MEPRON SUMMARY
MEPRON (atovaquone) is an antiprotozoal agent.
MEPRON Suspension is indicated for the prevention of Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX).
MEPRON Suspension is also indicated for the acute oral treatment of mild-to-moderate PCP in patients who are intolerant to TMP-SMX.
Prevention of PCP
The indication for prevention of PCP is based on the results of 2Â clinical trials comparing MEPRON Suspension to dapsone or aerosolized pentamidine in HIV-infected adult and adolescent patients at risk of PCP (CD4 count <200Â cells/mm3 or a prior episode of PCP) and intolerant to TMP-SMX.
Dapsone Comparative Study
This randomized, open-label trial enrolled a total of 1,057 patients at 48 study centers. Patients were randomized to receive 1,500 mg MEPRON Suspension once daily (n = 536) or 100 mg dapsone once daily (n = 521). Median follow-up was 24 months. Patients randomized to the dapsone arm who were seropositive for Toxoplasma gondii and had a CD4 count <100 cells/mm3 also received pyrimethamine and folinic acid. PCP event rates are shown in Table 3. There was no significant difference in mortality rates between the groups.
Aerosolized Pentamidine Comparative Study
This randomized, open-label trial enrolled a total of 549 patients at 35 study centers. Patients were randomized to receive 1,500 mg MEPRON Suspension once daily (n = 175), 750 mg MEPRON Suspension once daily (n = 188), or 300 mg aerosolized pentamidine once monthly (n = 186). Median follow-up was 11.3 months. The results of the PCP event rates appear in Table 3. There were no significant differences in mortality rates among the groups.
Table 3. Confirmed or Presumed/Probable PCP Events(As-Treated Analysis)*
| Assessment |
Study 115-211 |
Study 115-213 |
|
Atovaquone
1,500Â mg/day
(n = 527) |
Dapsone
100Â mg/day
(n = 510) |
Atovaquone
750Â mg/day
(n = 188) |
Atovaquone
1,500Â mg/day
(n = 172) |
Aerosolized
Pentamidine
300Â mg/month
(n = 169) |
| % |
15% |
19% |
23% |
18% |
17% |
|
Relative Risk†
(CI)‡
|
0.77
(0.57, 1.04) |
|
1.47
(0.86, 2.50) |
1.14
(0.63, 2.06) |
|
*Â Â Those events occurring during or within 30Â days of stopping assigned treatment.
†  Relative risk <1 favors atovaquone and values >1 favor comparator. These trials were designed to show superiority of atovaquone to the comparator. This was not shown.
‡  The confidence level of the interval for the dapsone comparative study was 95% and for the pentamidine comparative study was 97.5%.
An analysis of all PCP events (intent-to-treat analysis) showed results similar to those above.
Treatment of PCP
The indication for treatment of mild-to-moderate PCP is based on the results of comparative pharmacokinetic studies of the suspension and tablet formulations (see CLINICAL PHARMACOLOGY) and clinical efficacy studies of the tablet formulation which established a relationship between plasma atovaquone concentration and successful treatment. 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≤45Â mm Hg and PaO2≥60Â mm Hg on room air) and a randomized trial comparing MEPRON to IV pentamidine isethionate in patients with mild-to-moderate PCP intolerant to trimethoprim or sulfa-antimicrobials 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 408Â patients were enrolled into the trial at 37Â study centers. Eighty-six patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322Â patients with histologically confirmed PCP, 160 were randomized to receive MEPRON and 162 to TMP-SMX.
Study participants randomized to treatment with MEPRON were to receive 750Â mg MEPRON (three 250-mg tablets) 3 times daily for 21Â days and those randomized to TMP-SMX were to receive 320Â mg TMP plus 1,600Â mg SMX 3 times daily for 21Â days.
Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4Â 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 =Â 0.03) in mortality rates between the treatment groups. Among the 322Â patients with confirmed PCP, 13 of 160Â (8%) patients treated with MEPRON and 4 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 408Â randomized patients, there were 16Â (8%) deaths in the arm treated with MEPRON and 7 (3.4%) deaths in the TMP-SMX arm (P =Â 0.051). Of the 13Â patients treated with MEPRON who died, 4 died of PCP and 5Â died with a combination of bacterial infections and PCP; bacterial infections did not appear to be a factor in any of the 4Â 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 plasma atovaquone concentration data are available, 5 (63%) of the 8 patients with concentrations <5 mcg/mL died during participation in the study. However, only 1 (2.0%) of the 49 patients with day 4 plasma atovaquone concentrations ≥5 mcg/mL died.
Sixty-two percent of patients on MEPRON and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes (Table 4).
Table 4. Outcome of Treatment for PCP-Positive Patients Enrolled in the TMP-SMX Comparative Study
|
|
Number of Patients
(% of Total) |
|
| Outcome of Therapy*
|
MEPRON
(n = 160) |
TMP-SMX
(n = 162) |
P
Value |
| Therapy success |
99 |
(62%) |
103 |
(64%) |
0.75 |
| Therapy failure |
|
|
|
|
|
| Â Â -Lack of response |
28 |
(17%) |
10 |
(6%) |
<0.01 |
| Â Â -Adverse experience |
11 |
(7%) |
33 |
(20%) |
<0.01 |
| Â Â -Unevaluable |
22 |
(14%) |
16 |
(10%) |
0.28 |
| Required alternate PCP therapy during study |
55 |
(34%) |
55 |
(34%) |
0.95 |
*Â Â As defined by the protocol and described in study description above.
The failure rate due to lack of response was significantly larger for patients receiving MEPRON while the failure rate due to adverse experiences was significantly larger for patients receiving TMP-SMX.
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 unblinded, 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 either 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 750Â mg atovaquone (three 250-mg tablets) 3 times daily for 21Â days and those randomized to pentamidine isethionate were to receive a 3- to 4-mg/kg single IV infusion daily for 21Â days.
A total of 174Â patients were enrolled into the trial at 22Â study centers. Thirty-nine patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135Â 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 9 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 arm treated with MEPRON and 12 (14%) deaths in the pentamidine arm. For those patients for whom day 4 plasma atovaquone concentrations are available, 3 of 5 (60%) patients with concentrations <5 mcg/mL died during participation in the study. However, only 2 of 21 (9%) patients with day 4 plasma concentrations ≥5 mcg/mL died.
The therapeutic outcomes for the 134 patients who received study medication in this trial are presented in Table 5.
Table 5. Outcome of Treatment for PCP-Positive Patients Enrolled in the Pentamidine Comparative Study
|
| Primary Treatment |
| Salvage Treatment |
|
| Outcome of Therapy |
MEPRON
(n = 56) |
Pentamidine
(n = 53) |
P Value |
MEPRON
(n = 14) |
Pentamidine
(n = 11) |
P Value |
| Therapy success |
32 |
(57%) |
21 |
(40%) |
0.09 |
13 |
(93%) |
7 |
(64%) |
0.14 |
| Therapy failure |
|
|
|
|
|
|
|
|
|
|
| Â Â -Lack of response |
16 |
(29%) |
9 |
(17%) |
0.18 |
0 |
| 0 |
| — |
| Â Â -Adverse experience |
2 |
(3.6%) |
19 |
(36%) |
<0.01 |
0 |
| 3 |
(27%) |
0.07 |
| Â Â -Unevaluable |
6 |
(11%) |
4 |
(8%) |
0.75 |
1 |
(7%) |
1 |
(9%) |
1.00 |
| Required alternate PCP therapy during study |
19 |
(34%) |
29 |
(55%) |
0.04 |
0 |
| 4 |
(36%) |
0.03 |
|
