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.

2.1 Dosage for the Prevention of P. jiroveci 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. 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.

2.3 Important Administration Instructions

Administer MEPRON 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)].

MEPRON Foil Pouch

•

Open each 5-mL pouch by removing tab at perforation and tear at notch.

•

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 two pouches.

MEPRON Bottle

Shake bottle gently before administering the recommended dosage.

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.

6.1 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).

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%).

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.

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
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