atovaquone/proguanil

Contraindicated in:

Hypersensitivity to atovaquone or proguanil;
Severe renal impairment (CCr <30 mL/min).

Use Cautiously in:

Nausea or vomiting; may require repeat dosing and/or prophylactic use of antiemetics;
Severe malaria; oral agents are insufficient;
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk; recommend folate during pregnancy to minimize risk of neural tube defects;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Pedi: Children <5 kg (safety and effectiveness not established);
Geri: Dose carefully in older adults, considering age-related ↓ in body mass, hepatic/renal/cardiac function, concurrent disease states, and drug therapy.

Adv. Reactions/Side Effects ⬆ ⬇

Prophylaxis of Malaria

EENT: visual difficulties

GI: abdominal pain, oral ulcers

Treatment of Malaria

Derm: pruritus (↑ in children), photosensitivity

GI: abdominal pain, diarrhea, nausea, vomiting, anorexia, ↑liver enzymes

Hemat: neutropenia

Neuro: headache, dizziness, dreams, headache, insomnia, weakness

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS)

Interactions ⬆ ⬇

Drug-drug:

Rifampin, rifabutin, metoclopramideand tetracycline↓ atovaquone levels.

Availability ⬆ ⬇

(Generic available)

Tablets (adults): atovaquone 250 mg/proguanil 100 mg
Tablets (pediatric): atovaquone 62.5 mg/proguanil 25 mg

Route/Dosage ⬆ ⬇

Prevention of Malaria

PO (Adults and Children > 40 kg): One adult strength tablet (atovaquone 250 mg/proguanil 100 mg) once daily 1–2 days prior to entering endemic area and continued for 7 days following return.
PO (Children 31–40 kg): Three pediatric tablets (atovaquone 187.5 mg/proguanil 75 mg) once daily 1–2 days prior to entering endemic area and continued for 7 days following return.
PO (Children 21–30 kg): Two pediatric tablets (atovaquone 125 mg/proguanil 50 mg) once daily 1–2 days prior to entering endemic area and continued for 7 days following return.
PO (Children 11–20 kg): One pediatric tablet (atovaquone 62.5 mg/proguanil 25 mg) once daily 1–2 days prior to entering endemic area and continued for 7 days following return.

Treatment of Malaria

PO (Adults and Children >40 kg): Four adult tablets (total daily dose atovaquone 1 g/proguanil 400 mg) once daily for 3 days.
PO (Children 31–40 kg): Three adult tablets (total daily dose atovaquone 750 mg/proguanil 300 mg) once daily for 3 days .
PO (Children 21–30 kg): Two adult tablets (total daily dose atovaquone 500 mg/proguanil 300 mg) once daily for 3 days .
PO (Children 11–20 kg): One adult strength tablet (total daily dose atovaquone 250 mg/proguanil 150 mg) once daily for 3 days .
PO (Children 9–10 kg): Three pediatric tablets (total daily dose atovaquone 187.5 mg/proguanil 75 mg once daily for 3 days.
PO (Children 5–8 kg): Two pediatric tablets (total daily dose atovaquone 125 mg/proguanil 50 mg) once daily for 3 days.

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Atovaquone is a selective inhibitor of parasite mitochondrial transport.
Proguanil's metabolite, cycloguanil, is a dihydrofolate reductase inhibitor.
Both interfere with pyrimidine synthesis required for nucleic acids and replication are active against both erythrocytic and exoerythrocytic stages of Plasmodiumspp.

Therapeutic effects:

Prevention/treatment of malarial illness and its sequelae.

Classifications ⬆ ⬇

Therapeutic Classification: antimalarials

Pharmacokinetics ⬆ ⬇

Atovaquone

Absorption: Variably absorbed following oral administration, food enhances absorption.

Distribution: Extensively distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Undergoes enterohepatic recycling; >94% eliminated unchanged in feces.

Half-Life: Adults— 2–3 days; Children— 1–2 days.

Proguanil

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP2C19 isoenzyme and converted to cycloguanil, the pharmacologically active metabolite; primarily excreted in the urine.

Half-Life: Cycloguanil: Adults: 8.3 hr, elderly: 14.9 hr.

Canadian Brand Names ⬆ ⬇

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
atovaquone PO	unknown	1–8 hr; 24–96 hr‡	24 hr
proguanil PO	unknown	unknown	24 hr

‡Two peaks are due to enterohepatic recycling.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take medication exactly as directed and continue full course of therapy, even if feeling better. If vomiting occurs within 1 hr of dose, may take a repeat dose. Take missed doses as soon as remembered, unless almost time for next dose. Do not double doses.
Review methods of minimizing exposure to mosquitoes with patients receiving atovaquone/proguanil prophylactically (use insect repellent, wear long-sleeved shirt and long trousers, use screen or netting).
Advise patient to wear protective clothing and sunscreen to avoid photosensitivity reactions.
Rep: Advise female patients to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Risk of death and serious complications is higher with Falciparum malaria. Advise pregnant women anticipating travel to malarious area to discuss risks with health care professional.

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Indications ⬇

Contraind./Precautions ⬆ ⬇