Atovaquone and Proguanil Hydrochloride

Antimalarial; fixed combination containing atovaquone (hydroxynaphthoquinone derivative) and proguanil (biguanide derivative).1 161

Administration

Oral Administration

Administer orally with food or milky drink.1

Usually once daily as a single dose, given at same time each day.1

If vomiting occurs within 1 hour of taking a dose, repeat the dose.1 Antiemetic agents may be used if necessary.1 (See Drug Interactions: Metoclopramide.)

For children who have difficulty swallowing tablets, the tablets may be crushed and mixed with condensed milk just prior to administration.1 Tablets are not palatable if chewed due to bitter taste of proguanil.17

Dosage

Available as fixed-combination tablets (adult strength) containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride and fixed-combination pediatric tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.1

Dosage expressed in terms of the number of tablets (adult strength or pediatric)1 115 121 134 144 or as dose of atovaquone and dose of proguanil hydrochloride.1

Pediatric Patients

Dosage is based on weight.1 115 121 134 (See Table 1.)

Although safety and efficacy not established for prevention of malaria in pediatric patients weighing <11 kg,1 CDC and other experts state that pediatric patients weighing 5–8 kg† can receive ½ of a pediatric tablet once daily (31.3 mg/12.5 mg once daily) and those weighing 9–10 kg† can receive 3/4 of a pediatric tablet once daily (46.9 mg/18.8 kg once daily).115 121 134

Initiate prophylaxis 1–2 days prior to entering malarious area and continue during stay and for 7 days after leaving the area.1 115 121 134

If exposure occurred in areas where P. ovale or P. vivax is endemic, terminal prophylaxis with 14-day regimen of primaquine may be indicated;115 134 give during final 7 days of atovaquone/proguanil prophylaxis and then for an additional 7 days or, if not feasible, give for 14 days after atovaquone/proguanil prophylaxis discontinued.115

Use pediatric dosage recommended for treatment of uncomplicated malaria.115 134 (See Table 2.)

Initiate promptly if malaria suspected (fever, chills, or other influenza-like illness) and professional medical care not readily available.115 134

Only a temporary measure; obtain professional medical evaluation as soon as possible.115

Do not use for presumptive self-treatment of malaria in those taking the drug for prophylaxis.115 134

Dosage is based on weight.1 134 144 (See Table 2.)

Safety and efficacy not established for treatment of malaria in pediatric patients weighing <5 kg.1

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax†, CDC and other experts recommend the same dosage used for treatment of uncomplicated P. falciparum malaria.134 144 Because atovaquone/proguanil cannot prevent relapse of P. vivax malaria, 14-day regimen of primaquine indicated in conjunction with atovaquone/proguanil to provide a radical cure.134 143 144

Adults

A single tablet (adult strength) once daily (250 mg of atovaquone and 100 mg of proguanil hydrochloride once daily).1 115 121 134

Initiate prophylaxis 1–2 days prior to entering malarious area and continue during stay and for 7 days after leaving the area.1 115 134

If exposure occurred in areas where P. ovale or P. vivax is endemic, terminal prophylaxis with 14-day regimen of primaquine may be indicated;115 134 give during final 7 days of atovaquone/proguanil prophylaxis and then for an additional 7 days or, if not feasible, give for 14 days after atovaquone/proguanil prophylaxis discontinued.115

Use adult dosage recommended for treatment of uncomplicated malaria.115 134

Initiate presumptive self-treatment if malaria suspected (fever, chills, or other influenza-like illness) and professional medical care not readily available.115 134

Only a temporary measure; obtain professional medical evaluation as soon as possible.115

Do not use for presumptive self-treatment of malaria in those taking the drug for prophylaxis.115 134

For treatment of uncomplicated malaria caused by P. falciparum, 4 tablets (adult strength) once daily for 3 consecutive days (1 g of atovaquone and 400 mg of proguanil hydrochloride once daily for 3 consecutive days).1 134 144 To reduce incidence of nausea and vomiting, some clinicians suggest an alternative regimen of 2 tablets (adult strength) twice daily for 3 consecutive days.134

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax†, CDC and other experts recommend the same dosage used for treatment of uncomplicated P. falciparum malaria.134 144 Because atovaquone/proguanil cannot prevent relapse of P. vivax malaria, 14-day regimen of primaquine indicated in conjunction with atovaquone/proguanil to provide a radical cure.134 143 144

Special Populations

Hepatic Impairment

Dosage adjustments not needed in those with mild to moderate hepatic impairment; data not available regarding use in those with severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustments not needed in those with mild to moderate renal impairment (Clcr 30–80 mL/minute).1

Do not use for prevention of malaria in those with severe renal impairment (Clcr <30 mL/minute); use with caution for treatment of malaria in such patients.1 (See Renal Impairment under Cautions.)

