ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reaction is discussed in another section of the labeling: oHepatotoxicity [see Warnings and Precautions (5.2)].. oHepatotoxicity [see Warnings and Precautions (5.2)].. oPCP Prevention: The most frequent adverse reactions (>=25% that required discontinuation) were diarrhea, rash, headache, nausea, and fever. (6.1)oPCP Treatment: The most frequent adverse reactions (>=14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oPCP Prevention: The most frequent adverse reactions (>=25% that required discontinuation) were diarrhea, rash, headache, nausea, and fever. (6.1). oPCP Treatment: The most frequent adverse reactions (>=14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.Additionally, because many subjects who participated in clinical trials with MEPRON had complications of advanced human immunodeficiency virus (HIV) disease, it was often difficult to distinguish adverse reactions caused by MEPRON from those caused by underlying medical conditions.PCP Prevention TrialsIn clinical trials, MEPRON oral suspension was compared with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count <200 cells/mm3 or prior episode of PCP) and unable to tolerate TMP-SMX. Dapsone Comparative Trial: In the dapsone comparative trial (n 1,057), the majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Subjects received MEPRON oral suspension 1,500 mg once daily (n 536) or dapsone 100 mg once daily (n 521); median durations of exposure were 6.7 and 6.5 months, respectively. Adverse reaction data were collected only for adverse reactions requiring discontinuation of treatment, which occurred at similar frequencies in subjects treated with MEPRON oral suspension or dapsone (Table 1). Among subjects taking neither dapsone nor atovaquone at enrollment (n 487), adverse reactions requiring discontinuation of treatment occurred in 43% of subjects treated with dapsone and 20% of subjects treated with MEPRON oral suspension. Gastrointestinal adverse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with MEPRON oral suspension (Table 1).Table 1. Percentage (>2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention TrialAdverse ReactionAll SubjectsMEPRON Oral Suspension1,500 mg/day(n 536)%Dapsone100 mg/day(n 521)%Rash6.38.8Nausea4.10.6Diarrhea3.20.2Vomiting2.20.6Aerosolized Pentamidine Comparative Trial: In the aerosolized pentamidine comparative trial (n 549), the majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received MEPRON oral suspension once daily at dose of 750 mg (n 188) or 1,500 mg (n 175) or received aerosolized pentamidine 300 mg every weeks (n 186); the median durations of exposure were 6.2, 6.0, and 7.8 months, respectively. Table summarizes the clinical adverse reactions reported by >=20% of the subjects receiving either the 1,500-mg dose of MEPRON oral suspension or aerosolized pentamidine. Rash occurred more often in subjects treated with MEPRON oral suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with MEPRON oral suspension 1,500 mg once daily and in 7% of subjects treated with aerosolized pentamidine. The most frequent adverse reactions requiring discontinuation of dosing in the group receiving MEPRON oral suspension 1,500 mg once daily were rash (6%), diarrhea (4%), and nausea (3%). The most frequent adverse reaction requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%).Table 2. Percentage (>=20%) of Subjects with Selected Adverse Reactions in the Aerosolized Pentamidine Comparative PCP Prevention TrialAdverse ReactionMEPRON Oral Suspension1,500 mg/day(n 175)%Aerosolized Pentamidine(n 186)%Diarrhea4235Rash3928Headache2822Nausea2623Fever2518Rhinitis2417Other reactions occurring in >=10% of subjects receiving the recommended dose of MEPRON oral suspension (1,500 mg once daily) included vomiting, sweating, flu syndrome, sinusitis, pruritus, insomnia, depression, and myalgia. PCP Treatment TrialsSafety information is presented from clinical efficacy trials of the MEPRON tablet formulation: 1) randomized, double-blind trial comparing MEPRON tablets with TMP-SMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to-moderate PCP [(A-a)DO2] <=45 mm Hg and PaO2 >=60 mm Hg on room air; 2) randomized, open-label trial comparing MEPRON tablets with intravenous (IV) pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials.TMP-SMX Comparative Trial: In the TMP-SMX comparative trial (n 408), the majority of subjects were white (66%) and male (95%); the mean age was 36 years. Subjects received MEPRON 750 mg (three 250-mg tablets) times daily for 21 days or TMP 320 mg plus SMX 1,600 mg times daily for 21 days; median durations of exposure were 21 and 15 days, respectively.Table summarizes all clinical adverse reactions reported by >=10% of the trial population regardless of attribution. Nine percent of subjects who received MEPRON