Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine tablets (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 lamivudine tablets (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 lamivudine tablets (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).
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine tablets (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 ( 6.1)] . 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 lamivudine tablets (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 lamivudine tablets (HBV). There is insufficient evidence to determine whether re-initiation of lamivudine tablets (HBV) alters the course of posttreatment exacerbations of hepatitis.
5.3 Risk of HIV-1 Resistance if Lamivudine Tablets (HBV) Is Used in Patients With Unrecognized or Untreated HIV-1 Infection
Lamivudine tablets (HBV) 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 lamivudine tablets (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 lamivudine tablets (HBV), should be consulted. HIV counseling and testing should be offered to all patients before beginning lamivudine tablets (HBV) and periodically during treatment because of the risk of rapid emergence of resistant HIV and limitation of treatment options if lamivudine tablets (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.
Do not coadminister lamivudine tablets (HBV) with other lamivudine-containing products including EPIVIR (lamivudine), COMBIVIR (lamivudine/zidovudine), EPZICOM (abacavir/lamivudine), or TRIZIVIR (abacavir/lamivudine/zidovudine). Do not coadminister lamivudine tablets (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).
In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on– lamivudine tablets (HBV) re-appearance of HBV DNA after an initial decline below the solution-hybridization assay limit [see Microbiology ( 12.4)]. Subjects treated with lamivudine tablets (HBV) (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine tablets (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 lamivudine tablets (HBV) may aid in treatment decisions if emergence of viral mutants is suspected.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.1)].
- Exacerbation of hepatitis B after discontinuation of treatment [see Warnings and Precautions ( 5.2)].
- Risk of emergence of resistant HIV-1 infection [see Warnings and Precautions ( 5.3)] .
- Risk of emergence of resistant HBV infection [see Warnings and Precautions ( 5.4)].
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 practice.
Adverse Reactions in Clinical Trialsof Adults With Chronic Hepatitis B Virus Infection:Clinical adverse reactions (regardless of investigator’s causality assessment) reported in greater or equal to 10% of subjects who received lamivudine tablets (HBV) and reported at a rate greater than placebo are listed in Table 2.
Table 2. Clinical Adverse Reactions a Reported in ≥10% of Subjects who Received Lamivudine Tablets (HBV) for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials 1 to 3)
|Adverse Event||Lamivudine Tablets (HBV) (n = 332)||P lacebo ( n = 200)|
|Ear, Nose, and Throat|
|Ear, nose, and throat infections||25%||21%|
a Includes adverse events regardless of severity and causality assessment.
Specified laboratory abnormalities reported in subjects who received lamivudine tablets (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 Lamivudine Tablets (HBV)Than With Placebo (Trials 1 to 3) a
|Test (Abnormal Level)||Subjects With Abnormality/ Subjects With Observations|
|Lamivudine Tablets (HBV)||Placebo|
|Serum Lipase ≥2.5 x ULN b||10%||7%|
|CPK ≥7 x baseline||9%||5%|
|Platelets <50,000/mm 3||4%||3%|
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.
In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received lamivudine tablets (HBV) than in subjects who had received placebo. A comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued lamivudine tablets (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)
|Abnormal Value||Subjects With ALT Elevations/ Subjects With Observations a|
|Lamivudine Tablets (HBV) b||Placebo b|
|ALT ≥2 x baseline value||27%||19%|
|ALT ≥3 x baseline value c||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%|
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.
Adverse Reactions in Clinical Trialsof Pediatric Subjects With ChronicHepatitis B Virus 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 lamivudine tablets (HBV).
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