ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Prophylaxis: Common adverse reactions (>= 4%) in adults were diarrhea, dreams, oral ulcers, and headache; these events occurred in 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 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Prophylaxis: Common adverse reactions (>= 4%) in adults were diarrhea, dreams, oral ulcers, and headache; these events occurred in 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) 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 were better tolerated than the higher treatment doses. Prophylaxis of P. falciparum Malaria In 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 clinical trial for the prophylaxis of malaria, 125 pediatric patients (mean age: 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 treatment-related adverse experience in of 381 (0.8%) adults and of 125 pediatric patients. In placebo-controlled study of malaria prophylaxis with atovaquone and proguanil hydrochloride involving 330 pediatric patients (aged to 14 years) in Gabon, 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 malaria-endemic area received atovaquone and proguanil hydrochloride (n 1,004) for prophylaxis of malaria in 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 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 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 was discontinued prematurely due to treatment-related adverse experience in 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 (Percent of Subjects with Adverse Experiences Attributable to Therapy) Study 1Study 2Atovaquone and proguanil hydrochloride = 493 (28 days)bMefloquine = 483 (53 days)bAtovaquone and proguanil hydrochloriden 511 (26 days)bChloroquine plus Proguanil = 511 (49 days)bDiarrhea 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)16 (14)6 (4)7 (3)Insomnia (3)16 (13)4 (2)5 (2)Fever (<1)11 (1)8 (<1)8 (<1)Dizziness (2)14 (9)7 (3)8 (4)Vomiting (1)10 (2)8 (0)14 (2)Oral ulcers (6)6 (4)5 (4)7 (5)Pruritus (2)5 (2)3 (1)2 (<1)Visual difficulties (2)5 (3)3 (2)3 (2)Depression <1 (<1)5 (4)<1 (<1)1 (<1)Anxiety (<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. Mean duration of dosing based on recommended dosing regimens. In 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 (aged 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 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 of 436 (0.9%) adolescents and adults treated with atovaquone and proguanil hydrochloride. In controlled trials, 116 pediatric patients (weighing 11 to 40 kg) (mean age: 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 days in 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 of 116 (0.9%). In 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 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 with 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 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 population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone and proguanil hydrochloride. Blood and Lymphatic System DisordersNeutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil [see Contraindications 4)] Immune System DisordersAllergic reactions including anaphylaxis, angioedema, urticaria, and vasculitis. Nervous System DisordersSeizures and psychotic events (such as hallucinations); however, causal relationship has not been established. Gastrointestinal DisordersStomatitis. Hepatobiliary DisordersElevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported. Skin and Subcutaneous Tissue DisordersPhotosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of atovaquone and proguanil hydrochloride on male and female reproductive performance are unknown. AtovaquoneA 24-month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. In CD-1 mice, 24-month study showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least 15 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. Atovaquone administered by oral gavage in doses of 100, 300, or 1,000 mg/kg/day to adult male rats from 73 days prior to mating until 20 days after mating and to adult female rats from 14 days prior to mating until LD20 did not impair male or female fertility or early embryonic development at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure for the treatment of malaria based on AUC. ProguanilNo evidence of carcinogenic effect was observed in 24-month studies conducted in CD-1 mice at doses up to 16 mg/kg/day corresponding to 1.5 times the average human plasma exposure during prophylaxis of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average human plasma exposure during prophylaxis of malaria based on AUC. 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, dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation. Proguanil administered orally in doses of 4, 8, and 16 mg/kg/day to male rats from 29 days prior to mating until 27 days after mating and to females from 15 days prior to mating through GD7 revealed no adverse effects on adult male or female fertility or early embryonic development at doses up to 16 mg/kg/day (up to 0.04 times the average human exposure for the treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Atovaquone and proguanil hydrochloride tablets, fixed-dose combination of atovaquone and proguanil hydrochloride is an antimalarial agent [see Microbiology 12.4)] . 12.2 Pharmacodynamics. Cardiac EffectsThe effect of atovaquone and proguanil hydrochloride on the QT interval is unknown in humans.. 