Entecavir Sandoz

Entecavir Sandoz

entecavir

Manufacturer:

Sandoz

Distributor:

Zuellig
/
Agencia Lei Va Hong
Full Prescribing Info
Contents
Entecavir.
Description
Each 0.5 mg tablet contains 0.5 mg entecavir (as monohydrate).
Excipients/Inactive Ingredients: Tablet Core: Calcium carbonate, pregelatinized starch, carboxymethylcellulose sodium, soy polysaccharides, citric acid monohydrate, sodium stearyl fumarate. Coating: Hypromellose, titanium dioxide, macrogol, polysorbate 80.
Action
Pharmacotherapeutic Group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors. ATC Code: J05AF10.
Pharmacology: Pharmacodynamics: Mechanism of Action: Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine TP, entecavir-TP functionally inhibits the 3 activities of the viral polymerase: (1) priming of the HBV polymerase, (2) reverse transcription of the negative strand DNA from the pregenomic messenger RNA, and (3) synthesis of the positive strand HBV DNA. The entecavir-TP Ki for HBV DNA polymerase is 0.0012 μM. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β, and δ with Ki values of 18 to 40 μM. In addition, high exposures of entecavir had no relevant adverse effects on γ polymerase or mitochondrial DNA synthesis in HepG2 cells (Ki >160 μM).
Antiviral Activity: Entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir against LVDr HBV (rtL180M and rtM204V) was 0.026 μM (range 0.010-0.059 μM).
Recombinant viruses encoding adefovir-resistant substitutions at either rtN236T or rtA181V remained fully susceptible to entecavir.
An analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV-1 isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to >10 μM; the lower EC50 values were observed when decreased levels of virus were used in the assay.
In cell culture, entecavir selected for an M184I substitution at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir (see Precautions).
In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir at micromolar concentrations was not antagonistic to the anti-HIV activity in cell culture of these six NRTIs or emtricitabine.
Resistance in Cell Culture: Relative to wild-type HBV, LVDr viruses containing rtM204V and rtL180M substitutions within the reverse transcriptase exhibit 8-fold decreased susceptibility to entecavir. Incorporation of additional ETVr amino acid changes rtT184, rtS202 or rtM250 decreases entecavir susceptibility in cell culture. Substitutions observed in clinical isolates (rtT184A, C, F, G, I, L, M or S; rtS202 C, G or I; and/or rtM250I, L or V) further decreased entecavir susceptibility 16- to 741-fold relative to wild-type virus. The ETVr substitutions at residues rtT184, rtS202 and rtM250 alone have only a modest effect on entecavir susceptibility, and have not been observed in the absence of LVDr substitutions in more than 1000 patient samples sequenced. Resistance is mediated by reduced inhibitor binding to the altered HBV reverse transcriptase, and resistant HBV exhibits reduced replication capacity in cell culture.
Indications/Uses
Entecavir Sandoz is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see Pharmacology: Pharmacodynamics under Actions) 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 Precautions).
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 Pharmacology: Pharmacodynamics under Actions, Dosage & Administration and Precautions.
Entecavir Sandoz 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 Pharmacology: Pharmacodynamics under Actions, Dosage & Administration and Precautions.
Dosage/Direction for Use
Therapy should be initiated by a physician experienced in the management of chronic hepatitis B infection.
Compensated liver disease: Nucleoside naive patients: The recommended dose in adults is 0.5 mg once daily, with or without food.
Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance [LVDr] mutations) (see Pharmacology: Pharmacodynamics under Actions and Precautions): The recommended dose in adults is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) (see Pharmacology under Actions). In the presence of LVDr mutations, 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 (see Precautions).
Decompensated Liver Disease: The recommended dose for adult patients with decompensated liver disease is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) (see Pharmacology under Actions). For patients with lamivudine-refractory hepatitis B, see Pharmacology: Pharmacodynamics under Actions and Precautions.
Duration of Therapy: The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows: In HBeAg positive adult patients, treatment should be administered at least until 12 months after achieving HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection on two consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or there is loss of efficacy (see Precautions).
In HBeAg negative adult patients, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.
In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.
Paediatric Population: The decision to treat paediatric patients should be based on careful consideration of individual patient needs and with reference to current paediatric treatment guidelines including the value of baseline histological information. The benefits of long-term virologic suppression with continued therapy must be weighed against the risk of prolonged treatment, including the emergence of resistant hepatitis B virus.
Serum ALT should be persistently elevated for at least 6 months prior to treatment of paediatric patients with compensated liver disease due to HBeAg positive chronic hepatitis B; and for at least 12 months in patients with HBeAg negative disease.
Paediatric patients with body weight of at least 32.6 kg, should be administered a daily dose of one 0.5 mg tablet, with or without food.
Duration of Therapy for Paediatric Patients: The optimal duration of treatment is unknown. In accordance with current paediatric practice guidelines, treatment discontinuation may be considered as follows: In HBeAg positive paediatric patients, treatment should be administered for at least 12 months after achieving undetectable HBV DNA and HBeAg seroconversion (HBeAg loss and anti-HBe detection on two consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or there is loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation (see Precautions).
In HBeAg negative paediatric patients, treatment should be administered until HBs seroconversion or there is evidence of loss of efficacy.
Pharmacokinetics in paediatric patients with renal or hepatic impairment have not been studied.
Elderly: No dosage adjustment based on age is required. The dose should be adjusted according to the patient's renal function (see Dosage Recommendations in Renal Impairment and Pharmacology: Pharmacokinetics under Actions).
Gender and Race: No dosage adjustment based on gender or race is required.
Renal Impairment: The clearance of entecavir decreases with decreasing creatinine clearance (see Pharmacology under Actions). Dose adjustment is recommended for patients with creatinine clearance <50 ml/min, including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The dose can be adjusted by increasing the dosage interval, also shown in the table. 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. (See Table 1.)

