Pirfenidon Alster Pharma 801 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Pirfenidon Alster Pharma 267 mg, 534 mg, 801 mg film-coated tablets
Name of the drug substance (INN name):	Pirfenidon
Pharmaco-therapeutic group (ATC Code):	L04AX05
Pharmaceutical form(s) and strength(s):	Film-coated tablets
Reference Number(s) for the Decentralised Procedure	DE/H/7093/001–003/DC
Reference Member State:	DE
Concerned Member States:	DE/H/LU
Legal basis of application:	Article 10(1) generic application
Applicant (name and address)	APS Alster Pharma Service GmbH
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Delorbis Pharmaceuticals Ltd Industrial Area Athinon 17 V Ergates, Nicosia 2643 Cyprus

• I. INTRODUCTION

Based on the review of the data and the Applicant’s res­ponse to the questions raised by RMS and CMSs on quality, safety and efficacy, the application for Pirfenidon Alster Pharma 267 mg, 534 mg, 801 mg film-coated tablets , with the following indication:

<Invented name> is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF)

is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

N/A

• II.2 About the product

Pharmacological class

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX05.

Mode of action

The mechanism of action of pirfenidone has not been fully established. However, existing data suggest that pirfenidone exerts both antifibrotic and anti-inflammatory properties in a variety of in vitro systems and animal models of pulmonary fibrosis (bleomycin- and transplant-induced fibrosis).

IPF is a chronic fibrotic and inflammatory pulmonary disease affected by the synthesis and release of pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) and pirfenidone has been shown to reduce the accumulation of inflammatory cells in response to various stimuli.

Pirfenidone attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as, transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF).

Proposed clinical use

Pirfenidone is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF).

• II.3 General comments on the submitted dossier

This is an application for an ‘abridged’ 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 Pirfenidone 267 mg, 537 mg and 801 mg film-coated tablets, which is the generic version of the reference product containing the same active ingredient, marketed as Esbriet by Roche Registration GmbH. The product was first marketed in the Community under the brand Esbriet by InterMune Europe Ltd in 27/02/2011 and as such has been authorised in the Community for a period exceeding 10 years.

With Germany acting as RMS, APS Alster Pharma Service GmbH has applied for the Marketing Authorisations of “Pirfenidon Alster Pharma 267 mg, 534 mg, 801 mg film-coated tablets” in LU.

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

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..

GMP active substance

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

GCP

The Applicant declares that the BE study were conducted in accordance with Good Clinical Practice (GCP) as required by the International Conference on Harmonization (ICH) guidelines and in accordance with country-specific laws and regulations governing clinical studies of investigational products. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki. The Applicant has also provided the required statement that BE study conduct at sites outside the European Community complied with the ethical standards of Directive 2001/20/EC. So far, during the assessment, no relevant concerns were identified about the compliance with GCP or related regulatory and ethical standards. Thus, no request for a GCP inspection is considered necessary.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

  • III.1 Quality aspects

Drug Substance

The drug substance Pirfenidone is covered by a monograph of the Ph. Eur. The suitability of the drug substance to comply with the requirement outlined under the particular monograph has been assessed by EDQM.

No re-test period is mentioned on the Certificate. The manufacturer of the drug product has provided data to establish a re-test period.

Drug Product

The drug product is a film coated tablet containing Pirfenidone as drug substance.

The objective was to develop a conventional film coated tablet of Pirfenidone 267 mg, 534 mg and 801 mg strengths as a generic equivalent that is essentially similar to the reference product Esbriet®. Esbriet® 267 mg, 534 mg and 801 mg strengths are dose-weight proportionate. Hence test product was developed with dose-weight proportional formula.

The manufacturing process is a standard procedure, with a wet granulation step, compression step and film coating. Validation data for the manufacturing process have been provided for three batches each strength. The ten fold of the batch sizes is proposed concerning sizes for the market. All analytical methods have been described, validation data have been presented.

Degradation is not observed for the drug product, therefore just a limit for unspecified impurities and total impurities is presented in the specification. Information on reference standards and packaging used has been provided.

Stability data have been presented for the film-coated tablets each strength stored in bottles or blisters. The proposed shelf life of 36 months without any precaution advice is acceptable.

