ATOVAQUONE AND PROGUANIL HYDROCHLORIDE

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 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 tablets contains 62.5 mg of atovaquone USP and 25 mg of proguanil hydrochloride USP. The inactive ingredients in the tablet 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. Atovaquone Chemical Structure Proguanil HCl Chemical Structure

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.

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 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 day. Pediatric Patients The dosage for treatment of acute malaria in pediatric patients is based upon body weight (Table 2) Table 2 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 ).

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 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 )] Known serious hypersensitivity reactions to atovaquone or proguanil hydrochloride or any component of the formulation. ( 4 ) Prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min). (4)

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 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 for Prophylaxis of P. falciparum Malaria Percent of Subjects With Adverse Experiences a (Percent of Subjects With Adverse Experiences Attributable to Therapy) Study 1 Study 2 Atovaquone and proguanil hydrochloride n = 493 (28 days) b Mefloquine n = 483 (53 days) b Atovaquone and proguanil hydrochloride n = 511 (26 days) b Chloroquine plus Proguanil n = 511 (49 days) b 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) a Adverse experiences that started while receiving active study drug. b Mean duration of dosing based on recommended dosing regimens. In a third active-controlled study, atovaquone and proguanil hydrochloride (n = 110) was compared with chloroquine/proguanil (n = 111) for the prophylaxis of malaria in 221 non-immune pediatric patients (2 to 17 years). The mean duration of exposure was 23 days for atovaquone and proguanil hydrochloride, 46 days for chloroquine, and 43 days for proguanil, reflecting the different recommended dosage regimens for these products. Fewer patients treated with atovaquone and proguanil hydrochloride 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 atovaquone and proguanil hydrochloride or chloroquine/proguanil, respectively. Two patients discontinued prophylaxis with chloroquine/proguanil due to adverse events, while none of those receiving atovaquone and proguanil hydrochloride discontinued due to adverse events. Treatment of Acute, Uncomplicated P. falciparum Malaria: In 7 controlled trials, 436 adolescents and adults received atovaquone and proguanil hydrochloride for treatment of acute, uncomplicated P. falciparum malaria. The range of mean ages of subjects was 26 to 29 years; 79% of subjects were male. In these studies, 48% of subjects were classified as other racial/ethnic groups, primarily Asian; 42% of subjects were black and the remaining subjects were white. 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 (0.9%) adolescents and adults treated with atovaquone and proguanil hydrochloride . In 2 controlled trials, 116 pediatric patients (weighing 11 to 40 kg) (mean age 7 years) received atovaquone and proguanil hydrochloride for the treatment of malaria. The majority of subjects were black (72%); 28% were of other racial/ethnic groups, primarily Asian. 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 atovaquone and proguanil hydrochloride 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 atovaquone and proguanil hydrochloride, 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 atovaquone and proguanil hydrochloride for the treatment of uncomplicated P. falciparum malaria, only diarrhea (6%) occurred in ≥5% of patients as an adverse experience attributable to atovaquone and proguanil hydrochloride. 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 patients with malaria being treated with atovaquone and proguanil hydrochloride . The frequency of these abnormalities varied substantially across trials of treatment and were not observed in the randomized portions of the prophylaxis trials. One active-controlled trial evaluated the treatment of malaria in Thai adults (n = 182); the mean age of subjects was 26 years (range: 15 to 63 years); 80% of subjects were male. Early elevations of ALT and AST occurred more frequently in patients treated with atovaquone and proguanil hydrochloride (n = 91) compared to patients treated with an active control, mefloquine (n = 91). On Day 7, rates of elevated ALT and AST with atovaquone and proguanil hydrochloride and mefloquine (for patients who had normal baseline levels of these clinical laboratory parameters) were ALT 26.7% vs. 15.6%; AST 16.9% vs. 8.6%, respectively. By Day 14 of this 28-day study, the frequency of transaminase elevations equalized across the 2 groups. 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of atovaquone and proguanil hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone and proguanil hydrochloride. Blood and Lymphatic System Disorders: Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil [see Contraindications (4)] . Immune System Disorders: Allergic reactions including anaphylaxis, angioedema, and urticaria, and vasculitis. Nervous System Disorders: Seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established. Gastrointestinal Disorders: Stomatitis. Hepatobiliary Disorders: Elevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported. Skin and Subcutaneous Tissue Disorders: Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome

Administration with rifampin or rifabutin is known to reduce atovaquone concentrations; concomitant use with atovaquone and proguanil hydrochloride 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 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 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 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, 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