and 24% of subjects who received TMP-SMX discontinued therapy due to an adverse reaction. Among the subjects who discontinued, 4% of subjects receiving MEPRON and 8% of subjects in the TMP-SMX group discontinued therapy due to rash. The incidence of adverse reactions with MEPRON oral suspension at the recommended dose (750 mg twice daily) was similar to that seen with the tablet formulation.Table 3. Percentage (>=10%) of Subjects with Selected Adverse Reactions in the TMP-SMX Comparative PCP Treatment TrialAdverse ReactionMEPRON Tablets(n 203)%TMP-SMX(n 205)%Rash (including maculopapular)2334Nausea2144Diarrhea197Headache1622Vomiting1435Fever1425Insomnia109Two percent of subjects treated with MEPRON and 7% of subjects treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. Pentamidine Comparative Trial: In the pentamidine comparative trial (n 174), the majority of subjects in the primary therapy trial population (n 145) were white (72%) and male (97%); the mean age was 37 years. Subjects received MEPRON 750 mg (three 250-mg tablets) times daily for 21 days or 3- to 4-mg/kg single pentamidine isethionate IV infusion daily for 21 days; the median durations of exposure were 21 and 14 days, respectively.Table summarizes the clinical adverse reactions reported by >=10% of the primary therapy trial population regardless of attribution. Fewer subjects who received MEPRON reported adverse reactions than subjects who received pentamidine (63% vs. 72%). However, only 7% of subjects discontinued treatment with MEPRON due to adverse reactions, while 41% of subjects who received pentamidine discontinued treatment for this reason. Of the subjects who discontinued therapy with MEPRON, reported rash (4%). Rash was not severe in any subject. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).Table 4. Percentage (>=10%) of Subjects with Selected Adverse Reactions in the Pentamidine Comparative PCP Treatment Trial (Primary Therapy Group)Adverse ReactionMEPRON Tablets(n 73)%Pentamidine(n 71)%Fever4025Nausea2237Rash2213Diarrhea2131Insomnia1914Headache1828Vomiting1417Cough141Sweat103Monilia, oral103Laboratory abnormality was reported as the reason for discontinuation of treatment in of 73 subjects (3%) who received MEPRON, and in 14 of 71 subjects (20%) who received pentamidine. One subject (1%) receiving MEPRON had elevated creatinine and BUN levels and subject (1%) had elevated amylase levels. In this trial, elevated levels of amylase occurred in subjects (8% versus 4%) receiving MEPRON tablets or pentamidine, respectively.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of MEPRON oral suspension. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System DisordersMethemoglobinemia, thrombocytopenia.Immune System DisordersHypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria.Eye DisordersVortex keratopathy.Gastrointestinal DisordersPancreatitis.Hepatobiliary DisordersHepatitis, fatal liver failure.Skin and Subcutaneous Tissue DisordersErythema multiforme, Stevens-Johnson syndrome, and skin desquamation. Renal and Urinary DisordersAcute renal impairment.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Atovaquone is quinone antimicrobial drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics Relationship between Plasma Atovaquone Concentrations and Clinical OutcomeIn comparative clinical trial, HIV/AIDS subjects received atovaquone tablets 750 mg times daily or TMP-SMX for treatment of mild-to-moderate PCP for 21 days [see Clinical Studies (14.2)]; the relationship between atovaquone plasma concentrations and successful treatment outcome from 113 of these subjects for whom both steady-state drug concentrations and outcome data were available is shown in Table 6.Table 6. Relationship between Plasma Atovaquone Concentrations and Successful Treatment Outcomea Successful treatment outcome was defined as improvement in clinical and respiratory measures persisting at least weeks after cessation of therapy. Improvement in clinical and respiratory measures was assessed using composite of parameters that included oral body temperature, respiratory rate, and severity scores for cough, dyspnea, and chest pain/tightness.Steady-State Plasma Atovaquone Concentrations (mcg/mL)Successful Treatmenta No. of Successes/No. in Group(%)0 to <50/6 (0%)5 to <1018/26 (69%)10 to <1530/38 (79%)15 to <2018/19 (95%)>=2024/24 (100%)Cardiac EffectsThe effect of MEPRON oral suspension on the QT interval is unknown in humans.. 