Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3112
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MEPRON (Suspension)
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Dosage:<br/>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.<br/>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).<br/>Administration:<br/>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.<br/>Bottle: SHAKE BOTTLE GENTLY BEFORE USING.
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dailymed-instance:descripti... |
MEPRON (atovaquone) is an antiprotozoal agent. The chemical
name of atovaquone is trans-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.
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Pharmacokinetics:<br/>Absorption: Atovaquone is a highly
lipophilic compound with low aqueous solubility. The bioavailability of atovaquone
is highly dependent on formulation and diet. The suspension formulation provides
an approximately 2-fold increase in atovaquone bioavailability in the fasting
or fed state compared to the previously marketed tablet formulation. The absolute
bioavailability of a 750-mg dose of MEPRON Suspension administered under fed
conditions in 9 HIV-infected (CD4>100 cells/mm) volunteers
was 47%��15%. In the same study, the bioavailability of a
750-mg dose of the previously marketed tablet formulation was 23%��11%. Administering
atovaquone with food enhances its absorption by approximately 2 fold.
In one study, 16 healthy volunteers received a single dose of 750 mg
MEPRON Suspension after an overnight fast and following a standard breakfast
(23 g fat: 610 kCal). The mean (��SD) area under the concentration-time
curve (AUC) values were 324��115 and 801��320 hr���mcg/mL
under fasting and fed conditions, respectively, representing a 2.6��1.0-fold
increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone
concentrations was also evaluated in a multiple-dose, randomized, crossover
study in 19 HIV-infected volunteers (CD4<200 cells/mm)
receiving daily doses of 500 mg MEPRON Suspension. AUC was 280��114 hr���mcg/mL
when atovaquone was administered with food as compared to 169��77 hr���mcg/mL
under fasting conditions. Maximum plasma atovaquone concentration (C)
was 15.1��6.1 and 8.8��3.7 mcg/mL when
atovaquone was administered with food and under fasting conditions, respectively.<br/>Dose Proportionality: Plasma atovaquone concentrations do not increase proportionally
with dose. When MEPRON Suspension was administered with food at dosage regimens
of 500 mg once daily, 750 mg once daily, and 1,000 mg once
daily, average steady-state plasma atovaquone concentrations were 11.7��4.8,
12.5��5.8, and 13.5��5.1 mcg/mL, respectively.
The corresponding Cconcentrations were 15.1��6.1,
15.3��7.6, and 16.8��6.4 mcg/mL. When
MEPRON Suspension was administered to 5 HIV-infected volunteers at a
dose of 750 mg twice daily, the average steady-state plasma atovaquone
concentration was 21.0��4.9 mcg/mL and Cwas
24.0��5.7 mcg/mL. The minimum plasma atovaquone concentration
(C) associated with the 750-mg twice-daily regimen was 16.7��4.6 mcg/mL.<br/>Distribution: Following the intravenous administration of atovaquone,
the volume of distribution at steady state (Vd) was 0.60��0.17 L/kg
(n = 9). Atovaquone is extensively bound to plasma proteins (99.9%)
over the concentration range of 1 to 90 mcg/mL. In 3 HIV-infected
children who received 750 mg atovaquone as the tablet formulation 4 times
daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone
were 0.04, 0.14, and 0.26 mcg/mL, representing less than 1% of the plasma
concentration.<br/>Elimination: The plasma clearance of atovaquone following intravenous
(IV) administration in 9 HIV-infected volunteers was 10.4��5.5 mL/min
(0.15��0.09 mL/min/kg). The half-life of atovaquone was
62.5��35.3 hours after IV administration and ranged from
67.0��33.4 to 77.6��23.1 hours across
studies following administration of MEPRON Suspension. The half-life of atovaquone
is long due to presumed enterohepatic cycling and eventual fecal elimination.
In a study whereC-labelled atovaquone was administered to healthy
volunteers, greater than 94% of the dose was recovered as unchanged atovaquone
in the feces over 21 days. There was little or no excretion of atovaquone
in the urine (less than 0.6%). There is indirect evidence that atovaquone
may undergo limited metabolism; however, a specific metabolite has not been
identified.<br/>Special Populations:<br/>Pediatrics: In a study of MEPRON
Suspension in 27 HIV-infected, asymptomatic infants and children between
1 month and 13 years of age, the pharmacokinetics of atovaquone
were age dependent. These patients were dosed once daily with food for 12 days.