Contraindications

• Known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone, proguanil, or any ingredient in the formulation.1

• Prevention of malaria in patients with Clcr <30 mL/minute;1 pancytopenia has been reported in such patients receiving proguanil.1

Warnings/Precautions

Sensitivity Reactions

Allergic reactions, including anaphylaxis, angioedema, urticaria, and vasculitis, reported.1

Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome also reported.1

GI Effects

Nausea, vomiting, or diarrhea reported in 8–12% of adults receiving atovaquone/proguanil for treatment of uncomplicated malaria; vomiting reported in up to 19% of children.1

Atovaquone absorption reduced in patients with vomiting or diarrhea.1 Monitor for parasitemia and consider use of an antiemetic agent.1 (See Specific Drugs under Interactions.)

If severe or persistent vomiting or diarrhea occurs, consider alternative antimalarial.1

Hepatotoxicity

Elevations in liver function test values reported.1

Hepatitis and hepatic failure requiring liver transplantation reported in individuals receiving the drug for prophylaxis.1

Malaria Recrudescence

Do not use to treat recrudescence of malaria or malaria that occurs as a result of failure of treatment or prophylaxis with the drug.1 Use an alternative antimalarial.1

Selection and Use of Antimalarials

Do not use for initial treatment of severe malaria.1 143 Life-threatening, serious, or overwhelming malaria requires aggressive treatment with a parenteral antimalarial regimen.143 144

Not evaluated in patients with cerebral malaria or other manifestations of severe complicated malaria (e.g., hyperparasitemia, pulmonary edema, renal failure).1

Specific Populations

Category C.1

Manufacturer states use in pregnant women only if potential benefits justify risks to the fetus.1

CDC states use may be considered in pregnant women for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum when other treatment options not available or not tolerated and if potential benefits outweigh risks.143 CDC states do not use for prevention of malaria in pregnant women.115

Atovaquone distributed into milk in rats; proguanil distributed into human milk.1

Manufacturer states use with caution in nursing women.1

CDC states may be used for treatment of malaria in women breast-feeding infants of any weight when potential benefits outweigh possible risks to the infant (e.g., when a breast-feeding woman has acquired P. falciparum malaria in area with multidrug-resistant malaria and other treatment options not tolerated).115 CDC states do not use for prevention of malaria in women breast-feeding infants who weigh <5 kg.115

Safety and efficacy for prevention of malaria not established in children weighing <11 kg.1

Safety and efficacy for treatment of malaria not established in children weighing <5 kg.1

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.1

Consider the greater frequency of decreased hepatic, renal, and/or cardiac function, higher systemic exposure to cycloguanil (active metabolite of proguanil), and greater frequency of concomitant disease or drug therapy observed in geriatric individuals.1

Pharmacokinetics not studied in patients with severe hepatic impairment.1

Contraindicated for prevention of malaria if Clcr <30 mL/minute.

Use with caution for treatment of malaria if Clcr <30 mL/minute and only if benefits outweigh risks (e.g., increased drug concentrations).1

Common Adverse Effects

Abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia, dizziness, cough, and pruritus.1

Storage

Oral

25°C (may be exposed to 15–30°C).1

• Atovaquone/proguanil is a fixed combination of 2 antimalarial agents.1 3 4 5 6 7 8 9 10 13 14 15 Atovaquone is a hydroxynaphthoquinone derivative4 5 and proguanil hydrochloride is a biguanide derivative.1 3 4 5 6 7 8 9 10 13 14 15

• Atovaquone selectively inhibits mitochondrial electron transport in plasmodia and collapses mitochondrial membrane potential.1 5 6 7 8 10 Antimalarial activity of proguanil principally due to its active metabolite (cycloguanil);1 4 6 7 cycloguanil inhibits dihydrofolate reductase, leading to depletion of pyrimidine nucleotide pools and disruption in nucleic acid synthesis and cell replication.1 4 6 10

• Atovaquone and proguanil synergistic against erythrocytic stages of Plasmodium.5 6 7 13 Proguanil may lower concentration of atovaquone needed to collapse mitochondrial membrane potential.15

• Active against erythrocytic forms of most strains of Plasmodium falciparum, P. malariae, P. ovale, and P. vivax1 8 and exoerythrocytic forms of Plasmodium;1 no activity against P. vivax hypnozoites.3 8

• P. falciparum with decreased susceptibility to atovaquone or to proguanil/cycloguanil can be selected in vitro or in vivo.1