Epivir-HBV

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lactic Acidosis And Severe Hepatomegaly With Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including EPIVIR-HBV and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Most of these reports have described patients receiving nucleoside analogues for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Particular caution should be exercised when administering EPIVIR-HBV to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with EPIVIR-HBV should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Exacerbation Of Hepatitis After Discontinuation Of Treatment

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of EPIVIR-HBV (these have been primarily detected by serum ALT elevations, in addition to the re-emergence of HBV DNA commonly observed after stopping treatment; see Table 4 for 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 of hepatitis exacerbation after discontinuation of EPIVIR-HBV has not been clearly established. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with EPIVIR-HBV. There is insufficient evidence to determine whether re-initiation of EPIVIR-HBV alters the course of posttreatment exacerbations of hepatitis.

Risk of HIV-1 Resistance If EPIVIR-HBV Is Used In Patients With Unrecognized Or Untreated HIV-1 Infection

EPIVIR-HBV tablets and oral solution contain a lower lamivudine dose than the lamivudine dose in the following drugs used to treat HIV-1 infection:

  • EPIVIR® tablets and oral solution,
  • COMBIVIR® (lamivudine/zidovudine) tablets,
  • EPZICOM® (abacavir sulfate and lamivudine) tablets, and
  • TRIZIVIR® (abacavir, lamivudine, and zidovudine) tablets.

The formulation and dosage of lamivudine in EPIVIR-HBV are not approved for patients co-infected with HBV and HIV. If a decision is made to administer lamivudine to such patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen, and the prescribing information for EPIVIR, COMBIVIR, EPZICOM, or TRIZIVIR, as well as for EPIVIR-HBV, should be consulted. HIV counseling and testing should be offered to all patients before beginning EPIVIR-HBV and periodically during treatment because of the risk of rapid emergence of resistant HIV and limitation of treatment options if EPIVIR-HBV is prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV-1 infection or acquires HIV-1 infection during treatment.

Coadministration With Other Medications Containing Lamivudine Or Emtricitabine

Do not coadminister EPIVIR-HBV with other lamivudine-containing products including EPIVIR (lamivudine), COMBIVIR (lamivudine/zidovudine), EPZICOM (abacavir/lamivudine), or TRIZIVIR (abacavir/lamivudine/zidovudine).

Do not coadminister EPIVIR-HBV with emtricitabine-containing products including ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate), COMPLERA® (rilpivirine/emtricitabine/tenofovir disoproxil fumarate), EMTRIVA® (emtricitabine), STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate), or TRUVADA® (emtricitabine/tenofovir disoproxil fumarate).

Emergence Of Resistance-Associated HBV Substitutions

In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on- EPIVIR-HBV re-appearance of HBV DNA after an initial decline below the solution-hybridization assay limit [see Microbiology]. Subjects treated with EPIVIRHBV (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with EPIVIR-HBV without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations. In the controlled trials, when subjects developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their own previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including subjects from the liver transplant setting and from other clinical trials. In clinical practice, monitoring of ALT and HBV DNA levels during treatment with EPIVIR-HBV may aid in treatment decisions if emergence of viral mutants is suspected.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advice for the Patient
  • Advise patients to remain under the care of a physician while taking EPIVIR-HBV and discuss any new symptoms or concurrent medications with their physician.
  • Advise patients that EPIVIR-HBV is not a cure for hepatitis B, that the long-term treatment benefits of EPIVIR-HBV are unknown at this time, and, in particular, that the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown [see DOSAGE AND ADMINISTRATION].
  • Inform patients that deterioration of liver disease has occurred in some cases when treatment was discontinued. Instruct patients to discuss any changes in regimen with their physician [see WARNINGS AND PRECAUTIONS].
  • Inform patients that emergence of resistant hepatitis B virus and worsening of disease can occur during treatment, and they should promptly report any new symptoms to their physician [see WARNINGS AND PRECAUTIONS].
  • Counsel patients on the importance of testing for HIV to avoid inappropriate therapy and development of resistant HIV. HIV counseling and testing should be offered before starting EPIVIR-HBV and periodically during therapy.
  • Advise patients that EPIVIR-HBV tablets and EPIVIR-HBV oral solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR tablets, EPIVIR oral solution, COMBIVIR tablets, EPZICOM tablets, and TRIZIVIR tablets. EPIVIR-HBV should not be taken concurrently with EPIVIR, COMBIVIR, EPZICOM, or TRIZIVIR [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
  • Advise patients not to take EPIVIR-HBV with emtricitabine-containing medicines, such as ATRIPLA, COMPLERA, EMTRIVA, STRIBILD, or TRUVADA [see WARNINGS AND PRECAUTIONS].
  • Advise patients that treatment with EPIVIR-HBV has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination [see Use In Specific Populations].
  • Instruct patients to avoid doing things that can spread HBV infection to others.
    • Do not share needles or other injection equipment.
    • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
    • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Advise diabetic patients that each 20-mL dose of EPIVIR-HBV oral solution contains 4 grams of sucrose [see DESCRIPTION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice) and 200 times (rats) those observed in humans at the recommended therapeutic dose for chronic hepatitis B.

Mutagenesis

Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg producing plasma levels of 60 to 70 times those in humans at the recommended dose for chronic hepatitis B.

Impairment of Fertility

In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 80 to 120 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled trials of EPIVIR-HBV in pregnant women. Because animal reproduction studies are not always predictive of human response, EPIVIR-HBV should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Animal Data

Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. 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 60 times that for the adult HBV dose. 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 60 times those in humans.

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

Nursing Mothers

Lamivudine is excreted in human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily, 6 times the recommended dosage for hepatitis B infection) or combination therapy (150 mg lamivudine twice daily [3 times the recommended dosage for hepatitis B infection] and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue EPIVIR-HBV taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

Pediatric Use

EPIVIR-HBV is indicated for the treatment of chronic hepatitis B virus infection in pediatric patients aged 2 to 17 years [see INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, Clinical Studies]. The safety and efficacy of EPIVIR-HBV in pediatric patients younger than 2 years have not been established.

Geriatric Use

Clinical trials of EPIVIR-HBV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Patients With Impaired Renal Function

Reduction of the dosage of EPIVIR-HBV is recommended for patients with impaired renal function [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Patients With Impaired Liver Function

No dose adjustment for lamivudine is required for patients with impaired hepatic function.

Last reviewed on RxList: 1/6/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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