HEPTAVIR

A reverse transcriptase inhibitor and zalcitabine analog in which a sulfur atom replaces the 3' carbon of the pentose ring.

It is used to treat Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV).

Lamivudine is indicated in combination with other antiretrovirals the treatment of HIV infection and chronic hepatitis B (HBV).

In combination with dolutegravir, lamivudine is indicated for the treatment of HIV-1 in patients ≥12 years of age and weighing ≥25 kg.

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis.

When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA.

DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis.

Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.

Reverse transcriptase/RNaseH (Human immunodeficiency virus 1) Inhibitor DNA Binder Protein P (HBV-F) Inhibitor.

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients.

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

The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients.

When given with food, absorption is slower, compared to the fasted state.

Apparent volume of distribution, Intravenous administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

of lamivudine is a minor route of elimination.

In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite.

This biotransformation is catalyzed by sulfotransferases.

Hover over products below to view reaction partners Lamivudine Lamivudine sulfoxide Lamivudine-diphosphate-choline Lamivudine-diphosphate-ethanolamine Lamivudine-monophosphate Lamivudine-triphosphate.

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine.

Lamivudine is excreted in human breast milk and into the milk of lactating rats.

5-7 hours (healthy or HBV-infected patients).

Renal clearance = 199.7 ± 56.9 mL/min Renal clearance = 280.4 ± 75.2 mL/min Total clearance = 398.5 ± 69.1 mL/min.

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The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

Lamivudine and zidovudine tablets are contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine.

• Adults and Adolescents weighing greater than or equal to 30 kg: 1 tablet orally twice daily.

• Pediatrics weighing greater than or equal to 30 kg: 1 tablet orally twice daily.

• Because lamivudine and zidovudine tablet is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablet is not recommended in patients requiring dosage adjustment or with hepatic impairment or experiencing dose-limiting adverse reactions. 2.1 Recommended Dosage for Adults and Adolescents The recommended dosage of lamivudine and zidovudine tablet in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily. 2.2 Recommended Dosage for Pediatric Patients The recommended dosage of scored lamivudine and zidovudine tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily.

Before prescribing lamivudine and zidovudine tablets, children should be assessed for the ability to swallow tablets.

If a child is unable to reliably swallow a lamivudine and zidovudine tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) oral solution and RETROVIR (zidovudine) syrup. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because lamivudine and zidovudine is a fixed-dose tablet and cannot be dose adjusted, lamivudine and zidovudine tablets are not recommended for:

• pediatric patients weighing less than 30 kg.

• patients with creatinine clearance less than 50 mL per minute.

• patients with hepatic impairment.

• patients experiencing dose-limiting adverse reactions.

Liquid and solid oral formulations of the individual components of lamivudine and zidovudine tablets are available for these populations.

71335-0639-1: 6 Tablets in a BOTTLE NDC: 71335-0639-2: 60 Tablets in a BOTTLE NDC: 71335-0639-3: 4 Tablets in a BOTTLE.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine and zidovudine during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary Available data from the

APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population.

The APR uses the MACDP as the U.S. reference population for birth defects in the general population.

MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.

The background risk for major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose.

Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose.

However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose.

Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose.

However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose.

Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP.

The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa.

The trial 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.

These trials were not designed or powered to provide efficacy information.

Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans.

Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP.

The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens.

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.

Of the 363 neonates that were evaluated, 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 trial drug.

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]).

No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose.

Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 times higher than human exposure at the recommended daily dose.

Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta.

In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20).

In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily).

However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose.

An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days 6 through 18) showed increased fetal resorptions at the 500 mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose.

These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine.

In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC.

However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

Lamivudine and zidovudine tablet is not recommended for use in pediatric patients who weigh less than 30 kg because it is a fixed-dose combination tablet that cannot be adjusted for this patient population.

Clinical trials of lamivudine and zidovudine tablet did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

In general, caution should be exercised in the administration of lamivudine and zidovudine tablet in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.