Atovaquone Oral Suspension

1 INDICATIONS AND USAGE Atovaquone oral suspension is a quinone antimicrobial drug indicated for: Prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents aged 13 years and older who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). ( 1.1 ) Treatment of mild-to-moderate PCP in adults and adolescents aged 13 years and older who cannot tolerate TMP-SMX. ( 1.2 ) Limitations of Use ( 1.3 ): Treatment of severe PCP (alveolar arterial oxygen diffusion gradient [(A-a)DO2] >45 mm Hg) with atovaquone has not been studied. The efficacy of atovaquone in subjects who are failing therapy with TMP-SMX has also not been studied. 1.1 Prevention of Pneumocystis jirovecii Pneumonia Atovaquone oral suspension is indicated for the prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). 1.2 Treatment of Mild-to-Moderate Pneumocystis jirovecii Pneumonia Atovaquone oral suspension is indicated for the acute oral treatment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX. 1.3 Limitations of Use Clinical experience with atovaquone for the treatment of PCP has been limited to subjects with mild-to-moderate PCP (alveolar-arterial oxygen diffusion gradient [(A-a)DO2] ≤45 mm Hg). Treatment of more severe episodes of PCP with atovaquone has not been studied. The efficacy of atovaquone in subjects who are failing therapy with TMP-SMX has also not been studied.

2 DOSAGE AND ADMINISTRATION • Prevention of PCP: 1,500 mg (10 mL) once daily with food ( 2.1 ) • Treatment of PCP: 750 mg (5 mL) twice daily with food for 21 days ( 2.2 ) • Supplied in a unit dose cup Shake gently before use. ( 2.3 ) 2.1 Dosage for the Prevention of P. jirovecii Pneumonia The recommended oral dosage is 1,500 mg (10 mL) once daily administered with food. 2.2 Dosage for the Treatment of Mild-to-Moderate P. jirovecii Pneumonia The recommended oral dosage is 750 mg (5 mL) twice daily (total daily dose = 1,500 mg) administered with food for 21 days. 2.3 Important Administration Instructions Administer atovaquone oral suspension with food to avoid lower plasma atovaquone concentrations that may limit response to therapy [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )]. Atovaquone Oral Suspension Shake Unit dose cup gently before administering the recommended dosage.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] . • PCP Prevention: The most frequent adverse reactions (≥25% that required discontinuation) were diarrhea, rash, headache, nausea, and fever. ( 6.1 ) • PCP Treatment: The most frequent adverse reactions (≥ 14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8210 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. Additionally, because many subjects who participated in clinical trials with atovaquone had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by atovaquone from those caused by underlying medical conditions. PCP Prevention Trials In 2 clinical trials, atovaquone oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count <200 cells/mm3 or a prior episode of PCP) and unable to tolerate TMP-SMX. Dapsone Comparative Trial : In the dapsone comparative trial (n = 1,057), the majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Subjects received atovaquone oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521); median durations of exposure were 6.7 and 6.5 months, respectively. Adverse reaction data were collected only for adverse reactions requiring discontinuation of treatment, which occurred at similar frequencies in subjects treated with atovaquone oral suspension or dapsone (Table 1). Among subjects taking neither dapsone nor atovaquone at enrollment (n = 487), adverse reactions requiring discontinuation of treatment occurred in 43% of subjects treated with dapsone and 20% of subjects treated with atovaquone oral suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with atovaquone oral suspension (Table 1). Table 1. Percentage (>2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention Trial Adverse Reaction All Subjects Atovaquone Oral Suspension 1,500 mg/day (n=536) % Dapsone 100 mg/day (n=521) % Rash 6.3 8.8 Nausea 4.1 0.6 Diarrhea 3.2 0.2 Vomiting 2.2 0.6 Aerosolized Pentamidine Comparative Trial: In the aerosolized pentamidine comparative trial (n = 549), the majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received atovaquone oral suspension once daily at a dose of 750 mg (n = 188) or 1,500 mg (n = 175) or received aerosolized pentamidine 300 mg every 4 weeks (n = 186); the median durations of exposure were 6.2, 6.0, and 7.8 months, respectively. Table 2 summarizes the clinical adverse reactions reported by ≥20% of the subjects receiving either the 1,500-mg dose of atovaquone oral suspension or aerosolized pentamidine. Rash occurred more often in subjects treated with atovaquone oral suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with atovaquone oral suspension 1,500 mg once