Zidovudine 300 mg Tablet, Film Coated — NDC 65862-024-10 (Billing 65862-0024-10)

12 CLINICAL PHARMACOLOGY

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

12.3Pharmacokinetics Absorption and Bioavailability Following IV dosing, dose-independent kinetics was observed over the range of 1 to 5 mg per kg. The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg per kg every 4 hours were 1.1 and 0.1 mcg per mL, respectively. In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours.

The AUC was equivalent when zidovudine was administered as zidovudine tablets or syrup compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are summarized in Table 7. Table 7.

Zidovudine Pharmacokinetic Parameters in Adult Subjects a Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on chronic therapy with zidovudine. b Approximate range. Parameter Mean ± SD (except where noted) Oral bioavailability (%) 64 ± 10 (n = 5) Apparent volume of distribution (L/kg) 1.6 ± 0.6 (n = 8) Cerebrospinal fluid (CSF):plasma ratio a 0.6 [0.04 to 2.62] (n = 39) Systemic clearance (L/h/kg) 1.6 ± 0.6 (n = 6) Renal clearance (L/h/kg) 0.34 ± 0.05 (n = 9) Elimination half-life (h) b 0.5 to 3 (n = 19) Distribution The apparent volume of distribution of zidovudine, is 1.6 ±

0.6L per kg (Table 7); and binding to plasma protein is low (less than 38%). Metabolism and Elimination Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV.

GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of zidovudine.

The AMT AUC was one-fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours. Effect of Food on Absorption Zidovudine may be administered with or without food.

The zidovudine AUC was similar when a single dose of zidovudine was administered with food. Specific Populations Patients with Renal Impairment: Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single 200 mg oral dose (Table 8). Plasma concentrations of AMT were not determined.

No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min. Table 8. Zidovudine Pharmacokinetic Parameters in Subjects with Severe Renal Impairment a a Data are expressed as mean ± standard deviation.

Parameter Control Subjects (Normal Renal Function) (n = 6) Subjects with Renal Impairment (n = 14) CrCl (mL/min) 120 ± 8 18 ± 2 Zidovudine AUC (ng•h/mL) 1,400 ± 200 3,100 ± 300 Zidovudine half-life (h) 1.0 ± 0.2 1.4 ±

0.1Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in subjects with normal renal function.

Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis [see Dosage and Administration (2.5) ] . Patients with Hepatic Impairment: Data describing the effect of hepatic impairment on the… [Excerpted — this section continues on DailyMed.]

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

12.3Pharmacokinetics Absorption and Bioavailability Following IV dosing, dose-independent kinetics was observed over the range of 1 to 5 mg per kg. The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg per kg every 4 hours were 1.1 and 0.1 mcg per mL, respectively. In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours.

The AUC was equivalent when zidovudine was administered as zidovudine tablets or syrup compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are summarized in Table 7. Table 7.

Zidovudine Pharmacokinetic Parameters in Adult Subjects a Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on chronic therapy with zidovudine. b Approximate range. Parameter Mean ± SD (except where noted) Oral bioavailability (%) 64 ± 10 (n = 5) Apparent volume of distribution (L/kg) 1.6 ± 0.6 (n = 8) Cerebrospinal fluid (CSF):plasma ratio a 0.6 [0.04 to 2.62] (n = 39) Systemic clearance (L/h/kg) 1.6 ± 0.6 (n = 6) Renal clearance (L/h/kg) 0.34 ± 0.05 (n = 9) Elimination half-life (h) b 0.5 to 3 (n = 19) Distribution The apparent volume of distribution of zidovudine, is 1.6 ±

0.6L per kg (Table 7); and binding to plasma protein is low (less than 38%). Metabolism and Elimination Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV.

GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of zidovudine.

The AMT AUC was one-fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours. Effect of Food on Absorption Zidovudine may be administered with or without food.

The zidovudine AUC was similar when a single dose of zidovudine was administered with food. Specific Populations Patients with Renal Impairment: Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single 200 mg oral dose (Table 8). Plasma concentrations of AMT were not determined.

No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min. Table 8. Zidovudine Pharmacokinetic Parameters in Subjects with Severe Renal Impairment a a Data are expressed as mean ± standard deviation.

Parameter Control Subjects (Normal Renal Function) (n = 6) Subjects with Renal Impairment (n = 14) CrCl (mL/min) 120 ± 8 18 ± 2 Zidovudine AUC (ng•h/mL) 1,400 ± 200 3,100 ± 300 Zidovudine half-life (h) 1.0 ± 0.2 1.4 ±

0.1Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in subjects with normal renal function.

Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis [see Dosage and Administration (2.5) ] . Patients with Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited.

However, zidovudine is eliminated primarily by hepatic metabolism and it… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Therapy with zidovudine has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.

14.1Adults Combination Therapy Zidovudine in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA. The clinical efficacy of a combination regimen that includes zidovudine was demonstrated in trial ACTG 320. This trial was a multi-center, randomized, double-blind, placebo-controlled trial that compared zidovudine 600 mg per day plus EPIVIR 300 mg per day with zidovudine plus EPIVIR plus indinavir 800 mg three times daily.

The incidence of AIDS-defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm (6.1% versus 10.9%, respectively). Monotherapy In controlled trials of treatment-naive subjects conducted between 1986 and 1989, monotherapy with zidovudine, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These trials enrolled subjects with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in subjects with CD4+ cell counts between 200 and 500 cells per mm 3 (ACTG 016 and ACTG 019).

A survival benefit for monotherapy with zidovudine was not demonstrated in the latter 2 trials. Subsequent trials showed that the clinical benefit of monotherapy with zidovudine was time limited.

14.2Pediatric Patients ACTG 300 was a multi-center, randomized, double-blind trial that provided for comparison of EPIVIR plus zidovudine to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells per mm 3 , and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL.

The median duration that subjects remained on trial was approximately 10 months. Results are summarized in Table 11. Table 11.

Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death) Endpoint EPIVIR plus Zidovudine Tablets (n = 236) Didanosine (n = 235) HIV disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%)

14.3Prevention of Maternal-Fetal HIV-1 Transmission The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm 3 (median in the treated group: 560 cells per mm 3 ) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery.

Following birth, neonates received oral zidovudine syrup for 6 weeks. The trial showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%.

Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.

In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Two transplacental carcinogenicity studies were conducted in mice.

One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine administered in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender.

These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

Mutagenesis Zidovudine was mutagenic in a 5178Y/TK +/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose. Impairment of Fertility Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.