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 C22H19ClO3.
Mepron tablets are for oral administration. Each film-coated tablet contains 250 mg of atovaquone and the inactive ingredients hydroxypropyl cellulose, hydroxypropyl methyl-cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, titanium dioxide, and yellow iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action:Atovaquone is a hydroxyl-1,4-naphthoquinone, an analog of ubiquinone, with anti-pneumocystis activity. The mechanism of action against P .carinii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis.
Microbiology:
Pneumocystis carinii: Several laboratories, using different in vitro methodologies, have shown the IC50 (50% Inhibitory Concentration) of atovaquone against rat P. carinii to be in the range of 0.1 to 3.0 μg/mL.
Pharmacokinetics:
Atovaquone is a highly lipophilic compound with a low aqueous solubility. Pharmacokinetic and bioavailability studies indicate that the bioavailability of the drug is low, variable, and decreases significantly with single doses above 750 mg. Following single-dose administration of Mepron to fasted normal volunteers, the atovaquone plasma concentration-time profile displayed a distinct double-peak, with the first peak occurring between 1 and 8 hours after dosing and the second peak occurring 24 to 96 hours post-dose. This double-peak profile is suggestive of enterohepatic cycling, whereby drug in the systemic circulation is excreted into the bile and is subsequently reabsorbed.
The bioavailability of Mepron is increased approximately 3-fold when administered with meals. In particular, fat has been shown to enhance absorption significantly. In one study, 18 volunteers received a single dose of 500 mg Mepron after an overnight fast and following a breakfast (23 g fat: 642 kCal). The mean (±SD) AUC values were 93.8±45.7 and 288±77 hr μg/mL, under fasting and fed conditions, respectively. In another volunteer study where Mepron was administered under fasting conditions, with 28 g butter (23 g fat) and 56 g butter (46 g fat) on toast, mean AUC values increased 2.7- and 4.0-fold, respectively, compared to the fasting state. Significant difference in the bioavailability of Mepron have been observed between normal volunteers or HIV-seropositive asymptomatic volunteers and AIDS patients. Steady-state atovaquone plasma concentrations in the AIDS patients are about one-third to one-half the levels achieved in the asymptomatic HIV-infected volunteers. The reasons for this difference are not clear.
Atovaquone has a long half-life in normal volunteers (2.9±0.8 days; n=27) and in AIDS patients (2.2±0.6 days; n=14), due to presumed enterohepatic cycling and eventual fecal elimination. In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is no evidence that the drug is metabolized in man. Atovaquone is extensively bound to plasma proteins (>99.9%). In vitro binding interaction studies with phenytoin (15 μg/mL) did not show mutual displacement from binding proteins.
During a multiple-dose study of Mepron administered with food in cohorts of 4 HIV-seropositive asymptomatic volunteers, dose-proportionality was demonstrated for dosage regimens of 100 to 750 mg once daily. However, at does above 750 mg once daily with food, the relative oral bioavailability decreased. The maximum dose tested, 3000 mg once daily, produced a mean ± SD steady-state average plasma concentration of 40.0 ± 19.0 μg/mL compared to 26.9±10.0 μg/mL in volunteers receiving 750 mg once daily. In a multiple-dose escalation study (Table 1) conducted in volunteers with AIDS, where a single cohort of 15 individuals received 15- to 17-day consecutive courses of Mepron administered with food at regimens of 750, 1500, 3000 mg once daily, 750 mg twice daily, and 1500 mg twice daily, the lack of dose proportionality was also demonstrated; however, there was a modest increase in concentrations with increasing total daily dose. Altering dose intervals without changing total daily dose did not affect concentrations. In this study, the Cmax/Cmin concentration ratio values were low; approximately 1.5, and independent of the dosage regimen.
Table 1 Atovaquone AUC Values and Plasma Concentrations in Volunteers with AIDS*
|
Once Daily with Food
|
|
750 mg
(n = 15)
|
1500 mg
(n = 15)
|
3000 mg
(n = 14)
|
Steady-State AUC (hr μg/mL)
|
181±84
|
253±126
|
322±135
|
Steady-State Average Concentrations (μg/mL)
|
7.5±3.5
|
10.6±5.3
|
13.4±5.6
|
|
|
|
|
|
|
|
|
|
Twice Daily with Food
|
|
750 mg
(n = 12)
|
1500 mg
(n = 13)
|
|
Steady-State AUC (hr μg/mL)
|
231±59
|
314±109
|
|
Steady-State Average Concentrations (μg/mL)
|
9.6±2.5
|
13.1±4.5
|
|
*Mean±SD
In the controlled efficacy trials for the treatment of PCP where AIDS patients received 750 mg Mepron three times daily, the mean steady-state atovaquone concentration was 13.9±6.8 μg/mL (n+191).
