Entecavir HEC Pharm 0,5 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Name of the medicinal product in the RMS	Entecavir HEC Pharm 0,5 mg Filmtabletten Entecavir HEC Pharm 1 mg Filmtabletten
Name of the drug substance (INN name):	Entecavir
Pharmaco-therapeutic group (ATC Code):	J05AF10
Pharmaceutical form(s) and strength(s):	Film-coated tablet / 0,5 mg + 1mg
Reference Number(s) for the Decentralised Procedure	DE/H/5474/001–002/DC
Reference Member State:	DE
Concerned Member States:	Withdrawn: LU
Legal basis of application:	Generic application Art 10.1
Applicant (name and address)	HEC Pharm GmbH Gabriele-Tergit-Promenade 17 10963 Berlin Germany
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305b 14167 Berlin Germany

• I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for Entecavir HEC Pharm 0,5 mg / 1 mg Filmtabletten , in the treatment of chronic hepatitis B virus (HBV) infection in adults and nucleoside naive paediatric patients from 2 to < 18 years of age is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

For a generic application this section is not applicable.

• II.2 About the product

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.

Pharmacotherapeutic group: antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF10

Indication:

Entecavir is indicated for the treatment of chronic hepatitis B virus (HBV) infection 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

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. Special attention is required for patients with lamivudine-refractory hepatitis B.

Entecavir 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.

Posology and method of administration

Posology

Compensated liver disease

Nucleoside naïve 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): 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). 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.

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). Special recommendations apply for patients with lamivudine-refractory hepatitis B.

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.
• 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 oral solution or entecavir 0.5 mg film-coated tablets are 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 0.5 mg tablet or 10 ml (0.5 mg) of the oral solution, with or without food. The oral solution should be used 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.

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

Renal impairment: the clearance of entecavir decreases with decreasing creatinine clearance. 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 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 dosage
	Nucleoside naïve patients	Lamivudine-refractory or decompensated liver disease
≥ 50	0.5 mg once daily	1 mg once daily
30 – 49	0.25 mg daily* OR 0.5 mg every 48 hours	0.5 mg once daily
10 – 29	0.15 mg daily* OR 0.5 mg every 72 hours	0.3 mg daily* OR 0.5 mg every 48 hours
< 10 Haemodialysis or CAPD	0.05 mg daily* OR 0.5 mg every 5–7 days	0.1 mg daily* OR 0.5 mg every 72 hours
*for doses < 0.5 mg entecavir oral solution is recommended. on haemodialysis days, administer entecavir after haemodialysis.

Hepatic impairment:

No dose adjustment is required in patients with hepatic impairment.

Method of administration

Entecavir should be taken orally.

• II.3 General comments on the submitted dossier

This is an application for a generic medicinal product made in accordance with Article 10(1) of Directive 2001/83/EC (as amended by Directive 2004/27/EC) and therefore contains no new clinical or preclinical data, other than supporting literature where necessary, in accordance with the provisions of the article.

The application is for 0.5 mg and 1 mg film-coated tablets of entecavir, which is the generic version of the reference product containing the same active ingredient, marketed as Baraclude® by Bristol-Myers Squibb Pharma EEIG. The product was first marketed in the Community under the brand name Baraclude® (0.5 mg and 1 mg, tablets film-coated) by Bristol-Myers Squibb Pharma EEIG, registered since June 26th, 2006 and as such has been authorised in the Community for a period exceeding 10 years.

The generic medicinal product has the same qualitative and quantitative composition in active substances and the same pharmaceutical form (film-coated tablets) as the reference medicinal product. A bioequivalence study conducted for Entecavir HEC Pharm 1 mg film-coated tablets versus the reference medicinal product Baraclude 1 mg film-coated tablets has been submitted.

The applicant has requested a biowaiver for the 0.5 mg strength in accordance with the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr).

Relevant for the assessment is the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr) as well as the Guideline on Bioanalytical method validation (EMEA/CHMP/EW­P/192217/2009 Rev.1 Corr). Both guidelines were followed.

The applicant did not receive CHMP Scientific Advice pertinent to the clinical investigation.

