Malarone (Atovaquone and Proguanil Hcl)
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Malarone (Atovaquone and Proguanil Hcl)

MALARONE®
(atovaquone and proguanil hydrochloride) Tablets

MALARONE®
(atovaquone and proguanil hydrochloride) Pediatric Tablets

DRUG 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 trans-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 C22H19ClO3. The compound has the following structural formula:

Atovaquone Structural Formula Illustration

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 C11H16ClN5•HCl. The compound has the following structural formula:

Proguanil hydrochlorideStructural Formula Illustration

MALARONE (atovaquone and proguanil hcl) Tablets and MALARONE (atovaquone and proguanil hcl) Pediatric Tablets are for oral administration. Each MALARONE (atovaquone and proguanil hcl) Tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride and each MALARONE (atovaquone and proguanil hcl) 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.

What are the possible side effects of atovaquone and proguanil (Malarone, Malarone Pediatric)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • severe or uncontrolled vomiting or diarrhea;
  • fever, mouth sores;
  • problems with speech, balance, or walking;
  • severe skin rash;
  • nausea, stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); o
  • easy bruising, unusual...

Read All Potential Side Effects and See Pictures of Malarone »

What are the precautions when taking atovaquone and proguanil hcl (Malarone)?

Before taking atovaquone/proguanil, tell your doctor or pharmacist if you are allergic to either atovaquone or proguanil; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: current diarrhea, current vomiting, kidney problems, liver problems, mental/mood problems, seizures.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use...

Read All Potential Precautions of Malarone »

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Prevention of Malaria

MALARONE (atovaquone and proguanil hcl) is indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported (see Clinical Studies).

Treatment of Malaria

MALARONE (atovaquone and proguanil hcl) is indicated for the treatment of acute, uncomplicated P. falciparum malaria. MALARONE (atovaquone and proguanil hcl) has been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

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.

Prevention of Malaria

Prophylactic treatment with MALARONE (atovaquone and proguanil hcl) 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.

Adults: One MALARONE (atovaquone and proguanil hcl) Tablet (adult strength = 250 mg atovaquone/100 mg proguanil hydrochloride) per day.

Pediatric Patients: The dosage for prevention of malaria in pediatric patients is based upon body weight (Table 5).

Table 5. Dosage for Prevention of Malaria in Pediatric Patients

Weight (kg) Atovaquone/Proguanil HCl Total Daily Dose Dosage Regimen
11-20 62.5 mg/25 mg 1 MALARONE Pediatric Tablet daily
21-30 125 mg/50 mg 2 MALARONE Pediatric Tablets as a single dose daily
31-40 187.5 mg/75 mg 3 MALARONE Pediatric Tablets as a single dose daily
> 40 250 mg/100 mg 1 MALARONE Tablet (adult strength) as a single dose daily

Treatment of Acute Malaria

Adults: Four MALARONE (atovaquone and proguanil hcl) Tablets (adult strength; total daily dose 1 g atovaquone/400 mg proguanil hydrochloride) as a single dose daily for 3 consecutive days.

Pediatric Patients: The dosage for treatment of acute malaria in pediatric patients is based upon body weight (Table 6).

Table 6. Dosage for Treatment of Acute Malaria in Pediatric Patients

Weight (kg) Atovaquone/Proguanil HCl Total Daily Dose Dosage Regimen
5-8 125 mg/50 mg 2 MALARONE Pediatric Tablets daily for 3 consecutive days
9-10 187.5 mg/75 mg 3 MALARONE Pediatric Tablets daily for 3 consecutive days
11-20 250 mg/100 mg 1 MALARONE Tablet (adult strength) daily for 3 consecutive days
21-30 500 mg/200 mg 2 MALARONE Tablets (adult strength) as a single dose daily for 3 consecutive days
31-40 750 mg/300 mg 3 MALARONE Tablets (adult strength) as a single dose daily for 3 consecutive days
> 40 1 g/400 mg 4 MALARONE Tablets (adult strength) as a single dose daily for 3 consecutive days

MALARONE (atovaquone and proguanil hcl) Tablets may be crushed and mixed with condensed milk just prior to administration for children who may have difficulty swallowing tablets.

Patients With Renal Impairment

MALARONE (atovaquone and proguanil hcl) should not be used for malaria prophylaxis in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min). MALARONE (atovaquone and proguanil hcl) 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).