The average steady-state plasma atovaquone concentrations in the 24 patients
with available concentration data are shown in Table 1.<br/>Hepatic/Renal Impairment: The pharmacokinetics of atovaquone have not been studied
in patients with hepatic or renal impairment.<br/>Drug Interactions:<br/>Rifampin: In a study with
13 HIV-infected volunteers, the oral administration of rifampin 600 mg
every 24 hours with MEPRON Suspension 750 mg every 12 hours
resulted in a 52%��13% decrease in the average steady-state
plasma atovaquone concentration and a 37%��42% increase in
the average steady-state plasma rifampin concentration. The half-life of atovaquone
decreased from 82��36 hours when administered without
rifampin to 50��16 hours with rifampin. 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.<br/>Trimethoprim/Sulfamethoxazole (TMP-SMX): The possible interaction between atovaquone and TMP-SMX
was evaluated in 6 HIV-infected adult
volunteers as part of a larger multiple-dose, dose-escalation, and chronic
dosing study of MEPRON Suspension. In this crossover study, MEPRON Suspension
500 mg once daily, or TMP-SMX tablets (160 mg trimethoprim and 800 mg
sulfamethoxazole) twice daily, or the combination were administered with food
to achieve steady state. No difference was observed in the average steady-state
plasma atovaquone concentration after coadministration with TMP-SMX. Coadministration
of MEPRON with TMP-SMX resulted in a 17% and 8% decrease in average steady-state
concentrations of trimethoprim and sulfamethoxazole in plasma, respectively.
This effect is minor and would not be expected to produce clinically significant
events.<br/>Zidovudine: Data from 14 HIV-infected volunteers who were given atovaquone
tablets 750 mg every 12 hours with zidovudine 200 mg every
8 hours showed a 24%��12% decrease in zidovudine apparent
oral clearance, leading to a 35%��23% increase in plasma zidovudine
AUC. The glucuronide metabolite:parent ratio decreased from a mean of 4.5
when zidovudine was administered alone to 3.1 when zidovudine was administered
with atovaquone tablets. This effect is minor and would not be expected to
produce clinically significant events. Zidovudine had no effect on atovaquone
pharmacokinetics.<br/>Relationship Between Plasma Atovaquone Concentration and Clinical Outcome: In a comparative study
of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate Pneumocystis carinii 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. * Successful treatment was defined
as improvement in clinical and respiratory measures persisting at least 4 weeks
after cessation of therapy. This was based on data from patients for which
both outcome and steady-state plasma atovaquone concentration data are available. Based on logistic regression analysis. 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).
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MEPRON Suspension is contraindicated for patients who develop
or have a history of potentially life-threatening allergic reactions to any
of the components of the formulation.
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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. (A-a)DO=
[(713 x FiO)���(PaCO/0.8)]���PaO(mm
Hg) GlaxoSmithKline Research Triangle
Park, NC 27709 ��2006, GlaxoSmithKline. All rights
reserved.
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dailymed-instance:precautio... |
General: 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. If it
is necessary to treat patients with severe hepatic impairment, caution is
advised and administration should be closely monitored.<br/>Information for Patients: The importance of taking the prescribed dose of MEPRON should
be stressed. Patients should be instructed to take their daily doses of MEPRON
with meals, as the presence of food will significantly improve the absorption
of the drug.<br/>Drug Interactions: 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.<br/>Drug/Laboratory Test Interactions: It is not known if MEPRON interferes with clinical laboratory
test or assay results.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in rats were negative; 24-month
studies in mice showed treatment-related increases in incidence of hepatocellular
adenoma and hepatocellular carcinoma at all doses tested which ranged from
1.4 to 3.6 times the average steady-state plasma concentrations in humans
during acute treatment of Pneumocystis cariniipneumonia. Atovaquone was negative with or without metabolic activation
in the Ames Salmonella mutagenicity
assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte
cytogenetic assay. No evidence of genotoxicity was observed in the in vivo
Mouse Micronucleus assay.<br/>Pregnancy: Pregnancy Category C. Atovaquone was not teratogenic and
did not cause reproductive toxicity in rats at plasma concentrations up to
2 to 3 times the estimated human exposure. Atovaquone caused maternal toxicity
in rabbits at plasma concentrations that were approximately one half the estimated
human exposure. Mean fetal body lengths and weights were decreased and there
were higher numbers of early resorption and post-implantation loss per dam.
