Entecavir Tablet USP 1mg Taj Pharma

  1. Name of the medicinal product

Entecavir Tablet USP 0.5mg Taj Pharma
Entecavir Tablet USP 1mg Taj Pharma

  1. Qualitative and quantitative composition

a) Entecavir Tablet USP 0.5mg Taj Pharma
Each film-coated tablets contains:
Entecavir Monohydrate USP
Equivalent to Entecavir 0.5mg
Excipients: Q.S.

b) Entecavir Tablet USP 1mg Taj Pharma
Each film coated tablets contains:
Entecavir Monohydrate USP
Equivalent to Entecavir 1mg
Excipients: Q.S.

Excipients with known effect:

Each 0.5mg film-coated tablet contains 121mg lactose monohydrate.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet (tablet).

Entecavir Taj Pharma 0.5mg/1mg film-coated tablets

White oval shaped tablet with a size of about

  1. Clinical particulars
  • Therapeutic indications

Adult indication

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)

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.

Paediatric population

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.

  • Posology and method of administration

Therapy should be initiated by a physician experienced in the management of chronic hepatitis B infection.

Posology

Compensated liver disease

Nucleoside naïve patients: the recommended dose in adults is 0.5mg 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 sections 4.4 and 5.1): the recommended dose in adults is 1mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) (see section 5.2). In the presence of LVDr mutations, combination use of Entecavir Taj Pharma plus a second antiviral agent (which does not share cross-resistance with either lamivudine or Entecavir Taj Pharma) should be considered in preference to Entecavir Taj Pharma monotherapy (see section 4.4.).

Decompensated liver disease

The recommended dose for adult patients with decompensated liver disease is 1mg once daily, which must be taken on an empty stomach (more than 2 hours before and more than 2 hours after a meal) (see section 5.2). For patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1.

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 section 4.4).
  • 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

For appropriate dosing in the paediatric population, Entecavir Taj Pharma 0.5mg film-coated tablets are available and for dosages below 0.5mg an oral solution may be available.

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 0.5mg tablet with or without food. An oral solution may be available for patients with body weight less than 32.6 kg.

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 section 4.4).
  • 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 section 5.2).

Gender and race: no dosage adjustment based on gender or race is required.

Renal impairment: the clearance of Entecavir Taj Pharma decreases with decreasing creatinine clearance (see section 5.2). Dose adjustment is recommended for patients with creatinine clearance < 50 ml/min, including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A reduction of the daily dose using Entecavir Taj Pharma oral solution, as detailed in the table, is recommended. As an alternative, in case the oral solution is not available, 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.

Creatinine clearance (ml/min) Entecavir Taj Pharma dosage
Nucleoside naïve patients Lamivudine-refractory or decompensated liver disease
≥ 50 0.5mg once daily 1mg once daily
30 – 49 0.25mg once daily*

OR

0.5mg every 48 hours

0.5mg once daily
10 – 29 0.15mg once daily*

OR

0.5mg every 72 hours

0.3mg once daily*

OR

0.5mg every 48 hours

< 10

Haemodialysis or CAPD**

0.05mg once daily*

OR

0.5mg every 5-7 days

0.1mg once daily*

OR

0.5mg every 72 hours

* For doses < 0.5mg Entecavir Taj Pharma Entecavir Taj Pharma oral solution is recommended

** on haemodialysis days, administer Entecavir Taj Pharma after haemodialysis.

Hepatic impairment: no dose adjustment is required in patients with hepatic impairment.

Method of administration

Oral use.

  • Contraindications

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

  • Special warnings and precautions for use

Renal impairment: 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.

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 Taj Pharma-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 Taj Pharma-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 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 Taj Pharma 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 Taj Pharma 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 Taj Pharma resistance than patients without lamivudine resistance. The cumulative probability of emerging genotypic Entecavir Taj Pharma 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 Taj Pharma, 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 Taj Pharma plus a second antiviral agent (which does not share cross-resistance with either lamivudine or Entecavir Taj Pharma) should be considered in preference to Entecavir Taj Pharma monotherapy.

Pre-existing lamivudine-resistant HBV is associated with an increased risk for subsequent Entecavir Taj Pharma 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 Taj Pharma plus a second antiviral agent (which does not share cross-resistance with either lamivudine or Entecavir Taj Pharma) should be considered in preference to Entecavir Taj Pharma 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 section 5.1). Entecavir Taj Pharma 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 Taj Pharma on future treatment options.

Liver transplant recipients: renal function should be carefully evaluated before and during Entecavir Taj Pharma therapy in liver transplant recipients receiving cyclosporine or tacrolimus (see section 5.2).

Co-infection with hepatitis C or D: there are no data on the efficacy of Entecavir Taj Pharma in patients co-infected with hepatitis C or D virus.

Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving concomitant antiretroviral therapy: Entecavir Taj Pharma 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 Taj Pharma 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 Taj Pharma should not be used for HIV/HBV co-infected patients who are not receiving HAART. Entecavir Taj Pharma 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 Taj Pharma 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 Taj Pharma 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 Taj Pharma has not been proven to reduce the risk of transmission of HBV and therefore appropriate precautions should still be taken.

Lactose: this medicinal product contains 121mg of lactose in each 0.5mg daily dose or 242mg of lactose in each 1mg 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 Entecavir Taj Pharma oral solution is available for these individuals.

  • Interaction with other medicinal products and other forms of interaction

Since Entecavir Taj Pharma 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 Taj Pharma 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 Taj Pharma is coadministered with such medicinal products.

No pharmacokinetic interactions between Entecavir Taj Pharma and lamivudine, adefovir or tenofovir were observed.

Entecavir Taj Pharma 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 Taj Pharma.

Paediatric population

Interaction studies have only been performed in adults.

  • Fertility, pregnancy and 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 Taj Pharma 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 Taj Pharmashould not be used during pregnancy unless clearly necessary. There are no data on the effect of Entecavir Taj Pharma 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 Taj Pharma is excreted in human milk. Available toxicological data in animals have shown excretion of Entecavir Taj Pharma 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 Taj Pharma film coated tablets.

Fertility: toxicology studies in animals administered Entecavir Taj Pharma have shown no evidence of impaired fertility (see section 5.3).

  • 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.

  • Undesirable effects
  1. 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 Taj Pharma were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%). Exacerbations of hepatitis during and after discontinuation of Entecavir Taj Pharma therapy have also been reported (see section 4.4 and c. Description of selected adverse reactions).