• II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles

GMP:

The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with

which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.

GMP active substance

Regarding the statement on GMP for the active substance a declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.

GCP:

The RMS has been assured by the Applicant that the bioequivalence study, which was conducted in a country outside the community, was conducted in compliance with:

Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects, revised by the WMA General Assembly, Brazil, 2013)

ICH E6 Guidelines for GCP

ICMR guidelines for biomedical research on human subjects

EMEA guidelines

other applicable regulatory requirements.

Statements on GCP compliance, a tabular listing of previous inspections of NRAs of the clinical (by US FDA) and bioanalytical and statistical sites ((both by MHRA) as well as the final inspection reports of these inspections have been provided.

The study was initiated after obtaining approval from the Indian Regulatory Authority-Drugs Controller General of India [DCG (I)].

To date, no GCP-concerns have been identified.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

  • III.1 Quality aspects

Drug substance

The drug substance Entecavir monohydrate is a compendia substance.

Adequate drug substance specification and batch analysis data for the drug substance tested by the drug product manufacturer are provided.

The CEP stated a re-test period of 36 months if stored in double PE bags in aluminium tins.

Drug product

The products are film-coated tablets containing 0.5 and 1 mg Entecavir monohydrate packaged in blister package which consists of PA/AL/PVC film and push-through aluminium blister foil.

The pharmaceutical development has been described in detail.

A bioequivalence study comparing the 1 mg strength and the originator product Baraclude 1 mg was performed. Comparative dissolution profiles between the test and reference product used in bioequivalence study are provided for three pH values.

From the quality perspective the strength biowaiver for the 0.5 mg strength is sufficiently justified.

For further details see clinical assessment.

The manufacturing process including in-process controls and critical steps is described in detail. Satisfactorily process validation data are given.

The proposed release and shelf life specifications contains all parameters relevant for this pharmaceutical form. All acceptance criteria are sufficiently justified. The descriptions of the test procedures are adequate. Validation data for analytical methods are in accordance with the ICH validation guideline. Satisfactory batch analysis data are provided showing compliance with specifications.

Based on the stability results given the shelf-life of 2years for the drug product without storage conditions is acceptable.

• III.2 Non-clinical aspects

There are no objections to approval of Entecavir HEC Pharm 0,5/ 1 mg Filmtabletten from a non-clinical point of view.

Environmental Risk Assessment (ERA)

Since Entecavir HEC Pharm is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

• III.3 Clinical aspects

Pharmacokinetics

To support the application, the Applicant has submitted as report one bioequivalence study: A randomized, open label, balanced, two treatment, single period, single dose, parallel design, bioavailability study of Entecavir 1 mg film-coated tablets (test) and Baraclude® (Entecavir) 1 mg film-coated tablets of Bristol-Myers Squibb Pharma EEIG in healthy human adult subjects, under fasting conditions.

Both tablets are qualitatively the same and are quantitatively dose proportional and all biowaiver requirements are fulfilled. The bioequivalence study was conducted with the highest strength, which is in line with the guideline on the investigation of bioequivalence and the product-specific guidance.

The study design and the statistical analysis are scientifically sound and because of the long termination half-life of entecavir the parallel design of this study is acceptable.

A total of 22 venous blood samples (1 × 4 mL each) were collected at pre-dose 0.00 hour and at 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00 and 72.00 hours post dose in each period.

Test and reference products

Test product: Entecavir 1 mg film-coated tablets

Reference product: Baraclude® (entecavir) 1 mg film-coated tablet

Population(s) studied

60 healthy subjects (range 19 to 44 years) were enrolled in the pivotal bioequivalence study. All were South Asians of male gender and non-vegetarian. Weight of the subjects was within the normal range (Body Mass Index range 18.6 to 29.7 kg/m2) with a minimum of 51 kg. All were non-smokers and non-alcoholics.

The demographic characteristics for the individual treatment groups were provided, e.g. test and reference group. Both treatment groups were comparable in all known variables that may affect the pharmacokinetics of the active substance (e.g. age, body weight, sex, ethnic origin, smoking status, metabolic status, kidney function, etc.).