It is not clear whether these effects were caused by atovaquone directly or
were secondary to maternal toxicity. Concentrations of atovaquone in rabbit
fetuses averaged 30% of the concurrent maternal plasma concentrations. In
a separate study in rats given a singleC-radiolabelled dose,
concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and
60% (late gestation) of concurrent maternal plasma concentrations. There are
no adequate and well-controlled studies in pregnant women. MEPRON should be
used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.<br/>Nursing Mothers: It is not known whether atovaquone is excreted into human
milk. Because many drugs are excreted into human milk, caution should be exercised
when MEPRON is administered to a nursing woman. In a rat study, atovaquone
concentrations in the milk were 30% of the concurrent atovaquone concentrations
in the maternal plasma.<br/>Pediatric Use: Evidence of safety and effectiveness in pediatric patients
has not been established. A relationship between plasma atovaquone concentrations
and successful treatment of PCP has been established in adults (see Table 2).
In a study of MEPRON Suspension in 27 HIV-infected, asymptomatic infants
and children between 1 month and 13 years of age, the pharmacokinetics
of atovaquone were age-dependent (see CLINICAL PHARMACOLOGY: Special Populations).
No drug-related treatment-limiting adverse events were observed in the pharmacokinetic
study.<br/>Geriatric Use: Clinical studies of MEPRON
did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly
and younger patients. In general, dose selection for an elderly patient should
be cautious,reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.
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There is no known antidote
for atovaquone, and it is currently unknown if atovaquone is dialyzable. The
median lethal dose is higher than the maximum oral dose tested in mice and
rats (1,825 mg/kg/day). Overdoses up to 31,500 mg of atovaquone
have been reported. In 1 such patient who also took an unspecified dose of
dapsone, methemoglobinemia occurred. Rash has also been reported after overdose.
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atovaquone
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MEPRON (Suspension)
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dailymed-instance:adverseRe... |
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.<br/>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 = 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
treatedwith MEPRON Suspension (P<0.001).In both populations, the type of treatment-limiting
events differed between the 2 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���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%, 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 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.<br/>PCP Treatment Studies: 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 toan 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 (<1%). The most common adverse experience
requiring discontinuation of dosing in the TMP-SMX group was rash (8%). 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 (P<0.001). Of the 5 patients who discontinued therapy with
MEPRON, 3 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���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.<br/>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.<br/>Blood and Lymphatic System Disorders: Methemoglobinemia, thrombocytopenia.<br/>Immune System Disorders: Hypersensitivity
reactions including angioedema, bronchospasm, and throat tightness.<br/>Eye Disorders: Vortex keratopathy. Gastrointestinal
Disorders: Pancreatitis. Skin
and Subcutaneous Tissue Disorders: Erythema multiforme. Renal and Urinary Disorders: Acute renal
impairment.
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Clinical experience with MEPRON for the treatment of PCP
has been limited to patients with mild-to-moderate PCP [(A-a)DO���45 mm
Hg]. Treatment of more severe episodes of PCP has not been systematically
studied with this agent. Also, the efficacy of MEPRON in patients who are
failing therapy with TMP-SMX has not been systematically studied.
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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.<br/>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/mmor
a prior episode of PCP) and intolerant to TMP-SMX.<br/>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/mmalso
received pyrimethamine and folinic acid. PCP event rates are shown in Table
3. There was no significant difference in mortality rates between the groups.<br/>Aerosolized Pentamidine Comparative Study: This randomized, open-label
trial enrolled a total of 549 patients at35
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. * 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.<br/>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)DO]���45 mm
Hg and PaO���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:<br/>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). * 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).<br/>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 atthe 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.
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MEPRON
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