  1. 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 Taj Pharma (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 Taj Pharma 0.5mg daily (679 nucleoside-naive HBeAg positive or negative patients treated for a median of 53 weeks), Entecavir Taj Pharma 1mg 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 Taj Pharma 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 conditions: 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 Taj Pharma for a median duration of 96 weeks did not reveal any new safety signals.

  1. 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 Taj Pharma 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 Taj Pharma treated patients vs 11% of lamivudine treated patients. Among Entecavir Taj Pharma-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 Taj Pharma (see section 4.4). In studies in nucleoside-naive patients, 6% of Entecavir Taj Pharma-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 Taj Pharma-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 Taj Pharma-treated patients and no lamivudine-treated patients developed ALT elevations during post- treatment follow-up.

In the clinical trials Entecavir Taj Pharma 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.

  1. Paediatric Population

The safety of Entecavir Taj Pharma 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 195 HBeAg-positive nucleoside-treatment-naïve subjects treated with Entecavir Taj Pharma for a median duration of 99 weeks. The adverse reactions observed in paediatric subjects who received treatment with Entecavir Taj Pharma were consistent with those observed in clinical trials of Entecavir Taj Pharma in adults (see a. Summary of the safety profile and section 5.1).

  1. Other special populations

Experience in patients with decompensated liver disease: the safety profile of Entecavir Taj Pharma in patients with decompensated liver disease was assessed in a randomized open-label comparative study in which patients received treatment with Entecavir Taj Pharma 1mg/day (n = 102) or adefovir dipivoxil 10mg/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 Taj Pharma-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 Taj Pharma-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 Taj Pharma 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).

Gender/age: there was no apparent difference in the safety profile of Entecavir Taj Pharma with respect to gender (≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).

Reporting of suspected adverse reactions: 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.

  • Overdose

There is limited experience of Entecavir Taj Pharma overdose reported in patients. Healthy subjects who received up to 20mg/day for up to 14 days, and single doses up to 40mg had no unexpected adverse reactions. If overdose occurs, the patient must be monitored for evidence of toxicity and given standard supportive treatment as necessary.

  1. Pharmacological properties
    • Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors

Mechanism of action: Entecavir Taj Pharma, 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 Taj Pharma-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 Taj Pharma-TP Ki for HBV DNA polymerase is 0.0012 μM. Entecavir Taj Pharma-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 Taj Pharma had no relevant adverse effects on γ polymerase or mitochondrial DNA synthesis in HepG2 cells (Ki > 160 µM).

Antiviral activity: Entecavir Taj Pharma 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 Taj Pharma 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 Taj Pharma.

An analysis of the inhibitory activity of Entecavir Taj Pharma 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 Taj Pharma selected for an M184I substitution at micromolar concentrations, confirming inhibitory pressure at high Entecavir Taj Pharma concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to Entecavir Taj Pharma (see section 4.4).

In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir or zidovudine were not antagonistic to the anti-HBV activity of Entecavir Taj Pharma over a wide range of concentrations. In HIV antiviral assays, Entecavir Taj Pharma 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 Taj Pharma. Incorporation of additional ETVr amino acid changes rtT184, rtS202 or rtM250 decreases Entecavir Taj Pharma 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 Taj Pharma 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 Taj Pharma 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.

Clinical experience: the demonstration of benefit is based on histological, virological, biochemical, and serological responses after 48 weeks of treatment in active-controlled clinical trials of 1,633 adults with chronic hepatitis B infection, evidence of viral replication and compensated liver disease. The safety and efficacy of Entecavir Taj Pharma were also evaluated in an active-controlled clinical trial of 191 HBV- infected patients with decompensated liver disease and in a clinical trial of 68 patients co-infected with HBV and HIV.

In studies in patients with compensated liver disease, histological improvement was defined as a ≥ 2-point decrease in Knodell necro-inflammatory score from baseline with no worsening of the Knodell fibrosis score. Responses for patients with baseline Knodell Fibrosis Scores of 4 (cirrhosis) were comparable to overall responses on all efficacy outcome measures (all patients had compensated liver disease). High baseline Knodell necroinflammatory scores (> 10) were associated with greater histological improvement in nucleoside-naive patients. Baseline ALT levels ≥ 2 times ULN and baseline HBV DNA ≤ 9.0 log10 copies/ml were both associated with higher rates of virologic response (Week 48 HBV DNA < 400 copies/ml) in nucleoside-naive HBeAg-positive patients. Regardless of baseline characteristics, the majority of patients showed histological and virological responses to treatment.

Experience in nucleoside-naive patients with compensated liver disease:

Results at 48 weeks of randomised, double blind studies comparing Entecavir Taj Pharma (ETV) to lamivudine (LVD) in HBeAg positive (022) and HBeAg negative (027) patients are presented in the table.

Nucleoside Naive
HBeAg Positive (study 022) HBeAg Negative (study 027)
ETV

0.5mg once daily

LVD

100mg once daily

ETV

0.5mg once daily

LVD

100mg once daily

n 314a 314a 296a 287a
Histological improvementb 72%* 62% 70%* 61%
Ishak fibrosis score improvement 39% 35% 36% 38%
Ishak fibrosis score worsening 8% 10% 12% 15%
n 354 355 325 313
Viral load reduction (log10 copies/ml)c -6.86* -5.39 -5.04* -4.53
HBV DNA undetectable (< 300 copies/ml by PCR)c 67%* 36% 90%* 72%
ALT normalisation (≤ 1 times ULN) 68%* 60% 78%* 71%
HBeAg Seroconversion 21% 18%

*p value vs lamivudine < 0.05

a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2)

b a primary endpoint

c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml)

Experience in lamivudine-refractory patients with compensated liver disease:

In a randomised, double-blind study in HBeAg positive lamivudine-refractory patients (026), with 85% of patients presenting LVDr mutations at baseline, patients receiving lamivudine at study entry either switched to Entecavir Taj Pharma 1mg once daily, with neither a washout nor an overlap period (n = 141), or continued on lamivudine 100mg once daily (n = 145). Results at 48 weeks are presented in the table.

