atovaquone and proguanil hydrochloride

RECENT MAJOR CHANGES Warnings and Precautions, Severe Cutaneous Adverse Reactions ( 5.4 ) 3/2026

1 INDICATIONS AND USAGE Atovaquone and proguanil hydrochloride tablets are an antimalarial indicated for: prophylaxis of Plasmodium falciparum (P. falciparum) malaria, including in areas where chloroquine resistance has been reported ( 1.1 ) treatment of acute, uncomplicated P. falciparum malaria ( 1.2 ) 1.1 Prevention of Malaria Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of Plasmodium falciparum (P. falciparum) malaria, including in areas where chloroquine resistance has been reported. 1.2 Treatment of Malaria Atovaquone and proguanil hydrochloride tablets are indicated for the treatment of acute, uncomplicated P. falciparum malaria. Atovaquone and proguanil hydrochloride tablets have 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.

2 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. Atovaquone and proguanil hydrochloride tablets may be crushed and mixed with condensed milk just prior to administration to patients who may have difficulty swallowing tablets. • Atovaquone and proguanil hydrochloride tablets should be taken with food or a milky drink. Prophylaxis ( 2.1 ): • Start prophylaxis 1 or 2 days before entering a malaria-endemic area and continue daily during the stay and for 7 days after return. • Adults: One adult strength tablet per day. • Pediatric Patients: Dosage based on body weight (see Table 1). Treatment ( 2.2 ): • Adults: Four adult strength tablets as a single daily dose for 3 days. • Pediatric Patients: Dosage based on body weight (see Table 2). Renal Impairment ( 2.3 ): • Do not use for prophylaxis of malaria in patients with severe renal impairment. • Use with caution for treatment of malaria in patients with severe renal impairment. 2.1 Prevention of Malaria Start prophylactic treatment with atovaquone and proguanil hydrochloride tablets 1 or 2 days before entering a malaria-endemic area and continue daily during the stay and for 7 days after return. Adults One atovaquone and proguanil hydrochloride 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 1). Table 1. Dosage for Prevention of Malaria in Pediatric Patients Weight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 11 to 20 62.5 mg/25 mg 1 Atovaquone and proguanil hydrochloride pediatric tablet daily 21 to 30 125 mg/50 mg 2 Atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose 31 to 40 187.5 mg/75 mg 3 Atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose >40 250 mg/100 mg 1 Atovaquone and proguanil hydrochloride tablet (adult strength) as a single daily dose 2.2 Treatment of Acute Malaria Adults Four atovaquone and proguanil hydrochloride tablets (adult strength; total daily dose 1 g atovaquone/400 mg proguanil hydrochloride) as a single daily dose for 3 consecutive days. Pediatric Patients The dosage for treatment of acute malaria in pediatric patients is based upon body weight (Table 2). Table 2. Dosage for Treatment of Acute Malaria in Pediatric Patients Weight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 5 to 8 125 mg/50 mg 2 Atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days 9 to 10 187.5 mg/75 mg 3 Atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days 11 to 20 250 mg/100 mg 1 Atovaquone and proguanil hydrochloride tablet (adult strength) daily for 3 consecutive days 21 to 30 500 mg/200 mg 2 Atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days 31 to 40 750 mg/300 mg 3 Atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days >40 1 g/400 mg 4 Atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days 2.3 Renal Impairment Do not use atovaquone and proguanil hydrochloride tablets for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min) [see Contraindications ( 4 )] . Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment. [See Clinical Pharmacology ( 12.3 ).]

3 DOSAGE FORMS AND STRENGTHS Each atovaquone and proguanil hydrochloride tablet (adult strength) contains 250 mg atovaquone USP and 100 mg proguanil hydrochloride USP. Atovaquone and proguanil hydrochloride tablets are pinkish brown to brown colored, circular, biconvex beveled edge, film-coated tablets with ‘404’ debossed on one side and ‘G’ debossed on the other side. Atovaquone and proguanil hydrochloride pediatric tablets contain 62.5 mg atovaquone USP and 25 mg proguanil hydrochloride USP. Atovaquone and proguanil hydrochloride pediatric tablets are pinkish brown to brown colored, circular, biconvex beveled edged, film coated tablets with ‘70’ debossed on one side and ‘G’ debossed on the other side. • Tablets (adult strength): 250 mg atovaquone and 100 mg proguanil hydrochloride. ( 3 ) • Pediatric tablets: 62.5 mg atovaquone and 25 mg proguanil hydrochloride. ( 3 )

4 CONTRAINDICATIONS • Known serious hypersensitivity reactions to atovaquone or proguanil hydrochloride or any component of the formulation. ( 4.1 ) • Prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min). ( 4.2 ) 4.1 Hypersensitivity Atovaquone and proguanil hydrochloride is contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone or proguanil hydrochloride or any component of the formulation. 4.2 Severe Renal Impairment Atovaquone and proguanil hydrochloride is contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil [see Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]

