Malarone Information
Malarone () Description
Malarone () (atovaquone and proguanil hydrochloride) is a fixed-dose combination of the antimalarial agents atovaquone and proguanil hydrochloride. The chemical name of atovaquone is -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula CHClO. The compound has the following structural formula:
The chemical name of proguanil hydrochloride is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride is a white crystalline solid that is sparingly soluble in water. It has a molecular weight of 290.22 and the molecular formula CHClN•HCl. The compound has the following structural formula:
Malarone () Tablets and Malarone () Pediatric Tablets are for oral administration. Each Malarone () Tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride and each Malarone () Pediatric Tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. The inactive ingredients in both tablets are low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains hypromellose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide, and titanium dioxide.
Malarone () Clinical Pharmacology
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.
Concomitant treatment with has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.
Concomitant treatment with has also been associated with decreased bioavailability of atovaquone.
Concomitant administration of or is known to reduce atovaquone levels by approximately 50% and 34%, respectively (see PRECAUTIONS: Drug Interactions). The mechanisms of these interactions are unknown.
Concomitant administration of atovaquone (750 mg BID with food for 14 days) and indinavir (800 mg TID without food for 14 days) did not result in any change in the steady-state AUC and Cof indinavir but resulted in a decrease in the Cof indinavir (23% decrease [90% CI 8%, 35%]). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely (see PRECAUTIONS: Drug Interactions). Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.
Malarone () Contraindications
Malarone () is contraindicated in individuals with known hypersensitivity to atovaquone or proguanil hydrochloride or any component of the formulation. Rare cases of anaphylaxis following treatment with atovaquone/proguanil have been reported.
Malarone () is contraindicated for prophylaxis of malaria in patients with severe renal impairment (creatinine clearance
Malarone () Precautions
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.
Elevated liver function tests and rare cases of hepatitis have been reported with prophylactic use of Malarone () . A single case of hepatic failure requiring liver transplantation has also been reported with prophylactic use.
Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If Malarone () is used in patients who are vomiting (see DOSAGE AND ADMINISTRATION), parasitemia should be closely monitored and the use of an antiemetic considered. Vomiting occurred in up to 19% of pediatric patients given treatment doses of Malarone () . In the controlled clinical trials of Malarone () , 15.3% of adults who were treated with atovaquone/proguanil received an antiemetic drug during that part of the trial when they received atovaquone/proguanil. Of these patients, 98.3% were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required.
Parasite relapse occurred commonly when malaria was treated with Malarone () alone.
In the event of recrudescent infections after treatment with Malarone () or failure of chemoprophylaxis with Malarone () , patients should be treated with a different blood schizonticide.
Concomitant treatment with has been associated with approximately a 40% reduction in plasma concentrations of atovaquone. Parasitemia should be closely monitored in patients receiving tetracycline. While antiemetics may be indicated for patients receiving Malarone () , may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available.
Concomitant administration of or is known to reduce atovaquone levels by approximately 50% and 34%, respectively. The concomitant administration of Malarone () and rifampin or rifabutin is not recommended.
Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin-based anticoagulants. The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with Malarone () in patients on continuous treatment with coumarin-based anticoagulants. When these products are administered concomitantly, suitable coagulation tests should be closely monitored.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.
Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown.
Pregnancy Category C. 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 (see Information for Patients) in addition to antimalarials.
Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at maternal plasma concentrations up to 5 to 6.5 times the estimated human exposure during treatment of malaria. Following single-dose administration of C-labeled atovaquone to pregnant rats, concentrations of radiolabel in rat fetuses were 18% (mid-gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. In rabbits, atovaquone caused maternal toxicity at plasma concentrations that were approximately 0.6 to 1.3 times the estimated human exposure during treatment of malaria. 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. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations.
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 0.2-times the average human exposure based on AUC comparisons). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.
The combination of atovaquone and proguanil hydrochloride was not teratogenic in rats at plasma concentrations up to 1.7 and 0.10 times, respectively, the estimated human exposure during treatment of malaria. In rabbits, the combination of atovaquone and proguanil hydrochloride was not teratogenic or embryotoxic to rabbit fetuses at plasma concentrations up to 0.34 and 0.82 times, respectively, the estimated human exposure during treatment of malaria.
While there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in pregnant women, Malarone () may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of Malarone () acts by inhibiting the parasitic dihydrofolate reductase (see CLINICAL PHARMACOLOGY: Microbiology: Mechanism of Action). However, there are no clinical data indicating that folate supplementation diminishes drug efficacy, and 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.
Malarone () Adverse Reactions
Because Malarone () contains atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The higher treatment doses of Malarone () were less well tolerated than the lower prophylactic doses.
Among adults who received Malarone () for treatment of malaria, attributable adverse experiences that occurred in ≥5% of patients were abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), asthenia (8%), anorexia (5%), and dizziness (5%). Treatment was discontinued prematurely due to an adverse experience in 4 of 436 adults treated with Malarone () .
