Mepron tablets

Mepron is indicated for the acute oral treatment of mild to moderate Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX).

This indication is based on the results of a randomized, double-blind trial comparing Mepron to TMP-SMX in AIDS patients with mild to moderate PCP (defined in the study protocol as an alveolar-arterial oxygen diffusion gradient [(A-a)DO2]1≥ 45 mmHg and PaO2≥ 60 mmHg on room air) and a randomized trial comparing Mepron to intravenous pentamidine isethionate in patients with mild to moderate PCP intolerant to trimethoprim or sulfa-antimicrobials. These studies are summarized below:

TMP-SMX Comparative Study:

This double-blind, randomized trial initiated in 1990 was designed to compare the safety and efficacy of Mepron to that of TMP-SMX for the treatment of AIDS patients with histologically confirmed PCP. Only patients with mild to moderate PCP were eligible for enrollment.

A total of 408 patients were enrolled into the trial at 37 study centers. Eighty-six patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 patients with histologically confirmed PCP, 160 were randomized to receive Mepron and 162 to TMP-SMX. Study participants randomized to Mepron treatment were to receive 750 mg Mepron (three 250 mg tablets) three times daily for 21 days and those randomized to TMP-SMX were to receive 320 mg TMP plus 1600 mg SMX three times daily for 21 days.

Therapy success was defined as improvement in clinical and respiratory measures persisting at least four weeks after cessation of therapy. Therapy failures included lack of response, treatment discontinuation due to an adverse experience, and unevaluable.

There was a significant difference (P = 0.03) in mortality rates between the treatment groups. Among the 322 patients with confirmed PCP, 13 of 160 (8%) patients treated with Mepron and four of 162 (2.5%) patients receiving TMP-SMX died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all 408 randomized patients, there were 16 (8%) deaths in the Mepron arm and sever (3.4%) deaths in the TMP-SMX arm (P = 0.051). Of the 13 patients treated with Mepron who died, 4 died of PCP and 5 died with a combination of bacterial infections and PCP; bacterial infections did not appear to be a factor in any of the 4 deaths among TMP-SMX-treated patients.

A correlation between plasma atovaquone concentrations and death was demonstrated; in general, patients with lower plasma concentrations were more likely to die. For those patients for whom day 4 atovaquone plasma concentrations data are available, 5 (63%) of the 8 patients with concentration<5 μg/mL died during participation in the study. However, only 1 (2.0%) of the 49 patients with day 4 plasma concentration ≥ 5μg/mL died. (See Table 2)

The failure rate due to lack of response was significantly larger for Mepron patients while the failure rate due to adverse experiences was significantly larger for TMP-SMX patients.

There were no significant differences in the effect of either treatment on additional indicators of response (i.e., arterial blood gas measurements, vital signs, serum LDH levels, clinical symptoms, and chest radiographs).

Pentamidine Comparative Study:

This unblended, randomized trial initiated in 1991 was designed to compare the safety and efficacy of Mepron to that of pentamidine for the treatment of histologically confirmed mild or moderate PCP in AIDS patients. Approximately 80% of the patients had a history of intolerance to trimethoprim or sulfa-antimicrobials (the primary therapy group) or were experiencing intolerance to TMP-SMX with treatment of an episode of PCP at the time of enrollment in the study (the salvage treatment group).

Patients randomized to Mepron were to receive 750 mg atovaquone (three 250 mg tablets) three times daily for 21 days and those randomized to pentamidine isethionate were to receive a 3 to 4 mg/kg single intravenous infusion daily for 21 days.

*As defined by the protocol and described in study description above.

A total of 174 patients were enrolled into the trial at 22 study centers. Thirty-nine patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135 patients with histologically confirmed PCP, 70 were randomized to receive Mepron and 65 to pentamidine. One hundred and ten (110) of these were in the primary therapy group and 25 were in the salvage therapy group. One patient in the primary therapy group randomized to receive pentamidine did not receive study medication.

