Mepron () (atovaquone) is an antiprotozoal agent. The chemical name of atovaquone is -2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula CHClO. The compound has the following structural formula:
Mepron () Suspension is a formulation of micro-fine particles of atovaquone. The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. Mepron () Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor, poloxamer 188, purified water, saccharin sodium, and xanthan gum.
In a comparative study of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate pneumonia (PCP) (see INDICATIONS AND USAGE), where AIDS patients received 750 mg atovaquone tablets 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. This is shown in Table 2.
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A dosing regimen of Mepron () Suspension for the treatment of mild-to-moderate PCP has been 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 2). In an open-label PCP treatment study 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).
Absorption of orally administered Mepron () is limited but can be significantly increased when the drug is taken with food. Plasma atovaquone 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.
Rare cases of hepatitis, elevated liver function tests and one case of fatal liver failure have been reported in patients treated with atovaquone. A causal relationship between atovaquone use and these events could not be established because of numerous confounding medical conditions and concomitant drug therapies. (See ADVERSE REACTIONS.)
If it is necessary to treat patients with severe hepatic impairment, caution is advised and administration should be closely monitored.
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 () .
In the dapsone comparative study of Mepron () Suspension, adverse experience data were collected only for treatment-limiting events. Among the entire population (n = 1,057), 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 (
Table 7 summarizes the clinical adverse experiences reported by ≥20% 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 1,500 mg Mepron () Suspension once daily (25%, ≤0.001) or 750 mg Mepron () Suspension once daily (16%, = 0.004). The most common adverse experiences requiring discontinuation of dosing in the group receiving 1,500 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 ≥10% of the patients receiving the recommended dose of Mepron () included sweating, flu syndrome, pain, sinusitis, pruritus, insomnia, depression, and myalgia. Bronchospasm occurred more frequently in patients receiving aerosolized pentamidine (11%) than in patients receiving Mepron () 1,500 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.
Table 8 summarizes all the clinical adverse experiences reported by ≥5% 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 1 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 1 patient was vomiting (
Laboratory test abnormalities reported for ≥5% 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 ≥5% 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 (
Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 11. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 patients who received Mepron () . One patient (1%) had elevated creatinine and BUN levels and 1 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.
Mepron () Suspension (bright yellow, citrus flavored) containing 750 mg atovaquone in each teaspoonful (5 mL).
Bottle of 210 mL with child-resistant cap (NDC 0173-0665-18).
5-mL child-resistant foil pouch - unit dose pack of 42 (NDC 0173-0547-00).
GlaxoSmithKline
Research Triangle Park, NC 27709
©2008, GlaxoSmithKline. All rights reserved.
May 2008 MPR:1PI
