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Lamivudine

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Lamivudine Prescribing Information

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including Lamivudine tablets [HBV]). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted

[see Warnings and Precautions (

5.1 Exacerbations of Hepatitis after Discontinuation of Treatment

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re‑emergence of HBV DNA commonly observed after stopping treatment; see Table 4for more information regarding frequency of posttreatment ALT elevations

[see Adverse Reactions ]

. Although most events appear to have been self‑limited, fatalities have been reported in some cases. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment with Lamivudine tablets (HBV). There is insufficient evidence to determine whether re‑initiation of Lamivudine tablets (HBV) alters the course of posttreatment exacerbations of hepatitis.

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Lamivudine tablets (HBV) are not approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection because the lamivudine dosage in Lamivudine tablets (HBV) is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with Lamivudine tablets (HBV) and periodically during treatment

[see Warnings and Precautions (

5.2 Risk of HIV-1 Resistance if Lamivudine Tablets (HBV) are Used in Patients with Unrecognized or Untreated HIV-1 Infection

Lamivudine tablets (HBV) contain a lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection with EPIVIR tablets or with lamivudine-containing antiretroviral fixed-dose combination products.

Lamivudine tablets (HBV) are not appropriate for patients co-infected with HBV and HIV-1. If a patient with unrecognized or untreated HIV-1 infection is prescribed Lamivudine tablets (HBV) for the treatment of HBV, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV-1 treatment. HIV counseling and testing should be offered to all patients before beginning treatment with Lamivudine tablets (HBV) and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 and limitation of treatment options if Lamivudine tablets (HBV) are prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV-1 infection or who acquires HIV-1 infection during treatment.

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Lamivudine tablets (HBV) are indicated for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of hepatitis B viral replication and active liver inflammation

[see Clinical Studies (

14.1 Adult Subjects

The safety and efficacy of lamivudine (HBV) 100 mg once daily versus placebo were evaluated in 3 controlled trials in subjects with compensated chronic hepatitis B virus infection. All subjects were aged 16 years or older and had chronic hepatitis B virus infection (serum HBsAg‑positive for at least 6 months) accompanied by evidence of HBV replication (serum HBeAg‑positive and positive for serum HBV DNA) and persistently elevated ALT levels and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The results of these trials are summarized below.

•Trial 1 was a randomized, double-blind trial of lamivudine (HBV) 100 mg once daily versus placebo for 52 weeks followed by a 16-week no-treatment period in 141 treatment-naive U.S. subjects.
•Trial 2 was a randomized, double-blind, 3-arm trial that compared lamivudine (HBV) 25 mg once daily versus lamivudine (HBV) 100 mg once daily versus placebo for 52 weeks in 358 Asian subjects.
•Trial 3 was a randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis B despite previous treatment with interferon alfa. The trial compared lamivudine (HBV) 100 mg once daily for 52 weeks, followed by either lamivudine (HBV) 100 mg or matching placebo once daily for 16 weeks (Arm 1), versus placebo once daily for 68 weeks (Arm 2).

Principal endpoint comparisons for the histologic and serologic outcomes in subjects receiving lamivudine (HBV) (100 mg daily) or placebo in these trials are shown in the following tables.

Table 7. Histologic Response at Week 52 among Adult Subjects Receiving Lamivudine (HBV) 100 mg Once Daily or Placebo
^aImprovement was defined as a greater than or equal to 2-point decrease in the Knodell Histologic Activity Index (HAI) at Week 52 compared with pretreatment HAI. Subjects with missing data at baseline were excluded.
Assessment	Trial 1		Trial 2		Trial 3
Assessment	Lamivudine (HBV) (n = 62)	Placebo (n = 63)	Lamivudine (HBV) (n = 131)	Placebo (n = 68)	Lamivudine (HBV) (n = 110)	Placebo (n = 54)
Improvement^a	55%	25%	56%	26%	56%	26%
No Improvement	27%	59%	36%	62%	25%	54%
Missing Data	18%	16%	8%	12%	19%	20%

Table 8. HBeAg Seroconverters^aat Week 52 among Adult Subjects Receiving Lamivudine (HBV) 100 mg Once Daily or Placebo
^aThree-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis.
Seroconversion	Trial 1		Trial 2		Trial 3
Seroconversion	Lamivudine (HBV) (n = 63)	Placebo (n = 69)	Lamivudine (HBV) (n = 140)	Placebo (n = 70)	Lamivudine (HBV) (n = 108)	Placebo (n = 53)
Seroconverters	17%	6%	16%	4%	15%	13%

Normalization of serum ALT levels was more frequent with treatment of lamivudine (HBV) compared with placebo in Trials 1, 2, and 3.

The majority of subjects treated with lamivudine (HBV) showed a decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assay-detectable HBV DNA during treatment with lamivudine (HBV) was observed in approximately one-third of subjects after this initial response.

