"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
Vomiting and Diarrhea
Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If MALARONE is used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. [See DOSAGE AND ADMINISTRATION] Vomiting occurred in up to 19% of pediatric patients given treatment doses of MALARONE. 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 MALARONE alone.
In the event of recrudescent P. falciparum infections after treatment with MALARONE or failure of chemoprophylaxis with MALARONE, patients should be treated with a different blood schizonticide.
Severe or Complicated Malaria
MALARONE 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of MALARONE on male and female reproductive performance are unknown.
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.
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.
Use In Specific Populations
Pregnancy Category C
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.
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.
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 0.04-times 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. MALARONE 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. [See PATIENT INFORMATION.]
The proguanil component of MALARONE acts by inhibiting the parasitic dihydrofolate reductase [see CLINICAL PHARMACOLOGY]. 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 MALARONE.
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 MALARONE is administered to a nursing woman.
Prophylaxis of Malaria
Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg. The efficacy and safety of MALARONE have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more [see Clinical Studies].
Treatment of Malaria
Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg. The efficacy and safety of MALARONE for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more [see Clinical Studies].
Clinical trials of MALARONE did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the higher systemic exposure to cycloguanil, and the greater frequency of concomitant disease or other drug therapy. [See CLINICAL PHARMACOLOGY.]
Do not use MALARONE 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. [See CLINICAL PHARMACOLOGY.]
No dosage adjustments are needed in patients with mild or moderate hepatic impairment [see CLINICAL PHARMACOLOGY]. No trials have been conducted in patients with severe hepatic impairment.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/26/2016
Additional Malarone Information
Malarone - User Reviews
Malarone User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.