12.3 Pharmacokinetics. AbsorptionAtovaquone is highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability. Effect of Food: Atovaquone and proguanil hydrochloride should be taken with food or milky drink. Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC to times and max times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. DistributionAtovaquone is highly protein bound (> 99%) over the concentration range of to 90 mcg/mL. 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. population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients older than 15 years with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients 15 years and younger 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. EliminationThe elimination half-life of atovaquone is about to 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. The main routes of elimination are hepatic biotransformation and renal excretion.Metabolism: In 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, specific metabolite has not been identified. Between 40% to 60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via cytochrome P450 2C19 [CYP2C19]) and 4-chlorophenylbiguanide. Excretion: population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight >=11 kg are shown in Table 4. Table 4. Apparent Clearance for Atovaquone and Proguanil in Patients as Function of Body WeightAtovaquoneProguanilBody WeightnCL/F (L/h) Mean +- SD (range) nCL/F (L/h) Mean +- SD (range) 11 to 20 kg1591.34 +- 0.63 (0.52 to 4.26)14629.5 +- 6.5 (10.3 to 48.3)21 to 30 kg1171.87 +- 0.81 (0.52 to 5.38)11340.0 +- 7.5 (15.9 to 62.7)31 to 40 kg952.76 +- 2.07 (0.97 to 12.5)9149.5 +- 8.30 (25.8 to 71.5)>40 kg3686.61 +- 3.92 (1.32 to 20.3)28267.9 +- 19.9 (14.0 to 145)a SD Standard deviation. The pharmacokinetics of atovaquone and proguanil in patients with body weight less than 11 kg have not been adequately characterized. Specific PopulationsPediatric Patients: 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 days) than in adult patients (2 to days). In clinical trials, plasma trough concentrations of atovaquone and proguanil in pediatric patients weighing to 40 kg were within the range observed in adults after dosing by body weight. Geriatric Patients: In single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (aged 65 to 79 years) with those of 13 younger subjects (aged 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate: 2.36, 90% Cl: 1.70, 3.28). max was longer in elderly subjects (median hours) compared with younger subjects (median: hours) and average elimination half-life was longer in elderly subjects (mean: 14.9 hours) compared with younger subjects (mean: 8.3 hours). Patients with 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 atovaquone and proguanil hydrochloride for long-term prophylaxis (over months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance 30 mL/min), atovaquone max 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 4)] Patients with Hepatic Impairment: In single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, moderate, as indicated by the Child-Pugh method) with those of 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared with 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: to 1.63). Proguanil AUC, max, and its elimination half-life increased in subjects with mild hepatic impairment when compared with healthy subjects (Table 5). Also, the proguanil AUC and its elimination half-life increased in subjects with moderate hepatic impairment when compared with healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (C max and AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared with healthy volunteers (Table 5). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of atovaquone and proguanil hydrochloride have not been studied in patients with severe hepatic impairment. Table 5. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects with Mild and Moderate Hepatic Impairment Compared with Healthy VolunteersParameterComparisonProguanilCycloguanilAUC (0-inf) mild:healthy1.96 (1.51, 2.54)0.32 (0.22, 0.45)C max mild:healthy1.41 (1.16, 1.71)0.35 (0.24, 0.50)t 1/2 mild:healthy1.21 (0.92, 1.60)0.86 (0.49, 1.48)AUC (0-inf) moderate:healthy1.64 (1.14, 2.34)NDC max moderate:healthy0.97 (0.69, 1.36)NDt 1/2 moderate:healthy1.46 (1.05, 2.05)NDND Not determined due to lack of quantifiable data.a Ratio of geometric means. Mean difference. Drug Interaction StudiesThere are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose. Atovaquone is highly protein bound (> 99%) but does not displace other highly protein-bound drugs in vitro. Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown. Rifampin/Rifabutin: Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations by approximately 50% and 34%, respectively. The mechanisms of these interactions are unknown. Tetracycline: Concomitant treatment with tetracycline has been associated with approximately 40% reduction in plasma concentrations of atovaquone. Metoclopramide: Concomitant treatment with metoclopramide has been associated with decreased bioavailability of atovaquone. Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and max of indinavir but resulted in decrease in the trough of indinavir (23% decrease [90% CI: 8%, 35%]). 