12.3 Pharmacokinetics. Plasma atovaquone concentrations do not increase proportionally with dose following ascending repeat-dose administration of MEPRON oral suspension in healthy subjects. When MEPRON oral suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, mean (+-SD) steady-state plasma atovaquone concentrations were 11.7 +- 4.8, 12.5 +- 5.8, and 13.5 +- 5.1 mcg/mL, respectively. The corresponding mean (+-SD) Cmax concentrations were 15.1 +- 6.1, 15.3 +- 7.6, and 16.8 +- 6.4 mcg/mL.AbsorptionAtovaquone is highly lipophilic compound with low aqueous solubility. The mean (+-SD) absolute bioavailability of atovaquone from 750-mg dose of MEPRON oral suspension administered under fed conditions in HIV-1-infected (CD4 >100 cells/mm3) volunteers was 47% +- 15%.Effect of Food: Administering MEPRON oral suspension with food enhances atovaquone bioavailability. Sixteen healthy subjects received single 750-mg dose of MEPRON oral suspension after an overnight fast and following meal (23 fat: 610 kCal). The mean (+-SD) atovaquone AUC under fasting and fed conditions were 324 +- 115 and 801 +- 320 hmcg/mL, respectively, representing 2.6 +- 1.0-fold increase.DistributionFollowing IV administration of atovaquone, the mean (+-SD) volume of distribution at steady state (Vdss) was 0.60 +- 0.17 L/kg (n 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of to 90 mcg/mL. In HIV-1-infected children who received 750 mg atovaquone as the tablet formulation times daily for 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.EliminationThe mean (+-SD) 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 following administration of MEPRON oral suspension.Metabolism: The metabolism of atovaquone is unknown.Excretion: Following oral administration of 14C-labelled atovaquone to healthy subjects, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days.Specific PopulationsPatients with Hepatic or Renal Impairment: The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.HIV-Infected Subjects: When MEPRON oral suspension was administered to HIV-1-infected subjects at dose of 750 mg twice daily, the mean (+-SD) steady-state plasma atovaquone concentration was 21.0 +- 4.9 mcg/mL and mean (+-SD) Cmax was 24.0 +- 5.7 mcg/mL. The mean (+-SD) minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 +- 4.6 mcg/mL.In an open-label PCP trial in 18 HIV-1-infected subjects, administration of MEPRON oral suspension 750 mg twice daily with meals resulted in mean (+-SD) steady-state plasma atovaquone concentration of 22.0 +- 10.1 mcg/mL.The mean (+-SD) plasma clearance of atovaquone following IV administration in HIV-1-infected subjects was 10.4 +- 5.5 mL/min (0.15 +- 0.09 mL/min/kg).Drug Interaction StudiesRifampin/Rifabutin: In trial with 13 HIV-1-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with MEPRON oral suspension 750 mg every 12 hours resulted in 52% +- 13% decrease in the mean (+-SD) steady-state plasma atovaquone concentration and 37% +- 42% increase in the mean (+-SD) 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. In trial of 24 healthy volunteers, the oral administration of rifabutin 300 mg once daily with MEPRON oral suspension 750 mg twice daily resulted in 34% decrease in the mean steady-state plasma atovaquone concentration and 19% decrease in the mean steady-state plasma rifabutin concentration.Tetracycline: Concomitant treatment with tetracycline has been associated with 40% reduction in plasma concentrations of atovaquone.Metoclopramide: Concomitant treatment with metoclopramide has been associated with 50% reduction in steady-state atovaquone plasma concentrations.Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and Cmax of indinavir, but resulted in decrease in the Ctrough of indinavir (23% decrease [90% CI: 8%, 35%]).Trimethoprim/Sulfamethoxazole (TMP-SMX): Concomitant administration of MEPRON oral suspension 500 mg once daily (not the approved dosage) and TMP-SMX in HIV-infected adult subjects did not result in significant changes in either atovaquone or TMP-SMX exposure.Zidovudine: The administration of atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every hours to 14 HIV-1-infected subjects resulted in 24% +- 12% decrease in zidovudine apparent oral clearance, leading to 35% +- 23% increase in plasma zidovudine AUC. The glucuronide metabolite:parent ratio decreased from 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.. 12.4 Microbiology. Mechanism of ActionAtovaquone is hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jirovecii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone results in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and adenosine triphosphate (ATP) synthesis.Antimicrobial ActivityAtovaquone is active against P. jirovecii [see Clinical Studies (14)].ResistancePhenotypic resistance to atovaquone in vitro has not been demonstrated for P. jirovecii. However, in subjects who developed PCP after prophylaxis with atovaquone, DNA sequence analysis identified mutations in the predicted amino acid sequence of P. jirovecii cytochrome (a likely target site for atovaquone). The clinical significance of this is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Prevention of PCP. The indication for prevention of PCP is based on the