Lamivudine-refractory
HBeAg positive (study 026)
ETV 1.0mg once daily LVD 100mg once daily
n 124a 116a
Histological improvementb 55%* 28%
Ishak fibrosis score improvement 34%* 16%
Ishak fibrosis score worsening 11% 26%
n 141 145
Viral load reduction (log10 copies/ml)c -5.11* -0.48
HBV DNA undetectable (< 300 copies/ml by PCR)c 19%* 1%
ALT normalisation (≤ 1 times ULN) 61%* 15%
HBeAg Seroconversion 8% 3%

*p value vs lamivudine < 0.05

a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2)

b a primary endpoint.

c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml)

Results beyond 48 weeks of treatment:

Treatment was discontinued when prespecified response criteria were met either at 48 weeks or during the second year of treatment. Response criteria were HBV virological suppression (HBV DNA < 0.7 MEq/ml by bDNA) and loss of HBeAg (in HBeAg positive patients) or ALT < 1.25 times ULN (in HBeAg negative patients). Patients in response were followed for an additional 24 weeks off- treatment. Patients who met virologic but not serologic or biochemical response criteria continued blinded treatment. Patients who did not have a virologic response were offered alternative treatment.

Nucleoside-naive:

HBeAg positive (study 022): treatment with Entecavir Taj Pharma for up to 96 weeks (n = 354) resulted in cumulative response rates of 80% for HBV DNA < 300 copies/ml by PCR, 87% for ALT normalisation, 31% for HBeAg seroconversion and 2% for HBsAg seroconversion (5% for HBsAg loss). For lamivudine (n = 355), cumulative response rates were 39% for HBV DNA < 300 copies/ml by PCR, 79% for ALT normalisation, 26% for HBeAg seroconversion, and 2% for HBsAg seroconversion (3% for HBsAg loss).

At end of dosing, among patients who continued treatment beyond 52 weeks (median of 96 weeks), 81% of 243 Entecavir Taj Pharma-treated and 39% of 164 lamivudine-treated patients had HBV DNA < 300 copies/ml by PCR while ALT normalisation (≤ 1 times ULN) occurred in 79% of Entecavir Taj Pharma- treated and 68% of lamivudine-treated patients.

HBeAg negative (study 027): treatment with Entecavir Taj Pharma up to 96 weeks (n = 325) resulted in cumulative response rates of 94% for HBV DNA < 300 copies/ml by PCR and 89% for ALT normalisation versus 77% for HBV DNA < 300 copies/ml by PCR and 84% for ALT normalisation for lamivudine-treated patients (n = 313).

For 26 Entecavir Taj Pharma-treated and 28 lamivudine-treated patients who continued treatment beyond 52 weeks (median 96 weeks), 96% of Entecavir Taj Pharma-treated and 64% of lamivudine-treated patients had HBV DNA < 300 copies/ml by PCR at end of dosing. ALT normalisation (≤ 1 times ULN) occurred in 27% of Entecavir Taj Pharma-treated and 21% of lamivudine-treated patients at end of dosing.

For patients who met protocol-defined response criteria, response was sustained throughout the 24- week post-treatment follow-up in 75% (83/111) of Entecavir Taj Pharma responders vs 73% (68/93) for lamivudine responders in study 022 and 46% (131/286) of Entecavir Taj Pharma responders vs 31% (79/253) for lamivudine responders in study 027. By 48 weeks of post-treatment follow-up, a substantial number ofHBeAg negative patients lost response.

Liver biopsy results: 57 patients from the pivotal nucleoside-naive studies 022 (HBeAg positive) and 027 (HBeAg negative) who enrolled in a long-term rollover study were evaluated for long-term liver histology outcomes. The Entecavir Taj Pharma dosage was 0.5mg daily in the pivotal studies (mean exposure 85 weeks) and 1mg daily in the rollover study (mean exposure 177 weeks), and 51 patients in the rollover study initially also received lamivudine (median duration 29 weeks). Of these patients, 55/57 (96%) had histological improvement as previously defined (see above), and 50/57 (88%) had a ≥ 1- point decrease in Ishak fibrosis score. For patients with baseline Ishak fibrosis score ≥ 2, 25/43 (58%) had a ≥ 2-point decrease. All (10/10) patients with advanced fibrosis or cirrhosis at baseline (Ishak fibrosis score of 4, 5 or 6) had a ≥ 1 point decrease (median decrease from baseline was 1.5 points). At the time of the long-term biopsy, all patients had HBV DNA < 300 copies/ml and 49/57 (86%) had serum ALT ≤ 1 times ULN. All 57 patients remained positive for HBsAg.

Lamivudine-refractory:

HBeAg positive (study 026): treatment with Entecavir Taj Pharma for up to 96 weeks (n = 141) resulted in cumulative response rates of 30% for HBV DNA < 300 copies/ml by PCR, 85% for ALT normalisation and 17% for HBeAg seroconversion.

For the 77 patients who continued Entecavir Taj Pharma treatment beyond 52 weeks (median 96 weeks), 40% of patients had HBV DNA < 300 copies/ml by PCR and 81% had ALT normalisation (≤ 1 times ULN) at end of dosing.

Age/gender:

There was no apparent difference in efficacy for Entecavir Taj Pharma based on gender (≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).

Special populations

Patients with decompensated liver disease: in study 048, 191 patients with HBeAg positive or negative chronic HBV infection and evidence of hepatic decompensation, defined as a CTP score of 7 or higher, received Entecavir Taj Pharma 1mg once daily or adefovir dipivoxil 10mg once daily. Patients were either HBV-treatment-naïve or pretreated (excluding pretreatment with Entecavir Taj Pharma, adefovir dipivoxil, or tenofovir disoproxil fumarate). At baseline, patients had a mean CTP score of 8.59 and 26% of patients were CTP class C. The mean baseline Model for End Stage Liver Disease (MELD) score was 16.23. Mean serum HBV DNA by PCR was 7.83 log10 copies/ml and mean serum ALT was 100 U/l; 54% of patients were HBeAg positive, and 35% of patients had LVDr substitutions at baseline. Entecavir Taj Pharma was superior to adefovir dipivoxil on the primary efficacy endpoint of mean change from baseline in serum HBV DNA by PCR at week 24. Results for selected study endpoints at weeks 24 and 48 are shown in the table.

