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Mepron (Atovaquone) - Summary

 
 



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 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)*
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 Risk†

(CI)‡

0.77

(0.57, 1.04)

1.47

(0.86, 2.50)

1.14

(0.63, 2.06)

*  Those events occurring during or within 30 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≤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

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
  -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

*  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 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
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
  -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

See all Mepron indications & dosage >>

NEWS HIGHLIGHTS

Published Studies Related to Mepron (Atovaquone)

Prolonged Protection Provided by a Single Dose of Atovaquone-Proguanil for the Chemoprophylaxis of Plasmodium falciparum Malaria in a Human Challenge Model. [2011.11.03]
Background. We conducted a randomized, placebo-controlled, double-blind trial to establish the efficacy of atovaquone-proguanil to prevent malaria with the goal of simulating weekly dosing in a human Plasmodium falciparum challenge model.Methods.Postexposure prophylaxis 4 days after challenge was 100% effective.

Efficacy of atovaquone and azithromycin or imidocarb dipropionate in cats with acute cytauxzoonosis. [2011.01]
BACKGROUND: Imidocarb or a combination of atovaquone and azithromycin (A&A) has been suggested for treatment of cats with cytauxzoonosis, but neither has been prospectively evaluated for efficacy. HYPOTHESIS/OBJECTIVES: That survival to hospital discharge is improved by treatment with A&A as compared with imidocarb...

Malaria treatment with atovaquone-proguanil in malaria-immune adults: implications for malaria intervention trials and for pre-exposure prophylaxis of malaria. [2008.04]
Eighty adults in areas of Kenya where malaria is holoendemic received presumptive treatment with atovaquone-proguanil and were followed closely. The time to the first Plasmodium falciparum parasitemia was 32 days.This prolonged prophylaxis period has implications for study design when used in malaria intervention trials and cautiously suggests clinical investigation of potential preexposure prophylaxis of malaria.

Atovaquone plus cholestyramine in patients coinfected with Babesia microti and Borrelia burgdorferi refractory to other treatment. [2006.01]
Ten percent of US patients with Lyme disease are coinfected with Babesia microti. A double-blind, placebo-controlled, crossover trial enrolled 25 patients with confirmed Borrelia burgdorferi/B microti coinfection, abnormal visual contrast sensitivity (VCS), and persistent symptoms despite prior treatment with atovaquone and azithromycin...

Atovaquone-proguanil for treating uncomplicated malaria. [2005.10.19]
CONCLUSIONS: Data are limited but appear to suggest that atovaquone-proguanil is more effective than chloroquine, amodiaquine, and mefloquine. There are insufficient data for comparisons against sulfadoxine-pyrimethamine, halofantrine, artesunate plus mefloquine, quinine plus tetracycline, and dihydroartemisinin-piperaquine-trimethoprim-primaquine in treating malaria. There are not enough data to assess safety, but a number of adverse events were identified with all drugs. Large trials comparing atovaquone-proguanil with other new combination therapies are needed.

more studies >>

Clinical Trials Related to Mepron (Atovaquone)

Single Oral Dose Study of Atovaquone/Proguanil Hydrochloride Combination Tablets and Atovaquone Suspension [Completed]
This study will be a single-center, phase I, randomized, open, in fed condition, parallel, single dose study to evaluate the pharmacokinetics and the safety, tolerability of Atovaquone/proguanil combination tablets and atovaquone suspension in Japanese healthy male subjects. Serial blood samples will be collected for the determination of the plasma concentration of atovaquone, proguanil and cycloguanil after dosing of atovaquone 1000mg/proguanil 400 mg and the plasma atovaquone concentration of atovaquone 750 and 1500 mg. Safety assessments will be performed for each treatment group. CYP2C19 contribute to proguanil metabolism. CYP2C19 genotype will be determined in atovaquone/proguanil dosing group.