Patients With Hepatic Impairment

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).

HOW SUPPLIED

MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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).

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

GlaxoSmithKline. Research Triangle Park, NC 27709.

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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 (atovaquone and proguanil hcl) were less well tolerated than the lower prophylactic doses.

Among adults who received MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) .

Among pediatric patients (weighing 11 to 40 kg) who received MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) , 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 (atovaquone and proguanil hcl) for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥ 5% of patients as an adverse experience attributable to MALARONE (atovaquone and proguanil hcl) . 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 (atovaquone and proguanil hcl) . 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) for malaria. None were associated with untoward clinical events.

Among subjects who received MALARONE (atovaquone and proguanil hcl) for prophylaxis of malaria in placebo-controlled trials, adverse experiences occurred in similar proportions of subjects receiving MALARONE (atovaquone and proguanil hcl) or placebo (Table 3). The most commonly reported adverse experiences possibly attributable to MALARONE (atovaquone and proguanil hcl) or placebo were headache and abdominal pain. Prophylaxis with MALARONE (atovaquone and proguanil hcl) was discontinued prematurely due to a treatment-related adverse experience in 3 of 381 adults and 0 of 125 pediatric patients.

Table 3. Adverse Experiences in Placebo-Controlled Clinical Trials of MALARONE (atovaquone and proguanil hcl) for Prophylaxis of Malaria

Adverse Experience Percent of Subjects With Adverse Experiences (Percent of Subjects With Adverse Experiences Attributable to Therapy)
Adults Children and Adolescents
Placebo
n = 206
MALARONE*
n = 206
MALARONE
n = 381
Placebo
n = 140
MALARONE
n = 125
Headache 27 (7) 22 (3) 17 (5) 21 (14) 19 (14)
Fever 13 (1) 5 (0) 3 (0) 11 ( ≤ 1) 6 (0)
Myalgia 11 (0) 12 (0) 7 (0) 0 (0) 0 (0)
Abdominal pain 10 (5) 9 (4) 6 (3) 29 (29) 33 (31)
Cough 8 ( ≤ 1) 6 ( ≤ 1) 4 (1) 9 (0) 9 (0)
Diarrhea 8 (3) 6 (2) 4 (1) 3 (1) 2 (0)
Upper respiratory infection 7 (0) 8 (0) 5 (0) 0 (0) ≤ 1 (0)
Dyspepsia 5 (4) 3 (2) 2 (1) 0 (0) 0 (0)
Back pain 4 (0) 8 (0) 4 (0) 0 (0) 0 (0)
Gastritis 3 (2) 3 (3) 2 (2) 0 (0) 0 (0)
Vomiting 2 ( ≤ 1) 1 ( ≤ 1) ≤ 1 ( ≤ 1) 6 (6) 7 (7)
Flu syndrome 1 (0) 2 (0) 4 (0) 6 (0) 9 (0)
Any adverse experience 65 (32) 54 (17) 49 (17) 62 (41) 60 (42)
* 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 (atovaquone and proguanil hcl) involving 330 pediatric patients in a malaria-endemic area (see Clinical Studies), the safety profile of MALARONE (atovaquone and proguanil hcl) was consistent with that described above. The most common treatment-emergent adverse events with MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) . No routine laboratory data were obtained during this study.

Among subjects who received MALARONE (atovaquone and proguanil hcl) for prophylaxis of malaria in clinical trials with an active comparator, adverse experiences occurred in a similar or lower proportion of subjects receiving MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) , 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 (atovaquone and proguanil hcl) than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving MALARONE (atovaquone and proguanil hcl) than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving MALARONE (atovaquone and proguanil hcl) had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 4). Prophylaxis with MALARONE (atovaquone and proguanil hcl) was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers.