Week 24 Week 48
ETV

1mg once daily

Adefovir Dipivoxil 10mg once daily ETV

1mg once daily

Adefovir Dipivoxil 10mg once daily
n 100 91 100 91
HBV DNA a
Proportion undetectable (<300 copies/ml) b 49%* 16% 57%* 20%
Mean change from baseline

(log10 copies/ml) c

-4.48* -3.40 -4.66 -3.90
Stable or improved CTP score b,d 66% 71% 61% 67%
MELD score

Mean change from baseline c,e

-2.0 -0.9 -2.6 -1.7
HBsAg lossb 1% 0 5% 0
Normalization of:f
ALT (≤1 X ULN)b 46/78 (59%)* 28/71 (39%) 49/78 (63%)* 33/71 (46%)
Albumin (≥1 X LLN) b 20/82 (24%) 14/69 (20%) 32/82 (39%) 20/69 (29%)
Bilirubin (≤1 X ULN)b 12/75 (16%) 10/65 (15%) 15/75 (20%) 18/65 (28%)
Prothrombin time (≤1 X ULN)b 9/95 (9%) 6/82 (7%) 8/95 (8%) 7/82 (9%)

a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/ml).

b NC=F (noncompleter=failure), meaning treatment discontinuations before the analysis week, including reasons such as death, lack of efficacy, adverse event, noncompliance/loss-to-follow-up, are counted as failures (e.g., HBV DNA ≥ 300 copies/ml)

c NC=M (noncompleters=missing)

dDefined as decrease or no change from baseline in CTP score.

e Baseline mean MELD score was 17.1 for ETV and 15.3 for adefovir dipivoxil.

f Denominator is patients with abnormal values at baseline.

*p<0.05

ULN=upper limit of normal, LLN=lower limit of normal.

The time to onset of HCC or death (whichever occurred first) was comparable in the two treatment groups; on-study cumulative death rates were 23% (23/102) and 33% (29/89) for patients treated with Entecavir Taj Pharma and adefovir dipivoxil, respectively, and on-study cumulative rates of HCC were 12% (12/102) and 20% (18/89) for Entecavir Taj Pharma and adefovir dipivoxil, respectively.

For patients with LVDr substitutions at baseline, the percentage of patients with HBV DNA <300 copies/ml was 44% for Entecavir Taj Pharma and 20% for adefovir at week 24 and 50% for Entecavir Taj Pharma and 17% for adefovir at week 48.

HIV/HBV co-infected patients receiving concomitant HAART: study 038 included 67 HBeAg positive and 1 HBeAg negative patients co-infected with HIV. Patients had stable controlled HIV (HIV RNA < 400 copies/ml) with recurrence of HBV viraemia on a lamivudine-containing HAART regimen. HAART regimens did not include emtricitabine or tenofovir disoproxil fumarate. At baseline Entecavir Taj Pharma-treated patients had a median duration of prior lamivudine therapy of 4.8 years and median CD4 count of 494 cells/mm3 (with only 5 subjects having CD4 count < 200 cells/mm3). Patients continued their lamivudine-regimen and were assigned to add either Entecavir Taj Pharma 1mg once daily (n = 51) or placebo (n = 17) for 24 weeks followed by an additional 24 weeks where all received Entecavir Taj Pharma. At 24 weeks the reduction in HBV viral load was significantly greater with Entecavir Taj Pharma (-3.65 vs an increase of 0.11 log10 copies/ml). For patients originally assigned to Entecavir Taj Pharma treatment, the reduction in HBV DNA at 48 weeks was -4.20 log10 copies/ml, ALT normalisation had occurred in 37% of patients with abnormal baseline ALT and none achieved HBeAg seroconversion.

HIV/HBV co-infected patients not receiving concomitant HAART: Entecavir Taj Pharma has not been evaluated in HIV/HBV co-infected patients not concurrently receiving effective HIV treatment. Reductions in HIV RNA have been reported in HIV/HBV co-infected patients receiving Entecavir Taj Pharma monotherapy without HAART. In some cases, selection of HIV variant M184V has been observed, which has implications for the selection of HAART regimens that the patient may take in the future. Therefore, Entecavir Taj Pharma should not be used in this setting due to the potential for development of HIV resistance (see section 4.4).

Liver transplant recipients: the safety and efficacy of Entecavir Taj Pharma 1mg once daily were assessed in a single-arm study in 65 patients who received a liver transplant for complications of chronic HBV infection and had HBV DNA <172 IU/ml (approximately 1000 copies/ml) at the time of transplant. The study population was 82% male, 39% Caucasian, and 37% Asian, with a mean age of 49 years; 89% of patients had HBeAg-negative disease at the time of transplant. Of the 61 patients who were evaluable for efficacy (received Entecavir Taj Pharma for at least 1 month), 60 also received hepatitis B immune globulin (HBIg) as part of the post-transplant prophylaxis regimen. Of these 60 patients, 49 received more than 6 months of HBIg therapy. At Week 72 post-transplant, none of 55 observed cases had virologic recurrence of HBV [defined as HBV DNA ≥50 IU/ml (approximately 300 copies/ml)], and there was no reported virologic recurrence at time of censoring for the remaining 6 patients. All 61 patients had HBsAg loss post-transplantation, and 2 of these later became HBsAg positive despite maintaining undetectable HBV DNA (<6 IU/ml). The frequency and nature of adverse events in this study were consistent with those expected in patients who have received a liver transplant and the known safety profile of Entecavir Taj Pharma.

Paediatric population: Study 189 is an ongoing study of the efficacy and safety of Entecavir Taj Pharma among 180 nucleoside-treatment-naïve children and adolescents from 2 to < 18 years of age with HBeAg-positive chronic hepatitis B infection, compensated liver disease, and elevated ALT. Subjects were randomized (2:1) to receive blinded treatment with Entecavir Taj Pharma 0.015mg/kg up to 0.5mg/day (N = 120) or placebo (N = 60). The randomization was stratified by age group (2 to 6 years; > 6 to 12 years; and > 12 to < 18 years). Baseline demographics and HBV disease characteristics were comparable between the 2 treatment arms and across age cohorts. At study entry, the mean HBV DNA was 8.0 log10 IU/ml and mean ALT was 103 U/l across the study population. Results for main efficacy endpoints at Week 48 and Week 96 are presented in the table below.