12.4 Microbiology Mechanism of ActionThe constituents of atovaquone and proguanil hydrochloride tablets, atovaquone and proguanil hydrochloride, interfere with different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is selective inhibitor of parasite mitochondrial electron transport. Proguanil hydrochloride primarily exerts its effect by means of the metabolite cycloguanil, dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the Plasmodium parasite disrupts deoxythymidylate synthesis. Antimicrobial ActivityAtovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of P. Falciparum. Enhanced efficacy of the combination compared with either atovaquone or proguanil hydrochloride alone was demonstrated in clinical trials in both immune and non-immune patients [see Clinical Studies 14.1, 14.2)] ResistanceStrains 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Prevention of P. falciparum Malaria Atovaquone and proguanil hydrochloride was evaluated for prophylaxis of P. falciparum malaria in clinical trials in malaria-endemic areas and in active-controlled trials in non-immune travelers to malaria-endemic areas. Three placebo-controlled trials of 10 to 12 weeks duration were conducted among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. The mean age of subjects was 30 (range: 17 to 55), 32 (range: 16 to 64), and 10 (range: to 16) years, respectively. Of total of 669 randomized patients (including 264 pediatric patients aged to 16 years), 103 were withdrawn for reasons other than falciparum malaria- or drug-related adverse events (55% of these were lost to follow-up and 45% were withdrawn for protocol violations). The results are listed in Table 6.Table 6. Prevention of Parastextia in Placebo-Controlled Clinical Trials of Atovaquone and Proguanil hydrochloride for Prophylaxis of P. falciparum Malaria in Residents of Malaria-Endemic Areas Atovaquone and Proguanil hydrochloridePlaceboTotal number of patients randomized 326343Failed to complete study 5746Developed parastextia P. falciparum) 292a Free of parastextia during the 10- to 12-week period of prophylactic therapy. In another study, 330 Gabonese pediatric patients (weighing 13 to 40 kg and aged to 14 years) who had received successful open-label radical cure treatment with artesunate, were randomized to receive either atovaquone and proguanil hydrochloride (dosage based on body weight) or placebo in double-blind fashion for 12 weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165 children given atovaquone and proguanil hydrochloride and 18 of 165 patients given placebo withdrew from the study for reasons other than parastextia (primary reason was lost to follow-up). One out of 150 evaluable patients (<1%) who received atovaquone and proguanil hydrochloride developed P. falciparum parastextia while receiving prophylaxis with atovaquone and proguanil hydrochloride compared with 31 (22%) of the 144 evaluable placebo recipients. In 10-week study in 175 South African subjects who moved into malaria-endemic areas and were given prophylaxis with atovaquone and proguanil hydrochloride tablet daily, parastextia developed in 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 trials were conducted in non-immune travelers who visited malaria-endemic area. The mean duration of travel was 18 days (range: to 38 days). Of total of 1,998 randomized patients who received atovaquone and proguanil hydrochloride 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, withdrew because of an adverse experience, and 13 were discontinued for other reasons. These trials were not large enough to allow for statements of comparative efficacy. In addition, the true exposure rate to P. falciparum malaria in both trials is unknown. The results are listed in Table 7. Table 7. Prevention of Parastextia in Active-Controlled Clinical Trials of Atovaquone and Proguanil hydrochloride for Prophylaxis of P. falciparum Malaria in Non-Immune Travelers Atovaquone and proguanil hydrochlorideMefloquineChloroquine plus ProguanilTotal number of randomized patients who received study drug 1,004483511Failed to complete study 1464Developed parastextia P. falciparum) 003 Free of parastextia during the period of prophylactic therapy. third randomized, open-label study was conducted which included 221 otherwise healthy pediatric patients (weighing >=11 kg and aged to 17 years) who were at risk of contracting malaria by traveling to an endemic area. The mean duration of travel was 15 days (range: to 30 days). Prophylaxis with atovaquone and proguanil hydrochloride (n 110, dosage based on body weight) began or days before entering the endemic area and lasted until days after leaving the area. 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. Causal ProphylaxisIn separate trials 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 single dose of atovaquone 250 mg 24 hours prior to malaria challenge were protected from developing malaria, whereas all placebo-treated patients developed malaria. During the 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 of 328 (2.7%) who took atovaquone and proguanil hydrochloride. While new infections could not be distinguished from recrudescent infections, all but of the infections in patients treated with atovaquone and proguanil hydrochloride occurred more than 15 days after stopping therapy. The single case occurring on Day following cessation of therapy with atovaquone and proguanil hydrochloride probably represents failure of prophylaxis with atovaquone and proguanil hydrochloride. The possibility that delayed cases of P. falciparum malaria may occur sometime after stopping prophylaxis with atovaquone and proguanil hydrochloride cannot be ruled out. Hence, returning travelers developing febrile illnesses should be investigated for malaria. 