• III.2 Non-clinical aspects

Pharmacology, Pharmacokinetics, Toxicology

Pharmacodynamic, pharmacokinetic and toxicological properties of pirfenidone are well known. As pirfenidone is a widely used, well-known active substance, the applicant has not provided additional non-clinical studies and further non-clinical studies are not required. Overview based on literature review is, thus, appropriate.

The submitted non-clinical overview on the non-clinical pharmacology, pharmacokinetics and toxicology pirfenidone is considered adequate.

Environmental Risk Assessment (ERA)

Since the medicinal products are 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

Pirfenidone 267 mg/534 mg/801 mg film-coated tablet was developed as a generic medicinal product with reference to the brand leader Esbriet® 267 mg/534 mg/801 mg film-coated tablet, Roche Registrations GmbH.

A bioequivalence study was conducted between April 10, and 21, 2019, using the 801 mg strength. The reference product was Esbriet® 801 mg film-coated tablet, manufactured by Roche Registrations GmbH, Germany.

In a single-centre, single-dose, open-label, two-treatment, two-sequence, two-period, crossover bioequivalence study healthy 60 male subjects 18 to 45 years of age received either test or reference product in randomised order under fed conditions. 50 subjects completed the study per protocol and were analysed for pharmacokinetics. Study periods were separated by a washout of at least 9 days. Primary variables for the assessment of bioequivalence were AUC0-t and Cmax, and AUC0-inf, AUCres%, Tmax, T1/2, and ʎz were analysed as secondary variables. Blood samples were collected and adverse events recorded at appropriate intervals up to 24 hours after drug administration. Pirfenidone concentrations were analysed using a validated LC-ESI-MS/MS method with a validation range of 50.000 to 25000.000 ng/ml.

Arithmetic means (CV%) of the primary pharmacokinetic parameters for pirfenidone and bioequivalence assessment are given in the tables below. The bioequivalence was confirmed when the point estimates and 90% confidence intervals for AUC0-t and Cmax were within the generally accepted range of 80% to 125%.

Table 1: Arithmetic means ± SD (%CV); n = 50

Pharmacokinetic Parameter (Units)	Arithmetic Means (± SD)
	Test Product-T	Reference Product-R
AUC(0-t)	47691.165 ± 17203.6459	46326.604 ± 16877.5801
AUC(0-∞)	48156.906 ± 17468.9658	46701.720 ± 17000.6682
Cmax (ng/mL)	10952.147 ± 2947.7423	11424.465 ± 2793.7993
tmax (hr)	1.750 (0.50 – 4.50)	1.750 (0.50 – 4.50)

Table 2: Geometric means of the primary equivalence parameters and assessment of bioequivalence

Pharmacokinetic parameter (units)	Geometric Least Squares Means (Test, T)	Geometric Least Squares Means (Reference, R)	Ratio (T/R) (%)	90% Confidence Limits (T vs. R)	Intra Subject CV %	Power (%)
Cmax (ng/mL)	10433.826	11148.475	93.59	88.92 % –98.51%	15.15	100.00
AUC0-t (hr*ng/mL)	44420.222	43754.888	101.52	95.09% – 108.38%	19.43	99.99

Data from this study demonstrated that the test and the reference products were well tolerated. Total Six (06) AEs were reported during the study, out of which one (01) AE was clinically significant laboratory value during post study safety assessment. There were no deaths or serious AEs during the conduct of the study.

Pharmacodynamics

N/A

Clinical efficacy

N/A

Clinical safety

N/A

Legal Status

Medicinal product subject to medical prescription.

User Testing

The PL Esbriet film-coated tablets has been centrally approved. The product information has been updated via several variations. The text for the product information of Esbriet has been agreed upon all member states and is therefore harmonised within the EEA. All above mentioned facts imply that the package leaflet of pirfenidonehas been subject to successful user testing and complies with Article 59 of Directive 2001/83/EC, as amended.

Bridging for layout:

As parent leaflet for the layout bridging a corporate PL layout has been used, which has been tested in several Readability User Tests on products of the applicant. All tests have proven the patient friendliness of the layout, which supports patients in finding key safety messages in PLs.

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 MAH 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 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.

For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

• IV. BENEFIT RISK ASSESSMENT