The ASAP Study - Therapeutic Efficacy of Atovaquone-proguanil vs. Artesunate-atovaquone-proguanil in Cambodia [Recruiting]
This is a two-arm, randomized, open label Treatment Study evaluating the therapeutic efficacy, safety, tolerability and pharmacokinetics of a three-day course of Atovaquone-Proguanil (AP) or a three-day course of Atovaquone-Proguanil combined with 3 days of Artesunate (ASAP) in patients with uncomplicated Plasmodium falciparum malaria at selected sites in Cambodia. Atovaquone-proguanil, soon to adopted as a first line antimalarial agent by the National Malaria Control Program (CNM) in Cambodia in provinces with confirmed multidrug resistance, will be given with or without artesunate (AS) as a directly observed, standard three-day fixed dose combination treatment to all volunteers enrolled. The efficacy and safety of both drug combination as well as evidence for in vivo and in vitro resistance to their components will be monitored during the treatment period. All volunteers will receive a single dose of 15mg of primaquine as recommended by WHO with the first dose of AP or ASAP to block the transmission of malaria to mosquitoes. Resistance to AP and ASAP will be assessed by a combination of clinical, pharmacologic, and parasitological parameters including genomic signatures of selection during careful weekly follow-up visits for 6 weeks. Investigators will also be able to evaluate the effects of primaquine on the sexual stages of malaria (gametocytes).

Weekly Dosing of Malarone � for Prevention of Malaria [Completed]
The purpose of this study is to determine whether Malarone , which is a drug approved to prevent malaria when taken daily, will still effectively prevent malaria if taken weekly.

Antiretroviral Drug Interaction Study in Volunteers With HIV [Completed]
Background:

- People who are infected with the human immunodeficiency virus (HIV) are at risk of getting

certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain infection called toxoplasmosis. Most people with HIV take antiretroviral (ARV) drugs to treat HIV and lower the risk of infections. However, some ARV drugs may make other drugs used to treat PCP and toxoplasmosis less effective. Researchers want to test specific ARV drugs to see if they affect atovaquone, a drug used to treat PCP and toxoplasmosis. Objectives:

- To see if ARV drugs atazanavir-ritonavir or efavirenz lower the blood levels of

atovaquone. Eligibility:

- Individuals between 18 and 70 years of age who have HIV.

- Participants must be taking efavirenz or atazanavir-ritonavir, or not taking any ARV

drugs. Design:

- Participants will be screened with a physical exam and medical history. They will also

have blood and urine tests.

- This study has a screening visit and five study visits. Two of the study visits will

last about 12 hours; the other three visits will last about 1 hour each.

- Participants will receive either a low dose or high dose of atovaquone to take for 14

days. They will record doses and any symptoms on a diary card at home.

- After 14 days, participants will have a 12-hour visit to provide blood samples. There

will be a wash-out period with no doses for up to 6 weeks.

- After the wash-out period, participants will switch dose levels to either the high or

low dose.

- After 14 days, participants will have a 12-hour visit to provide blood samples.

Phase II Randomized Open-Label Trial of Atovaquone Plus Pyrimethamine and Atovaquone Plus Sulfadiazine for the Treatment of Acute Toxoplasmic Encephalitis [Completed]
To evaluate the efficacy, safety, and tolerance of atovaquone with either pyrimethamine or sulfadiazine in AIDS patients with toxoplasmic encephalitis. AIDS patients with toxoplasmic encephalitis who receive the standard therapy combination of sulfadiazine and pyrimethamine experience a high frequency of severe toxicity. Atovaquone, an antibiotic that has demonstrated efficacy against toxoplasmosis in animal models and in preclinical testing has been well tolerated, is now available as a suspension, which is more readily absorbed than the tablet form of the drug. The efficacy and safety of atovaquone in combination with sulfadiazine or pyrimethamine will be studied.

more trials >>

Reports of Suspected Mepron (Atovaquone) Side Effects

Chest Pain (5)Pericardial Effusion (4)Death (4)Myalgia (4)Neck Pain (4)Product Quality Issue (4)Pain in Extremity (4)Abdominal Pain (2)Drug Ineffective (2)Abdominal Pain Upper (2)more >>


Page last updated: 2011-12-09

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