Abacavir 300 mg Tablet, 60-count — NDC 31722-557-60 (Billing 31722-0557-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Abacavir is an antiretroviral agent [see Microbiology ( 12.4 )].

12.3Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day. Absorption: Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%.

Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (C max ) was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC (0 to 12 h) was 6.02 ± 1.73 mcg•hour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, C max was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC ∞ was 11.95 ± 2.51 mcg•hour per mL.

Effect of Food: Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC∞); therefore, abacavir tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of abacavir oral solution and abacavir tablets. Therefore, these products may be used interchangeably.

Distribution: The apparent volume of distribution after IV administration of abacavir was 0.86 ±

0.15L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC (0 to 6 h) to plasma abacavir AUC (0 to 6 h) ratio ranged from 27% to 33%. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration.

Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. Elimination: In single-dose trials, the observed elimination half-life (t 1/2 ) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ±

0.24L per hour per kg (mean ± SD). Metabolism: In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.

The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations. Excretion: Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14 C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine.

Fecal elimination accounted for 16% of the dose. Specific Populations Patients with Renal Impairment: The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.

Patients with Hepatic Impairment: The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )].

Pregnant Women : Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abac… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Abacavir is an antiretroviral agent [see Microbiology ( 12.4 )].

12.3Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day. Absorption: Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%.

Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (C max ) was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC (0 to 12 h) was 6.02 ± 1.73 mcg•hour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, C max was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC ∞ was 11.95 ± 2.51 mcg•hour per mL.

Effect of Food: Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC∞); therefore, abacavir tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of abacavir oral solution and abacavir tablets. Therefore, these products may be used interchangeably.

Distribution: The apparent volume of distribution after IV administration of abacavir was 0.86 ±

0.15L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC (0 to 6 h) to plasma abacavir AUC (0 to 6 h) ratio ranged from 27% to 33%. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration.

Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. Elimination: In single-dose trials, the observed elimination half-life (t 1/2 ) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ±

0.24L per hour per kg (mean ± SD). Metabolism: In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.

The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations. Excretion: Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14 C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine.

Fecal elimination accounted for 16% of the dose. Specific Populations Patients with Renal Impairment: The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.

Patients with Hepatic Impairment: The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )].

Pregnant Women : Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal t… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Adult Trials Therapy-Naive Adults CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either abacavir (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), white (51%), black (21%), and Hispanic (26%).

The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells per mm 3 , and median plasma HIV-1 RNA was 4.79 log 10 copies per mL. The outcomes of randomized treatment are provided in Table 7. Table 7.

Outcomes of Randomized Treatment through Week 48 (CNA30024) Outcome Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Responder a 69% (73%) 69% (71%) Virologic failures b 6% 4% Discontinued due to adverse reactions 14% 16% Discontinued due to other reasons c 10% 11% a Subjects achieved and maintained confirmed HIV-1 RNA less than or equal to 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test

1.0PCR). b Includes viral rebound, insufficient viral response according to the investigator, and failure to achieve confirmed less than or equal to 50 copies per mL by Week 48. c Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells per mm 3 in the group receiving abacavir and 155 cells per mm 3 in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving abacavir (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression.

CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either abacavir (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), white (73%), black (15%), and Hispanic (9%).

At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells per mm 3 , and median baseline plasma HIV-1 RNA was 4.8 log 10 copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8. Table 8.

Outcomes of Randomized Treatment through Week 48 (CNA3005) Outcome Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 265) Responder a 49% 50% Virologic failure b 31% 28% Discontinued due to adverse reactions 10% 12% Discontinued due to other reasons c 11% 10% a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL. b Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48. c Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.

Treatment response by plasma HIV-1 RNA strata is shown in Table 9. Table 9. Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005) Screening HIV-1 RNA (copies/mL) Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 265) <400 copies/mL n <400 copies/mL n ≥10,000 - ≤100,000 >100,000 50% 48% 166 96 48% 52% 165 100 In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subject… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats.

In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg. Mutagenicity Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes.

Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

Impairment of Fertility Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.

13.2Animal Toxicology and/or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.