14.2 Treatment of Acute, Uncomplicated P. falciparum Malaria Infections In Phase 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 (elimination of parastextia with no recurrent parastextia during follow-up for 28 days) 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. Atovaquone and proguanil hydrochloride was evaluated for treatment of acute, uncomplicated malaria caused by P. falciparum in Phase randomized, open-label, controlled clinical trials (N 1,030 enrolled in both treatment groups). The mean age of subjects was 27 years and 16% were children 12 years and younger; 74% of subjects were male. Evaluable patients included those whose outcomes at 28 days were known. Among 471 evaluable patients treated with the equivalent of atovaquone and proguanil hydrochloride tablets once daily for days, 464 had sensitive response (elimination of parastextia with no recurrent parastextia during follow-up for 28 days) (Table 8). Seven patients had response of RI resistance (elimination of parastextia but with recurrent parastextia between and 28 days after starting treatment). In these trials, the response to treatment with atovaquone and proguanil hydrochloride was similar to treatment with the comparator drug in trials. Table 8. Parasitological Response in Clinical Trials of Atovaquone and Proguanil hydrochloride for Treatment of P.falciparum Malaria Study SiteAtovaquone and Proguanil hydrochloride ComparatorEvaluable Patients (n)% Sensitive Response Drug(s)Evaluable Patients (n)% Sensitive Response Brazil7498.6%Quinine and tetracycline76100%Thailand79100%Mefloquine7986.1%France 21100%Halofantrine18100%Kenya c,d 8193.8%Halofantrine8390.4%Zambia80100%Pyrimethamine/ sulfadoxine (P/S)8098.8%Gabon 6398.4%Amodiaquine6381%Philippines54100%Chloroquine (Cq) Cq and P/S233230.4%87.5%Peru19100%ChloroquineP/S1377.7%100%a Atovaquone and proguanil hydrochloride tablets 1,000 mg atovaquone and 400 mg proguanil hydrochloride (or equivalent based on body weight for patients weighing <=40 kg) once daily for days. Elimination of parastextia with no recurrent parastextia during follow-up for 28 days. Patients hospitalized only for acute care. Follow-up conducted in outpatients. Study in pediatric patients aged to 12 years. When these trials were pooled and additional trials evaluating atovaquone and proguanil hydrochloride alone (without comparator arm) were added to the analysis, the overall efficacy (elimination of parastextia with no recurrent parastextia during follow-up for 28 days) in 521 evaluable patients was 98.7%. The efficacy of atovaquone and proguanil hydrochloride in the treatment of the erythrocytic phase of non-falciparum malaria was assessed in 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 days, parastextia cleared in 21 (91.3%) at days. Parasite relapse occurred commonly when P. vivax malaria was treated with atovaquone and proguanil hydrochloride alone. Relapsing malarias including P. vivax and P. ovale require additional treatment to prevent relapse. The efficacy of atovaquone and proguanil hydrochloride in treating acute uncomplicated P. falciparum malaria in children weighing >= and 11 kg was examined in an open-label, randomized trial conducted in Gabon. Patients received either atovaquone and proguanil hydrochloride (2 or atovaquone and proguanil hydrochloride pediatric tablets once daily depending upon body weight) for days (n 100) or amodiaquine (10 mg/kg/day) for days (n 100). In this study, the atovaquone and proguanil hydrochloride tablets were crushed and mixed with condensed milk just prior to administration. An adequate clinical response (elimination of parastextia with no recurrent parastextia during follow-up for 28 days) was obtained in 95% (87/92) of the evaluable pediatric patients who received atovaquone and proguanil hydrochloride and in 53% (41/78) of those evaluable who received amodiaquine. response of RI resistance (elimination of parastextia but with recurrent parastextia between 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 atovaquone and proguanil hydrochloride. There were cases of RIII in the amodiaquine arm.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The daily dose should be taken at the same time each day with food or milky drink. In the event of vomiting within hour after dosing, 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 milky drink. Prophylaxis 2.1): Start prophylaxis or days before entering malaria-endemic area and continue daily during the stay and for 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 single daily dose for 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. Atovaquone and proguanil hydrochloride tablets should be taken with food or milky drink. Start prophylaxis or days before entering malaria-endemic area and continue daily during the stay and for days after return. Adults: One adult strength tablet per day. Pediatric Patients: Dosage based on body weight (see Table 1). Adults: Four adult strength tablets as single daily dose for days. Pediatric Patients: Dosage based on body weight (see Table 2). 