MALARONE (atovaquone and proguanil hydrochloride) tablets (adult strength) and MALARONE (atovaquone and proguanil hydrochloride) pediatric tablets, for oral administration, contain 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 C 22 H 19 ClO 3 . The compound has the following structural formula: The chemical name of proguanil hydrochloride is 1-(4-chlorophenyl)-5-isopropyl-biguanide hydrochloride. Proguanil hydrochloride is a white crystalline solid that is sparingly soluble in water. It has a molecular weight of 290.22 and the molecular formula C 11 H 16 ClN 5 •HCl. The compound has the following structural formula: Each MALARONE tablet (adult strength) contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride and each MALARONE pediatric tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. The inactive ingredients in both tablets are low‑substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, poloxamer 188, povidone K30, and sodium starch glycolate. The tablet coating contains hypromellose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide, and titanium dioxide. Atovaquone chemical structure Proguanil hydrochloride chemical structure

MALARONE is an antimalarial indicated for: • prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported. • treatment of acute, uncomplicated P. falciparum malaria

Prevention of Malaria MALARONE is indicated for the prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported

Treatment of Malaria MALARONE is indicated for the treatment of acute, uncomplicated P. falciparum malaria. MALARONE 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.

Each MALARONE tablet (adult strength) contains 250 mg atovaquone and 100 mg proguanil hydrochloride. MALARONE tablets are pink, film‑coated, round, biconvex tablets engraved with “GX CM3” on one side. Each MALARONE pediatric tablet contains 62.5 mg atovaquone and 25 mg proguanil hydrochloride. MALARONE pediatric tablets are pink, film‑coated, round, biconvex tablets engraved with “GX CG7” on one side. • Tablets (adult strength): 250 mg atovaquone and 100 mg proguanil hydrochloride. • Pediatric tablets: 62.5 mg atovaquone and 25 mg proguanil hydrochloride.

The daily dose should be taken at the same time each day with food or a milky drink. In the event of vomiting within 1 hour after dosing, a repeat dose should be taken. MALARONE may be crushed and mixed with condensed milk just prior to administration to patients who may have difficulty swallowing tablets. • MALARONE should be taken with food or a milky drink. Prophylaxis : • 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 . Treatment : • Adults: Four adult strength tablets as a single daily dose for 3 days. • Pediatric Patients: Dosage based on body weight . Renal Impairment : • 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

Prevention of Malaria Start prophylactic treatment with MALARONE 1 or 2 days before entering a malaria‑endemic area and continue daily during the stay and for 7 days after return. Adults One MALARONE 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 11-20 62.5 mg/25 mg 1 MALARONE pediatric tablet daily 21-30 125 mg/50 mg 2 MALARONE pediatric tablets as a single daily dose 31-40 187.5 mg/75 mg 3 MALARONE pediatric tablets as a single daily dose >40 250 mg/100 mg 1 MALARONE tablet (adult strength) as a single daily dose 2.2 Treatment of Acute Malaria Adults Four MALARONE 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 5-8 125 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 daily dose for 3 consecutive days 31-40 750 mg/300 mg 3 MALARONE tablets (adult strength) as a single daily dose for 3 consecutive days >40 1 g/400 mg 4 MALARONE tablets (adult strength) as a single daily dose for 3 consecutive days 2.3 Renal Impairment Do not use MALARONE for malaria prophylaxis in patients with severe renal impairment (creatinine clearance <30 mL/min) . Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment.

• Atovaquone absorption may be reduced in patients with diarrhea or vomiting. If used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required. • In mixed P. falciparum and Plasmodium vivax infection, P. vivax relapse occurred commonly when patients were treated with MALARONE alone. • In the event of recrudescent P. falciparum infections after treatment or prophylaxis failure, patients should be treated with a different blood schizonticide. • Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use. • Severe Cutaneous Adverse Reactions (SCARs): Cases of SCARs such as Stevens‑Johnson syndrome (SJS) have been reported. SCARs can be life‑threatening or fatal. If symptoms or signs of SCARs develop, discontinue MALARONE immediately and institute appropriate therapy. • MALARONE has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria. Patients with severe malaria are not candidates for oral therapy. 5.1 Vomiting and Diarrhea Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If MALARONE is used in patients who are vomiting, parasitemia should be closely monitored and the use of an antiemetic considered. Vomiting occurred in up to 19% of pediatric patients given treatment doses of MALARONE. In the controlled clinical trials, 15.3% of adults received an antiemetic when they received atovaquone/proguanil and 98.3% of these patients were successfully treated. In patients with severe or persistent diarrhea or vomiting, alternative antimalarial therapy may be required

Relapse of Infection In mixed P. falciparum and Plasmodium vivax infections, P. vivax parasite relapse occurred commonly when patients were treated with MALARONE alone. In the event of recrudescent P. falciparum infections after treatment with MALARONE or failure of chemoprophylaxis with MALARONE, patients should be treated with a different blood schizonticide

Hepatotoxicity Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of MALARONE

Severe Cutaneous Adverse Reactions Cases of severe cutaneous adverse reactions (SCARs), including Stevens‑Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme (EM) have been reported in patients treated with MALARONE . SCARs can be life‑threatening or fatal. If symptoms or signs of SCARs develop, discontinue MALARONE immediately and institute appropriate therapy. Patients who have developed SCARs with the use of MALARONE must not receive MALARONE

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

• Administration with rifampin or rifabutin is known to reduce atovaquone concentrations; concomitant use with MALARONE is not recommended. • Proguanil may potentiate anticoagulant effect of warfarin and other coumarin-based anticoagulants. Caution advised when initiating or withdrawing MALARONE in patients on anticoagulants; coagulation tests should be closely monitored. • Tetracycline may reduce atovaquone concentrations; parasitemia should be closely monitored

Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations . The concomitant administration of MALARONE and rifampin or rifabutin is not recommended

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 MALARONE in patients on continuous treatment with coumarin-based anticoagulants. When these products are administered concomitantly, coagulation tests should be closely monitored

Tetracycline Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone . Parasitemia should be closely monitored in patients receiving tetracycline

Metoclopramide While antiemetics may be indicated for patients receiving MALARONE, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available

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 . Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough concentrations of indinavir.