Dosing & Uses
Dosage Forms & 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
Dosage Forms & 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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (2)
- dapsone topical
proguanil, dapsone topical. unspecified interaction mechanism. Avoid or Use Alternate Drug. Avoid coadministration of dapsone topical with oral dapsone or antimalarial medications because of the potential for hemolytic reactions.
atovaquone, dapsone topical. unspecified interaction mechanism. Avoid or Use Alternate Drug. Avoid coadministration of dapsone topical with oral dapsone or antimalarial medications because of the potential for hemolytic reactions. - efavirenz
efavirenz decreases levels of atovaquone by unspecified interaction mechanism. Avoid or Use Alternate Drug.
Monitor Closely (4)
- bupivacaine implant
atovaquone, bupivacaine implant. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Local anesthetics may increase the risk of developing methemoglobinemia when concurrently exposed to drugs that also cause methemoglobinemia.
proguanil, bupivacaine implant. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Local anesthetics may increase the risk of developing methemoglobinemia when concurrently exposed to drugs that also cause methemoglobinemia. - efavirenz
efavirenz decreases levels of proguanil by unspecified interaction mechanism. Use Caution/Monitor. May decrease serum concentrations of the active metabolite of proguanil.
- indinavir
indinavir will decrease the level or effect of atovaquone by unknown mechanism. Modify Therapy/Monitor Closely.
- metoclopramide intranasal
metoclopramide intranasal will increase the level or effect of atovaquone by Other (see comment). Use Caution/Monitor. Metoclopramide may decrease the absorption of atovaquone. Monitor for reduced therapeutic effect of atovaquone.
Minor (2)
- metoclopramide
metoclopramide decreases levels of atovaquone by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- tetracycline
tetracycline decreases levels of atovaquone by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown. Effect may be minor, due to pharmacodynamic synergism.
Adverse 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
Prophylaxis 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)
Hepatitis and increased transaminase levels reported with prophylactic use; monitor closely; use caution with existing hepatic impairment; hepatic enzyme elevations may persist for four weeks after treatment has ended
Not for treatment of cerebral malaria or other severe manifestations of complicated malaria
Absorption may be reduced in patients with diarrhea or vomiting; monitor closely, and consider antiemetic use; if severe, use alternative antimalarial
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; delayed cases of P. falciparum malaria may occur
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
Treatment failure reported in patients >100 kg; monitoring and follow up recommended in this patient group
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 & 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
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%)
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