Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: BRISTOL-MYERS SQUIBB PHARMA EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge UB8 1DH, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Dosage adjustment is recommended for patients with renal impairment (see section 4.2). The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline (see section 4.8). Among entecavir-treated patients on-treatment exacerbations had a median time of onset of 4-5 weeks. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy (see section 4.2). Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported.
Among entecavir-treated nucleoside naive patients, post-treatment exacerbations had a median time to onset of 23-24 weeks, and most were reported in HBeAg negative patients (see section 4.8). Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted.
A higher rate of serious hepatic adverse events (regardless of causality) has been observed in patients with decompensated liver disease, in particular in those with Child-Turcotte-Pugh (CTP) class C disease, compared with rates in patients with compensated liver function. Also, patients with decompensated liver disease may be at higher risk for lactic acidosis and for specific renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratory parameters should be closely monitored in this patient population (see also sections 4.8 and 5.1).
Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.
To differentiate between elevations in aminotransferases due to response to treatment and increases potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.
Mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with entecavir associated resistance (ETVr). In a small percentage of lamivudine-refractory patients, ETVr substitutions at residues rtT184, rtS202 or rtM250 were present at baseline. Patients with lamivudine-resistant HBV are at higher risk of developing subsequent entecavir resistance than patients without lamivudine resistance. The cumulative probability of emerging genotypic entecavir resistance after 1, 2, 3, 4 and 5 years treatment in the lamivudine-refractory studies was 6%, 15%, 36%, 47% and 51%, respectively. Virological response should be frequently monitored in the lamivudine-refractory population and appropriate resistance testing should be performed. In patients with a suboptimal virological response after 24 weeks of treatment with entecavir, a modification of treatment should be considered (see sections 4.5 and 5.1). When starting therapy in patients with a documented history of lamivudine-resistant HBV, combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy.
Pre-existing lamivudine-resistant HBV is associated with an increased risk for subsequent entecavir resistance regardless of the degree of liver disease; in patients with decompensated liver disease, virologic breakthrough may be associated with serious clinical complications of the underlying liver disease. Therefore, in patients with both decompensated liver disease and lamivudine-resistant HBV, combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy.
A lower rate of virologic response (HBV DNA <50 IU/ml) was observed in paediatric patients with baseline HBV DNA ≥8.0 log 10 IU/ml (see section 5.1). Entecavir should be used in these patients only if the potential benefit justifies the potential risk to the child (e.g. resistance). Since some paediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of entecavir on future treatment options.
Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus (see section 5.2).
There are no data on the efficacy of entecavir in patients co-infected with hepatitis C or D virus.
Entecavir has not been evaluated in HIV/HBV co-infected patients not concurrently receiving effective HIV treatment. Emergence of HIV resistance has been observed when entecavir was used to treat chronic hepatitis B infection in patients with HIV infection not receiving highly active antiretroviral therapy (HAART) (see section 5.1). Therefore, therapy with entecavir should not be used for HIV/HBV co-infected patients who are not receiving HAART. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use.
Entecavir has been studied in 68 adults with HIV/HBV co-infection receiving a lamivudine-containing HAART regimen (see section 5.1). No data are available on the efficacy of entecavir in HBeAg-negative patients co-infected with HIV. There are limited data on patients co-infected with HIV who have low CD4 cell counts (<200 cells/mm³).
Patients should be advised that therapy with entecavir has not been proven to reduce the risk of transmission of HBV and therefore appropriate precautions should still be taken.
This medicinal product contains 120.5 mg of lactose in each 0.5 mg daily dose or 241 mg of lactose in each 1 mg daily dose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. A lactose-free Baraclude oral solution is available for these individuals.
Since entecavir is predominantly eliminated by the kidney (see section 5.2), coadministration with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of either medicinal product. Apart from lamivudine, adefovir dipivoxil and tenofovir disoproxil fumarate, the effects of coadministration of entecavir with medicinal products that are excreted renally or affect renal function have not been evaluated. Patients should be monitored closely for adverse reactions when entecavir is coadministered with such medicinal products.
No pharmacokinetic interactions between entecavir and lamivudine, adefovir or tenofovir were observed.
Entecavir is not a substrate, an inducer or an inhibitor of cytochrome P450 (CYP450) enzymes (see section 5.2). Therefore CYP450 mediated drug interactions are unlikely to occur with entecavir.
Interaction studies have only been performed in adults.
Given that the potential risks to the developing foetus are unknown, women of childbearing potential should use effective contraception.
There are no adequate data from the use of entecavir in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Baraclude should not be used during pregnancy unless clearly necessary. There are no data on the effect of entecavir on transmission of HBV from mother to newborn infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
It is unknown whether entecavir is excreted in human milk. Available toxicological data in animals have shown excretion of entecavir in milk (for details see section 5.3). A risk to the infants cannot be excluded. Breast-feeding should be discontinued during treatment with Baraclude.
Toxicology studies in animals administered entecavir have shown no evidence of impaired fertility (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. Dizziness, fatigue and somnolence are common side effects which may impair the ability to drive and use machines.
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).
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.
Rare: anaphylactoid reaction
Common: insomnia
Common: headache, dizziness, somnolence
Common: vomiting, diarrhoea, nausea, dyspepsia
Common: increased transaminases
Uncommon: rash, alopecia
Common: fatigue
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.
Laboratory test abnormalities: In clinical studies with nucleoside-naive patients, 5% had ALT 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/mm³ in <1%.
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/mm³ in <1%.
In studies with nucleoside naive patients, on treatment ALT 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 log10/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
Acute exacerbations of hepatitis have been reported 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 23-24 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. In studies in 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.
Experience in patients with decompensated liver disease: the safety profile of entecavir in patients 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).
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/mm³ in 20%.
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 (see section 4.4).
There was no apparent difference in the safety profile of entecavir with respect to gender (≈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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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