COMBIVIR (lamivudine 150 mg / zidovudine 300 mg) Dailymed

Pregnancy Category C.

Pregnancy Category C. Fetal Risk Summary: There are no adequate and well-controlled studies of COMBIVIR (lamivudine and zidovudine) in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity and fetal malformations (zidovudine), and increased embryolethality (lamivudine). COMBIVIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to COMBIVIR and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Clinical Considerations: Treatment of HIV during pregnancy optimizes the health of both mother and fetus. Clinical trial data reviewed by FDA demonstrate that maternal zidovudine treatment significantly reduces vertical transmission of HIV-1 infection to the fetus [see Clinical Studies (14.2)]. Published data suggest that combination antiretroviral regimens may reduce the rate of vertical transmission even further. Pharmacokinetics of lamivudine and zidovudine in pregnant women are similar to the pharmacokinetics in nonpregnant women. No dose adjustments are needed during pregnancy. In a clinical trial, adverse events among HIV-1-infected women were not different among untreated women and women treated with zidovudine. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients (see Human data below). Data: Human Data: Lamivudine: Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa. The study assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. Lamivudine pharmacokinetics in pregnant women were similar to those seen in nonpregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug [see Clinical Studies (14.2)]. Zidovudine pharmacokinetics were studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant 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. Animal Data: Lamivudine: Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see Nonclinical Toxicology (13.2)]. Zidovudine: Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical Toxicology (13.2)].

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMBIVIR.

Pharmacokinetics in Adults: COMBIVIR: One COMBIVIR 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: The pharmacokinetic properties of lamivudine in fasting patients are summarized in Table 3. 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. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Zidovudine: The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 3. 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. Table 3. Pharmacokinetic Parametersa for Lamivudine and Zidovudine in Adults Parameter Lamivudine Zidovudine Oral bioavailability (%) 86 ± 16 N = 12 64 ± 10 n = 5 Apparent volume of distribution (L/kg) 1.3 ± 0.4 N = 20 1.6 ± 0.6 n = 8 Plasma protein binding (%) <36 <38 CSF:plasma ratiob 0.12 [0.04 to 0.47] n = 38c 0.60 [0.04 to 2.62] N = 39d Systemic clearance (L/hr/kg) 0.33 ± 0.06 N = 20 1.6 ± 0.6 n = 6 Renal clearance (L/hr/kg) 0.22 ± 0.06 N = 20 0.34 ± 0.05 n = 9 Elimination half-life (hr)e 5 to 7 0.5 to 3 a Data presented as mean ± standard deviation except where noted. b Median [range]. c Children. d Adults. e Approximate range. Effect of Food on Absorption of COMBIVIR: COMBIVIR may be administered with or without food. The lamivudine and zidovudine AUC following administration of COMBIVIR with food was similar when compared to fasting healthy subjects (n = 24). Special Populations: Pregnancy: See Use in Specific Populations (8.1). COMBIVIR: No data are available. Zidovudine: Zidovudine pharmacokinetics has been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that of nonpregnant 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. In a nonpregnant adult population, a potential for interaction has been identified. Nursing Mothers: See Use in Specific Populations (8.3). Pediatric Patients: COMBIVIR should not be administered to pediatric patients weighing less than 30 kg. Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age. Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine AUC∞ or lamivudine AUC∞ normalized for body weight. Race: Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined. Drug Interactions: See Drug Interactions (7). No drug interaction studies have been conducted using COMBIVIR Tablets. However, Table 4 presents drug interaction information for the individual components of COMBIVIR. Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr). Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS. Drugs That May Alter Lamivudine Blood Concentrations Coadministered Drug and Dose Lamivudine Dose n Lamivudine Concentrations Concentration of Coadministered Drug AUC Variability Nelfinavir   750 mg q 8 hr x 7 to 10 days single 150 mg 11 ↑AUC 10% 95% CI:1% to 20% ↔ Trimethoprim 160 mg/Sulfamethoxazole   800 mg daily x 5 days single 300 mg 14 ↑AUC 43% 90% CI:32% to 55% ↔ Drugs That May Alter Zidovudine Blood Concentrations Coadministered Drug and Dose Zidovudine Dose n Zidovudine Concentrations Concentration of Coadministered Drug AUC Variability Atovaquone   750 mg q 12 hr with food 200 mg q 8 hr 14 ↑AUC 31% Range23% to 78%b ↔ Clarithromycin   500 mg twice daily 100 mg q 4 hr x 7 days 4 ↓AUC 12% Range ↓34% to ↑14% Not Reported Fluconazole   400 mg daily 200 mg q 8 hr 12 ↑AUC 74% 95% CI:54% to 98% Not Reported Methadone   30 to 90 mg daily 200 mg q 4 hr 9 ↑AUC 43% Range16% to 64%b ↔ Nelfinavir   750 mg q 8 hr x 7 to 10 days single 200 mg 11 ↓AUC 35% Range28% to 41% ↔ Probenecid    500 mg q 6 hr x 2 days 2 mg/kg q 8 hr x 3 days 3 ↑AUC 106% Range100% to 170%b Not Assessed Rifampin   600 mg daily x 14 days 200 mg q 8 hrX 14 days 8 ↓AUC47% 90% CI:41% to 53% Not Assessed Ritonavir   300 mg q 6 hr x 4 days 200 mg q 8 hr x 4 days 9 ↓AUC 25% 95% CI:15% to 34% ↔ Valproic acid    250 mg or 500 mg q 8 hr x 4 days 100 mg q 8 hr x 4 days 6 ↑AUC 80% Range64% to 130%b Not Assessed ↑ = Increase; ↓= Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. a This table is not all inclusive. b Estimated range of percent difference. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.5)].

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

Lamivudine: Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. Zidovudine: Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.

The utility of zidovudine alone for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm (median in the treated group: 560 cells/mm) 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 study 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 study, 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.

The utility of zidovudine alone for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in the treated group: 560 cells/mm3) 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 study 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 study, 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.