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Mepron

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Mepron

Indications
Dosage
How Supplied

INDICATIONS

MEPRON Suspension is indicated for the prevention of Pneumocystis jiroveci 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 2 clinical trials comparing MEPRON Suspension to dapsone or aerosolized pentamidine in HIV-infected adult and adolescent patients at risk of PCP (CD4 count < 200 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)a

Assessment Study 115-211 Study 115-213
Atovaquone 1,500 mg/day
(n = 527)
Dapsone 100 mg/day
(n = 510)
Atovaquone 750 mg/day
(n = 188)
Atovaquone 1,500 mg/day
(n = 172)
Aerosolized Pentamidine 300 mg/month
(n = 169)
% 15 19 23 18 17
Relative Riskb (CI)c 0.77
(0.57, 1.04)
  1.47
(0.86, 2.50)
1.14
(0.63, 2.06)
 
aThose events occurring during or within 30 days of stopping assigned treatment.
bRelative 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.
cThe 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 ≤ 45 mm Hg and PaO2 ≥ 60 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 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 treatment with MEPRON were to receive 750 mg MEPRON (three 250-mg tablets) 3 times daily for 21 days and those randomized to TMP-SMX were to receive 320 mg TMP plus 1,600 mg SMX 3 times daily for 21 days.

Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4 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 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 408 randomized patients, there were 16 (8%) deaths in the arm treated with MEPRON and 7 (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 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

Outcome of Therapya Number of Patients (% of Total) P Value
MEPRON
(n = 160)
TMP-SM
X (n = 162)
Therapy success 99 -62 103 -64 0.75
Therapy failure
-Lack of response 28 (17) 10 (6) < 0.01
-Adverse experience 11 (7) 33 (20) < 0.01
-Unevaluable 22 (14) 16 (10) 0.28
Required alternate PCP therapy during study 55 -34 55 -34 0.95
aAs 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 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to pentamidine isethionate were to receive a 3- to 4-mg/kg single IV infusion daily for 21 days.

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 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

Outcome of Therapy Primary Treatment P Value Salvage Treatment P Value
MEPRON
(n = 56)
Pentamidine
(n = 53)
MEPRON
(n = 14)
Pentamidine
(n = 11)
Therapy success 32 -57% 21 -40% 0.09 13 -93% 7 -64% 0.14
Therapy failure
-Lack of response 16 (29%) 9 (17%) 0.18 0 0
-Adverse experience 2 (3.6%) 19 (36%) < 0.01 0 3 (27%) 0.07
-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

1(A-a)DO2 = [(713 x FiO2 ) – (PaCO2/0.8)] – PaO2 (mm Hg)

DOSAGE AND ADMINISTRATION

Dosage

Prevention of PCP: Adults and Adolescents (13 to 16 Years): The recommended oral dose is 1,500 mg (10 mL) once daily administered with a meal.

Treatment of Mild-to-Moderate PCP: Adults and Adolescents (13 to 16 Years): The recommended oral dose is 750 mg (5 mL) administered with meals twice daily for 21 days (total daily dose 1,500 mg).

Note: Failure to administer MEPRON Suspension with meals may result in lower plasma atovaquone concentrations and may limit response to therapy (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

Administration: Foil Pouch: Open pouch by removing tab at perforation and tear at notch. Take entire contents by mouth. Can be discharged into a dosing spoon or cup or directly into the mouth.

Bottle: SHAKE BOTTLE GENTLY BEFORE USING.

HOW SUPPLIED

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).

Store at 15° to 25°C (59° to 77°F). DO NOT FREEZE. Dispense in tight container as defined in USP.

5-mL child-resistant foil pouch - unit dose pack of 42 (NDC 0173-0547-00).

Store at 15° to 25°C (59° to 77°F). DO NOT FREEZE.

GlaxoSmithKline Research Triangle Park, NC 27709. Revised: 03/2013

Last reviewed on RxList: 3/21/2013
This monograph has been modified to include the generic and brand name in many instances.

Indications
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