Table 4. Adverse Experiences in Active-Controlled Clinical Trials of MALARONE (atovaquone and proguanil hcl) for Prophylaxis of Malaria

Adverse Experience Percent of Subjects With Adverse Experiences* (Percent of Subjects With Adverse Experiences Attributable toTherapy)
Study 1 Study 2
MALARONE
n = 493
Mefloquine
n = 483
MALARONE
n = 511
Chloroquine plus Proguanil
n = 511
Diarrhea 38 (8) 36 (7) 34 (5) 39 (7)
Nausea 14 (3) 20 (8) 11 (2) 18 (7)
Abdominal pain 17 (5) 16 (5) 14 (3) 22 (6)
Headache 12 (4) 17 (7) 12 (4) 14 (4)
Dreams 7 (7) 16 (14) 6 (4) 7 (3)
Insomnia 5 (3) 16 (13) 4 (2) 5 (2)
Fever 9 ( ≤ 1) 11 (1) 8 ( ≤ 1) 8 ( ≤ 1)
Dizziness 5 (2) 14 (9) 7 (3) 8 (4)
Vomiting 8 (1) 10 (2) 8 (0) 14 (2)
Oral ulcers 9 (6) 6 (4) 5 (4) 7 (5)
Pruritus 4 (2) 5 (2) 3 (1) 2 ( ≤ 1)
Visual difficulties 2 (2) 5 (3) 3 (2) 3 (2)
Depression ≤ 1 ( ≤ 1) 5 (4) ≤ 1 ( ≤ 1) 1 ( ≤ 1)
Anxiety 1 ( ≤ 1) 5 (4) ≤ 1 ( ≤ 1) 1 ( ≤ 1)
Any adverse experience 64 (30) 69 (42) 58 (22) 66 (28)
Any neuropsychiatric event 20 (14) 37 (29) 16 (10) 20 (10)
Any GI event 49 (16) 50 (19) 43 (12) 54 (20)
* Adverse experiences that started while receiving active study drug.

In a third active-controlled study, MALARONE (atovaquone and proguanil hcl) (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 (atovaquone and proguanil hcl) , 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving MALARONE (atovaquone and proguanil hcl) discontinued due to adverse events.

Post-Marketing Adverse Reactions

In addition to adverse events reported from clinical trials, the following events have been identified during world-wide post-approval use of MALARONE (atovaquone and proguanil hcl) . 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 (atovaquone and proguanil hcl) .

Blood and Lymphatic System Disorders: Neutropenia and rarely anemia. Pancytopenia in patients with severe renal impairment treated with proguanil.

Immune System Disorders: Allergic reactions including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis.

Nervous System Disorders: Rare cases of seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders: Stomatitis.

Hepatobiliary Disorders: Elevated liver function tests and rare cases of hepatitis, cholestasis; a single case of hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders: Photosensitivity, rash, and rare cases of erythema multiforme and Stevens-Johnson syndrome.

Read the Malarone (atovaquone and proguanil hcl) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Concomitant treatment with tetracycline 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 (atovaquone and proguanil hcl) , 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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.

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

No information provided.

PRECAUTIONS

General

MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) . 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 (atovaquone and proguanil hcl) . In the controlled clinical trials of MALARONE (atovaquone and proguanil hcl) , 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 (atovaquone and proguanil hcl) alone.

In the event of recrudescent P. falciparum infections after treatment with MALARONE (atovaquone and proguanil hcl) or failure of chemoprophylaxis with MALARONE (atovaquone and proguanil hcl) , patients should be treated with a different blood schizonticide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Atovaquone: Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from approximately 5 to 8 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.

Proguanil: No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice (doses up to 1.5 times the average systemic human exposure based on AUC) and in Wistar Hannover rats (doses up to 1.1 times the average systemic human exposure).

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 0.2-times the average human exposure based on AUC comparisons.) Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of MALARONE (atovaquone and proguanil hcl) on male and female reproductive performance are unknown.

Pregnancy

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.

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 (atovaquone and proguanil hcl) may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) .

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 MALARONE (atovaquone and proguanil hcl) is administered to a nursing woman.

Pediatric Use

Treatment of Malaria: The efficacy and safety of MALARONE (atovaquone and proguanil hcl) for the treatment of malaria have been established in controlled studies involving pediatric patients weighing 5 kg or more (see Clinical Studies). Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg.

Prophylaxis of Malaria: The efficacy and safety of MALARONE (atovaquone and proguanil hcl) have been established for the prophylaxis of malaria in controlled studies involving pediatric patients weighing 11 kg or more (see Clinical Studies). Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg.

Geriatric Use

Clinical studies of MALARONE (atovaquone and proguanil hcl) 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.

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There is no information on overdoses of MALARONE (atovaquone and proguanil hcl) 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.

