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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).

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.

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.

Dosage For The Prevention Of P. jiroveci Pneumonia

The recommended oral dosage is 1,500 mg (10 mL) once daily administered with food.

Dosage For The Treatment Of Mild-to-Moderate P. jiroveci Pneumonia

The recommended oral dosage is 750 mg (5 mL) twice daily (total daily dose = 1,500 mg) administered with food for 21 days.

Important Administration Instructions

Administer MEPRON oral suspension with food to avoid lower plasma atovaquone concentrations that may limit response to therapy.

MEPRON Foil Pouch

• Open each 5-mL pouch by folding along the dotted line and tearing open at horizontal slit as directed by arrow on pouch.
• For a 5-mL dose, take entire contents either by placing directly into the mouth or by dispensing into a dosing spoon (5 mL) or cup prior to administration by mouth.
• For a 10-mL dose, take the entire contents of 2 pouches.

MEPRON Bottle

Shake bottle gently before administering the recommended dosage.

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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Hepatotoxicity

Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone.

If treating patients with severe hepatic impairment, closely monitor patients following administration of MEPRON.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies in rats were negative; 24-month studies in mice (dosed with 50, 100, or 200 mg/kg/day), showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested, which correlated with 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of PCP. 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.

Use In Specific Populations

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.

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.

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

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.

The following adverse reactions are discussed in other sections of the labeling:

• Hepatotoxicity.

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 2 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

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

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

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)

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.

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.

In one patient who took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose. There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable.

Absorption

Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The absolute bioavailability of a 750-mg dose of MEPRON suspension administered under fed conditions in 9 HIV-1-infected (CD4 >100 cells/mm³) volunteers was 47% ± 15%.

Administering atovaquone with food enhances its absorption by approximately 2-fold. In one trial, 16 healthy volunteers received a single dose of 750 mg MEPRON suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values under fasting and fed conditions were 324 ± 115 and 801 ± 320 h•mcg/mL, respectively, representing a 2.6 ± 1.0-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover trial in 19 HIV-1-infected volunteers (CD4 <200 cells/mm³) receiving daily doses of 500 mg MEPRON suspension. AUC values under fasting and fed conditions were 169 ± 77 and 280 ± 114 h•mcg/mL, respectively. Maximum plasma atovaquone concentration (Cmax) values under fasting and fed conditions were 8.8 ± 3.7 and 15.1 ± 6.1 mcg/mL, respectively.

Dose Proportionality

Plasma atovaquone concentrations do not increase proportionally with dose. When MEPRON suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, average steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8, and 13.5 ± 5.1 mcg/mL, respectively. The corresponding Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL. When MEPRON suspension was administered to 5 HIV-1-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21.0 ± 4.9 mcg/mL and Cmax was 24.0 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL.

Distribution

Following IV administration of atovaquone, the 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 plasma clearance of atovaquone following IV administration in 9 HIV-1-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The 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 across trials following administration of MEPRON suspension. The half-life of atovaquone is due to presumed enterohepatic cycling and eventual fecal elimination. In a trial where 14C-labelled 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.

Hepatic/Renal Impairment

The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.

Relationship Between Plasma Atovaquone Concentration And Clinical Outcome

In a comparative trial of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP , where subjects with HIV/AIDS received atovaquone tablets 750 mg 3 times daily for 21 days, the mean steady-state atovaquone concentration was 13.9 ± 6.9 mcg/mL (n = 133). Analysis of these data established a relationship between plasma atovaquone concentration and successful treatment (Table 6).

Table 6: Relationship between Plasma Atovaquone Concentration and Successful Treatment

A dosing regimen of MEPRON suspension for the treatment of mild-to-moderate PCP was selected to achieve average plasma atovaquone concentrations of approximately 20 mcg/mL, because this plasma concentration was previously shown to be well-tolerated and associated with the highest treatment success rates (Table 6). In an open-label PCP treatment trial with MEPRON suspension, dosing regimens of 1,000 mg once daily, 750 mg twice daily, 1,500 mg once daily, and 1,000 mg twice daily were explored. The average steady-state plasma atovaquone concentration achieved at the 750-mg twice-daily dose given with meals was 22.0 ± 10.1 mcg/mL (n = 18).