In a human study where volunteers received Mepron at a dose of 750 mg four times daily for two weeks, the cerebrospinal fluid levels in three volunteers were 0.04 μg/mL, 0.14 μg/mL and 0.26 μg/mL. The corresponding CSF/plasma ratios were less than 1%.
The pharmacokinetics of atovaquone have been evaluated in 10 immunocompromised children (age: 5 months to 13 years; weight: 3.5 to 8.5 kg). The mean half-life was 2.7±1.6 days. A dosage regimen of 10 mg/kg once daily achieved a steady-state average concentration of 7.5±4.6 μg/mL (range 2.5 to 15.2 μg/mL). For 3 of these children who also received a dosage regimen of 40 mg/kg once daily, a steady-state average concentration of 14.0±2.2 μg/mL (range 10.9 to 15.6 μg/mL) was achieved.
The pharmacokinetics of Mepron has not been studied in patients with hepatic or renal impairment.
INDICATIONS AND USAGE
Mepron is indicated for the acute oral treatment of mild to moderate Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX).
This indication is based on 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 mmHg and PaO2≥ 60 mmHg on room air) and a randomized trial comparing Mepron to intravenous pentamidine isethionate in patients with mild to moderate PCP intolerant to trimethoprim or sulfa-antimicrobials. These studies 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 Mepron treatment were to receive 750 mg Mepron (three 250 mg tablets) three times daily for 21 days and those randomized to TMP-SMX were to receive 320 mg TMP plus 1600 mg SMX three times daily for 21 days.
Therapy success was defined as improvement in clinical and respiratory measures persisting at least four 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 four 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 Mepron arm and sever (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 atovaquone plasma concentrations data are available, 5 (63%) of the 8 patients with concentration<5 μg/mL died during participation in the study. However, only 1 (2.0%) of the 49 patients with day 4 plasma concentration ≥ 5μg/mL died. (See Table 2)
The failure rate due to lack of response was significantly larger for Mepron patients while the failure rate due to adverse experiences was significantly larger for TMP-SMX patients.
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 unblended, 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 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) three times daily for 21 days and those randomized to pentamidine isethionate were to receive a 3 to 4 mg/kg single intravenous infusion daily for 21 days.
Table 2 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.
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 nine 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 Mepron arm and 12 (14%) deaths in the pentamidine arm. For those patients for whom day 4 atovaquone plasma concentration are available, 3 of 5 (60%) patients with concentrations <5 μg/mL died during participation in the study. However, only 2 of 21 (9%) patients with day 4 plasma concentrations ≥5 μg/mL died.
The therapeutic outcomes for the 134 patients who received study medication in this trial are presented in Table 3.
Data on Chronic Use:
Mepron has not been systematically evaluated as a chronic suppressive agent to prevent the development of PCP in patients at high risk for Pneumocystis carinii disease. In a pilot dosing study of Mepron in AIDS patients, 5 of 31 patients had PCP breakthroughs: one patient at 750 mg once daily (after 20 days), three patients at 750 mg twice daily (after 14, 70, and 97 days), and one patient at 1500 mg twice daily (after 74 days). The dose used in the acute treatment studies (750 mg three times daily) was not studied and, therefore, there are no data on the rate of breakthrough at this dose.
CONTRAINDICATIONS
Mepron tablets are contraindicated for patients who develop or have a history of potentially life-threatening allergic reactions to any of the components of the formulation.
WARNINGS
Clinical experience with Mepron has been limited to patients with mild to moderate PCP [(A-a)DO2≤ 45 mmHg]. 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. Mepron has not been evaluated as an agent for PCP prophylaxis.
PRECAUTIONS
General
Absorption of orally administered Mepron is limited but can be significantly increased when the drug is taken with food. Mepron plasma 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.
Table 3 Outcome of Treatment for PCP-Positive Patients Enrolled in the Pentamidine Comparative Study
|
Primary Treatment
|
|
Outcome of
Therapy
|
Mepron
(n = 56)
|
Pentamidine
(n = 53)
|
P Value
|
Therapy
Success
|
32 (57%)
|
21 (40%)
|
0.09
|
Therapy Failure
- Lack of
Response
|
16 (29%)
|
9 (17%)
|
0.18
|
- Adverse
Experience
|
2 (3.6%)
|
19 (36%)
|
<0.01
|
- Unevaluable
|
6 (11%)
|
4 (8%)
|
0.75
|
Required Alternate
PCP Therapy During Study
|
19 (34%)
|
29 (55%)
|
0.04
|
|
|
|
|
|
|
|
|
|
Salvage Treatment
|
|
Outcome of
Therapy
|
Mepron
(n = 14)
|
Pentamidine
(n = 11)
|
P Value
|
Therapy
Success
|
13 (93%)
|
7 (64%)
|
0.14
|
Therapy Failure
- Lack of
Response
|
0
|
0
|
--
|
Adverse Experience
|
0
|
3 (27%)
|
0.07
|
- Unevaluable
|
1 (7%)
|
1 (9%)
|
1.00
|
Required
Alternate
PCP Therapy
During Study
|
0
|
4(36%)
|
0.03
|
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.
