Atovaquone and Proguanil

Pronunciation

(a TOE va kwone & pro GWA nil)

U.S. Brand Names

Malarone™

Synonyms

Proguanil and Atovaquone

Generic Available

Canadian Brand Names

Malarone™

Use

Prevention or treatment of acute, uncomplicated P. falciparum malaria

Pregnancy Risk Factor

Pregnancy Implications

Use in pregnant women only if the potential benefit outweighs the possible risk to the fetus. Because falciparum malaria can cause maternal death and fetal loss, pregnant women traveling to malaria-endemic areas must use personal protection against mosquito bites.

Lactation

Atovaquone: Excretion in breast milk unknown

Proguanil: Enters breast milk (small amounts)/use caution

Contraindications

Hypersensitivity to atovaquone, proguanil, or any component of the formulation; prophylactic use in severe renal impairment

Warnings/Precautions

Not indicated for severe or complicated malaria. Absorption of atovaquone may be decreased in patients who have diarrhea or vomiting; monitor closely and consider use of an antiemetic. If severe, consider use of an alternative antimalarial. Do not use with other medications containing proguanil. Administer with caution to patients with pre-existing renal disease. Not for use in patients <5 kg (treatment) or <11 kg (prophylaxis). Delayed cases of P. falciparum malaria may occur after stopping prophylaxis; travelers returning from endemic areas who develop febrile illnesses should be evaluated for malaria. Recrudescent infections or infections following prophylaxis with this agent should be treated with alternative agent(s).

Adverse Reactions

The following adverse reactions were reported in patients being treated for malaria. When used for prophylaxis, reactions are similar to those seen with placebo.

>10%: Gastrointestinal: Abdominal pain (17%), nausea (12%), vomiting (children 10% to 13%, adults 12%)

1% to 10%:

Central nervous system: Headache (10%), dizziness (5%)

Dermatologic: Pruritus (children 6%)

Gastrointestinal: Diarrhea (children 6%, adults 8%), anorexia (5%)

Neuromuscular & skeletal: Weakness (8%)

Postmarketing and/or case reports: Anaphylaxis, erythema multiforme, hallucinations, photosensitivity, psychotic episodes, rash, seizure, Stevens-Johnson syndrome, urticaria

Overdosage/Toxicology

Atovaquone: Overdoses of up to 31,500 mg have been reported. Rash has been reported as well as methemoglobinemia in one patient also taking dapsone. There is no known antidote and it is unknown if it is dialyzable.

Proguanil: Single doses of 1500 mg and 700 mg twice daily for two weeks have been reported without toxicity. Reversible hair loss, scaling of skin, reversible aphthous ulceration, and hematologic side effects have occurred. Epigastric discomfort and vomiting would also be expected.

There have been no reported overdoses with the atovaquone/proguanil combination.

Drug Interactions

Proguanil: Substrate (minor) of 1A2, 2C19, 3A4

Metoclopramide decreases bioavailability of atovaquone.

Rifabutin decreases atovaquone levels by 34%; concomitant use is not recommended.

Rifampin decreases atovaquone levels by 50%; concomitant use is not recommended.

Tetracycline decreases plasma concentrations of atovaquone by 40%; monitor closely

Ethanol/Nutrition/Herb Interactions

Food: Atovaquone taken with dietary fat increases the rate and extent of absorption.

Stability

Store tablets at 25°C (77°F)

Mechanism of Action

Atovaquone: Selectively inhibits parasite mitochondrial electron transport.

Proguanil: The metabolite cycloguanil inhibits dihydrofolate reductase, disrupting deoxythymidylate synthesis. Together, atovaquone/cycloguanil affect the erythrocytic and exoerythrocytic stages of development.

Pharmacodynamics/Kinetics

Atovaquone: See Atovaquone monograph.

Proguanil:

Absorption: Extensive

Distribution: 42 L/kg

Protein binding: 75%

Metabolism: Hepatic to active metabolites, cycloguanil (via CYP2C19) and 4-chlorophenylbiguanide

Half-life elimination: 12-21 hours

Excretion: Urine (40% to 60%)

Dosage

Oral:

Children (dosage based on body weight):

Prevention of malaria: Start 1-2 days prior to entering a malaria-endemic area, continue throughout the stay and for 7 days after returning. Take as a single dose, once daily.

11-20 kg: Atovaquone/proguanil 62.5 mg/25 mg

21-30 kg: Atovaquone/proguanil 125 mg/50 mg

31-40 kg: Atovaquone/proguanil 187.5 mg/75 mg

>40 kg: Atovaquone/proguanil 250 mg/100 mg

Treatment of acute malaria: Take as a single dose, once daily for 3 consecutive days.

5-8 kg: Atovaquone/proguanil 125 mg/50 mg

9-10 kg: Atovaquone/proguanil 187.5 mg/75 mg

11-20 kg: Atovaquone/proguanil 250 mg/100 mg

21-30 kg: Atovaquone/proguanil 500 mg/200 mg

31-40 kg: Atovaquone/proguanil 750 mg/300 mg

>40 kg: Atovaquone/proguanil 1 g/400 mg

Adults:

Prevention of malaria: Atovaquone/proguanil 250 mg/100 mg once daily; start 1-2 days prior to entering a malaria-endemic area, continue throughout the stay and for 7 days after returning

Treatment of acute malaria: Atovaquone/proguanil 1 g/400 mg as a single dose, once daily for 3 consecutive days

Elderly: Use with caution due to possible decrease in renal and hepatic function, as well as possible decreases in cardiac function, concomitant diseases, or other drug therapy.

Dosage adjustment in renal impairment: Should not be used as prophylaxis in severe renal impairment (Clcr<30 mL/minute). Alternative treatment regimens should be used in patients with Clcr<30 mL/minute. No dosage adjustment required in mild to moderate renal impairment.

Dosage adjustment in hepatic impairment: No dosage adjustment required in mild to moderate hepatic impairment. No data available for use in severe hepatic impairment.

Administration

Administer with food or milk at the same time each day. If vomiting occurs within 1 hour of administration, repeat the dose. For children who have difficulty swallowing tablets, tablets may be crushed and mixed with condensed milk just prior to administration.

Dietary Considerations

Must be taken with food or a milky drink.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Complete full course of therapy; do not discontinue or alter dosage without consulting prescriber. Take at the same time each day with full glass of milk or food. If vomiting occurs within 1 hour of taking dose, you may repeat the dose. You may experience nausea, vomiting, or loss of appetite (small frequent meals may help); or headache (If persistent, contact prescriber). Follow recommended precautions to avoid malaria exposure (use insect repellent, bednets, protective clothing). Notify prescriber if you develop fever after returning from or while visiting a malaria-endemic area. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May produce abnormal dreams; may rarely cause seizures and hallucinations

Mental Health: Effects on Psychiatric Treatment

Significant adverse GI effects; use caution with SSRIs

Dosage Forms

Tablet: Atovaquone 250 mg and proguanil hydrochloride 100 mg

Tablet, pediatric: Atovaquone 62.5 mg and proguanil hydrochloride 25 mg

International Brand Names

Malarone™ (CA)

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