results of clinical trials comparing MEPRON oral suspension with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (aged 13 to 18 years) and adult subjects at risk of PCP (CD4 count <200 cells/mm3 or prior episode of PCP) and unable to tolerate TMP-SMX.Dapsone Comparative TrialThis open-label trial enrolled 1,057 subjects, randomized to receive MEPRON oral suspension 1,500 mg once daily (n 536) or dapsone 100 mg once daily (n 521). The majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Median follow-up was 24 months. Subjects randomized to the dapsone arm who were seropositive for Toxoplasma gondii and had CD4 count <100 cells/mm3 also received pyrimethamine and folinic acid. PCP event rates are shown in Table 7. Mortality rates were similar.Aerosolized Pentamidine Comparative TrialThis open-label trial enrolled 549 subjects, randomized to receive MEPRON oral suspension 1,500 mg once daily (n 175), MEPRON oral suspension 750 mg once daily (n 188), or aerosolized pentamidine 300 mg once monthly (n 186). The majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Median follow-up was 11.3 months. The results of the PCP event rates appear in Table 7. Mortality rates were similar among the groups.Table 7. Confirmed or Presumed/Probable PCP Events (As-Treated Analysis)a Those events occurring during or within 30 days of stopping assigned treatment. Relative risk <1 favors MEPRON and values >1 favor comparator. Trial results did not show superiority of MEPRON to the comparator. The confidence level of the interval for the dapsone comparative trial was 95% and for the pentamidine comparative trial was 97.5%.AssessmentTrial 1Trial 2MEPRON Oral Suspension1,500 mg/day(n 527)Dapsone100 mg/day(n 510)MEPRON Oral Suspension750 mg/day(n 188)MEPRON Oral Suspension1,500 mg/day(n 172)AerosolizedPentamidine300 mg/month(n 169)%1519231817Relative Riskb (CI)c 0.77(0.57, 1.04)1.47(0.86, 2.50)1.14(0.63, 2.06)An analysis of all PCP events (intent-to-treat analysis) for both trials showed results similar to those shown in Table 7. 14.2 Treatment of PCP. The indication for treatment of mild-to-moderate PCP is based on the results of efficacy trials: randomized, double-blind trial comparing MEPRON tablets with TMP-SMX in subjects with HIV/AIDS and mild-to-moderate PCP (defined in the protocol as [(A-a)DO2] <=45 mm Hg and PaO2 >=60 mm Hg on room air) and randomized open-label trial comparing MEPRON tablets with IV pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials. Both trials were conducted with the tablet formulation using 750 mg times daily. Results from these efficacy trials established relationship between plasma atovaquone concentrations and successful outcome. Successful outcome was defined as improvement in clinical and respiratory measures persisting at least weeks after cessation of therapy [see Clinical Pharmacology (12.2)].TMP-SMX Comparative TrialThis double-blind, randomized trial compared the safety and efficacy of MEPRON tablets with that of TMP-SMX for the treatment of subjects with HIV/AIDS and histologically confirmed PCP. Only subjects with mild-to-moderate PCP were eligible for enrollment.A total of 408 subjects were enrolled into the trial. The majority of subjects were white (66%) and male (95%); the mean age was 36 years. Eighty-six subjects without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 subjects with histologically confirmed PCP, 160 were randomized to receive 750 mg MEPRON (three 250-mg tablets) times daily for 21 days and 162 were randomized to receive 320 mg TMP plus 1,600 mg SMX times daily for 21 days. Therapy success was defined as improvement in clinical and respiratory measures persisting at least weeks after cessation of therapy. Improvement in clinical and respiratory measures was assessed using composite of parameters that included oral body temperature, respiratory rate, severity scores for cough, dyspnea, and chest pain/tightness. Therapy failures included lack of response, treatment discontinuation due to an adverse experience, and unevaluable.There was significant difference (P 0.03) in mortality rates between the treatment groups favoring TMP-SMX. Among the 322 subjects with confirmed PCP, 13 of 160 (8%) subjects treated with MEPRON and of 162 (2.5%) subjects 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 subjects, there were 16 (8%) deaths among subjects treated with MEPRON and (3.4%) deaths among subjects treated with TMP-SMX (P 0.051). Of the 13 subjects with confirmed PCP and treated with MEPRON who died, died of PCP and died with combination of bacterial infections and PCP; bacterial infections did not appear to be factor in any of the deaths among TMP-SMX-treated subjects.A correlation between plasma atovaquone concentrations and death demonstrated that subjects with lower plasma concentrations were more likely to die. For those subjects