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 concentration of phenytoin (15 μg/mL), nor is the binding of phenytoin affected by the presence of atovaquone.
Drug/Laboratory Test Interactions
It is not known Mepron interferes with clinical laboratory test or assay results.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenicity studies in rats and mice have not been completed. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Culture Human Lymphocyte cytogenetic assay. No evidence of gene(?) toxicity was observed in the in vivo Mouse Micronucleus(?) assay.
Pregnancy
Pregnancy Category C. Atovaquone was not teratogenic and did not cause reproductive toxicity in rats in plasma concentrations up to 5 times the estimated human exposure. Atovaquone caused maternal toxicity in rabbit (?) plasma concentrations that were approximately equal to the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers (?) early resorption and post-implantation loss per dam. It is not clear whether these effects were caused by atovaquone 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 single 14C-radiolabelled dose, concentrations of (?) carbon in rat fetuses were 18% (middle gestation) and (?)% (late gestation) of concurrent maternal plasma concentrations. Thee are no adequate and well-controlled studies in pregnant women. Atovaquone should be used during pregnancy only if the potential benefit justifies the potential (?) to the fetus.
Nursing Mothers
It is not known whether Mepron is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised (?)
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.
Pediatric Use
there are no efficacy studies in children. Clinical experience with Mepron has not been systematically evaluated in patients greater than 65 years of age. Caution should be exercised when treating elderly patients reflecting the greater frequency of decreased hepatic, renal and cardiac function in this population.
ADVERSE REACTIONS
Because many patients who participated in clinical trials with Mepron had complications of advance 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.
Table 4 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. (See Table 4.)
Although an equal percentage of patients receiving Mepron and TMP-SMX reported at least one adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Nine percent of patients receiving Mepron were prematurely discontinued from therapy due to an adverse event versus 24% of patients receiving TMP-SMX. 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 Mepron dosing by more than one patient was the development of vomiting (<1%). Twenty-four percent of patients receiving TMP-SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving Mepron. The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%).
Table 4 Treatment-Emergent Adverse Experiences in the TMP-SMX Comparative PCP Treatment Study
Treatment-
Emergent
Adverse
Experience
|
Number of Patients with Treatment-Emergent Adverse Experience ((%) of Total)
|
|
Mepron
(n = 203)
|
TMP-SMX
(n = 205)
|
Rash (including
maculopapular)
|
47 (23%)
|
69 (34%)*
|
Nausea
|
43 (21%)
|
90 (44%)*
|
Diarrhea
|
39 (19%)
|
15 (7%)
|
Headache
|
33 (16%)
|
44 (22%)
|
Vomiting
|
29 (14%)
|
72 (35%)*
|
Fever
|
28 (14%)
|
52 (25%)*
|
Insomnia
|
20 (10%)
|
18 (9%)
|
Asthenia
|
17 (8%)
|
16 (8%)
|
Pruritus
|
11 (5%)
|
18 (9%)
|
Monilia, Oral
|
11 (5%)
|
21 (10%)
|
Abdominal Pain
|
9 (4%)
|
15 (7%)
|
Constipation
|
7 (3%)
|
35 (17%)*
|
Dizziness
|
7 (3%)
|
17 (8%)*
|
No. Patients
Discontinuing
Therapy due
to an Adverse
Experience
|
19 (9%)
|
50 (24%)*
|
No. Patients
Reporting at
least one Adverse
Experience
|
127 (63%)
|
134 (65%)
|
*P=<0.05