Entecavir Taj Pharma Placebo*
Week 48 Week 96 Week 48
n 120 120 60
HBV DNA < 50 IU/mL and HBeAg seroconversiona 24.2% 35.8% 3.3%
HBV DNA < 50 IU/mla 49.2% 64.2% 3.3%
HBeAg seroconversiona 24.2% 36.7% 10.0%
ALT normalizationa 67.5% 81.7% 23.3%
HBV DNA < 50 IU/mla

Baseline HBV

DNA < 8 log10 IU/ml

Baseline HBV DNA

≥ 8 log10 IU/ml

 

82.6% (38/46)

 

28.4% (21/74)

 

82.6% (38/46)

 

52.7% (39/74)

 

6.5% (2/31)

 

0% (0/29)

aNC=F (noncompleter=failure)

* Patients randomized to placebo who did not have HBe- seroconversion by Week 48 rolled over to open-label Entecavir Taj Pharma for the second year of the study; therefore randomized comparison data are available only through Week 48.

The paediatric resistance assessment is based on data from nucleoside-treatment-naive paediatric patients with HBeAg-positive chronic HBV infection in two ongoing clinical trials (028 and 189). The two trials provide resistance data in 183 patients treated and monitored in Year 1 and 180 patients treated and monitored in Year 2. Genotypic evaluations were performed for all patients with available samples who had virologic breakthrough through Week 96 or HBV DNA ≥ 50 IU/ml at Week 48 or Week 96 . During Year 2, genotypic resistance to ETV was detected in 2 patients (1.1% cumulative probability of resistance through Year 2).

Clinical resistance in Adults: patients in clinical trials initially treated with Entecavir Taj Pharma 0.5mg (nucleoside-naive) or 1.0mg (lamivudine-refractory) and with an on-therapy PCR HBV DNA measurement at or after Week 24 were monitored for resistance.

Through Week 240 in nucleoside-naive studies, genotypic evidence of ETVr substitutions at rtT184, rtS202, or rtM250 was identified in 3 patients treated with Entecavir Taj Pharma, 2 of whom experienced virologic breakthrough (see table). These substitutions were observed only in the presence of LVDr substitutions (rtM204V and rtL180M).

Emerging Genotypic Entecavir Taj Pharma Resistance Through Year 5, Nucleoside-Naive Studies
Year 1 Year 2 Year 3a Year 4a Year 5a
Patients treated and monitored for resistanceb 663 278 149 121 108
Patients in specific year with:
– emerging genotypic ETVrc 1 1 1 0 0
– genotypic ETVrc with virologic breakthroughd 1 0 1 0 0
Cumulative probability of:
– emerging genotypic ETVrc 0.2% 0.5% 1.2% 1.2% 1.2%
– genotypic ETVrc with virologic breakthroughd 0.2% 0.2% 0.8% 0.8% 0.8%

a Results reflect use of a 1-mg dose of Entecavir Taj Pharma for 147 of 149 patients in Year 3 and all patients in Years 4 and 5 and of combination Entecavir Taj Pharma-lamivudine therapy (followed by long-term Entecavir Taj Pharma therapy) for a median of 20 weeks for 130 of 149 patients in Year 3 and for 1 week for 1 of 121 patients in Year 4 in a rollover study.

b Includes patients with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week 58 (Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3), after week 156 through week 204 (Year 4), or after week 204 through week 252 (Year 5).

c Patients also have LVDr substitutions.

d ≥1 log10 increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the windowed time point.

ETVr substitutions (in addition to LVDr substitutions rtM204V/I ± rtL180M) were observed at baseline in isolates from 10/187 (5%) lamivudine-refractory patients treated with Entecavir Taj Pharma and monitored for resistance, indicating that prior lamivudine treatment can select these resistance substitutions and that they can exist at a low frequency before Entecavir Taj Pharma treatment. Through Week 240, 3 of the 10 patients experienced virologic breakthrough (≥ 1 log10 increase above nadir). Emerging Entecavir Taj Pharma resistance in lamivudine-refractory studies through Week 240 is summarized in the table.

Genotypic Entecavir Taj Pharma Resistance Through Year 5, Lamivudine-Refractory Studies
Year 1 Year 2 Year 3a Year 4 a Year 5 a
Patients treated and monitored for resistanceb 187 146 80 52 33
Patients in specific year with:
– emerging genotypic ETVrc 11 12 16 6 2
– genotypic ETVrc with virologic breakthroughd 2e 14 e 13 e e e
Cumulative probability of:
– emerging genotypic ETVrc 6.2% 15% 36.3% 46.6% 51.45%
– genotypic ETVrc with virologic breakthroughd 1.1% e 10.7% e 27% e 41.3% e 43.6% e

a Results reflect use of combination Entecavir Taj Pharma-lamivudine therapy (followed by long-term Entecavir Taj Pharma therapy) for a median of 13 weeks for 48 of 80 patients in Year 3, a median of 38 weeks for 10 of 52 patients in Year 4, and for 16 weeks for 1 of 33 patients in Year 5 in a rollover study.

b Includes patients with at least one on-therapy HBV DNA measurement by PCR at or after week 24 through week 58 (Year 1), after week 58 through week 102 (Year 2), after week 102 through week 156 (Year 3), after week 156 through week 204 (Year 4), or after week 204 through week 252 (Year 5).

c Patients also have LVDr substitutions.

d ≥1 log10 increase above nadir in HBV DNA by PCR, confirmed with successive measurements or at the end of the windowed time point.

e ETVr occurring in any year; virologic breakthrough in specified year.

Among lamivudine-refractory patients with baseline HBV DNA < 107 log10 copies/ml, 64% (9/14) achieved HBV DNA < 300 copies/ml at Week 48. These 14 patients had a lower rate of genotypic Entecavir Taj Pharma resistance (cumulative probability 18.8% through 5 years of follow-up) than the overall study population (see table). Also, lamivudine-refractory patients who achieved HBV DNA < 104 log10 copies/ml by PCR at Week 24 had a lower rate of resistance than those who did not (5-year cumulative probability 17.6% [n= 50] versus 60.5% [n= 135], respectively).

5.2 Pharmacokinetic properties

Absorption: Entecavir Taj Pharma is rapidly absorbed with peak plasma concentrations occurring between 0.5-1.5 hours. The absolute bioavailability has not been determined. Based on urinary excretion of unchanged drug, the bioavailability has been estimated to be at least 70%. There is a dose- proportionate increase in Cmax and AUC values following multiple doses ranging from 0.1-1mg. Steady-state is achieved between 6-10 days after once daily dosing with ≈ 2 times accumulation. Cmax and Cmin at steady-state are 4.2 and 0.3 ng/ml, respectively, for a dose of 0.5mg, and 8.2 and 0.5 ng/ml, respectively, for 1mg. The tablet and oral solution were bioequivalent in healthy subjects; therefore, both forms may be used interchangeably

Administration of 0.5mg Entecavir Taj Pharma with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs. 0.75 hour fasted), a decrease in Cmax of 44-46%, and a decrease in AUC of 18-20%. The lower Cmax and AUC when taken with food is not considered to be of clinical relevance in nucleoside-naive patients but could affect efficacy in lamivudine-refractory patients (see section 4.2).

