EPIVIR HBV (Page 2 of 6)

5.2 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 used to treat HIV-1 infection with EPIVIR tablets and oral solution or with lamivudine-containing antiretroviral fixed-dose combination products.

EPIVIR-HBV is not appropriate for patients co-infected with HBV and HIV-1. If a patient with unrecognized or untreated HIV-1 infection is prescribed EPIVIR-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 EPIVIR-HBV and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 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 who acquires HIV-1 infection during treatment.

5.3 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 assay limit [see Microbiology (12.4)]. Subjects treated with EPIVIR-HBV (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 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 order to reduce the risk of resistance in patients receiving monotherapy with EPIVIR-HBV, a switch to an alternative regimen should be considered if serum HBV DNA remains detectable after 24 weeks of treatment. Optimal therapy should be guided by resistance testing.

5.4 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, including EPIVIR-HBV. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. 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. 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

Exacerbations of hepatitis B after discontinuation of treatment [see Warnings and Precautions (5.1)].
Risk of emergence of resistant HIV-1 infection [see Warnings and Precautions (5.2)].
Risk of emergence of resistant HBV infection [see Warnings and Precautions (5.3)].
Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.4)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience in Adult Subjects with Chronic HBV Infection

Clinical adverse reactions (regardless of investigator’s causality assessment) reported in greater than or equal to 10% of subjects who received EPIVIR-HBV and reported at a rate greater than in subjects who received placebo are listed in Table 2.

Table 2. Clinical Adverse Reactionsa Reported in Greater than or Equal to 10% of Subjects Who Received EPIVIR-HBV for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials 1-3)
a Includes adverse events regardless of severity and causality assessment.

Adverse Event

EPIVIR-HBV (n = 332)

Placebo (n = 200)

Ear, Nose, and Throat

Ear, nose, and throat infections

25%

21%

Sore throat

13%

8%

Gastrointestinal

Diarrhea

14%

12%

Specified laboratory abnormalities reported in subjects who received EPIVIR-HBV and reported at a rate greater than in subjects who received placebo are listed in Table 3.

Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with EPIVIR-HBV than with Placebo (Trials 1-3)a
a Includes subjects treated for 52 to 68 weeks.b Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information.ULN = Upper limit of normal.

Test (Abnormal Level)

Subjects with Abnormality/Subjects with

Observations

EPIVIR-HBV

Placebo

Serum Lipase ≥2.5 x ULNb

10%

7%

CPK ≥7 x baseline

9%

5%

Platelets <50,000/mm3

4%

3%

In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received EPIVIR-HBV than in subjects who had received placebo. A comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued EPIVIR-HBV at Week 52 and subjects in the same trials who received placebo throughout the treatment course is shown in Table 4.

Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials 1 and 3)
a Each subject may be represented in one or more category.b During treatment phase.c Comparable to a Grade 3 toxicity in accordance with modified WHO criteria.ULN = Upper limit of normal.

Abnormal Value

Subjects with ALT Elevation/ Subjects with Observationsa

EPIVIR-HBVb

Placebob

ALT ≥2 x baseline value

27%

19%

ALT ≥3 x baseline valuec

21%

8%

ALT ≥2 x baseline value and absolute ALT >500 IU/L

15%

7%

ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value

0.7%

0.9%

Clinical Trials Experience in Pediatric Subjects with Chronic HBV Infection

Most commonly observed adverse reactions in the pediatric trials were similar to those in adult trials. Posttreatment transaminase elevations were observed in some subjects followed after cessation of EPIVIR-HBV.

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