Atovaquone

12.1 Mechanism of Action Atovaquone is a quinone antimicrobial drug [see Clinical Pharmacology ( 12.4 )] .

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)DO 2 ] >45 mm Hg) with atovaquone oral suspension has not been studied. The efficacy of atovaquone oral suspension 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)DO 2 ] ≤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 Bottles: Shake bottle 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 Bottle Shake bottle 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 Hetero Labs Limited at 1-866-495-1995 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/mm 3 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, 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 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

7 DRUG INTERACTIONS Concomitant administration of rifampin or rifabutin reduces atovaquone concentrations; concomitant use with atovaquone oral suspension is not recommended. ( 7.1 ) Concomitant administration of tetracycline reduces atovaquone concentrations; use caution when coadministering. Monitor patients for potential loss of efficacy of atovaquone if coadministration of tetracycline is necessary. ( 7.2 ) Concomitant administration with metoclopramide reduces atovaquone concentrations; administer concomitantly only if other antiemetics are not available. ( 7.3 ) Concomitant administration of indinavir reduces indinavir trough concentrations; use caution when coadministering. Monitor patients for potential loss of efficacy of indinavir if coadministration is necessary. ( 7.4 ) 7.1 Rifampin/Rifabutin Concomitant administration of rifampin or rifabutin and atovaquone oral suspension is known to reduce atovaquone concentrations [see Clinical Pharmacology ( 12.3 )] . Concomitant administration of atovaquone oral suspension and rifampin or rifabutin is not recommended. 7.2 Tetracycline Concomitant administration of tetracycline and atovaquone oral suspension has been associated with a reduction in plasma concentrations of atovaquone [see Clinical Pharmacology ( 12.3 )]. Caution should be used when prescribing tetracycline concomitantly with atovaquone oral suspension. Monitor patients for potential loss of efficacy of atovaquone if coadministration is necessary. 7.3 Metoclopramide Metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available [see Clinical Pharmacology ( 12.3 )]. 7.4 Indinavir Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and C max of indinavir but resulted in a decrease in the C trough of indinavir [see Clinical Pharmacology ( 12.3 )]. Caution should be exercised when prescribing atovaquone oral suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if coadministration with atovaquone oral suspension is necessary.