14.2 Pediatric Subjects

The safety and efficacy of lamivudine (HBV) were evaluated in a double‑blind clinical trial in 286 subjects aged 2 to 17 years, who were randomized (2:1) to receive 52 weeks of lamivudine (HBV) (3 mg per kg once daily to a maximum of 100 mg once daily) or placebo. All subjects had compensated chronic hepatitis B accompanied by evidence of hepatitis B virus replication (positive serum HBeAg and positive for serum HBV DNA by a research branched‑chain DNA assay) and persistently elevated serum ALT levels. The combination of loss of HBeAg and reduction of HBV DNA to below the assay limit of the research assay, evaluated at Week 52, was observed in 23% of subjects treated with lamivudine (HBV) and 13% of placebo-treated subjects. Normalization of serum ALT was achieved and maintained to Week 52 more frequently in subjects treated with lamivudine (HBV) compared with placebo (55% versus 13%). As in the adult controlled trials, most subjects treated with lamivudine (HBV) had decreases in HBV DNA below the assay limit early in treatment, but about one-third of subjects with this initial response had reappearance of assay‑detectable HBV DNA during treatment. Adolescents (aged 13 to 17 years) showed less evidence of treatment effect than younger pediatric subjects.

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The following points should be considered when initiating therapy with Lamivudine tablets (HBV):

•Due to high rates of resistance development in treated patients, initiation of treatment with Lamivudine tablets (HBV) should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate.
•Lamivudine tablets (HBV) have not been evaluated in patients co-infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis delta virus.
•Lamivudine tablets (HBV) have not been evaluated in liver transplant recipients or in patients with chronic hepatitis B virus infection with decompensated liver disease.

•Adults: 100 mg, once daily. (
2.2 Recommended Dosage for Adult Patients
The recommended oral dosage of Lamivudine tablets (HBV) is 100 mg once daily.
)
•Pediatric Patients aged 2 to 17 years: 3 mg per kg once daily up to 100 mg once daily. Prescribe the oral solution formulation of lamivudine (EPIVIR-HBV) for pediatric patients requiring less than 100 mg daily. (
2.3 Recommended Dosage for Pediatric Patients
The recommended oral dosage of Lamivudine (HBV) for pediatric patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg. The oral solution formulation of lamivudine (EPIVIR-HBV) should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets.
)

•Patients with Renal Impairment: Doses of Lamivudine tablets (HBV) must be adjusted in accordance with renal function. (

2.4 Patients with Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1

[see Clinical Pharmacology ]

Table 1. Dosage of Lamivudine (HBV) in Adult Patients with Renal Impairment^a
^aThe oral solution formulation of lamivudine (EPIVIR-HBV) should be prescribed for patients requiring a dosage of less than 100 mg.
Creatinine Clearance (mL/min)	Recommended Dosage of Lamivudine Tablets (HBV)
≥50	100 mg once daily
30-49	100 mg first dose, then 50 mg once daily
15-29	100 mg first dose, then 25 mg once daily
5-14	35 mg first dose, then 15 mg once daily
<5	35 mg first dose, then 10 mg once daily

Following correction of the dosage for renal impairment, no additional dosage modification of lamivudine (HBV) is required after routine (4-hour) hemodialysis or peritoneal dialysis

[see Clinical Pharmacology ]

There are insufficient data to recommend a specific dosage of lamivudine (HBV) in pediatric patients with renal impairment.

)

•Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or emtricitabine. (
2.5 Important Administration Instructions
- •Lamivudine tablets (HBV) may be administered with or without food.
- •Lamivudine tablets (HBV) and the oral solution formulation of lamivudine (EPIVIR-HBV) may be used interchangeably
  [see Clinical Pharmacology ]
  .
- •The oral solution formulation of lamivudine (EPIVIR-HBV) should be used for doses less than 100 mg.
- •Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or medications that contain emtricitabine.
)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine 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 substantial difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% reported in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as a U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occur at less than 20 weeks’ gestation. Of over 12,900 women exposed to lamivudine in the APR, less than 2% were HBV mono-infected. The majority of women exposed to lamivudine in the APR were HIV-1–infected and were treated with higher doses of lamivudine compared with HBV mono-infected women. In addition to lamivudine, HIV-1–infected women were also treated with other concomitant medications for HIV-1 infection

(see Data)

. The estimated rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.

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 developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C_max) 60 times the recommended clinical dose

(see Data).

Data

Human Data:

Based on prospective reports from the APR of over 12,900 exposures to lamivudine during pregnancy resulting in live births (including over 5,400 exposed in the first trimester and over 7,500 exposed in the second/third trimester), there was no difference between the overall risk of birth defects with lamivudine compared with the background birth defect rate of 2.7% observed in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers are similar at similar doses. Lamivudine pharmacokinetics were studied in pregnant women with HIV-1 infection during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily (6 times the recommended daily dosage for HBV) without other antiretrovirals. 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 concentrations (n = 8).

Animal Data:

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 53 or more times higher than human exposure at the recommended daily dose. Evidence of early embryolethality in the absence of maternal toxicity was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C_max) 60 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 at plasma concentrations (C_max) 104 times higher than human exposure.

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