for whom Day plasma atovaquone concentration data are available, (63%) of subjects with concentrations <5 mcg/mL died during participation in the trial. However, only (2.0%) of the 49 subjects with Day plasma atovaquone concentrations >=5 mcg/mL died.Sixty-two percent of subjects on MEPRON and 64% of subjects on TMP-SMX were classified as protocol-defined therapy successes (Table 8).Table 8. Outcome of Treatment for PCP-Positive Subjects Enrolled in the TMP-SMX Comparative Triala As defined by the protocol and described in trial description above.Outcome of Therapya Number of Subjects (%)MEPRON Tablets(n 160)TMP-SMX(n 162)Therapy success9962%10364%Therapy failure due to: -Lack of response2817%106% -Adverse reaction117%3320% -Unevaluable2214%1610%Required alternate PCP therapy during trial5534%5534%The failure rate due to lack of response was significantly higher for subjects receiving MEPRON, while the failure rate due to an adverse reaction was significantly higher for subjects receiving TMP-SMX.Pentamidine Comparative TrialThis unblinded, randomized trial was designed to compare the safety and efficacy of MEPRON with that of pentamidine for the treatment of histologically-confirmed mild or moderate PCP in subjects with HIV/AIDS. Approximately 80% of the subjects either had 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 trial (the salvage treatment group). total of 174 subjects were enrolled into the trial. Subjects were randomized to receive MEPRON 750 mg (three 250-mg tablets) times daily for 21 days or pentamidine isethionate 3- to 4-mg/kg single IV infusion daily for 21 days. The majority of subjects were white (72%) and male (97%); the mean age was approximately 37 years. Thirty-nine subjects without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135 subjects 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 subject in the primary therapy group randomized to receive pentamidine did not receive trial medication.There was no difference in mortality rates between the treatment groups. Among the 135 subjects with confirmed PCP, 10 of 70 (14%) subjects receiving MEPRON and of 65 (14%) subjects receiving pentamidine died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all subjects, there were 11 (12.5%) deaths among those treated with MEPRON and 12 (14%) deaths among those treated with pentamidine. Among subjects for whom Day plasma atovaquone concentrations were available, of (60%) subjects with concentrations <5 mcg/mL died during participation in the trial. However, only of 21 (9%) subjects with Day plasma concentrations >=5 mcg/mL died. The therapeutic outcomes for the 134 subjects who received trial medication in this trial are presented in Table 9.Table 9. Outcome of Treatment for PCP-Positive Subjects (%) Enrolled in the Pentamidine Comparative TrialOutcome of TherapyPrimary TreatmentSalvage TreatmentMEPRON(n 56)Pentamidine(n 53)MEPRON(n 14)Pentamidine(n 11)Therapy success3257%2140%1393%764%Therapy failure due to: -Lack of response1629%917%00 -Adverse reaction23.6%1936%0327% -Unevaluable611%48%17%19%Required alternate PCP therapy during trial1934%2955%0436%.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oPrevention of PCP: 1,500 mg (10 mL) once daily with food (2.1)oTreatment of PCP: 750 mg (5 mL) twice daily with food for 21 days (2.2)oSupplied in foil pouches and bottles:oFoil Pouch: For 5-mL dose, take entire contents by mouth either by dispensing into spoon or cup or directly into the mouth. For 10-mL dose, take entire contents of pouches. (2.3)oBottle: Shake bottle gently before use. (2.3). oPrevention of PCP: 1,500 mg (10 mL) once daily with food (2.1). oTreatment of PCP: 750 mg (5 mL) twice daily with food for 21 days (2.2). oSupplied in foil pouches and bottles:. oFoil Pouch: For 5-mL dose, take entire contents by mouth either by dispensing into spoon or cup or directly into the mouth. For 10-mL dose, take entire contents of pouches. (2.3). oBottle: Shake bottle gently before use. (2.3). 2.1 Dosage for the Prevention of P. jirovecii Pneumonia. The recommended oral dosage is 1,500 mg (10 mL) once daily administered with food.. 2.2 Dosage for the Treatment of Mild-to-Moderate P. jirovecii Pneumonia. The recommended oral dosage is 750 mg (5 mL) twice daily (total daily dose 1,500 mg) administered with food for 21 days.. 2.3 Important Administration Instructions. Administer MEPRON oral suspension with food to avoid low plasma atovaquone concentrations that may limit response to therapy [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. MEPRON Foil PouchoOpen each 5-mL pouch by folding along the dotted line and tearing open at horizontal slit as directed by arrow on pouch.oFor 5-mL dose, take entire contents either by placing directly into the mouth or by dispensing into dosing spoon (5 mL) or cup prior to administration by mouth. oFor 10-mL dose, take the entire contents of pouches.MEPRON BottleShake bottle gently before administering the recommended dosage.. oOpen each 5-mL pouch by folding along the dotted line and tearing open at horizontal slit as directed by arrow on pouch.. oFor 5-mL dose, take entire contents either by placing directly into the mouth or by dispensing into dosing spoon (5 mL) or cup prior to administration by mouth. oFor 10-mL dose, take the entire contents of pouches.