There was no difference in mortality rates between the treatment groups. Among the 135 patients with confirmed PCP, 10 of 70 (14%) patients randomized to Mepron and nine of 65 (14%) patients randomized to pentamidine died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all randomized patients, there were 11 (12.5%) deaths in the Mepron arm and 12 (14%) deaths in the pentamidine arm. For those patients for whom day 4 atovaquone plasma concentration are available, 3 of 5 (60%) patients with concentrations <5 μg/mL died during participation in the study. However, only 2 of 21 (9%) patients with day 4 plasma concentrations ≥5 μg/mL died.

The therapeutic outcomes for the 134 patients who received study medication in this trial are presented in Table 3.

Data on Chronic Use:

Mepron has not been systematically evaluated as a chronic suppressive agent to prevent the development of PCP in patients at high risk for Pneumocystis carinii disease. In a pilot dosing study of Mepron in AIDS patients, 5 of 31 patients had PCP breakthroughs: one patient at 750 mg once daily (after 20 days), three patients at 750 mg twice daily (after 14, 70, and 97 days), and one patient at 1500 mg twice daily (after 74 days). The dose used in the acute treatment studies (750 mg three times daily) was not studied and, therefore, there are no data on the rate of breakthrough at this dose.

Clinical experience with Mepron has been limited to patients with mild to moderate PCP [(A-a)DO2≤ 45 mmHg]. Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of Mepron in patients who are failing therapy with TMP-SMX has not been systematically studied. Mepron has not been evaluated as an agent for PCP prophylaxis.

General

Absorption of orally administered Mepron is limited but can be significantly increased when the drug is taken with food. Mepron plasma concentrations have been shown to correlate with the likelihood of successful treatment and survival. Therefore, parenteral therapy with other agents should be considered for patients who have difficulty taking Mepron with food (see CLINICAL PHARMACOLOGY). Gastrointestinal disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials.

Based upon the spectrum of in vitro antimicrobial activity, atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral or fungal pneumonia or mycobacterial diseases. Clinical deterioration in patients may be due to infections with other pathogens, as well as progressive PCP. All patients with acute PCP should be carefully evaluated for other possible causes of pulmonary disease and treated with additional agents as appropriate.

Information for Patients

The importance of taking the prescribed dose of Mepron should be stressed. Patients should be instructed to take their daily doses of Mepron with meals as the presence of food will significantly improve the absorption of the drug.

Drug Interactions

atovaquone is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering Mepron concurrently with other highly plasma protein bound drugs with narrow therapeutic indices as competition for binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentration of phenytoin (15 μg/mL), nor is the binding of phenytoin affected by the presence of atovaquone.

Drug/Laboratory Test Interactions

It is not known Mepron interferes with clinical laboratory test or assay results.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenicity studies in rats and mice have not been completed. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Culture Human Lymphocyte cytogenetic assay. No evidence of gene(?) toxicity was observed in the in vivo Mouse Micronucleus(?) assay.

Pregnancy

Pregnancy Category C. Atovaquone was not teratogenic and did not cause reproductive toxicity in rats in plasma concentrations up to 5 times the estimated human exposure. Atovaquone caused maternal toxicity in rabbit (?) plasma concentrations that were approximately equal to the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers (?) early resorption and post-implantation loss per dam. It is not clear whether these effects were caused by atovaquone 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, concentrations of (?) carbon in rat fetuses were 18% (middle gestation) and (?)% (late gestation) of concurrent maternal plasma concentrations. Thee are no adequate and well-controlled studies in pregnant women. Atovaquone should be used during pregnancy only if the potential benefit justifies the potential (?) to the fetus.

Nursing Mothers

It is not known whether Mepron is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised (?)

Mepron is administered to a nursing woman. In a rat study, atovaquone. Concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.

Pediatric Use

there are no efficacy studies in children. Clinical experience with Mepron has not been systematically evaluated in patients greater than 65 years of age. Caution should be exercised when treating elderly patients reflecting the greater frequency of decreased hepatic, renal and cardiac function in this population.

There have been no reports of overdosage from the oral administration of Mepron.

Adults: The recommended oral dose is 750 mg (three 250 mg tablets) administered with food three times a day for ?1 days (total daily dose 2250 mg). Failure to administer Mepron with food may result in lower atovaquone plasma concentrations and may limit response to therapy (see CLINICAL PHARMACOLOGY and PRECAUTIONS).