Laboratory test abnormalities reported for ≥5% of the study population during the treatment period are summarized in Table 5. 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 treat with TMP-SMX. (See Table 5) Table 6 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 five patients who discontinued therapy with Mepron, three 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%). (See Table 6)
Table 5 Treatment-Emergent Laboratory Test Abnormalities in the TMP-SMX Comparative PCP Treatment Study
Laboratory Test Abnormality
|
Patients Developing a Laboratory Test Abnormality
(%) of Total
|
Mepron
|
TMP/SMX
|
Anemia (Hgb < 8.0 gm/dL)
|
6%
|
7%
|
Neutropenia
(ANC <750 c/mm3
|
3%
|
9%
|
Elevated ALT (>5 X ULN)
|
6%
|
16%
|
Elevated AST (>5 X ULN)
|
4%
|
14%
|
Elevated Alkaline Phosphatase (>2.5 X ULN)
|
8%
|
6%
|
Elevated Amylase
(>1.5 X ULN)
|
7%
|
12%
|
Hyponatremia (<0.96 X LLN)
|
7%
|
26%
|
ULN = upper limit of normal range
LLN = lower limit of normal range
Table 6 Treatment-Emergent Adverse Experiences in the Pentamidine Comparative PCP Treatment Study (Primary Therapy Group)
Treatment-
Emergent
Adverse
Experience
|
Number of Patients with
Treatment-Emergent
Adverse Experience (%) of Total
|
Mepron
(n = 73)
|
TMP-SMX
(n = 71)
|
Fever
|
29(40%)
|
18(25%)
|
Nausea
|
16(22%)
|
26(37%)
|
Rash
|
16(22%)
|
9(13%)
|
Diarrhea
|
15(21%)
|
22(31%)
|
Insomnia
|
14(19%)
|
10(14%)
|
Headache
|
13(18%)
|
20(28%)
|
Vomiting
|
10(14%)
|
12(17%)
|
Cough
|
10(14%)
|
1(1%)
|
Abdominal Pain
|
7(10%)
|
8(11%)
|
Pain
|
7(10%)
|
7(10%)
|
Sweat
|
7(10%)
|
2(3%)
|
Monilia, Oral
|
7(10%)
|
2(3%)
|
Asthenia
|
6(8%)
|
10(14%)
|
Dizziness
|
6(8%)
|
10(14%)
|
Anxiety
|
5(7%)
|
7(10%)
|
Anorexia
|
5(7%)
|
7(10%)
|
Sinusitis
|
5(7%)
|
4(6%)
|
Dyspepsia
|
4(5%)
|
7(10%)
|
Rhinitis
|
4(5%)
|
5(7%)
|
Taste Perversion
|
2(3%)
|
9(13%)*
|
Hypoglycemia
|
1(1%)
|
11(15%)*
|
Hypotension
|
1(1%)
|
7(10%)
|
No. Patients
Discontinuing
Therapy due
to an Adverse
Experience
|
5(7%)
|
29(41%)†
|
No. Patients
Reporting at
least one Adverse
Experience
|
46(63%)
|
51(72%)
|
* P =< 0.05
†P = < 0.001
Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 7. Laboratory abnormality was reported as the reason for discontinuation of treatment in two of 73 patients who received Mepron. One patient (1%) had elevated creatinine and BUN levels and one 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 leucopenia (4%).
Table 7 Treatment-Emergent Laboratory Test Abnormalities in the Pentamidine Comparative PCP Treatment Study
Laboratory Test Abnormality
|
Patients Developing a
Laboratory Test
Abnormality (%) of Total)
|
Mepron
|
Pentamidine
|
Anemia (Hgb < 8.0 gm/dL)
|
4%
|
9%
|
Neutropenia
(ANC <750 cells/mm3)
|
5%
|
9%
|
Hyponatremia
(<0.96 X LLN)
|
10%
|
10%
|
Hyperkalemia
(>1.18 X ULN)
|
0%
|
5%
|
Alkaline Phosphatase
(>2.5 X ULN)
|
5%
|
2%
|
Hyperglycemia
(>1.8 X ULN)
|
9%
|
13%
|
Elevated AST (>5 X ULN)
|
0%
|
5%
|
Elevated Amylase
(>1.5 X ULN)
|
8%
|
4%
|
Elevated Creatinine
(>1.5 X ULN)
|
0%
|
7%
|
ULN = upper limit of normal range
LLN = lower limit of normal range
OVERDOSAGE
There have been no reports of overdosage from the oral administration of Mepron.
DOSAGE AND ADMINISTRATION
Adults: The recommended oral dose is 750 mg (three 250 mg tablets) administered with food three times a day for ?1 days (total daily dose 2250 mg). Failure to administer Mepron with food may result in lower atovaquone plasma concentrations and may limit response to therapy (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
Mepron tablets, 250 mg, are yellow, round, film-coated tablets engraved with “P7F” and “WELLCOME.”
Bottles of 200 (NDC 0081-0126-62)
Store at 15° to 25°C (59° to 77°F).
Dispense in well-closed container as defined in U.S.P., if product package is subdivided.
1(A-a)DO2=[(713 X FiO2) − (PaCO2/0.8)] - Pa CO2 (mmHg)
U.S. Patent No. 5053432
U.S. Patent No. 4981874 (Use Patent) 403624
April 1994 RL-2330
Revised: 01/2007GlaxoSmithKline