6 ADVERSE REACTIONS . Prophylaxis: Common adverse reactions (≥4%) in adults were diarrhea, dreams, oral ulcers, and headache; these events occurred in a similar or lower proportion of subjects receiving atovaquone and proguanil hydrochloride than an active comparator. Common adverse reactions (≥5%) in pediatric patients included abdominal pain, headache, cough, and vomiting. ( 6.1 ) Treatment: Common adverse reactions (≥5%) in adolescents and adults were abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia, and dizziness. Common adverse reactions (≥6%) in pediatric patients included vomiting, pruritus, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888)721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Because atovaquone and proguanil hydrochloride tablets contain atovaquone and proguanil hydrochloride, the type and severity of adverse reactions associated with each of the compounds may be expected. The lower prophylactic doses of atovaquone and proguanil hydrochloride were better tolerated than the higher treatment doses. Prophylaxis of P. falciparum Malaria: In 3 clinical trials (2 of which were placebo-controlled) 381 adults (mean age 31 years) received atovaquone and proguanil hydrochloride for the prophylaxis of malaria; the majority of adults were black (90%) and 79% were male. In a clinical trial for the prophylaxis of malaria, 125 pediatric patients (mean age 9 years) received atovaquone and proguanil hydrochloride; all subjects were black and 52% were male. Adverse experiences reported in adults and pediatric patients considered attributable to therapy occurred in similar proportions of subjects receiving atovaquone and proguanil hydrochloride or placebo in all studies. Prophylaxis with atovaquone and proguanil hydrochloride was discontinued prematurely due to a treatment-related adverse experience in 3 of 381 (0.8%) adults and 0 of 125 pediatric patients. In a placebo-controlled study of malaria prophylaxis with atovaquone and proguanil hydrochloride involving 330 pediatric patients (aged 4 to 14 years) in Gabon, a malaria-endemic area, the safety profile of atovaquone and proguanil hydrochloride was consistent with that observed in the earlier prophylactic studies in adults and pediatric patients. The most common treatment-emergent adverse events with atovaquone and proguanil hydrochloride were abdominal pain (13%), headache (13%), and cough (10%). Abdominal pain (13% vs. 8%) and vomiting (5% vs. 3%) were reported more often with atovaquone and proguanil hydrochloride than with placebo. No patient withdrew from the study due to an adverse experience with atovaquone and proguanil hydrochloride. No routine laboratory data were obtained during this study. Non-immune travelers visiting a malaria-endemic area received MALARONE (n = 1,004) for prophylaxis of malaria in 2 active-controlled clinical trials. In one study (n = 493), the mean age of subjects was 33 years and 53% were male; 90% of subjects were white, 6% of subjects were black and the remaining were of other racial/ethnic groups. In the other study (n = 511), the mean age of subjects was 36 years and 51% were female; the majority of subjects (97%) were white. Adverse experiences occurred in a similar or lower proportion of subjects receiving atovaquone and proguanil hydrochloride tablets than an active comparator (Table 3). Fewer neuropsychiatric adverse experiences occurred in subjects who received atovaquone and proguanil hydrochloride tablets than mefloquine. Fewer gastrointestinal adverse experiences occurred in subjects receiving atovaquone and proguanil hydrochloride tablets t …

7 DRUG INTERACTIONS Administration with rifampin or rifabutin is known to reduce atovaquone concentrations; concomitant use with atovaquone and proguanil hydrochloride tablets is not recommended. ( 7.1 ) Proguanil may potentiate anticoagulant effect of warfarin and other coumarin-based anticoagulants. Caution advised when initiating or withdrawing atovaquone and proguanil hydrochloride tablets in patients on anticoagulants; coagulation tests should be closely monitored. ( 7.2 ) Tetracycline may reduce atovaquone concentrations; parasitemia should be closely monitored. ( 7.3 ) 7.1 Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations [see Clinical Pharmacology (12.3) ] . The concomitant administration of atovaquone and proguanil hydrochloride tablets and rifampin or rifabutin is not recommended. 7.2 Anticoagulants 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 atovaquone and proguanil hydrochloride tablets in patients on continuous treatment with coumarin-based anticoagulants. When these products are administered concomitantly, coagulation tests should be closely monitored. 7.3 Tetracycline Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone [see Clinical Pharmacology (12.3) ] . Parasitemia should be closely monitored in patients receiving tetracycline. 7.4 Metoclopramide While antiemetics may be indicated for patients receiving atovaquone and proguanil hydrochloride tablets, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available [see Clinical Pharmacology (12.3) ] . 7.5 Indinavir Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and C max of indinavir but resulted in a decrease in the C trough of indinavir [see Clinical Pharmacology (12.3) ] . Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough concentrations of indinavir.

