What is the recommended dosage and administration of Malarone (atovaquone/proguanil) for a patient requiring antimalarial prophylaxis or treatment, considering factors such as weight and underlying medical conditions like impaired renal function?

Malarone (Atovaquone/Proguanil) Dosing and Administration

For malaria prophylaxis, adults should take one adult-strength tablet (250 mg atovaquone/100 mg proguanil) daily starting 1-2 days before travel, continuing throughout the stay, and for 7 days after leaving the malarious area; for treatment of acute uncomplicated malaria, adults require four adult-strength tablets once daily for 3 consecutive days. 1

Prophylaxis Dosing

Adults

• One adult-strength tablet (250 mg atovaquone/100 mg proguanil) once daily 1
• Start 1-2 days before entering malarious area 1
• Continue daily during stay 1
• Continue for only 7 days after return (shorter than traditional antimalarials due to causal prophylactic activity against hepatic stages) 1, 2
• Take at the same time each day with food or a milky drink 1

Pediatric Dosing (Weight-Based)

The dosing is stratified by weight categories to achieve safe and effective plasma concentrations 3:

• 11-20 kg: 1 pediatric tablet (62.5 mg/25 mg) daily 4
• 21-30 kg: 2 adult tablets daily 4
• 31-40 kg: 3 adult tablets daily 4
• >40 kg: 4 adult tablets daily (full adult dose) 4

For treatment of uncomplicated malaria in children, weight-based dosing from guidelines shows 5:

• 5-8 kg: 2 pediatric tablets daily for 3 days
• 9-10 kg: 3 pediatric tablets daily for 3 days
• 11-20 kg: 1 adult tablet daily for 3 days
• 21-30 kg: 2 adult tablets daily for 3 days
• 31-40 kg: 3 adult tablets daily for 3 days
• >40 kg: 4 adult tablets daily for 3 days

Treatment Dosing for Acute Uncomplicated Malaria

Adults

• Four adult-strength tablets (total 1000 mg atovaquone/400 mg proguanil) once daily for 3 consecutive days 1
• Take with food or milky drink 1
• If vomiting occurs within 1 hour of dosing, repeat the dose 1

Efficacy

• Cure rates exceed 98% in clinical trials for P. falciparum malaria 6
• Significantly more effective than mefloquine, amodiaquine, and chloroquine in comparative trials 6
• Protective efficacy of 95-100% for prophylaxis 2

Special Populations

Renal Impairment

Critical dosing adjustments are required based on creatinine clearance 1:

• Mild impairment (CrCl 50-80 mL/min): No dose adjustment needed 1
• Moderate impairment (CrCl 30-50 mL/min): No dose adjustment for prophylaxis or treatment 1
• Severe impairment (CrCl <30 mL/min):
  • Contraindicated for prophylaxis 1
  • May be used with caution for treatment only if benefits outweigh risks of drug accumulation 1
  • Proguanil and cycloguanil half-lives are prolonged with potential for toxicity 1

For patients on dialysis, no dose adjustment is needed as drugs are largely metabolized and excreted through the liver 5

Hepatic Impairment

• Mild to moderate impairment: No dose adjustment needed 1
• Severe impairment: Not studied; use with caution 1
• Proguanil AUC increases and cycloguanil formation decreases in hepatic impairment, but atovaquone pharmacokinetics remain relatively stable 1

Pregnancy

• Chloroquine and proguanil have a long history of safe use during pregnancy 5
• Pregnant women should avoid malarious areas if possible due to increased risk of severe malaria 5
• The combination atovaquone/proguanil has limited safety data in pregnancy compared to chloroquine/proguanil

Elderly

• No dose adjustment required 1
• Cycloguanil exposure increases (AUC 2.36-fold) with longer half-life (14.9 vs 8.3 hours) 1
• Monitor for adverse effects given altered pharmacokinetics 1

Administration Considerations

Food Requirements

• Must be taken with food or a milky drink 1
• Dietary fat increases atovaquone absorption 2-3 fold (AUC) and 5-fold (Cmax) compared to fasting 3
• This is critical for achieving therapeutic levels 3

Drug Interactions

Avoid or use caution with the following 1:

• Tetracycline: Reduces atovaquone levels by ~40% 1
• Metoclopramide: Decreases atovaquone bioavailability 1
• Rifampin: Reduces atovaquone levels by ~50% 1
• Rifabutin: Reduces atovaquone levels by ~34% 1
• Indinavir: Atovaquone decreases indinavir trough levels by 23% 1

Clinical Context and Positioning

First-Line Status

• Malarone is considered first-line for uncomplicated P. falciparum malaria in most current guidelines (except Canadian where ACTs remain unavailable) 5
• Alternative to artemisinin-based combination therapies (ACTs) when those are contraindicated or for patients from Southeast Asia with ACT resistance 5
• Second-line option after artemether-lumefantrine or dihydroartemisinin-piperaquine in recent European guidelines 5

Advantages Over Other Antimalarials

• Fewer neuropsychiatric adverse events than mefloquine 2, 7
• Fewer gastrointestinal adverse events than chloroquine plus proguanil 2
• Shorter post-travel prophylaxis period (7 days vs 4 weeks) due to causal prophylactic activity 2
• Excellent safety profile with severe adverse events rarely reported 7
• No cross-resistance with other antimalarial agents 2

Common Pitfalls

• Failure to take with food: This is the most common error and significantly reduces efficacy 3
• Premature discontinuation: Must complete full 7 days post-travel for prophylaxis 1
• Use in severe renal impairment for prophylaxis: This is contraindicated 1
• Ignoring vomiting within 1 hour: Requires repeat dosing 1

Tolerability

Most common adverse events are headache and abdominal pain, occurring at rates similar to placebo 2, 7. Significantly fewer patients discontinue atovaquone/proguanil compared to chloroquine/proguanil or mefloquine 2.