Proguanil

12.1 Mechanism of Action Atovaquone and proguanil hydrochloride tablets, a fixed-dose combination of atovaquone and proguanil hydrochloride, are an antimalarial agent [see Microbiology (12.4) ] .

1 INDICATIONS AND USAGE Atovaquone and proguanil hydrochloride tablets are an antimalarial indicated for: prophylaxis of Plasmodium 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 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 11-20 62.5 mg/25 mg 1 atovaquone and proguanil hydrochloride pediatric tablet daily 21-30 125 mg/50 mg 2 atovaquone and proguanil hydrochloride pediatric tablets as a single daily dose 31-40 187.5 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 5-8 125 mg/50 mg 2 atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days 9-10 187.5 mg/75 mg 3 atovaquone and proguanil hydrochloride pediatric tablets daily for 3 consecutive days 11-20 250 mg/100 mg 1 atovaquone and proguanil hydrochloride tablet (adult strength) daily for 3 consecutive days 21-30 500 mg/200 mg 2 atovaquone and proguanil hydrochloride tablets (adult strength) as a single daily dose for 3 consecutive days 31-40 750 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) .]

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 tablets 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 with 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 tablets 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 tablets 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 tablets; 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 tablets or placebo in all studies. Prophylaxis with atovaquone and proguanil hydrochloride tablets 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 tablets involving 330 pediatric patients (aged 4 to 14 years) in Gabon, a malaria-endemic area, the safety profile of atovaquone and proguanil hydrochloride tablets 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 tablets 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 tablets than with placebo. No patient withdrew from the study due to an adverse experience with atovaquone and proguanil hydrochloride tablets. No routine laboratory data were obtained during this study. Non-immune travelers visiting a malaria-endemic area received atovaquone and proguanil hydrochloride tablets (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 than chloroquine/proguanil. Compared with active comparator drugs, subjects receiving atovaquone and proguanil hydrochloride tablets had fewer adverse experiences overall that were attributed to prophylactic therapy (Table 3). Prophylaxis with atovaquone and proguanil hydrochloride tablets was discontinued prematurely due to a treatment-related adverse experience in 7 of 1,004 travelers. Table 3. Adverse Experiences in Active-Controlled Clinical Trials of Atovaquone and Proguanil Hydrochloride Tablets for Prophylaxis of P. falciparum Malaria Percent of Subjects with Adverse Experiences Adverse experiences that started while receiving active study drug. (Percent of Subjects with Adverse Experiences Attributable to Therapy) Study 1 Study 2 Atovaquone and Proguanil Hydrochloride Tablets n = 493 (28 days) Mean duration of dosing based on recommended dosing regimens. Mefloqu

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.