Atovaquone and proguanil

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include stomach discomfort, vomiting, mouth sores, hair loss, easy bruising or bleeding, and peeling of the skin on your hands or feet.

Malaria is spread by the bites of certain kinds of infected female mosquitoes. If you are living in, or will be traveling to, an area where there is a chance of getting malaria, the following mosquito-control measures will help to prevent infection:

• Remain in air-conditioned or well-screened rooms to reduce contact with mosquitoes.
• If possible, sleep under mosquito netting, preferably netting coated or soaked with permethrin, to avoid being bitten by malaria-carrying mosquitoes.
• Wear long-sleeved shirts or blouses and long trousers to protect your arms and legs, especially from dusk through dawn when mosquitoes are out.
• Apply mosquito repellent, preferably one containing DEET, to uncovered areas of the skin from dusk through dawn when mosquitoes are out.
• Use a pyrethrum-containing flying insect spray to kill mosquitoes in living and sleeping quarters during evening and nighttime hours.

Contact your doctor right away if you experience cough, difficulty swallowing, dizziness, fast heartbeat, hives, itching, puffiness or swelling of the eyelids or around the eyes, face, lips or tongue, shortness of breath, skin rash, tightness in chest, unusual tiredness or weakness, or wheezing. These could be symptoms of an allergic reaction.

Atovaquone and proguanil may cause your skin to be more sensitive to sunlight than it is normally. Be sure to wear protective clothing and a hat or apply a product to the skin that prevents sunburn before going outside.

• If you have an allergy to atovaquone, proguanil, or any other part of atovaquone and proguanil.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have kidney problems.
• If you are taking any of these drugs: Rifabutin or rifampin.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take atovaquone and proguanil with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use atovaquone and proguanil as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• If using to prevent malaria, start this medicine before traveling to the high risk place.
• To gain the most benefit, do not miss doses.
• Keep taking atovaquone and proguanil as you have been told by your doctor or other health care provider, even if you feel well.
• Take this medicine at the same time of day.
• Take with food or a milky drink.
• If you throw up within 1 hour of taking atovaquone and proguanil, take 1 more dose.
• You may crush the tablet and mix it with condensed milk.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of Atovaquone and Proguanil hydrochloride on male and female reproductive performance are unknown.

Atovaquone: A 24-month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. In CD-1 mice, a 24-month study showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least 15 times the average steady-state plasma concentrations in humans during prophylaxis of malaria.

Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Atovaquone did not impair fertility in male and female rats at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC.

Proguanil: No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice at doses up to 16 mg/kg/day corresponding to 1.5 times the average human plasma exposure during prophylaxis of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average human plasma exposure during prophylaxis of malaria based on AUC.

Proguanil was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma mutagenesis assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil, a dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation.

A fertility study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.04-times the average human exposure during treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

Animal Toxicology and/or Pharmacology

Fibrovascular proliferation in the right atrium, pyelonephritis, bone marrow hypocellularity, lymphoid atrophy, and gastritis/enteritis were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 12 mg/kg/day (approximately 3.9 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Bile duct hyperplasia, gall bladder mucosal atrophy, and interstitial pneumonia were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 4 mg/kg/day (approximately 1.3 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Mucosal hyperplasia of the cecum and renal tubular basophilia were observed in rats treated with proguanil hydrochloride for 6 months at a dose of 20 mg/kg/day (approximately 1.6 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be reversible.

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.

Absorption

Atovaquone: The rate and extent of absorption is increased when administered with dietary fat.

Proguanil: Extensive

Distribution

Vd:

Atovaquone: Children and Adults: ~8.8 L/kg

Proguanil: Children >15 years and Adults and 31-110 kg: 1617-2502 L; Pediatric patients ≤15 years and 11-56 kg: 462-966 L; concentrated in erythrocytes

Metabolism

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

Excretion

Atovaquone: Feces (>94% as unchanged drug); urine (<0.6%)

Proguanil: Urine (40% to 60%)

Half-Life Elimination

Atovaquone: 2-3 days (adults), 1-2 days (children)

Proguanil: 12-21 hours

Protein Binding

Atovaquone: >99%

Proguanil: 75%

Malaria prevention: Prophylaxis of Plasmodium falciparum malaria, including areas where chloroquine resistance has been reported

Malaria treatment: Treatment of acute, uncomplicated P. falciparum malaria

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%)

Hepatic: Increased serum ALT (27%; increased liver function test values typically normalized after ~ 4 weeks), increased serum AST (17%; increased liver function test values typically normalized after ~4 weeks)

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%)

<1% (Limited to important or life-threatening): Anaphylaxis (rare), anemia (rare), angioedema, cholestasis, erythema multiforme (rare), hallucination, hepatic failure (case report), hepatitis (rare), neutropenia, pancytopenia (with severe renal impairment), psychotic reaction (rare), seizure (rare), skin photosensitivity, skin rash, Stevens-Johnson syndrome (rare), stomatitis, urticaria, vasculitis (rare)

Prophylactic therapy should start 1 or 2 days before entering a malaria-endemic area and continued daily during the stay and for 7 days after return.

250 mg atovaquone/100 mg proguanil (one adult strength tablet) orally once a day

Less than 5 kg ABW (actual body weight): Safety and efficacy has not been established.

5 to 8 kg ABW: 125 mg atovaquone/50 mg proguanil (2 pediatric tablets) once daily for 3 consecutive days.

9 to 10 kg ABW: 187.5 mg atovaquone/75 mg proguanil (3 pediatric tablets) once daily for 3 consecutive days.

11 to 20 kg ABW: 250 mg atovaquone/100 mg proguanil (one adult strength or four pediatric tablets as a single dose) orally once a day for 3 consecutive days

21 to 30 kg ABW: 500 mg atovaquone/200 mg proguanil (two adult strength tablets as a single dose) orally once a day for 3 consecutive days

31 to 40 kg ABW: 750 mg atovaquone/300 mg proguanil (three adult strength tablets as a single dose) orally once a day for 3 consecutive days

Greater than 40 kg ABW: 1 g atovaquone/400 mg proguanil (four adult strength tablets as a single dose) orally once a day for 3 consecutive days

No dosage adjustment necessary in patients with CrCl greater than or equal to 30 mL/min

For patients with CrCl less than 30 mL/min, atovaquone-proguanil is contraindicated for prophylaxis of plasmodium falciparum malaria.

It may be used with caution for the treatment of malaria in patients with severe renal impairment (CrCl less than 30 mL/min), only if the benefits of the 3-day regimen outweigh the potential risks associated with increased drug exposure.