May 25, 2016
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Combivir

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Combivir




CLINICAL PHARMACOLOGY

Mechanism Of Action

COMBIVIR is an antiretroviral agent [see Microbiology].

Pharmacokinetics

Pharmacokinetics in Adults

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: 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.

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/h/kg) 0.33 ± 0.06 n = 20 1.6 ± 0.6 n = 6
Renal clearance (L/h/kg) 0.22 ± 0.06 n = 20 0.34 ± 0.05 n = 9
Elimination half-life (h)e 5 to 7 0.5 to 3
aData presented as mean ±standard deviation except where noted.
bMedian [range].
cChildren.
dAdults.
eApproximate 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 with fasting healthy subjects (n = 24).

Special Populations

Renal Impairment: COMBIVIR: 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).

Hepatic Impairment: COMBIVIR: 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).

Pregnancy: 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.

Gender

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.

Race

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 Interactions

No drug interaction trials have been conducted using COMBIVIR 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).

Other Interactions

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

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 subjects [see WARNINGS AND PRECAUTIONS].

Table 4 presents drug interaction information for the individual components of COMBIVIR.

Table 4: Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa

Coadministered Drug and Dose Drug and Dose n Concentrations of Lamivudine or Zidovudine Concentration of Coadministered Drug
AUC Variability
Nelfinavir 750 mg every 8 h x 7 to 10 days Lamivudine single 150 mg 11 ↑10% 95% CI: 1% to 20%
Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine single 300 mg 14 ↑43% 90% CI: 32% to 55%
Atovaquone 750 mg every 12 h with food Zidovudine 200 mg every 8 h 14 ↑31% Range 23% to 78%b
Clarithromycin 500 mg twice daily Zidovudine 100 mg every 4 h x 7 days 4 ↓12% Range ↓34% to ↑14% Not Reported
Fluconazole 400 mg daily Zidovudine 200 mg every 8 h 12 ↑74% 95% CI: 54% to 98% Not Reported
Methadone 30 to 90 mg daily Zidovudine 200 mg every 4 h 9 ↑43% Range 16% to 64%b
Nelfinavir 750 mg every 8 h x 7 to 10 days Zidovudine single 200 mg 11 ↓35% Range 28% to 41%
Probenecid 500 mg every 6 h x 2 days Zidovudine 2 mg/kg every 8 h x 3 days 3 ↑106% Range 100% to 170%b Not Assessed
Rifampin 600 mg daily x 14 days Zidovudine 200 mg every 8 h x 14 days 8 ↓47% 90% CI: 41% to 53% Not Assessed
Ritonavir 300 mg every 6 h x 4 days Zidovudine 200 mg every 8 h x 4 days 9 ↓25% 95% CI: 15% to 34%
Valproic acid 250 mg or 500 mg every 8 h x 4 days Zidovudine 100 mg every 8 h x 4 days 6 ↑80% Range 64% to 130%b Not Assessed
↑ = Increase; ↓= Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
aThis table is not all inclusive.
bEstimated range of percent difference.

Microbiology

Mechanism of Action

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

Lamivudine plus Zidovudine: In HIV-1–infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity.

Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.

Zidovudine: The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Neither lamivudine nor zidovudine were antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine).

Resistance

In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.

Lamivudine: Lamivudine-resistant isolates of HIV-1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-treated subjects showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (M184V/I).

Zidovudine: HIV-1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analog mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions.

In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.

Cross-resistance

Cross-resistance has been observed among NRTIs. Cross-resistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a substitution at codon 184, which confers resistance to lamivudine.

TAM substitutions are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir.

Animal Toxicology And/Or Pharmacology

Lamivudine

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg per kg per day and 1,000 mg per kg per 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 per kg per 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 per kg per day and rabbits given 500 mg per kg per 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 per kg per day (very near the oral median lethal dose in rats of 3,683 mg per 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 per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less.

Clinical Studies

One COMBIVIR tablet given twice daily is an alternative regimen to EPIVIR tablets 150 mg twice daily plus RETROVIR 600 mg per day in divided doses.

Adults

The NUCB3007 (CAESAR) trial was conducted using EPIVIR 150-mg tablets (150 mg twice daily) and RETROVIR 100-mg capsules (2 x 100 mg 3 times daily). CAESAR was a multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 (median 122) CD4 cells per mm³ at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 5.

Table 5: Number of Subjects (%) with at Least 1 HIV-1 Disease-progression Event or Death

Endpoint Current Therapy
(n = 460)
EPIVIR plus Current Therapy
(n = 896)
EPIVIR plus a NNRTIa plus Current Therapy
(n = 460)
HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%)
Death 27 (5.9%) 23 (2.6%) 14 (3.0%)
aAn investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Prevention Of Maternal-Fetal HIV-1 Transmission

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 per mm³ (median in the treated group: 560 cells per 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 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.

Last reviewed on RxList: 10/8/2015
This monograph has been modified to include the generic and brand name in many instances.

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