Analytical methods

The plasma samples of subjects were analysed using a validated LC-MS/MS method by solid phase extraction method over a validated concentration of 0.59 ng/mL to 20.600 ng/m for entecavir. 13C3, 15N entecavir hydrochlorid was used as internal standard.

Out of a total of 1320 plasma samples analysed, altogether 155 samples (11.7%) were re-analysed. The most common reason for reanalysis was because of ISTD variation ± 50% (88 samples) or incomplete analysis (66 samples).

The analytical method was validated, including pre-study (in 2017) and within-study validation.

The stability testing of the stock solutions supports the conditions the QC pool and calibration curve standards were exposed to during the bioanalysis.

Incurred samples reanalysis was performed and confirmed reliability of the initial results.

Pharmacokinetic Variables

Using the estimated concentration time profiles of entecavir, the following variables were calculated: AUC0–72h and Cmax as primary pharmacokinetic variables and Tmax, Kel, t½ and NKEL as secondary pharmacokinetic variables.

Statistical methods

The pharmacokinetic parameters for entecavir were calculated from the drug concentration vs. time profile by non-compartmental model using Plasma (200) of Phoenix® WinNonlin version 6.4.

Analysis of variance was carried out by employing procedure of SAS® Version 9.4 (SAS Institute Inc., Cary NC, USA) for log-transformed pharmacokinetic parameters Cmax and AUC0–72 using General

Linear Model (PROC GLM procedure) of SAS®. The ANOVA model included treatment as a fixed effect. The treatment effect was tested at 5% level of significance, using the residual error (mean square error or MSE) from the ANOVA as the error term.

Each analysis of variance included calculation of least-square means, the difference between the adjusted formulation means and the standard error associated with the difference.

The 90 % CIs for the ratio of the test to reference product of the geometric least square means of the pharmacokinetic parameters Cmax, and AUC0–72 were calculated for the log-transformed data.

Non-parametric analysis of Tmax was performed on untransformed data of entecavir, using the Wilcoxon signed-rank test.

The 90% confidence interval of the relative mean AUC0–72 and Cmax of the test and reference product were to be at least 80.00% and not more than 125.00% for log-transformed data.

Results:

Pharmacokinetic Conclusion

The Test Product (Entecavir HEC Pharm 1 mg film-coated tablets) when compared with the Reference Product (Baraclude® 1 mg tablets (Bristol-Myers Squibb Pharma EEIG)) meets the predefined bioequivalence criteria in terms of rate and extent of absorption after administration of single dose as set in the protocol.

The applicant has requested a biowaiver for the lower strength Entecavir HEC Pharm 0.5 mg film-coated tablets based on the bioequivalence study with the 1 mg formulation. The qualitative and quantitative composition of the different strengths is dose proportional. Both strengths of Entecavir HEC Pharm are manufactured by the same process and manufacturer. Entecavir has linear pharmacokinetics over the therapeutic dose range. The bioequivalence study is conducted with the highest strength, which is in line with the guideline on the investigation of bioequivalence and the product-specific guidance. The comparative dissolution testing supports a biowaiver for the 0.5 mg tablet. Therefore, the biowaiver request for the 0.5 mg strength is acceptable.

Pharmacodynamics

No such studies are required for this application.

Clinical efficacy

See assessment of bioequivalence study under “Pharmacokinetics”.

Clinical safety

The two products had similar safety profiles. There are no new safety concerns arising from the study. No significant or serious adverse events or deaths were reported during the study.

Legal Status

Subject to medical prescription.

User Testing

The Applicant provided a User Testing Report for Entecavir HEC Pharm 0.5 mg film-coated tablet and a bridging report for Entecavir HEC Pharm 1 mg film-coated tablets. This is acceptable.

Summary Pharmacovigilance system

The applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmaco­vigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

The applicant has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.

Safety specification

According to the applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.

Pharmacovigilance plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMP

The submitted Risk Management Plan is considered acceptable.

The applicant/MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the RMS;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.
• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
• In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

• IV. BENEFIT RISK ASSESSMENT