Distribution: the estimated volume of distribution for Entecavir Taj Pharma is in excess of total body water. Protein binding to human serum protein in vitro is ≈ 13%.

Biotransformation: Entecavir Taj Pharma is not a substrate, inhibitor or inducer of the CYP450 enzyme system. Following administration of 14C-Entecavir Taj Pharma, no oxidative or acetylated metabolites and minor amounts of the phase II metabolites, glucuronide and sulfate conjugates, were observed.

Elimination: Entecavir Taj Pharma is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady-state of about 75% of the dose. Renal clearance is independent of dose and ranges between 360-471 ml/min suggesting that Entecavir Taj Pharma undergoes both glomerular filtration and net tubular secretion. After reaching peak levels, Entecavir Taj Pharma plasma concentrations decreased in a bi- exponential manner with a terminal elimination half-life of ≈ 128-149 hours. The observed drug accumulation index is ≈ 2 times with once daily dosing, suggesting an effective accumulation half-life of about 24 hours.

Hepatic impairment: pharmacokinetic parameters in patients with moderate or severe hepatic impairment were similar to those in patients with normal hepatic function.

Renal impairment: Entecavir Taj Pharma clearance decreases with decreasing creatinine clearance. A 4 hour period of haemodialysis removed ≈ 13% of the dose, and 0.3% was removed by CAPD. The pharmacokinetics of Entecavir Taj Pharma following a single 1mg dose in patients (without chronic hepatitis B infection) are shown in the table below:

Baseline Creatinine Clearance (ml/min)
Unimpaired

> 80

Mild

> 50; ≤ 80

Moderate

30-50

Severe

20- < 30

Severe

Managed with Haemodialysis

Severe

Managed with CAPD

(n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 4)
Cmax (ng/ml) 8.1 10.4 10.5 15.3 15.4 16.6
(CV%) (30.7) (37.2) (22.7) (33.8) (56.4) (29.7)
AUC(0-T) 27.9 51.5 69.5 145.7 233.9 221.8
(ng·h /ml)

(CV)

(25.6) (22.8) (22.7) (31.5) (28.4) (11.6)
CLR (ml/min) 383.2 197.9 135.6 40.3 NA NA
(SD) (101.8) (78.1) (31.6) (10.1)
CLT/F (ml/min) 588.1 309.2 226.3 100.6 50.6 35.7
(SD) (153.7) (62.6) (60.1) (29.1) (16.5) (19.6)

Post-Liver transplant: Entecavir Taj Pharma exposure in HBV-infected liver transplant recipients on a stable dose of cyclosporine A or tacrolimus (n = 9) was ≈ 2 times the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in Entecavir Taj Pharma exposure in these patients (see section 4.4).

Gender: AUC was 14% higher in women than in men, due to differences in renal function and weight. After adjusting for differences in creatinine clearance and body weight there was no difference in exposure between male and female subjects.

Elderly: the effect of age on the pharmacokinetics of Entecavir Taj Pharma was evaluated comparing elderly subjects in the age range 65-83 years (mean age females 69 years, males 74 years) with young subjects in the age range 20-40 years (mean age females 29 years, males 25 years). AUC was 29% higher in elderly than in young subjects, mainly due to differences in renal function and weight. After adjusting for differences in creatinine clearance and body weight, elderly subjects had a 12.5% higher AUC than young subjects. The population pharmacokinetic analysis covering patients in the age range 16-75 years did not identify age as significantly influencing Entecavir Taj Pharma pharmacokinetics.

Race: the population pharmacokinetic analysis did not identify race as significantly influencing Entecavir Taj Pharma pharmacokinetics. However, conclusions can only be drawn for the Caucasian and Asian groups as there were too few subjects in the other categories.

Paediatric population: the steady-state pharmacokinetics of Entecavir Taj Pharma were evaluated (study 028) in 24 nucleoside naïve and 19 lamivudine-experienced HBeAg-positive paediatric subjects from 2 to < 18 years of age with compensated liver disease. Entecavir Taj Pharma exposure among nucleoside naïve subjects receiving once daily doses of Entecavir Taj Pharma 0.015mg/kg up to a maximum dose of 0.5mg was similar to the exposure achieved in adults receiving once daily doses of 0.5mg. The Cmax, AUC (0- 24), and Cmin for these subjects was 6.31 ng/ml, 18.33 ng h/ml, and 0.28 ng/ml, respectively.

Entecavir Taj Pharma exposure among lamivudine-experienced subjects receiving once daily doses of Entecavir Taj Pharma 0.030mg/kg up to a maximum dose of 1.0mg was similar to the exposure achieved in adults receiving once daily doses of 1.0mg. The Cmax, AUC (0-24), and Cmin for these subjects was 14.48 ng/ml, 38.58 ng·h/ml, and 0.47 ng/ml, respectively.

5.3 Preclinical safety data

In repeat-dose toxicology studies in dogs, reversible perivascular inflammation was observed in the central nervous system, for which no-effect doses corresponded to exposures 19 and 10 times those in humans (at 0.5 and 1mg respectively). This finding was not observed in repeat-dose studies in other species, including monkeys administered Entecavir Taj Pharma daily for 1 year at exposures ≥ 100 times those in humans.

In reproductive toxicology studies in which animals were administered Entecavir Taj Pharma for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at high exposures. Testicular changes (seminiferous tubular degeneration) were evident in repeat-dose toxicology studies in rodents and dogs at exposures ≥ 26 times those in humans. No testicular changes were evident in a 1-year study in monkeys.

