Summary of the safety profile: In patients with compensated liver disease, the most common adverse reactions of any severity with at least a possible relation to entecavir were headache, fatigue, dizziness and nausea.
Exacerbations of hepatitis during and after discontinuation of entecavir therapy have also been reported.
List of adverse reactions: Assessment of adverse reactions is based on experience in which patients with chronic hepatitis B infection and compensated liver disease received double-blind treatment with entecavir or lamivudine for up to 107 weeks. The safety profiles, including laboratory abnormalities, were comparable for entecavir 0.5 mg daily, entecavir 1 mg daily and lamivudine.
Adverse reactions considered at least possibly related to treatment with entecavir are listed by body system organ class. Within each group, undesirable effects are presented in order of decreasing seriousness.
Immune system disorders: Rare: Anaphylactoid reaction.
Psychiatric disorder: Common: Insomnia.
Nervous system disorders: Common: Headache, dizziness, somnolence.
Gastrointestinal disorder: Common: Vomiting, diarrhoea, nausea, dyspepsia.
Hepatobiliary disorders: Common: Increased transaminases.
Skin and subcutaneous tissue disorders: Uncommon: Rash, alopecia.
General disorders and administration site conditions: Common: Fatigue.
Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or drug exposures.
Treatment beyond 48 weeks: Continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety signals.
Description of selected adverse reactions: Laboratory test abnormalities: Among nucleoside-naive patients, number of patients had ALT elevations > 3 times baseline and ALT elevations > 2 times baseline together with total bilirubin > 2 times upper limit of normal (ULN) and > 2 times baseline. Albumin levels < 2.5 g/dl, amylase levels > 3 times baseline, lipase levels > 3 times baseline and platelets < 50,000/mm3 occurred in some patients. Among lamivudine-refractory patients, number of patients had ALT elevations > 3 times baseline and ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Amylase levels > 3 times baseline, lipase levels > 3 times baseline and platelets < 50,000/mm3 occurred in some patients.
Exacerbations during treatment: In nucleoside naive patients and lamivudine-refractory patients, on treatment ALT elevations > 10 times ULN and > 2 times baseline occurred in entecavir treated patients vs lamivudine treated patients.
Among entecavir-treated patients, on-treatment ALT elevations had a median time to onset of 4-5 weeks, generally resolved with continued treatment, and, in a majority of cases, were associated with a ≥ 2 log10/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
Exacerbations after discontinuation of treatment: Acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B virus therapy, including therapy with entecavir. In nucleoside-naive patients, some entecavir-treated patients and lamivudine-treated patients experienced ALT elevations (> 10 times ULN and > 2 times reference [minimum of baseline or last end-of-dosing measurement]) during post-treatment follow-up. Among entecavir-treated nucleoside-naïve patients, ALT elevations had a median time to onset of 23-24 weeks, and almost of ALT elevations occurred in HBeAg negative patients. In lamivudine-refractory patients, with only limited numbers of patients being followed up, a few number of entecavir-treated patients and no lamivudine-treated patients developed ALT elevations during post-treatment follow-up.
Entecavir treatment was discontinued if patients achieved a prespecified response. If treatment is discontinued without regard to treatment response, the rate of post-treatment ALT flares could be higher.
Paediatric population: The safety of entecavir in paediatric patients from 2 to < 18 years of age is based on trials in patients with chronic HBV infection. These trials provide experience in number of HBeAg-positive nucleoside-treatment-naïve patients treated with entecavir for a median duration of 99 weeks. The adverse reactions observed in paediatric patients who received treatment with entecavir were consistent with those observed in adults.
Other special populations: Experience in patients with decompensated liver disease: The safety profile of entecavir in patients with decompensated liver disease was assessed, in which patients received treatment with entecavir 1 mg/day or adefovir dipivoxil 10 mg/day. Relative to the adverse reactions noted in section List of adverse reactions, one additional adverse reaction [decrease in blood bicarbonate] was observed in entecavir-treated patients through week 48. The causes of death were generally liver-related, as expected in this population. Serious adverse events were generally liver-related. Patients with high baseline CTP score were at higher risk of developing serious adverse events.
Laboratory test abnormalities: Through week 48 among entecavir-treated patients with decompensated liver disease, none had ALT elevations both > 10 times ULN and > 2 times baseline and few patients had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Albumin levels < 2.5 g/dl, lipase levels > 3 times baseline and platelets < 50,000/mm3 occurred in several patients.
Experience in patients co-infected with HIV: The safety profile of entecavir in a limited number of HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviral therapy) regimens was similar to the safety profile in monoinfected HBV patients.
Gender/age: There was no apparent difference in the safety profile of entecavir with respect to gender or age.