Lamivudine 300 mg, Nevirapine 400 mg, Zidovudine 600 mg (ER) Tablets

Lamivudine is an antiviral agent with activity against HBV [see Microbiology ( 12.4)].

Pharmacokinetics in Adults — The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects.

Absorption and Bioavailability:Following single oral doses of 100 mg, the peak serum lamivudine concentration (C max) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg per mL and 1.05 ± 0.32 mcg per mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC [0 to 24h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (C max), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably.

After oral administration of lamivudine once daily to HBV-infected adults, the AUC and C maxincreased in proportion to dose over the range from 5 mg to 600 mg once daily.

Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg-per mL oral solution.

Effects of Food on Oral Absorption: Lamivudine tablets (HBV) may be administered with or without food. The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states.

Distribution:The apparent volume of distribution after IV administration of lamivudine to 20 HIV-1-infected subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.

Binding of lamivudine to human plasma proteins is less than 36%. In vitrostudies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism:Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by cytochrome P450 enzymes.

Elimination:The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.

In most single-dose trials with plasma sampling for up to 48 or 72 hours after dosing, the observed mean elimination half-life (t½) ranged from 13 to 19 hours. In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per kg.

Specific Populations — Patients with Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy adults and in adults with impaired renal function, with and without hemodialysis (Table 5).

T maxwas not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see Dosage and Administration ( 2.4)] .

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, ß, γ, or δ) are not inhibited by nevirapine.

[see Drug Interactions (7)] — Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects.

While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A.

Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.

Because of the design of the drug interaction trials (addition of 28 days of nevirapine therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by comparison to historical controls.

Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table 5 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

Lamivudine and zidovudine tablet is an antiretroviral agent [see Microbiology ( 12.4)].

Pharmacokinetics in Adults — One lamivudine and zidovudine tablet was bioequivalent to 1 EPIVIR tablet (150 mg) plus 1 RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine:Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3'-amino-3'-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3.

aData presented as mean ± standard deviation except where noted.

Effect of Food on Absorption of Lamivudine and Zidovudine Tablet:Lamivudine and zidovudine tablet may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine tablet with food was similar when compared with fasting healthy subjects (n = 24).

Specific Populations — Patients with Renal Impairment: Lamivudine and Zidovudine Tablet:The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).

Patients with Hepatic Impairment: Lamivudine and Zidovudine Tablet:The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).

Pregnant Women: Lamivudine:Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Zidovudine:Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Geriatric Patients:The pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age.

Male and Female Patients:There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components.

Racial Groups: Lamivudine:There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component.

Zidovudine:The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interaction Studies — No drug interaction trials have been conducted using lamivudine and zidovudine tablets.

Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.