1 INDICATIONS AND USAGE MEPRON suspension is a quinone antimicrobial drug indicated for: •Prevention of Pneumocystis jiroveci 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 MEPRON has not been studied. •The efficacy of MEPRON in subjects who are failing therapy with TMP-SMX has also not been studied. 1.1 Prevention of Pneumocystis jiroveci Pneumonia MEPRON® suspension is indicated for the prevention of Pneumocystis jiroveci 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 jiroveci Pneumonia MEPRON 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 MEPRON 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 MEPRON has not been studied. The efficacy of MEPRON in subjects who are failing therapy with TMP-SMX has also not been studied.
3 DOSAGE FORMS AND STRENGTHS MEPRON is a bright yellow, citrus-flavored, oral suspension containing 750 mg of atovaquone in 5 mL. MEPRON is supplied in 210-mL bottles or 5-mL foil pouches. Oral suspension: 750 mg per 5 mL. (3)
4 CONTRAINDICATIONS MEPRON suspension is contraindicated in patients who develop or have a history of hypersensitivity reactions (e.g., angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of MEPRON. Known serious allergic/hypersensitivity reaction (e.g., angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of MEPRON. (4)
5 WARNINGS AND PRECAUTIONS •Failure to administer MEPRON suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Patients with gastrointestinal disorders may have limited absorption resulting in suboptimal atovaquone concentrations. (5.1) •Hepatotoxicity: Elevated liver chemistry tests and cases of hepatitis and fatal liver failure have been reported. (5.2) 5.1 Risk of Limited Oral Absorption Absorption of orally administered MEPRON suspension is limited but can be significantly increased when the drug is taken with food. Failure to administer MEPRON suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Consider therapy with other agents in patients who have difficulty taking MEPRON suspension with food or in patients who have gastrointestinal disorders that may limit absorption of oral medications [see Clinical Pharmacology (12.3)]. 5.2 Hepatotoxicity Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone [see Adverse Reactions (6.2)]. If treating patients with severe hepatic impairment, closely monitor patients following administration of MEPRON.
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 GlaxoSmithKline at 1-888-825-5249 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 MEPRON had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by MEPRON from those caused by underlying medical conditions. PCP Prevention Trials In two clinical trials, MEPRON 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 MEPRON 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 MEPRON 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 MEPRON suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with MEPRON 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 MEPRON 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 MEPRON 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 MEPRON suspension or aerosolized pentamidine. Rash occurred more often in subjects treated with MEPRON suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment‑limiting adverse reactions occurred in 25% of subjects treated with MEPRON 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 MEPRON 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 MEPRON 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 MEPRON 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 MEPRON tablet formulation: 1) a randomized, double‑blind trial comparing MEPRON 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 MEPRON 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 MEPRON 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 MEPRON and 24% of subjects who received TMP‑SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving MEPRON and 8% of subjects in the TMP-SMX group discontinued therapy due to rash. The incidence of adverse reactions with MEPRON 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 MEPRON 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 MEPRON 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 MEPRON 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 MEPRON reported adverse reactions than subjects who received pentamidine (63% vs. 72%). However, only 7% of subjects discontinued treatment with MEPRON due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the 5 subjects who discontinued therapy with MEPRON, 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 MEPRON 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 MEPRON, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving MEPRON 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 MEPRON tablets or pentamidine, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MEPRON 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.
7 DRUG INTERACTIONS •Concomitant administration of rifampin or rifabutin reduces atovaquone concentrations; concomitant use with MEPRON 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 MEPRON 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 MEPRON suspension is known to reduce atovaquone concentrations [see Clinical Pharmacology (12.3)]. Concomitant administration of MEPRON suspension and rifampin or rifabutin is not recommended. 7.2 Tetracycline Concomitant administration of tetracycline and MEPRON 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 MEPRON suspension. Monitor patients for potential loss of efficacy of MEPRON 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 Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir [see Clinical Pharmacology (12.3)]. Caution should be exercised when prescribing MEPRON suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if coadministration with MEPRON suspension is necessary.
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. MEPRON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human exposure (dose of 1,000 mg/kg/day in rats). Atovaquone caused maternal toxicity in rabbits at plasma concentrations that were approximately one-half the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers of early resorption and post‑implantation loss per dam (dose of 1,200 mg/kg/day in rabbits). It is not clear whether these effects were caused by atovaquone directly or were secondary to maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations. In a separate study in rats given a single 14C‑radiolabelled dose (1,000 mg/kg), concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. 8.3 Nursing Mothers It is not known whether atovaquone is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when MEPRON is administered to a nursing woman. In a rat study (with doses of 10 and 250 mg/kg), atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. 8.4 Pediatric Use Evidence of safety and effectiveness in pediatric patients (aged 12 years and younger) has not been established. In a trial of MEPRON suspension administered once daily with food for 12 days to 27 HIV-1-infected, asymptomatic infants and children aged between 1 month and 13 years, the pharmacokinetics of atovaquone were age-dependent. The average steady-state plasma atovaquone concentrations in the 24 subjects with available concentration data are shown in Table 5. Table 5. Average Steady-state Plasma Atovaquone Concentrations in Pediatric Subjects Age Dose of MEPRON Suspension 10 mg/kg 30 mg/kg 45 mg/kg Average Css in mcg/mL (mean ± SD) 1-3 months 5.9 (n = 1) 27.8 ± 5.8 (n = 4) _ >3-24 months 5.7 ± 5.1 (n = 4) 9.8 ± 3.2 (n = 4) 15.4 ± 6.6 (n = 4) >2-13 years 16.8 ± 6.4 (n = 4) 37.1 ± 10.9 (n = 3) _ Css = Concentration at steady state. 8.5 Geriatric Use Clinical trials of MEPRON did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.