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Film Coated Tablets
12 x 62.5 mg/25 mg
Film Coated Tablets
12 x 250 mg/100 mg
Prevention of Malaria: Start prophylactic treatment 1 or 2 days before entering a malaria-endemic area and continue daily during the stay and for 7 days after return.
Adults: One tablet of MALARONE Tablets For Adults (250 mg atovaquone/100 mg proguanil hydrochloride) per day.
Paediatric Patients: The dosage for prevention of malaria in paediatric patients is based upon body weight
Treatment of Acute Malaria
Adults: Four Tablets For Adults (total daily dose 1 g atovaquone/400 mg proguanil hydrochloride) as a single daily dose for 3 consecutive days.
Paediatric Patients: The dosage for treatment of acute malaria in paediatric patients is based upon body weight.
Renal Impairment: Do not use this product for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min). Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment.
For full details see prescribing information.
Prevention of malaria: Prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported.
Treatment of malaria: The treatment of acute, uncomplicated P. falciparum malaria. Effective in regions where the drugs chloroquine, halofantrine, mefloquine and amodiaquine may have unacceptable failure rates, presumably due to drug resistance. Recommended for pediatric patients who weigh over 11 kg.
Individuals with known hypersensitivity to atovaquone or proguanil HCl or any component of the formulation. For prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min).
Vomiting and Diarrhea: Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. Vomiting occurred in up to 19% of paediatric patients given treatment doses of this product. In the controlled clinical trials, 15.3% of adults received an antiemetic when they received atovaquone/proguanil and 98.3% of these patients were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.
Relapse of Infection: In mixed P. falciparum and Plasmodium vivax infections, P. vivax parasite relapse occurred commonly when patients were treated with this product alone. In the event of recrudescent P. falciparum infections after treatment or failure of chemoprophylaxis with this product, patients should be treated with a different blood schizonticide.
Hepatotoxicity: Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use.
Severe or Complicated Malaria: This product has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therapy.
Higher treatment doses were less well tolerated than the lower prophylactic doses. Among adults treated for malaria: abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia and dizziness. Among pediatric patients: vomiting, pruritus. Patients who received prophylactic treatment: headache, abdominal pain.
For full details see prescribing information.
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose. Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro.
Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.
Rifampin/Rifabutin: Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations by approximately 50% and 34%, respectively. The mechanisms of these interactions are unknown.
Tetracycline: Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.
Metoclopramide: Concomitant treatment with metoclopramide has been associated with decreased bioavailability of atovaquone. Indinavir: Concomitant administration of atovaquone (750 mg twice-daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir (23% decrease [90% CI = 8%, 35%]).
Activity In Vitro and In Vivo: Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared to either atovaquone or proguanil hydrochloride alone was demonstrated in clinical trials in both immune and non-immune patients.
Drug Resistance: Strains of P. falciparum with decreased susceptibility to atovaquone or proguanil/cycloguanil alone can be selected in vitro or in vivo. The combination of atovaquone and proguanil hydrochloride may not be effective for treatment of recrudescent malaria that develops after prior therapy with the combination.
Pregnancy and Lactation
Pregnancy Category C
Atovaquone: In a pre- and post-natal study in rats, atovaquone did not produce adverse effects in offspring at doses up to 1,000 mg/kg/day corresponding to AUC exposures of approximately 7.3 times the estimated human exposure during treatment of malaria. Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations up to 7.3 times the estimated human exposure during treatment of malaria based on AUC. In rabbits, atovaquone caused adverse fetal effects and maternal toxicity at a dose of 1,200 mg/kg/day corresponding to plasma concentrations that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. Adverse fetal effects in rabbits, including decreased fetal body lengths and increased early resorptions and post-implantation losses, were observed only in the presence of maternal toxicity.
Proguanil: A pre- and post-natal study in Sprague-Dawley rats revealed no adverse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.04times the average human exposure based on AUC). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted. Atovaquone and Proguanil: The combination of atovaquone and proguanil hydrochloride was not teratogenic in pregnant rats at atovaquone:proguanil hydrochloride (50:20 mg/kg/day) corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at atovaquone:proguanil hydrochloride (100:40 mg/kg/day) corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC. There are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women. This product should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population. Maternal death and fetal loss are both known complications of falciparum malaria in pregnancy. In pregnant women who must travel to malaria-endemic areas, personal protection against mosquito bites should always be employed in addition to antimalarials. The proguanil component acts by inhibiting the parasitic dihydrofolate reductase. However, there are no clinical data indicating that folate supplementation diminishes drug efficacy. For women of childbearing age receiving folate supplements to prevent neural tube birth defects, such supplements may be continued while taking this product.
Nursing Mothers: It is not known whether atovaquone is excreted into human milk. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma. Proguanil is excreted into human milk in small quantities. Caution should be exercised when administered to a nursing woman.
There is no information on overdoses of this product substantially higher than the doses recommended for treatment. There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable. Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose. Overdoses of proguanil hydrochloride as large as 1,500 mg have been followed by complete recovery, and doses as high as 700 mg twice daily have been taken for over 2 weeks without serious toxicity. Adverse experiences occasionally associated with proguanil hydrochloride doses of 100 to 200 mg/day, such as epigastric discomfort and vomiting, would be likely to occur with overdose. There are also reports of reversible hair loss and scaling of the skin on the palms and/or soles, reversible aphthous ulceration, and hematologic side effects.