CONTRAINDICATIONS

MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) (see CLINICAL PHARMACOLOGY: Special Populations: Renal Impairment).

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Microbiology

Mechanism of Action: The constituents of MALARONE (atovaquone and proguanil hcl) , atovaquone and proguanil hydrochloride, interfere with 2 different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is a selective inhibitor of parasite mitochondrial electron transport. Proguanil hydrochloride primarily exerts its effect by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis.

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 studies in both immune and non-immune patients (see Clinical Studies).

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.

Pharmacokinetics

Absorption: Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability.

Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and Cmax 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. MALARONE (atovaquone and proguanil hcl) Tablets should be taken with food or a milky drink.

Proguanil hydrochloride is extensively absorbed regardless of food intake.

Distribution: Atovaquone is highly protein bound ( > 99%) over the concentration range of 1 to 90 mcg/mL. A population pharmacokinetic analysis demonstrated that the apparent volume of distribution of atovaquone (V/F) in adult and pediatric patients after oral administration is approximately 8.8 L/kg.

Proguanil is 75% protein bound. A population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients > 15 years of age with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients ≤15 years of age with body weights from 11 to 56 kg, the V/F of proguanil ranged from 462 to 966 L.

In human plasma, the binding of atovaquone and proguanil was unaffected by the presence of the other.

Metabolism: In a study where 14C-labeled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified. Between 40% to 60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via CYP2C19) and 4-chlorophenylbiguanide. The main routes of elimination are hepatic biotransformation and renal excretion.

Elimination: The elimination half-life of atovaquone is about 2 to 3 days in adult patients.

The elimination half-life of proguanil is 12 to 21 hours in both adult patients and pediatric patients, but may be longer in individuals who are slow metabolizers.

A population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to the body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight ≥ 11 kg are shown in Table 1.

Table 1. Apparent Clearance for Atovaquone and Proguanil in Patients as a Function of Body Weight

  Atovaquone   Proguanil
Body Weight N CL/F (L/hr) Mean ± SD* (range) N CL/F (L/hr) Mean ± SD* (range)
11-20 kg 159 1.34 ± 0.63
(0.52-4.26)
146 29.5 ± 6.5
(10.3-48.3)
21-30 kg 117 1.87 ± 0.81
(0.52-5.38)
113 40.0 ± 7.5
(15.9-62.7)
31-40 kg 95 2.76 ± 2.07
(0.97-12.5)
91 49.5 ± 8.30
(25.8-71.5)
> 40 kg 368 6.61 ± 3.92
(1.32-20.3)
282 67.9 ± 19.9
(14.0-145)
* SD = standard deviation.

The pharmacokinetics of atovaquone and proguanil in patients with body weight below 11 kg have not been adequately characterized.

Special Populations

Pediatrics: The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half-life of atovaquone is shorter in pediatric patients (1 to 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough levels of atovaquone and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight.

Geriatrics: In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (age 65 to 79 years) to 13 younger subjects (age 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate = 2.36, CI = 1.70, 3.28). Tmax was longer in elderly subjects (median 8 hours) compared with younger subjects (median 4 hours) and average elimination half-life was longer in elderly subjects (mean 14.9 hours) compared with younger subjects (mean 8.3 hours).

Hepatic Impairment: In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 moderate, as indicated by the Child-Pugh method) to 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared to healthy subjects, there were no marked differences ( ≤ 50%) in the rate or extent of systemic exposure of atovaquone. However, in subjects with moderate hepatic impairment, the elimination half-life of atovaquone was increased (point estimate = 1.28, 90% CI = 1.00 to 1.63). Proguanil AUC, Cmax, and its t1/2 increased in subjects with mild hepatic impairment when compared to healthy subjects (Table 2). Also, the proguanil AUC and its t1/2 increased in subjects with moderate hepatic impairment when compared to healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (Cmax and AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared to healthy volunteers (Table 2). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of MALARONE (atovaquone and proguanil hcl) have not been studied in patients with severe hepatic impairment.

