ATOVAQUONE 750 mg/5mL Suspension — NDC 70748-299-01 (Billing 70748-0299-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Atovaquone is a quinone antimicrobial drug [see Clinical Pharmacology ( 12.4 )] .

12.3Pharmacokinetics Absorption Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The absolute bioavailability of a 750-mg dose of atovaquone oral suspension administered under fed conditions in 9 HIV-1-infected (CD4 >100 cells/mm 3 ) volunteers was 47% ± 15%.

Administering atovaquone with food enhances its absorption by approximately 2-fold. In one trial, 16 healthy volunteers received a single dose of 750 mg atovaquone oral 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 under fasting and fed conditions were 324 ± 115 and 801 ± 320 h●mcg/mL, respectively, representing a 2.6 ± 1-fold increase.

The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover trial in 19 HIV-1-infected volunteers (CD4 <200 cells/mm 3 ) receiving daily doses of 500 mg atovaquone oral suspension. AUC values under fasting and fed conditions were 169 ± 77 and 280 ± 114 h●mcg/mL, respectively. Maximum plasma atovaquone concentration (C max ) values under fasting and fed conditions were 8.8 ± 3.7 and 15.1 ± 6.1 mcg/mL, respectively.

Dose Proportionality Plasma atovaquone concentrations do not increase proportionally with dose. When atovaquone oral 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 C max concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL.

When atovaquone oral suspension was administered to 5 HIV-1-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and C max was 24 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (C min ) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL. Distribution Following IV administration of atovaquone, the volume of distribution at steady state (Vd ss ) was 0.60 ±

0.17L/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-1-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.

Elimination The plasma clearance of atovaquone following IV administration in 9 HIV-1-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 ± 33.4 to 77.6 ± 23.1 hours across trials following administration of atovaquone oral suspension. The half-life of atovaquone is due to presumed enterohepatic cycling and eventual fecal elimination.

In a trial where 14 C-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.

Hepatic/Renal Impairment The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment. Relationship between Plasma Atovaquone Concentration and Clinical Outcome In a comparative trial of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP [see Clinical Studies ( 14.2 )] , where subjects with HIV/AIDS received atovaquone tablets 750 mg 3 times daily for 21 days, the… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Atovaquone is a quinone antimicrobial drug [see Clinical Pharmacology ( 12.4 )] .

12.3Pharmacokinetics Absorption Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The absolute bioavailability of a 750-mg dose of atovaquone oral suspension administered under fed conditions in 9 HIV-1-infected (CD4 >100 cells/mm 3 ) volunteers was 47% ± 15%.

Administering atovaquone with food enhances its absorption by approximately 2-fold. In one trial, 16 healthy volunteers received a single dose of 750 mg atovaquone oral 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 under fasting and fed conditions were 324 ± 115 and 801 ± 320 h●mcg/mL, respectively, representing a 2.6 ± 1-fold increase.

The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover trial in 19 HIV-1-infected volunteers (CD4 <200 cells/mm 3 ) receiving daily doses of 500 mg atovaquone oral suspension. AUC values under fasting and fed conditions were 169 ± 77 and 280 ± 114 h●mcg/mL, respectively. Maximum plasma atovaquone concentration (C max ) values under fasting and fed conditions were 8.8 ± 3.7 and 15.1 ± 6.1 mcg/mL, respectively.

Dose Proportionality Plasma atovaquone concentrations do not increase proportionally with dose. When atovaquone oral 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 C max concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL.

When atovaquone oral suspension was administered to 5 HIV-1-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and C max was 24 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (C min ) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL. Distribution Following IV administration of atovaquone, the volume of distribution at steady state (Vd ss ) was 0.60 ±

0.17L/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-1-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.

Elimination The plasma clearance of atovaquone following IV administration in 9 HIV-1-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 ± 33.4 to 77.6 ± 23.1 hours across trials following administration of atovaquone oral suspension. The half-life of atovaquone is due to presumed enterohepatic cycling and eventual fecal elimination.

In a trial where 14 C-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.

Hepatic/Renal Impairment The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment. Relationship between Plasma Atovaquone Concentration and Clinical Outcome In a comparative trial of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP [see Clinical Studies ( 14.2 )] , where subjects with HIV/AIDS received atovaquone tablets 750 mg 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 betwee… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Prevention of PCP The indication for prevention of PCP is based on the results of 2 clinical trials comparing atovaquone 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/mm 3 or a prior episode of PCP) and unable to tolerate TMP-SMX. Dapsone Comparative Trial This open-label trial enrolled 1,057 subjects, randomized to receive atovaquone 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 a CD4 count <100 cells/mm 3 also received pyrimethamine and folinic acid.

PCP event rates are shown in Table 7. Mortality rates were similar. Aerosolized Pentamidine Comparative Trial This open-label trial enrolled 549 subjects, randomized to receive atovaquone oral suspension 1,500 mg once daily (n = 175), atovaquone 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 a Those events occurring during or within 30 days of stopping assigned treatment. b Relative risk <1 favors atovaquone and values >1 favor comparator.

Trial results did not show superiority of atovaquone to the comparator. c The confidence level of the interval for the dapsone comparative trial was 95% and for the pentamidine comparative trial was 97.5%. An analysis of all PCP events (intent-to-treat analysis) for both trials showed results similar to those shown in Table 7. Assessment Trial 1 Trial 1 Atovaquone Oral Suspension 1,500 mg/day (n = 527) Dapsone 100 mg/day (n = 510) Atovaquone Oral Suspension 750 mg/day (n = 188) Atovaquone Oral Suspension 1,500 mg/day (n = 172) Aerosolized Pentamidine 300 mg/month (n = 169) % 15 19 23 18 17 Relative Risk b (CI) c 0.77 (0.57, 1.04) 1.47 (0.86, 2.50) 1.14 (0.63, 2.06)

14.2Treatment of PCP The indication for treatment of mild-to-moderate PCP is based on the results of 2 efficacy trials: a randomized, double-blind trial comparing atovaquone tablets with TMP-SMX in subjects with HIV/AIDS and mild-to-moderate PCP (defined in the protocol as [(A-a)DO 2 ] ≤45 mm Hg and PaO 2 ≥60 mm Hg on room air) and a randomized open-label trial comparing atovaquone 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 three times daily. Results from these efficacy trials established a relationship between plasma atovaquone concentration and successful outcome. Successful outcome was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy.

Comparative pharmacokinetic trials of the oral suspension and tablet formulations established the currently recommended oral suspension dose of 750 mg twice daily [see Clinical Pharmacology ( 12.3 )] . TMP-SMX Comparative Trial This double-blind, randomized trial compared the safety and efficacy of atovaquone 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 exclu… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies in rats were negative; 24-month studies in mice (dosed with 50, 100, or 200 mg/kg/day), showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested, which correlated with 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of PCP. 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.