Entecavir Accord · 4.3 Contraindications · 1

HOS-098359 · has-adverse-reaction-information · PDF-Seite 8

a. Summary of the safety profile In clinical trials 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 trials 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, adverse reactions 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 conditions: common : fatigue Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or medicinal product 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 trials with nucleoside-naive patients, 5% had ALT elevations > 3 times baseline, and < 1% had ALT elevations > 2 times baseline

Auszug; vollständigen Abschnitt im Original lesen.

HOS-098355 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-098354 · has-indication-information · PDF-Seite 2

Entecavir Accord is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see section 5.1) in adults with: • compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis. • decompensated liver disease (see section 4.4) 2 For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B, see sections 4.2, 4.4 and 5.1. Entecavir Accord is also indicated for the treatment of chronic HBV infection in nucleoside naive paediatric patients from 2 to < 18 years of age with compensated liver disease who have evidence of active viral replication and persistently elevated serum ALT levels, or histological evidence of moderate to severe inflammation and/or fibrosis. With respect to the decision to initiate treatment in paediatric patients, see sections 4.2, 4.4, and 5.1.

HOS-098357 · has-interaction-information · PDF-Seite 7

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 medicinal product interactions are unlikely to occur with entecavir. Paediatric population Interaction studies have only been performed in adults.

HOS-098358 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential: given that the potential risks to the developing foetus are unknown, women of childbearing potential should use effective contraception. Pregnancy: 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. Entecavir Accord 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. Breast-feeding: 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 Entecavir Accord. Fertility: toxicology studies in animals administered entecavir have shown no evidence of impaired fertility (see section 5.3). 7

HOS-098356 · has-warning-information · PDF-Seite 5

Renal impairment: dose 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. Exacerbations of hepatitis: 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. Patients with decompensated liver disease: 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). Lactic acidosis and severe hepatomegaly with steatosis: occurrences

Auszug; vollständigen Abschnitt im Original lesen.