Table 2. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Volunteers

Parameter Comparison Proguanil Cycloguanil
AUC(0-inf)* mild:healthy 1.96 (1.51, 2.54) 0.32 (0.22, 0.45)
Cmax* mild:healthy 1.41 (1.16, 1.71) 0.35 (0.24, 0.50)
t1/2 mild:healthy 1.21 (0.92, 1.60) 0.86 (0.49, 1.48)
AUC(0-inf)* moderate:healthy 1.64 (1.14, 2.34) ND
Cmax* moderate:healthy 0.97 (0.69, 1.36) ND
t1/2 moderate:healthy 1.46 (1.05, 2.05) ND
ND = not determined due to lack of quantifiable data.
* Ratio of geometric means.
Mean difference.

Renal Impairment: In patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), oral clearance and/or AUC data for atovaquone, proguanil, and cycloguanil are within the range of values observed in patients with normal renal function (creatinine clearance > 80 mL/min). In patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clearance > 80 mL/min) and the oral clearance of atovaquone was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of MALARONE (atovaquone and proguanil hcl) for long-term prophylaxis (over 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance ≤ 30 mL/min), atovaquone Cmax and AUC are reduced but the elimination half-lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing (see CONTRAINDICATIONS).

Drug Interactions

There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.

Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone.

Concomitant treatment with metoclopramide has also been associated with decreased bioavailability of atovaquone.

Concomitant administration of rifampin or rifabutin 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 Cmax of indinavir but resulted in a decrease in the Ctrough of 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.

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/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.

Clinical Studies

Treatment of Acute Malarial Infections

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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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).

Table 7. Parasitological Response in Clinical Trials of MALARONE (atovaquone and proguanil hcl) for Treatment of P. falciparum Malaria

Study Site MALARONE* Comparator
Evaluable Patients (n) % Sensitive Response Drug(s) Evaluable Patients (n) % Sensitive Response
Brazil 74 98.6% Quinine and tetracycline 76 100.0%
Thailand 79 100.0% Mefloquine 79 86.1%
France 21 100.0% Halofantrine 18 100.0%
Kenya‡,§ 81 93.8% Halofantrine 83 90.4%
Zambia 80 100.0% Pyrimethamine/ sulfadoxine (P/S) 80 98.8%
Gabon 63 98.4% Amodiaquine 63 81.0%
Philippines 54 100.0% Chloroquine (Cq) Cq and P/S 23 32 30.4% 87.5%
Peru 19 100.0% Chloroquine P/S 13 7 7.7% 100.0%
* MALARONE (atovaquone and proguanil hcl) = 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 parasitemia with no recurrent parasitemia 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 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) conducted in Zambia and the results are presented in Table 7. Efficacy rates for MALARONE (atovaquone and proguanil hcl) in this study population were high and comparable to other populations studied.

The efficacy of MALARONE (atovaquone and proguanil hcl) 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, parasitemia cleared in 21 (91.3%) at 7 days. Parasite relapse occurred commonly when P. vivax malaria was treated with MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) (2 or 3 MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) and in 53% (41/78) of those who received amodiaquine. A response of RI resistance (elimination of parasitemia but with recurrent parasitemia 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 (atovaquone and proguanil hcl) . There were 4 cases of RIII in the amodiaquine arm.

Prevention of Malaria

MALARONE (atovaquone and proguanil hcl) 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.

Table 8. Prevention of Parasitemia in Placebo-Controlled Clinical Trials of MALARONE (atovaquone and proguanil hcl) for Prophylaxis of P. falciparum Malaria in Residents of Malaria-Endemic Areas

  MALARONE    Placebo
Total number of patients randomized 326 341
Failed to complete study 57 44
Developed parasitemia (P. falciparum) 2 92

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 (atovaquone and proguanil hcl) (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 (atovaquone and proguanil hcl) 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 ( ≤ 1%) who received MALARONE (atovaquone and proguanil hcl) developed P. falciparum parasitemia while receiving prophylaxis with MALARONE (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 (atovaquone and proguanil hcl) 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 listed in Table 9.

Table 9. Prevention of Parasitemia in Active-Controlled Clinical Trials of MALARONE (atovaquone and proguanil hcl) for Prophylaxis of P. falciparum Malaria in Non-Immune Travelers

  MALARONE   Mefloquine Chloroquine plus Proguanil
Total number of randomized patients who received study drug 1,004 483 511
Failed to complete study 14 6 4
Developed parasitemia (P. falciparum) 0 0 3

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 (atovaquone and proguanil hcl) (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.

