Adverse reactions : תופעות לוואי

4.8   Undesirable effects
 a. Summary of the safety profile
In clinical studies in patients with compensated liver disease, the most common adverse reactions of any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%). Exacerbations of hepatitis during and after discontinuation of entecavir therapy have also been reported (see section 4.4 and c. Description of selected adverse reactions).
 b. Tabulated list of adverse reactions
Assessment of adverse reactions is based on experience from postmarketing surveillance and four clinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liver disease received double-blind treatment with entecavir (n = 862) or lamivudine (n = 858) for up to 107 weeks (see section 5.1). In these studies, the safety profiles, including laboratory abnormalities, were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative patients treated for a median of 53 weeks), entecavir 1 mg daily (183 lamivudine-refractory patients treated for a median of 69 weeks), and lamivudine.

Adverse reactions considered at least possibly related to treatment with entecavir are listed by body system organ class. Frequency is defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Immune system disorders:                                              rare: anaphylactoid reaction 
Psychiatric disorders:                                                common: insomnia 
Nervous system disorders:                                             common: headache, dizziness, somnolence 
Gastrointestinal disorders:                                           common: vomiting, diarrhoea, nausea, dyspepsia 
Hepatobiliary disorders                                               common: increased transaminases 
Skin and subcutaneous tissue disorders:                               uncommon: rash, alopecia 
General disorders and administration site                             common: fatigue conditions:

Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or drug exposures (see section 4.4).

Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety signals.
 c. Description of selected adverse reactions

Laboratory test abnormalities : In clinical studies with nucleoside-naive patients, 5% had ALT U                              U


 elevations > 3 times baseline, and < 1% had 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 occurred in < 1% of patients, amylase levels > 3 times baseline in 2%, lipase levels > 3 times baseline in 11% and platelets < 50,000/mm 3 in < 1%.
P   P



In clinical studies with lamivudine-refractory patients, 4% had ALT elevations > 3 times baseline, and < 1% had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Amylase levels > 3 times baseline occurred in 2% of patients, lipase levels > 3 times baseline in 18% and platelets < 50,000/mm 3 in < 1%.          P   P



Exacerbations during treatment: in studies with nucleoside naive patients, on treatment ALT U                                  U


 elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 4% of lamivudine treated patients. In studies with lamivudine-refractory patients, on treatment ALT elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 11% of 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 log 10 /ml reduction in viral load that preceded or coincided with the 23T R   R23T



ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.

Exacerbations after discontinuation of treatment: acute exacerbations of hepatitis have been reported U                                                                        U 

 in patients who have discontinued anti-hepatitis B virus therapy, including therapy with entecavir (see section 4.4). In studies in nucleoside-naive patients, 6% of entecavir-treated patients and 10% of 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-naive patients, ALT elevations had a median time to onset of                          19T 


23-24 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. In studies in            19T


 lamivudine-refractory patients, with only limited numbers of patients being followed up, 11% of entecavir-treated patients and no lamivudine-treated patients developed ALT elevations during post- treatment follow-up.

In the clinical trials 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.
 d. Other special populations

Experience in patients with decompensated liver disease: the safety profile of entecavir in patients U                                                                                 U 

 with decompensated liver disease was assessed in a randomized open-label comparative study in which patients received treatment with entecavir 1 mg/day (n = 102) or adefovir dipivoxil 10 mg/day (n = 89) (study 048). Relative to the adverse reactions noted in section b. Tabulated list of adverse reactions, one additional adverse reaction [decrease in blood bicarbonate (2%)] was observed in entecavir-treated patients through week 48. The on-study cumulative death rate was 23% (23/102), and causes of death were generally liver-related, as expected in this population. The on-study cumulative rate of hepatocellular carcinoma (HCC) was 12% (12/102). Serious adverse events were generally liver-related, with an on-study cumulative frequency of 69%. Patients with high baseline CTP score were at higher risk of developing serious adverse events (see section 4.4).

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 1% of patients had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Albumin levels < 2.5 g/dl occurred in 30% of patients, lipase levels > 3 times baseline in 10% and platelets < 50,000/mm 3 in 20%.
P   P



Experience in patients co-infected with HIV: the safety profile of entecavir in a limited number of U                                             U



HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviral therapy) regimens was similar to the safety profile in monoinfected HBV patients (see section 4.4).

Gender/age: there was no apparent difference in the safety profile of entecavir with respect to gender U              U



(≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go v.il