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 or days before entering malaria-endemic area and continue daily during the stay and for days after return. Adults One atovaquone and proguanil hydrochloride tablet (adult strength 250 mg atovaquone/100 mg proguanil hydrochloride) per day. Pediatric PatientsThe dosage for prevention of malaria in pediatric patients is based upon body weight (Table 1). Table 1. Dosage for Prevention of Malaria in Pediatric PatientsWeight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen 11 to 20 62.5 mg/25 mg Atovaquone and proguanil hydrochloride pediatric tablet daily 21 to 30 125 mg/50 mg Atovaquone and proguanil hydrochloride pediatric tablets as single daily dose 31 to 40 187.5 mg/75 mg Atovaquone and proguanil hydrochloride pediatric tablets as single daily dose 40 250 mg/100 mg Atovaquone and proguanil hydrochloride tablet (adult strength) as single daily dose 2.2 Treatment of Acute Malaria AdultsFour atovaquone and proguanil hydrochloride tablets (adult strength; total daily dose g atovaquone/400 mg proguanil hydrochloride) as single daily dose for consecutive days.Pediatric PatientsThe 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 PatientsWeight (kg) Atovaquone/ Proguanil HCl Total Daily Dose Dosage Regimen to 125 mg/50 mg Atovaquone and proguanil hydrochloride pediatric tablets daily for consecutive days to 10 187.5 mg/75 mg Atovaquone and proguanil hydrochloride pediatric tablets daily for consecutive days 11 to 20 250 mg/100 mg Atovaquone and proguanil hydrochloride tablet (adult strength) daily for consecutive days 21 to 30 500 mg/200 mg Atovaquone and proguanil hydrochloride tablets (adult strength) as single daily dose for consecutive days 31 to 40 750 mg/300 mg Atovaquone and proguanil hydrochloride tablets (adult strength) as single daily dose for consecutive days >40 g/400 mg Atovaquone and proguanil hydrochloride tablets (adult strength) as single daily dose for 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 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)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 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; parastextia should be closely monitored. 7.3) 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; parastextia 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 reduction in plasma concentrations of atovaquone [see Clinical Pharmacology 12.3)] Parastextia 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 max of indinavir but resulted in decrease in the 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients should be instructed: to take atovaquone and proguanil hydrochloride tablets at the same time each day with food or milky drink. to take repeat dose of atovaquone and proguanil hydrochloride if vomiting occurs within hour after dosing. to take dose as soon as possible if dose is missed, then return to their normal dosing schedule. However, if dose is skipped, the patient should not double the next dose. that rare serious adverse events such as hepatitis, severe skin reactions, neurological events, and hematological events have been reported when atovaquone and proguanil hydrochloride was used for the prophylaxis or treatment of malaria. to consult healthcare professional regarding alternative forms of prophylaxis if prophylaxis with atovaquone and proguanil hydrochloride is prematurely discontinued for any reason. that protective clothing, insect repellents, and bed nets 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 malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria. that falciparum malaria carries 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. Manufactured for:Glenmark Pharmaceuticals Inc., USAMahwah, NJ 07430 Questions (888) 721-7115 www.glenmarkpharma-us.com December 2019. to take atovaquone and proguanil hydrochloride tablets at the same time each day with food or milky drink. to take repeat dose of atovaquone and proguanil hydrochloride if vomiting occurs within hour after dosing. to take dose as soon as possible if dose is missed, then return to their normal dosing schedule. However, if dose is skipped, the patient should not double the next dose. that rare serious adverse events such as hepatitis, severe skin reactions, neurological events, and hematological events have been reported when atovaquone and proguanil hydrochloride was used for the prophylaxis or treatment of malaria. to consult healthcare professional regarding alternative forms of prophylaxis if prophylaxis with atovaquone and proguanil hydrochloride is prematurely discontinued for any reason. that protective clothing, insect repellents, and bed nets 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 malaria-endemic area and inform their healthcare professional that they may have been exposed to malaria. that falciparum malaria carries 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of atovaquone and proguanil hydrochloride on male and female reproductive performance are unknown. AtovaquoneA 24-month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 54 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. In CD-1 mice, 24-month study showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least 15 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. Atovaquone administered by oral gavage in doses of 100, 300, or 1,000 mg/kg/day to adult male rats from 73 days prior to mating until 20 days after mating and to adult female rats from 14 days prior to mating until LD20 did not impair male or female fertility or early embryonic development at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 7.3 times the estimated human exposure for the treatment of malaria based on AUC. ProguanilNo evidence of carcinogenic effect was observed in 24-month studies conducted in CD-1 mice at doses up to 16 mg/kg/day corresponding to 1.5 times the average human plasma exposure during prophylaxis of malaria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average human plasma exposure during prophylaxis of malaria based on AUC. 