Atovaquone And Proguanil Hydrochloride Pediatric

1 INDICATIONS AND USAGE Atovaquone and proguanil hydrochloride tablets are an antimalarial indicated for: • prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported. ( 1.1 ) • treatment of acute, uncomplicated P. falciparum malaria. ( 1.2 ) 1.1 Prevention of Malaria Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of Plasmodium falciparum malaria, including in areas where chloroquine resistance has been reported. 1.2 Treatment of Malaria Atovaquone and proguanil hydrochloride tablets are indicated for the treatment of acute, uncomplicated P. falciparum malaria. Atovaquone and proguanil hydrochloride tablets have been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

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

6 ADVERSE REACTIONS • Prophylaxis: Common adverse reactions (≥ 4%) in adults were diarrhea, dreams, oral ulcers, and headache; these events occurred in a similar or lower proportion of subjects receiving atovaquone and proguanil hydrochloride than an active comparator. Common adverse reactions (≥ 5%) in pediatric patients included abdominal pain, headache, cough, and vomiting. ( 6.1 ) • Treatment: Common adverse reactions (≥ 5%) in adolescents and adults were abdominal pain, nausea, vomiting, headache, diarrhea, asthenia, anorexia, and dizziness. Common adverse reactions (≥ 6%) in pediatric patients included vomiting, pruritus, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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 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 atovaquone and proguanil hydrochloride (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 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 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 (aged 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 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 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, 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.

12.3 Pharmacokinetics Absorption Atovaquone is a 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 a milky drink. Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and C max 5 times over fasting. The absolute bioavailability of the tablet formulation of atovaquone when taken with food is 23%. Distribution Atovaquone is highly protein bound (> 99%) over the concentration range of 1 to 90 mcg/mL. A 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. A 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. Elimination The elimination half-life of atovaquone is about 2 to 3 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 a study where 14 C-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, a 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: A 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 a Function of Body Weight Atovaquone Proguanil Body Weight n CL/F (L/h) Mean ± SD a (range) n CL/F (L/h) Mean ± SD a (range) 11 to 20 kg 159 1.34 ± 0.63 (0.52 to 4.26) 146 29.5 ± 6.5 (10.3 to 48.3) 21 to 30 kg 117 1.87 ± 0.81 (0.52 to 5.38) 113 40.0 ± 7.5 (15.9 to 62.7) 31 to 40 kg 95 2.76 ± 2.07 (0.97 to 12.5) 91 49.5 ± 8.30 (25.8 to 71.5) >40 kg 368 6.61 ± 3.92 (1.32 to 20.3) 282 67.9 ± 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 Populations Pediatric 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 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough concentrations of atovaquone and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight. Geriatric Patients : In a 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). T max was longer in elderly subjects (median 8 hours) compared with younger subjects (median: 4 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 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance < 30 mL/min), atovaquone C 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 a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 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: 1 to 1.63). Proguanil AUC, C 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 Volunteers Parameter Comparison Proguanil Cycloguanil AUC (0-inf) a mild:healthy 1.96 (1.51, 2.54) 0.32 (0.22, 0.45) C max a mild:healthy 1.41 (1.16, 1.71) 0.35 (0.24, 0.50) t 1/2 b mild:healthy 1.21 (0.92, 1.60) 0.86 (0.49, 1.48) AUC (0-inf) a moderate:healthy 1.64 (1.14, 2.34) ND C max a moderate:healthy 0.97 (0.69, 1.36) ND t 1/2 b moderate:healthy 1.46 (1.05, 2.05) ND ND = Not determined due to lack of quantifiable data. a Ratio of geometric means. b Mean difference. Drug Interaction Studies There 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 a 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 C max of indinavir but resulted in a decrease in the C trough of indinavir (23% decrease [90% CI: 8%, 35%]).