In pregnant rats and rabbits administered Entecavir Taj Pharma, no effect levels for embryotoxicity and maternal toxicity corresponded to exposures ≥ 21 times those in humans. In rats, maternal toxicity, embryo- foetal toxicity (resorptions), lower foetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at high exposures. In rabbits, embryo-foetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at high exposures. In a peri-postnatal study in rats, no adverse effects on offspring were observed. In a separate study wherein Entecavir Taj Pharma was administered to pregnant lactating rats at 10mg/kg, both foetal exposure to Entecavir Taj Pharma and secretion of Entecavir Taj Pharma into milk were demonstrated. In juvenile rats administered Entecavir Taj Pharma from postnatal days 4 to 80, a moderately reduced acoustic startle response was noted during the recovery period (postnatal days 110 to 114) but not during the dosing period at AUC values ≥ 92 times those in humans at the 0.5mg dose or paediatric equivalent dose. Given the exposure margin, this finding is considered of unlikely clinical significance.

No evidence of genotoxicity was observed in an Ames microbial mutagenicity assay, a mammalian- cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. A micronucleus study and a DNA repair study in rats were also negative. Entecavir Taj Pharma was clastogenic to human lymphocyte cultures at concentrations substantially higher than those achieved clinically.

Two-year carcinogenicity studies: in male mice, increases in the incidences of lung tumours were observed at exposures ≥ 4 and ≥ 2 times that in humans at 0.5mg and 1mg respectively. Tumour development was preceded by pneumocyte proliferation in the lung which was not observed in rats, dogs, or monkeys, indicating that a key event in lung tumour development observed in mice likely was species-specific. Increased incidences of other tumours including brain gliomas in male and female rats, liver carcinomas in male mice, benign vascular tumours in female mice, and liver adenomas and carcinomas in female rats were seen only at high lifetime exposures. However, the no effect levels could not be precisely established. The predictivity of the findings for humans is not known.

  1. Pharmaceutical particulars
    • List of excipients

0.5mg film-coated tablets

Tablet core:

Microcrystalline cellulose

Lactose monohydrate

Maize starch pregelatinised

Crospovidone (Type A)

Magnesium stearate

Tablet coating:

Titanium dioxide

Hypromellose

Macrogol 400

Polysorbate 80

  • Incompatibilities

Not applicable.

  • Shelf life

2 years

  • Special precautions for storage

Do not store above 30°C. Store in the original package.

  • Nature and contents of container

Each film coated tablets contains active substance is Entecavir Taj Pharma.

Packaging type:

Each film-coated tablet are in OPA-Alu-PVC/Alu perforated unit dose blisters.

Pack size:

Each pack contains 10, 15, 20, 25, 30, 40, 50 and 60 film coated tablets.

Each box contains 60, 120, 240, 360, 500 and 1000 film coated tablets.

Not all pack sizes may be marketed.

  • Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Entecavir Taj Pharma Tablets USP 1mg Taj Pharma

Package leaflet: Information for the user

Entecavir Tablets USP 0.5mg film-coated Taj Pharma
Entecavir Tablets USP 1mg film-coated Taj Pharma

Entecavir Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Entecavir Taj Pharma tablets is and what it is used for
  2. What you need to know before you take Entecavir Taj Pharma tablets
  3. How to take Entecavir Taj Pharma tablets
  4. Possible side effects
  5. How to store Entecavir Taj Pharma tablets
  6. Contents of the pack and other information

1. What Entecavir Taj Pharma tablets is and what it is used for

Entecavir Taj Pharma tablets are anti-viral medicines, used to treat chronic (long term) hepatitis B virus (HBV) infection in adults.

Entecavir Taj Pharma tablets can be used in people whose liver is damaged but still functions properly (compensated liver disease) and in people whose liver is damaged and does not function properly (decompensated liver disease).

Entecavir Taj Pharma tablets are also used to treat chronic (long term) HBV infection in children and adolescents aged 2 years to less than 18 years.

Entecavir Taj Pharma tablets can be used in children whose liver is damaged but still functions properly (compensated liver disease).

Infection by the hepatitis B virus can lead to damage to the liver. Entecavir Taj Pharma tablets reduces the amount of virus in your body, and improves the condition of the liver.

  1. What you need to know before you take Entecavir Taj Pharma tablets

Do not take Entecavir Taj Pharma tablets

if you are allergic to Entecavir Taj Pharma or any of the other ingredients of this medicine (listed in section 6).

Warning and precautions

Talk to your doctor or pharmacist before taking Entecavir Taj Pharma tablets

  • if you have ever had problems with your kidneys, tell your doctor. This is important because Entecavir Taj Pharma is eliminated from your body through the kidneys and your dose or dosing schedule may need to be adjusted.
  • do not stop taking Entecavir Taj Pharma tablets without your doctor’s advice since your hepatitis may worsen after stopping treatment. When your treatment with Entecavir Taj Pharma tablets is stopped, your doctor will continue to monitor you and take blood tests for several months.
  • discuss with your doctor whether your liver functions properly and, if not, what the possible effects on your Entecavir Taj Pharma tablets treatment may be.
  • if you are also infected with HIV (human immunodeficiency virus) be sure to tell your doctor. You should not take Entecavir Taj Pharma tablets to treat your hepatitis B infection unless you are taking medicines for HIV at the same time, as the effectiveness of future HIV treatment may be reduced. Entecavir Taj Pharma tablets will not control your HIV infection.
  • taking Entecavir Taj Pharma tablets will not stop you from infecting other people with hepatitis B virus (HBV) through sexual contact or body fluids (including blood contamination). So, it is important to take appropriate precautions to prevent others from becoming infected with HBV. A vaccine is available to protect those at risk from becoming infected with HBV.
  • Entecavir Taj Pharma tablets belongs to a class of medicines that can cause lactic acidosis (excess of lactic acid in your blood) and enlargement of the liver. Symptoms such as nausea, vomiting and stomach pain might indicate the development of lactic acidosis.

This rare but serious side effect has occasionally been fatal. Lactic acidosis occurs more often in women, particularly if they are very overweight. Your doctor will monitor you regularly while you are receiving Entecavir Taj Pharma tablets

  • if you have previously received treatment for chronic hepatitis B, please inform your doctor.

Children and adolescents

Entecavir Taj Pharma tablets should not be used for children below 2 years of age or weighing less than 10 kg.

Other medicines and Entecavir Taj Pharma tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Entecavir Taj Pharma tablets with food and drink

In most cases you may take Entecavir Taj Pharma tablets with or without food. However, if you have had a previous treatment with a medicine containing the active substance lamivudine you should consider the following. If you were switched over to Entecavir Taj Pharma tablets because the treatment with lamivudine was not successful, you should take Entecavir Taj Pharma tablets on an empty stomach once daily. If your liver disease is very advanced, your doctor will also instruct you to take

Entecavir Taj Pharma tablets on an empty stomach. Empty stomach means at least 2 hours after a meal and at least 2 hours before your next meal.