Causal Prophylaxis: In separate studies with small numbers of volunteers, atovaquone and proguanil hydrochloride were independently shown to have causal prophylactic activity directed against liver-stage parasites of P. falciparum. Six patients given a single dose of atovaquone 250 mg 24 hours prior to malaria challenge were protected from developing malaria, whereas all 4 placebo-treated patients developed malaria.

During the 4 weeks following cessation of prophylaxis in clinical trial participants who remained in malaria-endemic areas and were available for evaluation, malaria developed in 24 of 211 (11.4%) subjects who took placebo and 9 of 328 (2.7%) who took MALARONE (atovaquone and proguanil hcl) . While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with MALARONE (atovaquone and proguanil hcl) occurred more than 15 days after stopping therapy, probably representing new infections. The single case occurring on day 8 following cessation of therapy with MALARONE (atovaquone and proguanil hcl) probably represents a failure of prophylaxis with MALARONE (atovaquone and proguanil hcl) .

The possibility that delayed cases of P. falciparum malaria may occur some time after stopping prophylaxis with MALARONE (atovaquone and proguanil hcl) cannot be ruled out. Hence, returning travelers developing febrile illnesses should be investigated for malaria.

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Patients should be instructed:

  • to take MALARONE (atovaquone and proguanil hcl) tablets at the same time each day with food or a milky drink.
  • to take a repeat dose of MALARONE (atovaquone and proguanil hcl) 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.
  • that rare serious adverse events such as hepatitis, severe skin reactions, neurological, and hematological events have been reported when MALARONE (atovaquone and proguanil hcl) was used for the prophylaxis or treatment of malaria.
  • to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with MALARONE (atovaquone and proguanil hcl) 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).

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Patients should be instructed:

  • to take MALARONE (atovaquone and proguanil hcl) tablets at the same time each day with food or a milky drink.
  • to take a repeat dose of MALARONE (atovaquone and proguanil hcl) 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.
  • that rare serious adverse events such as hepatitis, severe skin reactions, neurological, and hematological events have been reported when MALARONE (atovaquone and proguanil hcl) was used for the prophylaxis or treatment of malaria.
  • to consult a healthcare professional regarding alternative forms of prophylaxis if prophylaxis with MALARONE (atovaquone and proguanil hcl) 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).

Last reviewed on RxList: 10/7/2009
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Malarone Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

ATOVAQUONE/PROGUANIL - ORAL

(a-TOE-va-kwone/proe-GWAHN-il)

COMMON BRAND NAME(S): Malarone

USES: This medication contains 2 medicines: atovaquone and proguanil. It is used to prevent and treat malaria caused by mosquito bites in countries where malaria is common. Malaria parasites can enter the body through these mosquito bites, and then live in body tissues such as red blood cells or the liver. This medication is used to kill the malaria parasites living inside red blood cells and other tissues. In some cases, you may need to take a different medication (such as primaquine) to complete your treatment. Both medications may be needed for a complete cure and to prevent the return of infection (relapse). Atovaquone/proguanil belongs to a class of drugs known as antimalarials.

The United States Centers for Disease Control provide updated guidelines and travel recommendations for the prevention and treatment of malaria in different parts of the world. Discuss the most recent information with your doctor before traveling to areas where malaria occurs.

HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start taking this medication, and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth with food or a milky drink (such as whole milk, milkshake) that contains fat. If you vomit within 1 hour of taking a dose, repeat the dose. If you have persistent vomiting after taking atovaquone/proguanil, contact a doctor immediately. You may need another medication to prevent vomiting or a different malaria medication.

Swallow the tablet whole because of its bitter taste. Do not chew. If you have trouble swallowing tablets, this medication may be crushed and mixed with condensed milk. Take the entire mixture immediately. Do not save for future use.

Dosage is based on your medical condition, on whether you are preventing or treating the illness, and your response to treatment. Dosage in children is also based on weight.

To prevent illness, take atovaquone/proguanil usually once daily at the same time each day, or as directed by your doctor. Start this medication 1-2 days before you enter the malarious area; continue while in the area and for 7 days after leaving.

If needed, primaquine can be taken for 14 days starting during the last week of treatment with atovaquone/proguanil or starting immediately after you have finished treatment.

To treat malaria, take this medication usually once daily for 3 days. Follow your doctor's instructions.

It is very important to continue taking this medication exactly as prescribed by your doctor. To help you remember, take it at the same time each day for the entire prescribed time.