Click on icon to see table/diagram/image

Hepatic Impairment: No dose adjustment is required in patients with hepatic impairment.
Administration: Entecavir Sandoz should be taken orally.
Overdosage
There is limited experience of entecavir overdose reported in patients. Healthy subjects who received up to 20 mg/day for up to 14 days, and single doses up to 40 mg had no unexpected adverse reactions. If overdose occurs, the patient must be monitored for evidence of toxicity and given standard supportive treatment as necessary.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Special Precautions
Renal impairment: Dosage adjustment is recommended for patients with renal impairment (see Dosage & Administration). 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 Adverse Reactions). 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 Dosage & Administration). 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 Adverse Reactions). 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 Pharmacology: Pharmacodynamics under Actions and Adverse Reactions).
Lactic acidosis and severe hepatomegaly with steatosis: 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.
Resistance and specific precaution for lamivudine-refractory patients: 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 Pharmacology: Pharmacodynamics under Actions and Interactions). 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.
Paediatric population: A lower rate of virologic response (HBV DNA <50 IU/ml) was observed in paediatric patients with baseline HBV DNA ≥8.0 log10 IU/ml (see Pharmacology: Pharmacodynamics under Actions). 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.
Liver transplant recipients: Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus (see Pharmacology under Actions).
Co-infection with hepatitis C or D: There are no data on the efficacy of entecavir in patients co-infected with hepatitis C or D virus.
Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving concomitant antiretroviral therapy: 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 Pharmacology: Pharmacodynamics under Actions). 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.
HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: Entecavir has been studied in 68 adults with HIV/HBV co-infection receiving a lamivudine-containing HAART regimen (see Pharmacology: Pharmacodynamics under Actions). 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).
General: 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.
Effects on Ability to Drive and Use Machines: 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.
Use In Pregnancy & Lactation
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. The potential risk for humans is unknown. Entecavir Sandoz 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. A risk to the infants cannot be excluded. Breast-feeding should be discontinued during treatment with Entecavir Sandoz.
Fertility: Toxicology studies in animals administered entecavir have shown no evidence of impaired fertility.
Adverse Reactions
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 Description of Selected Adverse Reactions as follows and Precautions).
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 Pharmacology: Pharmacodynamics under Actions). 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. (See Table 2.)

Click on icon to see table/diagram/image

Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or drug exposures (see Precautions).
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: 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%.
Exacerbations During Treatment: 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.
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 (see Precautions). 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.
Paediatric Population: The safety of entecavir in paediatric patients from 2 to <18 years of age is based on two ongoing clinical trials in subjects with chronic HBV infection; one Phase 2 pharmacokinetic trial (study 028) and one Phase 3 trial (study 189). These trials provide experience in 173 HBeAg-positive nucleoside- treatment-naive subjects treated with entecavir for a median duration of 60 weeks. The adverse reactions observed in paediatric subjects who received treatment with entecavir were consistent with those observed in clinical trials of entecavir in adults (see Summary of the Safety Profile previously and Pharmacology: Pharmacodynamics under Actions).
Other Special Populations: 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 Table 2, 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 Precautions).
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/mm3 in 20%.
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 (see Precautions).
Gender/Age: 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).
Drug Interactions
Since entecavir is predominantly eliminated by the kidney (see Pharmacology under Actions), coadministration with medicinal products that reduce renal function or compete for active tubular secretion may increase serum oncentrations 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 Pharmacology under Actions). Therefore CYP450 mediated drug interactions are unlikely to occur with entecavir.
Paediatric Population: Interaction studies have only been performed in adults.
MIMS Class
ATC Classification
J05AF10 - entecavir ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
FC tab 0.5 mg x 30's.
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