8 USE IN SPECIFIC POPULATIONS Renal impairment: contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment. ( 8.6 ) 8.1 Pregnancy Risk Summary Available data from published literature and postmarketing experience with use of atovaquone and proguanil hydrochloride tablets in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. The proguanil component of atovaquone and proguanil hydrochloride tablets acts to inhibit parasitic dihydrofolate reductase; however, pregnant women and females of reproductive potential should continue folate supplementation to prevent neural tube defects [see Clinical Pharmacology (12.4) ] . Pregnant women with malaria are at increased risk for adverse pregnancy outcomes (see Clinical Considerations ) . Atovaquone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis was not associated with fetal malformations at plasma exposures approximately 7 times and equal to, respectively, the estimated human exposure for the treatment of malaria based on AUC. Proguanil administered to pregnant rats and rabbits during the period of organogenesis was not associated with embryo-fetal toxicity at maternally toxic plasma exposures approximately 0.07 and 0.8 times, respectively, the estimated human exposure for treatment of malaria based on AUC (see Data ) . The combination of atovaquone and proguanil hydrochloride given orally by gavage during the period of organogenesis was not associated with embryo-fetal developmental effects in pregnant rats or rabbits at atovaquone:proguanil hydrochloride doses of 50:20 mg/kg/day and 100:40 mg/kg/day, respectively (1.7 and 0.1 times and 0.3 and 0.5 times, respectively, the estimated human exposure for treatment of malaria). In a pre- and post-natal study with atovaquone and another pre- and post-natal study with proguanil, neither compound impaired the growth, development, or reproductive ability of first generation offspring at maternal AUC exposures of approximately 7.3 and 0.04 times, respectively, the estimated human AUC exposure for treatment of malaria (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Data Animal Data Atovaquone Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 6 to GD15) in pregnant rats did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma exposures up to 7.3 times the estimated human exposure for the treatment of malaria based on AUC. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day by gavage during organogenesis (GD6 to GD18) was associated with decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to plasma exposures that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. In a pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first generation offspring at doses up to 1,000 mg/kg/day corresponding to AUC exposures of approximately 7.3 times the estimated human exposure during treatment of malaria. Atovaquone crossed the placenta and was present in f …

12.1 Mechanism of Action 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.

11 DESCRIPTION Atovaquone and proguanil hydrochloride tablets (adult strength) and Atovaquone and proguanil hydrochloride pediatric tablets, for oral administration, contain a fixed-dose combination of the antimalarial agents atovaquone, USP and proguanil hydrochloride, USP. The chemical name of atovaquone, USP is trans -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone, USP is a yellow crystalline solid that is freely soluble in N-methyl-2-pyrrolidone and in tetrahydrofuran; soluble in chloroform; sparingly soluble in acetone and dimethyl sulfoxide; slightly soluble in octanol, ethyl acetate, polyethylene glycol 200; very slightly soluble in 0.1N sodium hydroxide; insoluble in water. It has a molecular weight of 366.84 g/mol and the molecular formula C 22 H 19 ClO 3 . The compound has the following structural formula: The chemical name of proguanil hydrochloride, USP is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride, USP is a white crystalline powder slightly soluble in water, sparingly soluble in alcohol, practically insoluble in methylene chloride. It has a molecular weight of 290.22 g/mol and the molecular formula C 11 H 16 ClN 5 •HCl. The compound has the following structural formula: Each atovaquone and proguanil hydrochloride tablet (adult strength) contains 250 mg of atovaquone, USP and 100 mg of proguanil hydrochloride, USP and each atovaquone and proguanil hydrochloride pediatric tablet contains 62.5 mg of atovaquone, USP and 25 mg of proguanil hydrochloride, USP. The inactive ingredients in both tablets are colloidal silicon dioxide, ferric oxide red, hypromellose 2910, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, polyethylene glycol 400, polyethylene glycol 8000, povidone K30, sodium starch glycolate and titanium dioxide.

10 OVERDOSAGE There is no information on overdoses of atovaquone and proguanil hydrochloride tablets substantially higher than the doses recommended for treatment. There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable. Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose. Overdoses of proguanil hydrochloride as large as 1,500 mg have been followed by complete recovery, and doses as high as 700 mg twice daily have been taken for over 2 weeks without serious toxicity. Adverse experiences occasionally associated with proguanil hydrochloride doses of 100 to 200 mg/day, such as epigastric discomfort and vomiting, would be likely to occur with overdose. There are also reports of reversible hair loss and scaling of the skin on the palms and/or soles, reversible aphthous ulceration, and hematologic side effects.

16 HOW SUPPLIED/STORAGE AND HANDLING Atovaquone and proguanil hydrochloride tablets, containing 250 mg atovaquone, USP and 100 mg proguanil hydrochloride, USP are pinkish brown to brown colored, circular, biconvex beveled edge, film-coated tablets with ‘404’ debossed on one side and ‘G’ debossed on the other side. NDC 71335-3160-1: 10 TABLETs in a BOTTLE NDC 71335-3160-2: 24 TABLETs in a BOTTLE NDC 71335-3160-3: 5 TABLETs in a BOTTLE NDC 71335-3160-4: 12 TABLETs in a BOTTLE NDC 71335-3160-5: 100 TABLETs in a BOTTLE Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504