MALARONE®
(atovaquone and proguanil hydrochloride)
Tablets
MALARONE®
(atovaquone and proguanil hydrochloride)
Pediatric Tablets

MALARONE has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasliia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therapy.

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), parasliia 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 P. vivax malaria was 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.

Patients should be instructed:

• to take MALARONE tablets at the same time each day with food or a milky drink.
• to take a repeat dose of MALARONE if vomiting occurs within 1 hour after dosing.
• to take a dose as soon as possible if a dose is missed, then return to their normal dosing schedule. However, if a dose is skipped, the patient should not double the next dose.
• to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with MALARONE is prematurely discontinued for any reason.
• that protective clothing, insect repellents, and bednets are important components of malaria prophylaxis.
• that no chemoprophylactic regimen is 100% effective; therefore, patients should seek medical attention for any febrile illness that occurs during or after return from a malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria.
• that falciparum malaria carries a higher risk of death and serious complications in pregnant women than in the general population. Pregnant women anticipating travel to malarious areas should discuss the risks and benefits of such travel with their physicians (see Pregnancy section).

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone. Parasliia should be closely monitored in patients receiving tetracycline. While antiemetics may be indicated for patients receiving MALARONE, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively. The concomitant administration of MALARONE and rifampin or rifabutin is not recommended.

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 ¹⁴C-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.

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.

Clinical studies of MALARONE did not include sufficient numbers of subjects aged 65 and over 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 (see CLINICAL PHARMACOLOGY: Special Populations: Geriatrics), and the greater frequency of concomitant disease or other drug therapy.

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 <11 kg body weight) who received MALARONE for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥5% of patients as an adverse experience attributable to MALARONE. In 3 patients (3%), treatment was discontinued prematurely due to an adverse experience.

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.

^* Subjects receiving the recommended dose of atovaquone and proguanil hydrochloride in placebo-controlled trials.

^†Subjects receiving the recommended dose of atovaquone and proguanil hydrochloride in any trial.

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.

^*Adverse experiences that started while receiving active study drug.

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 (<1% vs. 7%) than children who received chloroquine/proguanil. Oral ulceration (2% vs. 2%), vivid dreams (2% vs. <1%), and blurred vision (0% vs. 2%) occurred in similar proportions of patients receiving either MALARONE or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving MALARONE discontinued due to adverse events.

In addition to adverse events reported from clinical trials, the following events have been identified during world-wide post-approval use of MALARONE or its components, atovaquone and proguanil hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to MALARONE.

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.

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.

Prophylactic treatment with MALARONE should be started 1 or 2 days before entering a malaria-endemic area and continued daily during the stay and for 7 days after return.

MALARONE should not be used for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min). MALARONE may be used with caution for the treatment of malaria in patients with severe renal impairment (creatinine clearance <30 mL/min), only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment). No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) and moderate (creatinine clearance 30 to 50 mL/min) renal impairment (see CLINICAL PHARMACOLOGY: Special Populations).

No dosage adjustments are needed in patients with mild to moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY: Special Populations: Hepatic Impairment).

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).

Storeat 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).

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.

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 P. falciparum. 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 P. falciparum 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 parasliia with no recurrent parasliia during follow-up for 28 days) (see Table 7). Seven patients had a response of RI resistance (elimination of parasliia but with recurrent parasliia 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).

* MALARONE = 1,000 mg atovaquone and 400 mg proguanil hydrochloride (or equivalent based on body weight for patients weighing ≤40 kg) once daily for 3 days.

^†Elimination of parasliia with no recurrent parasliia during follow-up for 28 days.

^‡Patients hospitalized only for acute care. Follow-up conducted in outpatients.

^§ Study in pediatric patients 3 to 12 years of age.

Eighteen of 521 (3.5%) evaluable patients with acute falciparummalaria 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 P. vivax and treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days, parasliia cleared in 21 (91.3%) at 7 days. Parasite relapse occurred commonly when P. vivax malaria was treated with MALARONE alone. Seven patients in Gabon with malaria due to P. ovale or P. malariae were treated with atovaquone/proguanil hydrochloride 1,000 mg/400 mg daily for 3 days. All 6 evaluable patients (3 with P. malariae, 2 with P. ovale, and 1 with mixed P. falciparum and P. ovale) were cured at 28 days. Relapsing malarias including P. vivax and P. ovale require additional treatment to prevent relapse.

The efficacy of MALARONE in treating acute uncomplicated P. falciparum malaria in children weighing ≥5 and <11 kg was examined in an open-label, randomized trial conducted in Gabon. Patients received either MALARONE (2 or 3 MALARONE Pediatric Tablets once daily depending upon body weight) for 3 days (n = 100) or amodiaquine (10 mg/kg/day) for 3 days (n = 100). In this study, the MALARONE Tablets were crushed and mixed with condensed milk just prior to administration. In the per-protocol population, adequate clinical response was obtained in 95% (87/92) of the pediatric patients who received MALARONE and in 53% (41/78) of those who received amodiaquine. A response of RI resistance (elimination of parasliia but with recurrent parasliia between 7 and 28 days after starting treatment) was noted in 3% and 40% of the patients, respectively. Two cases of RIII resistance (rising parasite count despite therapy) were reported in the patients receiving MALARONE. There were 4 cases of RIII in the amodiaquine arm.

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 uled 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 parasliia (primary reason was lost to follow-up). In the per-protocol population, 1 out of 150 patients (<1%) who received MALARONE developed P. falciparum parasliia while receiving prophylaxis with MALARONE compared with 31 (22%) of the 144 placebo recipients.

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, parasliia 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 P. falciparum malaria in both studies is unknown. The results are uled 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 P.falciparum 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.