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, dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation. Proguanil administered orally in doses of 4, 8, and 16 mg/kg/day to male rats from 29 days prior to mating until 27 days after mating and to females from 15 days prior to mating through GD7 revealed no adverse effects on adult male or female fertility or early embryonic development at doses up to 16 mg/kg/day (up to 0.04 times the average human exposure for the treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted. 13.2 Animal Toxicology and/or Pharmacology. Fibrovascular proliferation in the right atrium, pyelonephritis, bone marrow hypocellularity, lymphoid atrophy, and gastritis/enteritis were observed in dogs treated with proguanil hydrochloride for months at dose of 12 mg/kg/day (approximately 3.9 times the recommended daily human dose for malaria prophylaxis on mg/m basis). Bile duct hyperplasia, gall bladder mucosal atrophy, and interstitial pneumonia were observed in dogs treated with proguanil hydrochloride for months at dose of mg/kg/day (approximately 1.3 times the recommended daily human dose for malaria prophylaxis on mg/m basis). Mucosal hyperplasia of the cecum and renal tubular basophilia were observed in rats treated with proguanil hydrochloride for months at dose of 20 mg/kg/day (approximately 1.6 times the recommended daily human dose for malaria prophylaxis on mg/m basis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be reversible.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAtovaquone is highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone shows considerable inter-individual variability. Effect of Food: Atovaquone and proguanil hydrochloride should be taken with food or milky drink. Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC to times and max times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. DistributionAtovaquone is highly protein bound (> 99%) over the concentration range of to 90 mcg/mL. 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. population pharmacokinetic analysis demonstrated that the apparent V/F of proguanil in adult and pediatric patients older than 15 years with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients 15 years and younger 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. EliminationThe elimination half-life of atovaquone is about to 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. The main routes of elimination are hepatic biotransformation and renal excretion.Metabolism: In 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, specific metabolite has not been identified. Between 40% to 60% of proguanil is excreted by the kidneys. Proguanil is metabolized to cycloguanil (primarily via cytochrome P450 2C19 [CYP2C19]) and 4-chlorophenylbiguanide. Excretion: population pharmacokinetic analysis in adult and pediatric patients showed that the apparent clearance (CL/F) of both atovaquone and proguanil are related to body weight. The values CL/F for both atovaquone and proguanil in subjects with body weight >=11 kg are shown in Table 4. Table 4. Apparent Clearance for Atovaquone and Proguanil in Patients as Function of Body WeightAtovaquoneProguanilBody WeightnCL/F (L/h) Mean +- SD (range) nCL/F (L/h) Mean +- SD (range) 11 to 20 kg1591.34 +- 0.63 (0.52 to 4.26)14629.5 +- 6.5 (10.3 to 48.3)21 to 30 kg1171.87 +- 0.81 (0.52 to 5.38)11340.0 +- 7.5 (15.9 to 62.7)31 to 40 kg952.76 +- 2.07 (0.97 to 12.5)9149.5 +- 8.30 (25.8 to 71.5)>40 kg3686.61 +- 3.92 (1.32 to 20.3)28267.9 +- 19.9 (14.0 to 145)a SD Standard deviation. The pharmacokinetics of atovaquone and proguanil in patients with body weight less than 11 kg have not been adequately characterized. Specific PopulationsPediatric Patients: 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 days) than in adult patients (2 to days). In clinical trials, plasma trough concentrations of atovaquone and proguanil in pediatric patients weighing to 40 kg were within the range observed in adults after dosing by body weight. Geriatric Patients: In single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (aged 65 to 79 years) with those of 13 younger subjects (aged 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate: 2.36, 90% Cl: 1.70, 3.28). max was longer in elderly subjects (median hours) compared with younger subjects (median: hours) and average elimination half-life was longer in elderly subjects (mean: 14.9 hours) compared with younger subjects (mean: 8.3 hours). Patients with 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 atovaquone and proguanil hydrochloride for long-term prophylaxis (over months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance 30 mL/min), atovaquone max 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 4)] Patients with Hepatic Impairment: In single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, moderate, as indicated by the Child-Pugh method) with those of 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared with 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: to 1.63). Proguanil AUC, max, and its elimination half-life increased in subjects with mild hepatic impairment when compared with healthy subjects (Table 5). Also, the proguanil AUC and its elimination half-life increased in subjects with moderate hepatic impairment when compared with healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (C max and AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared with healthy volunteers (Table 5). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment. The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of atovaquone and proguanil hydrochloride have not been studied in patients with severe hepatic impairment. Table 5. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects with Mild and Moderate Hepatic Impairment Compared with Healthy VolunteersParameterComparisonProguanilCycloguanilAUC (0-inf) mild:healthy1.96 (1.51, 2.54)0.32 (0.22, 0.45)C max mild:healthy1.41 (1.16, 1.71)0.35 (0.24, 0.50)t 1/2 mild:healthy1.21 (0.92, 1.60)0.86 (0.49, 1.48)AUC (0-inf) moderate:healthy1.64 (1.14, 2.34)NDC max moderate:healthy0.97 (0.69, 1.36)NDt 1/2 moderate:healthy1.46 (1.05, 2.05)NDND Not determined due to lack of quantifiable data.a Ratio of geometric means. Mean difference. Drug Interaction StudiesThere are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose. Atovaquone is highly protein bound (> 99%) but does not displace other highly protein-bound drugs in vitro. Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown. Rifampin/Rifabutin: Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations by approximately 50% and 34%, respectively. The mechanisms of these interactions are unknown. Tetracycline: Concomitant treatment with tetracycline has been associated with approximately 40% reduction in plasma concentrations of atovaquone. Metoclopramide: Concomitant treatment with metoclopramide has been associated with decreased bioavailability of atovaquone. Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and max of indinavir but resulted in decrease in the trough of indinavir (23% decrease [90% CI: 8%, 35%]).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published literature and postmarketing experience with use of atovaquone and proguanil hydrochloride in pregnant women are insufficient to identify 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 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 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 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 ConsiderationsDisease-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. DataAnimal Data: Atovaquone: Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 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 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 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 fetal rat and rabbit tissue. Proguanil: Proguanil administered orally to pregnant rats during organogenesis (GD6 to GD17) was not associated with fetal malformations, but increased ureter variations at maternally toxic dose of 20 mg/kg/day corresponding to plasma concentration approximately equal to 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Proguanil given orally by gavage at maternally toxic dose of 40 mg/kg/day to pregnant rabbits during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal effects at plasma concentration up to 0.8 times the estimated human exposure for the treatment of malaria based on AUC. In pre- and post-natal study in female rats, proguanil hydrochloride administered in oral doses of 4, 8, or 16 mg/kg/day from GD6 until LD20 did not impair the growth, development, or reproductive ability of first generation offspring or the survivability of second generation offspring at doses up to 16 mg/kg/day (0.04 times the average human exposure based on AUC). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted. Atovaquone and Proguanil: The combination of atovaquone and proguanil hydrochloride administered orally to pregnant rats in atovaquone:proguanil hydrochloride doses of 12.5:5, 25:10, and 50:20 mg/kg/day during organogenesis (GD6 to GD17) did not produce maternal toxicity or adverse embryo-fetal developmental effects with doses up to 50:20 mg/kg/day corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride administered orally in atovaquone:proguanil hydrochloride doses of 25:10, 50:20, or 100:40 mg/kg/day during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal developmental effects at maternally toxic dose of 100:40 mg/kg/day corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal impairment: contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment. 8.6) Renal impairment: contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment. 8.6) 8.1 Pregnancy. Risk SummaryAvailable data from published literature and postmarketing experience with use of atovaquone and proguanil hydrochloride in pregnant women are insufficient to identify 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 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 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 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 ConsiderationsDisease-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. DataAnimal Data: Atovaquone: Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 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 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 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 fetal rat and rabbit tissue. Proguanil: Proguanil administered orally to pregnant rats during organogenesis (GD6 to GD17) was not associated with fetal malformations, but increased ureter variations at maternally toxic dose of 20 mg/kg/day corresponding to plasma concentration approximately equal to 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Proguanil given orally by gavage at maternally toxic dose of 40 mg/kg/day to pregnant rabbits during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal effects at plasma concentration up to 0.8 times the estimated human exposure for the treatment of malaria based on AUC. In pre- and post-natal study in female rats, proguanil hydrochloride administered in oral doses of 4, 8, or 16 mg/kg/day from GD6 until LD20 did not impair the growth, development, or reproductive ability of first generation offspring or the survivability of second generation offspring at doses up to 16 mg/kg/day (0.04 times the average human exposure based on AUC). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted. Atovaquone and Proguanil: The combination of atovaquone and proguanil hydrochloride administered orally to pregnant rats in atovaquone:proguanil hydrochloride doses of 12.5:5, 25:10, and 50:20 mg/kg/day during organogenesis (GD6 to GD17) did not produce maternal toxicity or adverse embryo-fetal developmental effects with doses up to 50:20 mg/kg/day corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride administered orally in atovaquone:proguanil hydrochloride doses of 25:10, 50:20, or 100:40 mg/kg/day during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal developmental effects at maternally toxic dose of 100:40 mg/kg/day corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC. 8.2 Lactation. Risk SummaryThere are no data on the presence of atovaquone in human milk; however, proguanil is present in human milk. Atovaquone is present in rat milk (see Data). When drug is present in animal milk, it is likely the drug will be present in human milk. There are no data on the effects of atovaquone and proguanil on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for atovaquone and proguanil hydrochloride and any potential adverse effect on the breastfed child from atovaquone and proguanil hydrochloride or from the underlying maternal condition. DataIn rat study with doses of 10 and 250 mg/kg, given orally by gavage on postpartum Day 11, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.. 8.4 Pediatric Use. Prophylaxis of MalariaSafety and effectiveness have not been established in pediatric patients who weigh less than 11 kg. The efficacy and safety of atovaquone and proguanil hydrochloride have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more [see Clinical Studies 14.1)] Treatment of MalariaSafety and effectiveness have not been established in pediatric patients who weigh less than kg. The efficacy and safety of atovaquone and proguanil hydrochloride for the treatment of malaria have been established in controlled trials involving pediatric patients weighing kg or more [see Clinical Studies 14.2)] . 8.5 Geriatric Use. Clinical trials of atovaquone and proguanil hydrochloride did not include sufficient numbers of subjects aged 65 years and older 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, and the greater frequency of concomitant disease or other drug therapy. [See Clinical Pharmacology 12.3).] 8.6 Renal Impairment Do not use atovaquone and proguanil hydrochloride 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. [See Clinical Pharmacology 12.3).] 8.7 Hepatic Impairment No dosage adjustments are needed in patients with mild or moderate hepatic impairment [see Clinical Pharmacology 12.3)] No trials have been conducted in patients with severe hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Atovaquone absorption may be reduced in patients with diarrhea or vomiting. If used in patients who are vomiting, parastextia 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. 5.1) In mixed P. falciparum and Plasmodium vivax infection, P. vivax relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone. 5.2) In the event of recrudescent P. falciparum infections after treatment or prophylaxis failure, patients should be treated with different blood schizonticide. 5.2) Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use. 5.3) Atovaquone and proguanil hydrochloride 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. 5.4) Atovaquone absorption may be reduced in patients with diarrhea or vomiting. If used in patients who are vomiting, parastextia 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. 5.1) In mixed P. falciparum and Plasmodium vivax infection, P. vivax relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone. 5.2) In the event of recrudescent P. falciparum infections after treatment or prophylaxis failure, patients should be treated with different blood schizonticide. 5.2) Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use. 5.3) Atovaquone and proguanil hydrochloride 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. 5.4) 5.1 Vomiting and Diarrhea Absorption of atovaquone may be reduced in patients with diarrhea or vomiting. If atovaquone and proguanil hydrochloride is used in patients who are vomiting, parastextia should be closely monitored and the use of an antiemetic considered. [See Dosage and Administration 2).] Vomiting occurred in up to 19% of pediatric patients given treatment doses of atovaquone and proguanil hydrochloride. 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. 5.2 Relapse of Infection In mixed P. falciparum and Plasmodium vivax infections, P. vivax parasite relapse occurred commonly when patients were treated with atovaquone and proguanil hydrochloride alone. In the event of recrudescent P. falciparum infections after treatment with atovaquone and proguanil hydrochloride or failure of chemoprophylaxis with atovaquone and proguanil hydrochloride, patients should be treated with different blood schizonticide. 5.3 Hepatotoxicity Elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of atovaquone and proguanil hydrochloride. 5.4 Severe or Complicated Malaria Atovaquone and proguanil hydrochloride has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparastextia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therapy.