Because many patients who participated in clinical trials with MEPRON had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by MEPRON from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by MEPRON.

PCP Prevention Studies

In the dapsone comparative study of MEPRON Suspension, adverse experience data were collected only for treatment- limiting events. Among the entire population (n = 1057), treatment- limiting events occurred at similar frequencies in patients treated with MEPRON Suspension or dapsone (Table 6). Among patients who were taking neither dapsone nor atovaquone at enrollment (n = 487), treatment- limiting events occurred in 43% of patients treated with dapsone and 20% of patients treated with MEPRON Suspension (P <0.001). In both populations, the type of treatment- limiting events differed between the two treatment arms. Hypersensitivity reactions (rash, fever, allergic reaction) and anemia were more common in patients treated with dapsone, while gastrointestinal events (nausea, diarrhea, and vomiting) were more common in patients treated with MEPRON Suspension.

Table 7 summarizes the clinical adverse experiences reported by ³20% of patients in any group in the aerosolized pentamidine comparative study of MEPRON Suspension (n = 549), regardless of attribution. The incidence of adverse experiences at the recommended dose was similar to that seen with aerosolized pentamidine. Rash was the only individual adverse experience that occurred significantly more commonly in patients treated with both dosages of MEPRON Suspension (39% to 46%) than in patients treated with aerosolized pentamidine (28%). Among patients treated with MEPRON Suspension, there was no evidence of a dose- related increase in the incidence of adverse experiences. Treatment- limiting adverse experiences occurred less often in patients treated with aerosolized pentamidine (7%) than in patients treated with 1500 mg MEPRON Suspension once daily (25%, P£ 0.001) or 750 mg MEPRON Suspension once daily (16%, P = 0.004). The most common adverse experiences requiring discontinuation of dosing in the group receiving 1500 mg MEPRON Suspension once daily were rash (6%), diarrhea (4%), and nausea (3%). The most common adverse experience requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%).

Other events occurring in ³10% of the patients receiving the recommended dose of MEPRON included sweating, flu syndrome, pain, sinusitis, pruritis, insomnia, depression and myalgia. Bronchospasm occurred more frequently in patients receiving aerosolized pentamidine (11%) than in patients receiving MEPRON 1500 mg/ day (4%) and MEPRON 750 mg/ day (2%).

Neither MEPRON nor aerosolized pentamidine was associated with a substantial change from baseline values in any measured laboratory parameter, nor were there any significant differences in any measured laboratory parameter between MEPRON and aerosolized pentamidine. Some patients had laboratory abnormalities considered serious by the investigator or that contributed to discontinuation of therapy.

PCP Treatment Studies

Table 8 summarizes all the clinical adverse experiences reported by ³5% of the study population during the TMP- SMX comparative study of MEPRON (n = 408), regardless of attribution. The incidence of adverse experiences with MEPRON Suspension at the recommended dose was similar to that seen with the tablet formulation of atovaquone.

Although an equal percentage of patients receiving MEPRON and TMP- SMX reported at least one adverse experience, more patients receiving TMP- SMX required discontinuation of therapy due to an adverse event. Twenty- four percent of patients receiving TMP- SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving MEPRON. Four percent of patients receiving MEPRON had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving MEPRON were mild and did not require the discontinuation of dosing. The only other clinical adverse experience that led to premature discontinuation of dosing of MEPRON by more than one patient was vomiting (<1%). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%).

Laboratory test abnormalities reported for ³5% of the study population during the treatment period are summarized in Table 9. Two percent of patients treated with MEPRON and 7% of patients treated with TMP- SMX had therapy prematurely discontinued due to elevations in ALT/ AST. In general, patients treated with MEPRON developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX.

ULN = upper limit of normal range.
LLN = lower limit of normal range.

Table 10 summarizes the clinical adverse experiences reported by ³5% of the primary therapy study population (n = 144) during the comparative trial of MEPRON and intravenous pentamidine, regardless of attribution. A slightly lower percentage of patients who received MEPRON reported occurrence of adverse events than did those who received pentamidine (63% vs 72%). However, only 7% of patients discontinued treatment with MEPRON due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (P < 0.001). Of the five patients who discontinued therapy with MEPRON, three reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of MEPRON was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).

Laboratory test abnormalities reported in ³5% of patients in the pentamidine comparative study are presented in Table 11. Laboratory abnormality was reported as the reason for discontinuation of treatment in two of 73 patients who received MEPRON. One patient (1%) had elevated creatinine and BUN levels and one patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leukopenia (4%).

ULN = upper limit of normal range.
LLN = lower limit of normal range.

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during post- approval use of MEPRON. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to MEPRON.

Blood and Lymphatic: Methemoglobinemia, thrombocytopenia.

Eye: Vortex keratopathy.

Hepatobiliary Tract and Pancreas: Pancreatitis.

Skin: Allergic reactions including erythema multiforme.

Urology: Acute renal impairment.

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 concentrations of phenytoin (15 mcg/ mL), nor is the binding of phenytoin affected by the presence of atovaquone.

Rifampin: Coadministration of rifampin and MEPRON Suspension results in a significant decrease in average steady- state plasma atovaquone concentrations (see CLINICAL PHARMACOLOGY: Drug Interactions). Alternatives to rifampin should be considered during the course of PCP treatment with MEPRON.

Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with MEPRON and rifabutin.

Drug/ Laboratory Test Interactions: It is not known if MEPRON interferes with clinical laboratory test or assay results.

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