Among pediatric patients (weighing 11 to 40 kg) who received Malarone () for the treatment of malaria, attributable adverse experiences that occurred in ≥5% of patients were vomiting (10%) and pruritus (6%). Vomiting occurred in 43 of 319 (13%) pediatric patients who did not have symptomatic malaria but were given treatment doses of Malarone () for 3 days in a clinical trial. The design of this clinical trial required that any patient who vomited be withdrawn from the trial. Among pediatric patients with symptomatic malaria treated with Malarone () , treatment was discontinued prematurely due to an adverse experience in 1 of 116 (0.9%).
In a study of 100 pediatric patients (5 to
Abnormalities in laboratory tests reported in clinical trials were limited to elevations of transaminases in malaria patients being treated with Malarone () . The frequency of these abnormalities varied substantially across studies of treatment and were not observed in the randomized portions of the prophylaxis trials.
In one phase III trial of malaria treatment in Thai adults, early elevations of ALT and AST were observed to occur more frequently in patients treated with Malarone () compared to patients treated with an active control drug. Rates for patients who had normal baseline levels of these clinical laboratory parameters were: Day 7: ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%. By day 14 of this 28-day study, the frequency of transaminase elevations equalized across the 2 groups.
In this and other studies in which transaminase elevations occurred, they were noted to persist for up to 4 weeks following treatment with Malarone () for malaria. None were associated with untoward clinical events.
Among subjects who received Malarone () for prophylaxis of malaria in placebo-controlled trials, adverse experiences occurred in similar proportions of subjects receiving Malarone () or placebo (Table 3). The most commonly reported adverse experiences possibly attributable to Malarone () or placebo were headache and abdominal pain. Prophylaxis with Malarone () was discontinued prematurely due to a treatment-related adverse experience in 3 of 381 adults and 0 of 125 pediatric patients.
In an additional placebo-controlled study of malaria prophylaxis with Malarone () involving 330 pediatric patients in a malaria-endemic area (see CLINICAL STUDIES), the safety profile of Malarone () was consistent with that described above. The most common treatment-emergent adverse events with Malarone () were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with Malarone () than with placebo, while fever (5% vs. 12%) and diarrhea (1% vs. 5%) were more common with placebo. No patient withdrew from the study due to an adverse experience with Malarone () . No routine laboratory data were obtained during this study.
Among subjects who received Malarone () for prophylaxis of malaria in clinical trials with an active comparator, adverse experiences occurred in a similar or lower proportion of subjects receiving Malarone () than an active comparator (Table 4). The mean durations of dosing and the periods for which the adverse experiences are summarized in Table 4, were 28 days (Study 1) and 26 days (Study 2) for Malarone () , 53 days for mefloquine, and 49 days for chloroquine plus proguanil (reflecting the different recommended dosing regimens). Fewer neuropsychiatric adverse experiences occurred in subjects who received Malarone () than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving Malarone () than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving Malarone () had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 4). Prophylaxis with Malarone () was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers.
In a third active-controlled study, Malarone () (n = 110) was compared with chloroquine/proguanil (n = 111) for the prophylaxis of malaria in 221 non-immune pediatric patients (see CLINICAL STUDIES). The mean duration of exposure was 23 days for Malarone () , 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with Malarone () reported abdominal pain (2% vs. 7%) or nausea (
Malarone () Overdosage
There is no information on overdoses of Malarone () substantially higher than the doses recommended for treatment.
There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable. The median lethal dose is higher than the maximum oral dose tested in mice and rats (1,825 mg/kg/day). 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.
Malarone () Dosage And Administration
The daily dose should be taken at the same time each day with food or a milky drink. In the event of vomiting within 1 hour after dosing, a repeat dose should be taken.
Malarone () How Supplied
Malarone () Tablets, containing 250 mg atovaquone and 100 mg proguanil hydrochloride, are pink, film-coated, round, biconvex tablets engraved with “GX CM3” on one side.
Bottle of 100 tablets with child-resistant closure (NDC 0173-0675-01).
Unit Dose Pack of 24 (NDC 0173-0675-02).
Malarone () Pediatric Tablets, containing 62.5 mg atovaquone and 25 mg proguanil hydrochloride, are pink, film-coated, round, biconvex tablets engraved with “GX CG7” on one side.
Bottle of 100 tablets with child-resistant closure (NDC 0173-0676-01).
Malarone () Animal Toxicology
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/mbasis). 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/mbasis). 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/mbasis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be reversible.
Malarone () Clinical Studies
In 3 phase II clinical trials, atovaquone alone, proguanil hydrochloride alone, and the combination of atovaquone and proguanil hydrochloride were evaluated for the treatment of acute, uncomplicated malaria caused by . Among 156 evaluable patients, the parasitological cure rate was 59/89 (66%) with atovaquone alone, 1/17 (6%) with proguanil hydrochloride alone, and 50/50 (100%) with the combination of atovaquone and proguanil hydrochloride.