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oConcomitant administration of rifampin or rifabutin reduces atovaquone concentrations; concomitant use with MEPRON oral suspension is not recommended. (7.1)oConcomitant administration of tetracycline reduces atovaquone concentrations; use caution when coadministering. Monitor patients for potential loss of efficacy of MEPRON if coadministration of tetracycline is necessary. (7.2)oConcomitant administration with metoclopramide reduces atovaquone concentrations; administer concomitantly only if other antiemetics are not available. (7.3)oConcomitant administration of indinavir reduces indinavir trough concentrations; use caution when coadministering. Monitor patients for potential loss of efficacy of indinavir if coadministration is necessary. (7.4) oConcomitant administration of rifampin or rifabutin reduces atovaquone concentrations; concomitant use with MEPRON oral suspension is not recommended. (7.1). oConcomitant administration of tetracycline reduces atovaquone concentrations; use caution when coadministering. Monitor patients for potential loss of efficacy of MEPRON if coadministration of tetracycline is necessary. (7.2). oConcomitant administration with metoclopramide reduces atovaquone concentrations; administer concomitantly only if other antiemetics are not available. (7.3). oConcomitant administration of indinavir reduces indinavir trough concentrations; use caution when coadministering. Monitor patients for potential loss of efficacy of indinavir if coadministration is necessary. (7.4) 7.1 Rifampin/Rifabutin. Concomitant administration of rifampin or rifabutin and MEPRON oral suspension is known to reduce atovaquone concentrations [see Clinical Pharmacology (12.3)]. Concomitant administration of MEPRON oral suspension and rifampin or rifabutin is not recommended.. 7.2 Tetracycline. Concomitant administration of tetracycline and MEPRON oral suspension has been associated with reduction in plasma concentrations of atovaquone [see Clinical Pharmacology (12.3)]. Caution should be used when prescribing tetracycline concomitantly with MEPRON oral suspension. Monitor patients for potential loss of efficacy of MEPRON if coadministration is necessary.. 7.3 Metoclopramide. Metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available [see Clinical Pharmacology (12.3)]. 7.4 Indinavir. Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and Cmax of indinavir but resulted in decrease in the Ctrough of indinavir [see Clinical Pharmacology (12.3)]. Caution should be exercised when prescribing MEPRON oral suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if coadministration with MEPRON oral suspension is necessary.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. MEPRON oral suspension is quinone antimicrobial drug indicated for: oPrevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents aged 13 years and older who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). (1.1)oTreatment of mild-to-moderate PCP in adults and adolescents aged 13 years and older who cannot tolerate TMP-SMX. (1.2)Limitations of Use (1.3):oTreatment of severe PCP (alveolar arterial oxygen diffusion gradient [(A-a)DO2] >45 mm Hg) with MEPRON has not been studied.oThe efficacy of MEPRON in subjects who are failing therapy with TMP-SMX has also not been studied.. oPrevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents aged 13 years and older who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). (1.1). oTreatment of mild-to-moderate PCP in adults and adolescents aged 13 years and older who cannot tolerate TMP-SMX. (1.2). oTreatment of severe PCP (alveolar arterial oxygen diffusion gradient [(A-a)DO2] >45 mm Hg) with MEPRON has not been studied.. oThe efficacy of MEPRON in subjects who are failing therapy with TMP-SMX has also not been studied.. 1.1 Prevention of Pneumocystis jirovecii Pneumonia MEPRON oral suspension is indicated for the prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). 1.2 Treatment of Mild-to-Moderate Pneumocystis jirovecii Pneumonia. MEPRON oral suspension is indicated for the acute oral treatment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX.. 1.3 Limitations of Use. Clinical experience with MEPRON for the treatment of PCP has been limited to subjects with mild-to-moderate PCP (alveolar-arterial oxygen diffusion gradient [(A-a)DO2] <=45 mm Hg). Treatment of more severe episodes of PCP with MEPRON has not been studied. The efficacy of MEPRON in subjects who are failing therapy with TMP-SMX has also not been studied.