daily and in 7% of subjects treated with aerosolized pentamidine. The most frequent adverse reactions requiring discontinuation of dosing in the group receiving atovaquone oral suspension 1,500 mg once daily were rash (6%), diarrhea (4%), and nausea (3%). The most frequent adverse reaction requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%). Table 2. Percentage (≥20%) of Subjects with Selected Adverse Reactions in the Aerosolized Pentamidine Comparative PCP Prevention Trial Adverse Reaction All Subjects Atovaquone Oral Suspension 1,500 mg/day (n=175) % Aerosolized Pentamidine (N=186) % Diarrhea 42 35 Rash 39 28 Headache 28 22 Nausea 26 23 Fever 25 18 Rhinitis 24 17 Other reactions occurring in ≥10% of subjects receiving the recommended dose of atovaquone oral suspension (1,500 mg once daily) included vomiting, sweating, flu syndrome, sinusitis, pruritus, insomnia, depression, and myalgia. PCP Treatment Trials Safety information is presented from 2 clinical efficacy trials of the atovaquone tablet formulation: 1) a randomized, double-blind trial comparing atovaquone tablets with TMP-SMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to-moderate PCP [(A-a)DO2] ≤45 mm Hg and PaO2 ≥60 mm Hg on room air; 2) a randomized, open-label trial comparing atovaquone tablets with intravenous (IV) pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials. TMP-SMX Comparative Trial: In the TMP-SMX comparative trial (n = 408), the majority of subjects were white (66%) and male (95%); the mean age was 36 years. Subjects received atovaquone 750 mg (three 250-mg tablets) 3 times daily for 21 days or TMP 320 mg plus SMX 1,600 mg 3 times daily for 21 days; median durations of exposure were 21 and 15 days, respectively. Table 3 summarizes all clinical adverse reactions reported by ≥10% of the trial population regardless of attribution. Nine percent of subjects who received atovaquone and 24% of subjects who received TMP-SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving atovaquone and 8% of subjects in the TMP-SMX group discontinued therapy due to rash. The incidence of adverse reactions with atovaquone oral suspension at the recommended dose (750 mg twice daily) was similar to that seen with the tablet formulation. Table 3. Percentage (≥10%) of Subjects with Selected Adverse Reactions in the TMP-SMX Comparative PCP Treatment Trial Adverse Reaction Atovaquone Tablets (n=203) % TMP-SMX (n=205) % Rash (including maculopapular 23 34 Nausea 21 44 Diarrhea 19 7 Headache 16 22 Vomiting 14 35 Fever 14 25 Insomnia 10 9 Two percent of subjects treated with atovaquone and 7% of subjects treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. Pentamidine Comparative Trial: In the pentamidine comparative trial (n = 174), the majority of subjects in the primary therapy trial population (n = 145) were white (72%) and male (97%); the mean age was 37 years. Subjects received atovaquone 750 mg (three 250-mg tablets) 3 times daily for 21 days or a 3- to 4-mg/kg single pentamidine isethionate IV infusion daily for 21 days; the median durations of exposure were 21 and 14 days, respectively. Table 4 summarizes the clinical adverse reactions reported by ≥10% of the primary therapy trial population regardless of attribution. Fewer subjects who received atovaquone reported adverse reactions than subjects who received pentamidine (63% vs. 72%). However, only 7% of subjects discontinued treatment with atovaquone due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the 5 subjects who discontinued therapy with atovaquone, 3 reported rash (4%). Rash was not severe in any subject. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%). Table 4. Percentage (≥10%) of Subjects with Selected Adverse Reactions in the Pentamidine Comparative PCP Treatment Trial (Primary Therapy Group) Adverse Reaction Atovaquone Tablets (n=73) % Pentamidine (n=71) % Fever 40 25 Nausea 22 37 Rash 22 13 Diarrhea 21 31 Insomnia 19 14 Headache 18 28 Vomiting 14 17 Cough 14 1 Sweat 10 3 Monilia, oral 10 3 Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 subjects (3%) who received atovaquone, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving atovaquone had elevated creatinine and BUN levels and 1 subject (1%) had elevated amylase levels. In this trial, elevated levels of amylase occurred in subjects (8% versus 4%) receiving atovaquone tablets or pentamidine, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atovaquone oral suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders Methemoglobinemia, thrombocytopenia. Immune System Disorders Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria. Eye Disorders Vortex keratopathy. Gastrointestinal Disorders Pancreatitis. Hepatobiliary Disorders Hepatitis, fatal liver failure. Skin and Subcutaneous Tissue Disorders Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation. Renal and Urinary Disorders Acute renal impairment.