Children and adolescents (from 2 to less than 18 years of age) can take Entecavir Taj Pharma tablets with or without food.

Pregnancy, breast-feeding and fertility

Tell your doctor if you are pregnant or planning to become pregnant. It has not been demonstrated that Entecavir Taj Pharma tablets is safe to use during pregnancy. Entecavir Taj Pharma tablets must not be used during pregnancy unless specifically directed by your doctor. It is important that women of childbearing age receiving treatment with Entecavir Taj Pharma tablets use an effective method of contraception to avoid becoming pregnant.

You should not breast-feed during treatment with Entecavir Taj Pharma tablets Tell your doctor if you are breast- feeding. It is not known whether Entecavir Taj Pharma, the active ingredient in Entecavir Taj Pharma tablets, is excreted in human breast milk.

Driving and using machines

Dizziness, tiredness (fatigue) and sleepiness (somnolence) are common side effects which may impair your ability to drive and use machines. If you have any concerns consult your doctor.

Entecavir Taj Pharma tablets contains lactose

This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

  1. How to take Entecavir Taj Pharma tablets

Not all patients need to take the same dose of Entecavir Taj Pharma tablets.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

For adults the recommended dose is either 0.5mg or 1mg once daily orally (by mouth).

Your dose will depend on:

  • whether you have been treated for HBV infection before, and what medicine you received.
  • whether you have kidney problems. Your doctor may prescribe a lower dose for you or instruct you to take it less often than once a day.
  • the condition of your liver.

For children and adolescents (from 2 to less than 18 years of age), your child’s doctor will decide the right dose based on your child’s weight. Children weighing at least 32.6 kg may take the 0.5mg tablet or an Entecavir Taj Pharma oral solution may be available. For patients weighing from 10 kg to 32.5 kg, an Entecavir Taj Pharma oral solution is recommended. All dosing will be taken once daily orally (by mouth). There are no recommendations for Entecavir Taj Pharma in children less than 2 years of age or weighing less than 10 kg.

Your child’s doctor will decide the right dose based on your child’s weight.

For children and adolescents (from 2 to less than 18 years of age), weighing at least 32.6 kg and requiring a dose of 0.5mg (=halve a tablet of 1mg), Entecavir Taj Pharma tablets 0.5mg tablets are also available.

All dosing will be taken once daily orally (by mouth).

For children and adolescents weighing less than 32.6 kg and for dosages below 0.5mg an Entecavir Taj Pharma oral solution may be available.

Your child’s doctor will decide the right dose based on your child’s weight.

Your doctor will advise you on the dose that is right for you. Always take the dose recommended by your doctor to ensure that your medicine is fully effective and to reduce the development of resistance to treatment. Take Entecavir Taj Pharma tablets as long as your doctor has told you. Your doctor will tell you if and when you should stop the treatment.

Some patients must take Entecavir Taj Pharma tablets on an empty stomach (see Entecavir Taj Pharma tablets with food and drink in Section 2). If your doctor instructs you to take Entecavir Taj Pharma tablets on an empty stomach, empty stomach means at least 2 hours after a meal and at least 2 hours before your next meal. The tablet can be divided into equal doses.

If you take more Entecavir Taj Pharma tablets than you should

Contact your doctor at once.

If you forget to take Entecavir Taj Pharma tablets

It is important that you do not miss any doses. If you miss a dose of Entecavir Taj Pharma tablets, take it as soon as possible, and then take your next scheduled dose at its regular time. If it is almost time for your next dose, do not take the missed dose. Wait and take the next dose at the regular time.

Do not take a double dose to make up for a forgotten dose.

Do not stop Entecavir Taj Pharma tablets without your doctor’s advice

Some people get very serious hepatitis symptoms when they stop taking Entecavir Taj Pharma tablets. Tell your doctor immediately about any changes in symptoms that you notice after stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Patients treated with Entecavir Taj Pharma tablets have reported the following side effects:

  • common (at least 1 in 100 patients): headache, insomnia (inability to sleep), fatigue (extreme tiredness), dizziness, somnolence (sleepiness), vomiting, diarrhoea, nausea, dyspepsia (indigestion), and increased blood levels of liver enzymes.
  • uncommon (at least 1 in 1,000 patients): rash, hair loss.
  • rare (at least 1 in 10,000 patients): severe allergic reaction.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

  1. How to store Entecavir Taj Pharma tablets

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister or carton after EXP.

That expiry date refers to the last day of that month.

Do not store above 30°C. Store in the original package.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Entecavir Taj Pharma film-coated tablets contains

Entecavir Taj Pharma film-coated tablets 0.5mg:

The active substance is Entecavir Taj Pharma. Each film-coated tablet contains Entecavir Taj Pharma monohydrate corresponding to 0.5mg Entecavir Taj Pharma.

The other ingredients are:

Tablet core: lactose monohydrate, microcrystalline cellulose, maize starch pregelatinised, crospovidone (Type A) and magnesium stearate.

Tablet coating: titanium dioxide, hypromellose, macrogol 400 and polysorbate 80.

Entecavir Taj Pharma film-coated tablets 1mg:

The active substance is Entecavir Taj Pharma. Each film-coated tablet contains Entecavir Taj Pharma monohydrate corresponding to 1mg Entecavir Taj Pharma.

The other ingredients are:

Tablet core: lactose monohydrate, microcrystalline cellulose, maize starch pregelatinised,crospovidone (Type A) and magnesium stearate.

Tablet coating: titanium dioxide, hypromellose, macrogol 400, polysorbate 80 and red iron oxide

What Entecavir Taj Pharma film coated tablets looks like and contents of the pack

Entecavir Taj Pharma film coated tablets 0.5mg:

Entecavir Taj Pharma film-coated tablets are white and oval-shaped with a break line on both sides.

Entecavir Taj Pharma film coated tablets 1mg:

Entecavir Taj Pharma film-coated tablets are pink and oval-shaped with a break line on both sides.

Packaging type:

Each film-coated tablet are in OPA-Alu-PVC/Alu perforated unit dose blisters.

Pack size:

Each pack contains 10, 15, 20, 25, 30, 40, 50 and 60 film coated tablets.

Each box contains 60, 120, 240, 360, 500 and 1000 film coated tablets.

Not all pack sizes may be marketed.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

 

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Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.