used for prophylaxis of Plasmodium falciparum in severe renal impairment (CrCl <30 mL/min)
Cautions
Administration does not provide radical cure, nor does it prevent delayed primary attacks of P vivax and P ovale
Patients with severe malaria are not candidates for oral therapy; not evaluated in treatment of cerebral malaria or severe manifestations of malaria (eg, hyperparasitemia, pulmonary edema, renal failure)
Elevated LFTs and rare cases of hepatitis have been reported
Absorption may be reduced in patients with diarrhea or vomiting; monitor closely, and consider antiemetic use
Monotherapy may result in parasite relapse of P vivax malaria
Recrudescent P falciparum infection or chemoprophylactic failure after monotherapy should be treated with different schizonticide
Prophylaxis should not be prematurely discontinued
Complete prophylaxis includes therapy, protective clothing, insect repellents, and bednets
No chemoprophylactic regimen is 100% effective; patient should seek medical care for any febrile illness that occurs
P falciparum malaria carries higher risk of death and serious complications in pregnant women; patient should discuss risks and benefits of travel, and if travel cannot be avoided, additional prophylaxis, including protective clothing, must be employed
Pregnancy and lactation
Pregnancy category: C
Lactation: Proguanil is excreted into milk in small quantities, but excretion of atovaquone is unknown; use with caution
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Malarone (atovaquone-proguanil)
Mechanism of action
Antiparasitic activity
Atovaquone: Selective inhibitor of parasite mitochondrial electron transport
Proguanil: Primary effect through metabolite cycloguanil, a dihydrofolate reductase inhibitor in malaria parasite, which leads to disruption of deoxythymidylate synthesis
Absorption
Bioavailability: Oral absorption of atovaquone is poor but increases to 23% with high-fat meal (AUC increased 2-3 times and Cmax 5 times over fasting); administer with food or milk; proguanil is extensively absorbed
Distribution
Protein bound: Atovaquone, >99%; proguanil, 75%
Vd: Atovaquone, 8.8 L/kg
Metabolism
Proguanil is metabolized to cycloguanil (primarily by CYP2C19)
Elimination
Half-life: Atovaquone, 2-3 days; proguanil, 12-21 hr
Clearance: Atovaquone, 1.32-6.61 L/hr; proguanil, 29.5-67.9 L/hr
Excretion: Atovaquone, feces as unchanged drug (94%); proguanil, urine (40-60%)