12.3 Pharmacokinetics Plasma atovaquone concentrations do not increase proportionally with dose following ascending repeat-dose administration of atovaquone oral suspension in healthy subjects. When atovaquone oral suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, mean (±SD) steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8, and 13.5 ± 5.1 mcg/mL, respectively. The corresponding mean (±SD) C max concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL. Absorption Atovaquone is a highly lipophilic compound with low aqueous solubility. The mean (±SD) absolute bioavailability of atovaquone from a 750-mg dose of atovaquone oral suspension administered under fed conditions in 9 HIV-1–infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%. Effect of Food: Administering atovaquone oral suspension with food enhances atovaquone bioavailability. Sixteen healthy subjects received a single 750-mg dose of atovaquone oral suspension after an overnight fast and following a meal (23 g fat: 610 kCal). The mean (±SD) atovaquone AUC under fasting and fed conditions were 324 ± 115 and 801 ± 320 h•mcg/mL, respectively, representing a 2.6 ± 1.0-fold increase. Distribution Following IV administration of atovaquone, the mean (±SD) volume of distribution at steady state (Vdss) was 0.60 ± 0.17 L/kg (n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 mcg/mL. In 3 HIV-1-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14, and 0.26 mcg/mL, representing less than 1% of the plasma concentration. Elimination The mean (±SD) half-life of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67.0 ± 33.4 to 77.6 ± 23.1 hours following administration of atovaquone oral suspension. Metabolism: The metabolism of atovaquone is unknown. Excretion: Following oral administration of 14C-labelled atovaquone to healthy subjects, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. Specific Populations Patients with Hepatic or Renal Impairment : The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment. HIV-Infected Subjects: When atovaquone oral suspension was administered to 5 HIV-1–infected subjects at a dose of 750 mg twice daily, the mean (±SD) steady-state plasma atovaquone concentration was21.0 ± 4.9 mcg/mL and mean (±SD) C max was 24.0 ± 5.7 mcg/mL. The mean (±SD) minimum plasma atovaquone concentration (C min ) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL. In an open-label PCP trial in 18 HIV-1–infected subjects, administration of atovaquone oral suspension 750 mg twice daily with meals resulted in a mean (±SD) steady-state plasma atovaquone concentration of 22.0 ± 10.1 mcg/mL. The mean (±SD) plasma clearance of atovaquone following IV administration in 9 HIV-1–infected subjects was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). Drug Interaction Studies Rifampin/Rifabutin : In a trial with 13 HIV-1–infected volunteers, the oral administration of rifampin 600 mg every 24 hours with atovaquone oral suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the mean (±SD) steady-state plasma atovaquone concentration and a 37% ± 42% increase in the mean (±SD) steady-state plasma rifampin concentration. The half-life of atovaquone decreased from 82 ± 36 hours when administered without rifampin to 50 ± 16 hours with rifampin. In a trial of 24 healthy volunteers, the oral administration of rifabutin 300 mg once daily with atovaquone oral suspension 750 mg twice daily resulted in a 34% decrease in the mean steady-state plasma atovaquone concentration and a 19% decrease in the mean steady-state plasma rifabutin concentration. Tetracycline: Concomitant treatment with tetracycline has been associated with a 40% reduction in plasma concentrations of atovaquone. Metoclopramide: Concomitant treatment with metoclopramide has been associated with a 50% reduction in steady-state atovaquone plasma concentrations. 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%]). Trimethoprim/Sulfamethoxazole (TMP-SMX): Concomitant administration of atovaquone oral suspension 500 mg once daily (not the approved dosage) and TMP-SMX in 6 HIV-infected adult subjects did not result in significant changes in either atovaquone or TMP-SMX exposure. Zidovudine: The administration of atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours to 14 HIV-1 infected subjects resulted in a 24% ± 12% decrease in zidovudine apparent oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide metabolite:parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1 when zidovudine was administered with atovaquone tablets. This effect is minor and would not be expected to produce clinically significant events. Zidovudine had no effect on atovaquone pharmacokinetics.