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Plasma atovaquone concentrations do not increase proportionally with dose following ascending repeat-dose administration of MEPRON oral suspension in healthy subjects. When MEPRON oral suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, mean (+-SD) steady-state plasma atovaquone concentrations were 11.7 +- 4.8, 12.5 +- 5.8, and 13.5 +- 5.1 mcg/mL, respectively. The corresponding mean (+-SD) Cmax concentrations were 15.1 +- 6.1, 15.3 +- 7.6, and 16.8 +- 6.4 mcg/mL.AbsorptionAtovaquone is highly lipophilic compound with low aqueous solubility. The mean (+-SD) absolute bioavailability of atovaquone from 750-mg dose of MEPRON oral suspension administered under fed conditions in HIV-1-infected (CD4 >100 cells/mm3) volunteers was 47% +- 15%.Effect of Food: Administering MEPRON oral suspension with food enhances atovaquone bioavailability. Sixteen healthy subjects received single 750-mg dose of MEPRON oral suspension after an overnight fast and following meal (23 fat: 610 kCal). The mean (+-SD) atovaquone AUC under fasting and fed conditions were 324 +- 115 and 801 +- 320 hmcg/mL, respectively, representing 2.6 +- 1.0-fold increase.DistributionFollowing IV administration of atovaquone, the mean (+-SD) volume of distribution at steady state (Vdss) was 0.60 +- 0.17 L/kg (n 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of to 90 mcg/mL. In HIV-1-infected children who received 750 mg atovaquone as the tablet formulation times daily for 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.EliminationThe mean (+-SD) 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 following administration of MEPRON oral suspension.Metabolism: The metabolism of atovaquone is unknown.Excretion: Following oral administration of 14C-labelled atovaquone to healthy subjects, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days.Specific PopulationsPatients with Hepatic or Renal Impairment: The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.HIV-Infected Subjects: When MEPRON oral suspension was administered to HIV-1-infected subjects at dose of 750 mg twice daily, the mean (+-SD) steady-state plasma atovaquone concentration was 21.0 +- 4.9 mcg/mL and mean (+-SD) Cmax was 24.0 +- 5.7 mcg/mL. The mean (+-SD) minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 +- 4.6 mcg/mL.In an open-label PCP trial in 18 HIV-1-infected subjects, administration of MEPRON oral suspension 750 mg twice daily with meals resulted in mean (+-SD) steady-state plasma atovaquone concentration of 22.0 +- 10.1 mcg/mL.The mean (+-SD) plasma clearance of atovaquone following IV administration in HIV-1-infected subjects was 10.4 +- 5.5 mL/min (0.15 +- 0.09 mL/min/kg).Drug Interaction StudiesRifampin/Rifabutin: In trial with 13 HIV-1-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with MEPRON oral suspension 750 mg every 12 hours resulted in 52% +- 13% decrease in the mean (+-SD) steady-state plasma atovaquone concentration and 37% +- 42% increase in the mean (+-SD) 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. In trial of 24 healthy volunteers, the oral administration of rifabutin 300 mg once daily with MEPRON oral suspension 750 mg twice daily resulted in 34% decrease in the mean steady-state plasma atovaquone concentration and 19% decrease in the mean steady-state plasma rifabutin concentration.Tetracycline: Concomitant treatment with tetracycline has been associated with 40% reduction in plasma concentrations of atovaquone.Metoclopramide: Concomitant treatment with metoclopramide has been associated with 50% reduction in steady-state atovaquone plasma concentrations.Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and Cmax of indinavir, but resulted in decrease in the Ctrough of indinavir (23% decrease [90% CI: 8%, 35%]).Trimethoprim/Sulfamethoxazole (TMP-SMX): Concomitant administration of MEPRON oral suspension 500 mg once daily (not the approved dosage) and TMP-SMX in HIV-infected adult subjects did not result in significant changes in either atovaquone or TMP-SMX exposure.Zidovudine: The administration of atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every hours to 14 HIV-1-infected subjects resulted in 24% +- 12% decrease in zidovudine apparent oral clearance, leading to 35% +- 23% increase in plasma zidovudine AUC. The glucuronide metabolite:parent ratio decreased from 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from postmarketing experience with use of MEPRON in pregnant women are insufficient to identify drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with HIV who are infected with PCP are at increased risk of adverse pregnancy outcomes (see Clinical