Do not take more or less of this drug than prescribed. Do not stop taking this drug before completing the full treatment unless directed to do so by your doctor, even if you feel better or do not feel sick. Skipping or changing your dose without approval from your doctor may cause prevention/treatment to be ineffective, cause the amount of parasite to increase, make the infection more difficult to treat (resistant), or worsen side effects.

It is important to prevent mosquito bites (such as by using appropriate insect repellents, wearing clothes that cover most of the body, remaining in air-conditioned or well-screened areas, using mosquito nets and insect-killing sprays). Buy insect repellent before traveling. The most effective insect repellents contain diethyltoluamide (DEET). Ask your doctor or pharmacist to recommend the appropriate strengths of mosquito repellent for you/your children.

No drug treatment is completely effective in preventing malaria. Seek immediate medical attention if you develop symptoms of malaria (such as fever, chills, headache, other flu-like symptoms). Malaria can return, even months after completing this prescription. Quick treatment of malaria infection is needed to prevent serious, possibly fatal, outcomes.

When using atovaquone/proguanil for treatment, tell your doctor if your condition persists or worsens.

Disclaimer

Malarone Consumer (continued)

SIDE EFFECTS: See also How to Use section.

Side effects may include nausea, vomiting, abdominal pain, headache, diarrhea, weakness, loss of appetite, and dizziness. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but very serious side effects occur: signs of serious liver problems (such as persistent/severe nausea and vomiting, abdominal pain, unexplained tiredness, dark urine, yellowing eyes/skin), signs of anemia (such as worsening tiredness, rapid breathing, pale skin/lips/nails, fast heartbeat while resting), signs of severe infection (such as high fever, severe chills, body aches, sore throat).

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Malarone (atovaquone and proguanil hcl) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking atovaquone/proguanil, tell your doctor or pharmacist if you are allergic to either atovaquone or proguanil; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: current diarrhea, current vomiting, kidney problems, liver problems, mental/mood problems, seizures.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

During pregnancy, this medication should be used only when clearly needed. While you are pregnant, traveling to an area with malaria places you and your infant at a much higher risk for death and other problems. Discuss the risks and benefits of malaria prevention with your doctor.

It is not known if atovaquone passes into breast milk and may have undesirable effects on a nursing infant. The proguanil in this medication passes into breast milk and the effects of this medication on a nursing infant are not known. The CDC recommends against using this product for malaria prevention if you are breastfeeding an infant weighing less than 11 pounds (5 kilograms). Consult your doctor before breast-feeding.

Disclaimer

Malarone Consumer (continued)

DRUG INTERACTIONS: The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring.

To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval.

Some products that may interact with this drug include: penicillamine, "blood thinners" (such as warfarin).

Other medications can affect the removal of atovaquone/proguanil from your body, which may affect how atovaquone/proguanil works. Examples include metoclopramide, rifampin, rifabutin, tetracycline, among others.

This medication can speed up the removal of other medications from your body, which may affect how they work. An example of an affected drug is indinavir. Other medications may also be affected.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as blood cell counts, liver tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Malarone Patient Information Including Side Effects

Brand Names: Malarone, Malarone Pediatric

Generic Name: atovaquone and proguanil (Pronunciation: a TOE va kwone and pro GWAHN il)

What is atovaquone and proguanil (Malarone)?

Atovaquone and proguanil are medications to treat malaria, a disease caused by parasites. These medicines work by interfering with the growth of parasites in the red blood cells of the human body.

Parasites that cause malaria typically enter the body through the bite of a mosquito. Malaria is common in areas such as Africa, South America, and Southern Asia.

The combination of atovaquone and proguanil is used to treat or prevent malaria.

Atovaquone and proguanil may also be used for purposes not listed in this medication guide.

Malarone

round, pink, imprinted with GXCM3

What are the possible side effects of atovaquone and proguanil (Malarone)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • severe or uncontrolled vomiting or diarrhea;
  • fever, mouth sores;
  • problems with speech, balance, or walking;
  • severe skin rash;
  • nausea, stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); o
  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin.

Less serious side effects may include:

  • mild stomach pain or upset stomach;
  • mild diarrhea;
  • headache;
  • mild itching;
  • weakness; or
  • dizziness.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Malarone (atovaquone and proguanil hcl) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about atovaquone and proguanil (Malarone)?