Malarone () was evaluated for treatment of acute, uncomplicated malaria caused by in 8 phase III controlled clinical trials. Among 471 evaluable patients treated with the equivalent of 4 Malarone () Tablets once daily for 3 days, 464 had a sensitive response (elimination of parasitemia with no recurrent parasitemia during follow-up for 28 days) (see Table 7). Seven patients had a response of RI resistance (elimination of parasitemia but with recurrent parasitemia between 7 and 28 days after starting treatment). In these trials, the response to treatment with Malarone () was similar to treatment with the comparator drug in 4 trials, and better than the response to treatment with the comparator drug in the other 4 trials.
The overall efficacy in 521 evaluable patients was 98.7% (Table 7).
*
†
‡
§
Eighteen of 521 (3.5%) evaluable patients with acute falciparum malaria presented with a pretreatment serum creatinine greater than 2.0 mg/dL (range 2.1 to 4.3 mg/dL). All were successfully treated with Malarone () and 17 of 18 (94.4%) had normal serum creatinine levels by day 7.
Data from a phase II trial of atovaquone conducted in Zambia suggested that approximately 40% of the study population in this country were HIV-infected patients. The enrollment criteria were similar for the phase III trial of Malarone () conducted in Zambia and the results are presented in Table 7. Efficacy rates for Malarone () in this study population were high and comparable to other populations studied.
The efficacy of Malarone () in the treatment of the erythrocytic phase of nonfalciparum malaria was assessed in a small number of patients. Of the 23 patients in Thailand infected with and treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days, parasitemia cleared in 21 (91.3%) at 7 days. Parasite relapse occurred commonly when malaria was treated with Malarone () alone. Seven patients in Gabon with malaria due to or were treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days. All 6 evaluable patients (3 with , 2 with , and 1 with mixed and ) were cured at 28 days. Relapsing malarias including and require additional treatment to prevent relapse.
The efficacy of Malarone () in treating acute uncomplicated malaria in children weighing ≥5 and
Malarone () was evaluated for prophylaxis of malaria in 5 clinical trials in malaria-endemic areas and in 3 active-controlled trials in non-immune travelers to malaria-endemic areas.
Three placebo-controlled studies of 10 to 12 weeks’ duration were conducted among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. Of a total of 669 randomized patients (including 264 pediatric patients 5 to 16 years of age), 103 were withdrawn for reasons other than falciparum malaria or drug-related adverse events. (Fifty-five percent of these were lost to follow-up and 45% were withdrawn for protocol violations.) The results are listed in Table 8.
In another study, 330 Gabonese pediatric patients (weighing 13 to 40 kg, and aged 4 to 14 years) who had received successful open-label radical cure treatment with artesunate, were randomized to receive either Malarone () (dosage based on body weight) or placebo in a double-blind fashion for 12 weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165 children given Malarone () and 18 of 165 patients given placebo withdrew from the study for reasons other than parasitemia (primary reason was lost to follow-up). In the per-protocol population, 1 out of 150 patients (
In a 10-week study in 175 South African subjects who moved into malaria-endemic areas and were given prophylaxis with 1 Malarone () Tablet daily, parasitemia developed in 1 subject who missed several doses of medication. Since no placebo control was included, the incidence of malaria in this study was not known.
Two active-controlled studies were conducted in non-immune travelers who visited a malaria-endemic area. The mean duration of travel was 18 days (range 2 to 38 days). Of a total of 1,998 randomized patients who received Malarone () or controlled drug, 24 discontinued from the study before follow-up evaluation 60 days after leaving the endemic area. Nine of these were lost to follow-up, 2 withdrew because of an adverse experience, and 13 were discontinued for other reasons. These studies were not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to malaria in both studies is unknown. The results are listed in Table 9.
A third randomized, open-label study was conducted which included 221 otherwise healthy pediatric patients (weighing ≥11 kg and 2 to 17 years of age) who were at risk of contracting malaria by traveling to an endemic area. The mean duration of travel was 15 days (range 1 to 30 days). Prophylaxis with Malarone () (n = 110, dosage based on body weight) began 1 or 2 days before entering the endemic area and lasted until 7 days after leaving the area. A control group (n = 111) received prophylaxis with chloroquine/proguanil dosed according to WHO guidelines. No cases of malaria occurred in either group of children. However, the study was not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to malaria in this study is unknown.
In a malaria challenge study conducted in healthy US volunteers, atovaquone alone prevented malaria in 6 of 6 individuals, whereas 4 of 4 placebo-treated volunteers developed malaria.
Malarone () Principal Display Panel
See accompanying prescribing information for Dosage and Administration.
Store at 25C (77F); excursions permitted to 15 to 30C (59to 86F) (see USP Controlled Room Temperature).
Do not use if printed safety seal under cap is broken or missing.
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in Canada
Rev. 3/10
A079205
Malarone () Principal Display Panel
See accompanying prescribing information for Dosage and Administration.
Store at 25C (77F); excursions permitted to 15 to 30C (59to 86F) (see USP Controlled Room Temperature).
Do not use if printed safety seal under cap is broken or missing.
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in Canada
Rev. 3/10
A079206