Considerations). Atovaquone given orally by gavage to pregnant rats and rabbits during organogenesis did not cause fetal malformations at plasma concentrations up to times and 0.5 times, respectively, the estimated human exposure based on steady-state plasma concentrations (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with HIV who are infected with PCP are at increased risk of severe illness and maternal death associated with PCP compared with non-pregnant women.DataAnimal Data: Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day to pregnant rats during organogenesis (Gestation Day [GD] to GD15) did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations approximately times the estimated human exposure during the treatment of PCP based on steady-state plasma concentrations. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day during organogenesis (GD6 to GD18) caused decreased fetal body length at maternally toxic dose of 1,200 mg/kg/day corresponding to plasma concentration that is approximately 0.5 times the estimated human exposure based on steady-state plasma concentrations. In pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first generation offspring at doses up to 1,000 mg/kg/day corresponding to approximately times the estimated human exposure based on steady-state plasma concentrations during the treatment of PCP. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended in mothers with HIV-1 infection due to the potential for HIV-1 transmission. (8.2). 8.1 Pregnancy. Risk SummaryAvailable data from postmarketing experience with use of MEPRON in pregnant women are insufficient to identify drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with HIV who are infected with PCP are at increased risk of adverse pregnancy outcomes (see Clinical Considerations). Atovaquone given orally by gavage to pregnant rats and rabbits during organogenesis did not cause fetal malformations at plasma concentrations up to times and 0.5 times, respectively, the estimated human exposure based on steady-state plasma concentrations (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with HIV who are infected with PCP are at increased risk of severe illness and maternal death associated with PCP compared with non-pregnant women.DataAnimal Data: Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day to pregnant rats during organogenesis (Gestation Day [GD] to GD15) did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations approximately times the estimated human exposure during the treatment of PCP based on steady-state plasma concentrations. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day during organogenesis (GD6 to GD18) caused decreased fetal body length at maternally toxic dose of 1,200 mg/kg/day corresponding to plasma concentration that is approximately 0.5 times the estimated human exposure based on steady-state plasma concentrations. In pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first generation offspring at doses up to 1,000 mg/kg/day corresponding to approximately times the estimated human exposure based on steady-state plasma concentrations during the treatment of PCP. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue. 8.2 Lactation Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. There are no data on the presence of atovaquone in human milk, the effects on the breastfed child, or the effects on milk production. Atovaquone was detected in rat milk when lactating rats were administered oral atovaquone (see Data). When drug is present in animal milk, it is likely the drug will be present in human milk. Because of the potential for HIV-1 transmission to HIV-negative infants, instruct mothers with HIV-1 not to breastfeed if they are taking MEPRON for the prevention or treatment of PCP.DataIn rat study with doses of 10 and 250 mg/kg given orally by gavage on postpartum Day 11, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.. 8.4 Pediatric Use. Evidence of safety and effectiveness in pediatric patients (aged 12 years and younger) has not been established. In trial of MEPRON oral suspension administered once daily with food for 12 days to 27 HIV-1-infected, asymptomatic infants and children aged between month and 13 years, the pharmacokinetics of atovaquone were age-dependent. The average steady-state plasma atovaquone concentrations in the 24 subjects with available concentration data are shown in Table 5.Table 5. Average Steady-state Plasma Atovaquone Concentrations in Pediatric SubjectsCss Concentration at steady state.AgeDose of MEPRON Oral Suspension10 mg/kg30 mg/kg45 mg/kgAverage Css in mcg/mL (mean +- SD)1-3 months5.9(n 1)27.8 +- 5.8(n 4)>3-24 months5.7 +- 5.1(n 4)9.8 +- 3.2(n 4)15.4 +- 6.6(n 4)>2-13 years16.8 +- 6.4(n 4)37.1 +- 10.9(n 3). 8.5 Geriatric Use. Clinical trials of MEPRON did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.