You should not use this medication if you are allergic to atovaquone or proguanil. You should not use this medication to prevent malaria if you have severe kidney disease.

Before using this medication, tell your doctor if you have liver or kidney disease, severe complications from infection with malaria, or uncontrolled vomiting or diarrhea.

Take atovaquone and proguanil at the same time each day with food or a milky drink.

If you vomit within 1 hour after taking this medication, take another dose. If your vomiting continues, call your doctor.

If you are taking this medicine to prevent malaria, start taking it 1 or 2 days before entering an area where malaria is common. Take the medication every day during your stay and for at least 7 days after you leave. If you stop taking the medicine early for any reason, contact a healthcare professional about another form of malaria prevention.

If you are taking this medicine to treat malaria, take the medication every day for 3 days in a row.

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

In addition to taking atovaquone and proguanil, use protective clothing, insect repellents, and mosquito netting around your bed to further prevent mosquito bites that could cause malaria.

Contact your doctor as soon as possible if you have been exposed to malaria, or if you have a fever or other symptoms of illness during or after a stay in an area where malaria is common.

No medication is 100% effective in treating or preventing malaria. For best results, keep using the medication as directed. Talk with your doctor if you have fever, vomiting, or diarrhea during your treatment.

Side Effects Centers

Malarone Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking atovaquone and proguanil (Malarone)?

You should not use this medication if you are allergic to atovaquone or proguanil. You should not use this medication to prevent malaria if you have severe kidney disease.

To make sure you can safely take atovaquone and proguanil, tell your doctor if you have any of these other conditions:

  • kidney disease;
  • liver disease;
  • severe complications from malaria; or
  • uncontrolled vomiting or diarrhea.

FDA pregnancy category C. It is not known whether atovaquone and proguanil will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Malaria is more likely to cause death in a pregnant woman. If you are pregnant, talk with your doctor about the risks of traveling to areas where malaria is common.

Atovaquone and proguanil can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Atovaquone and proguanil should not be used to treat malaria in a child who weighs less than 11 pounds, and should not be used to prevent malaria in a child who weighs less than 24 pounds.

How should I take atovaquone and proguanil (Malarone)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Use atovaquone and proguanil regularly to best prevent malaria. If you stop using the medication early for any reason, talk to your doctor about other forms of malaria prevention.

Take atovaquone and proguanil at the same time each day with food or a milky drink.

If you vomit within 1 hour after taking this medication, take another dose. If your vomiting continues, call your doctor.

If you are taking this medicine to prevent malaria:

  • Start taking the medicine 1 or 2 days before entering an area where malaria is common. Continue taking the medicine every day during your stay and for at least 7 days after you leave the area.
  • If you stop taking the medicine early for any reason, contact a healthcare professional about another form of malaria prevention.

If you are taking this medicine to treat malaria:

  • Take the medicine every day for 3 days in a row.
  • Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

In addition to taking atovaquone and proguanil, use protective clothing, insect repellents, and mosquito netting around your bed to further prevent mosquito bites that could cause malaria.

To be sure this medication is not causing harmful effects, your liver function will need to be checked with frequent blood tests. Visit your doctor regularly.

Contact your doctor as soon as possible if you have been exposed to malaria, or if you have fever or other symptoms of illness during or after a stay in an area where malaria is common.

No medication is 100% effective in treating or preventing malaria. For best results, keep using the medication as directed. Talk with your doctor if you have fever, vomiting, or diarrhea during your treatment.

Store at room temperature away from moisture and heat.

Side Effects Centers

Malarone Patient Information including If I Miss a Dose

What happens if I miss a dose (Malarone)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Malarone)?

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.

What should I avoid while taking atovaquone and proguanil (Malarone)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

What other drugs will affect atovaquone and proguanil (Malarone)?

Tell your doctor about all other medicines you use, especially:

  • a blood thinner such as warfarin (Coumadin);
  • rifabutin (Mycobutin);
  • rifampin (Rifadin, Rifater, Rifamate, Rimactane);
  • tetracycline (Brodspec, Panmycin, Sumycin, Tetracap); or
  • metoclopramide (Reglan).

This list is not complete and other drugs may interact with atovaquone and proguanil. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about atovaquone and proguanil.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 5.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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