Zusammenfassung der Merkmale des Arzneimittels - Pirfenidon Rontis 267 mg Filmtabletten
| Proposed name of the medicinal product in the RMS | Pirfenidone beta 267 mg Filmtabletten Pirfenidone beta 534 mg Filmtabletten Pirfenidone beta 801 mg Filmtabletten Pirfenidone Rontis 267 mg Filmtabletten Pirfenidone Rontis 534 mg Filmtabletten Pirfenidone Rontis 801 mg Filmtabletten |
| Name of the drug substance (INN name): | Pirfenidone |
| Pharmaco-therapeutic group(ATC Code): | L04AX05 |
| Pharmaceutical form(s) and strength(s): | film-coated tablets 267mg, 534mg & 801mg |
| Reference Number(s) for the Decentralised Procedure | DE/H/7073+7111/001–003/DC |
| Reference Member State: | DE |
| Concerned Member States: | DE/H/MT |
| Legal basis of application: | Article 10(1) generic application |
| Applicant (name and address) | Rontis Hellas Medical and Pharmaceutical Products S.A., Sorou 38, Marousi 15125 Attiki, Greece |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | PharOS MT Ltd HF62X, Hal Far Industrial Estate Birzebbugia BBG3000, Malta Rontis Hellas Medical and Pharmaceutical Products S.A., Sorou 38, Marousi, 15125 Attiki, Greece Manufacturing address: P.O Box 3012 Larisa Industrial Area 41004 Larisa, Greece |
Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs, the RMS considers that the application for Pirfenidone beta / Rontis / film-coated tablets 267mg, 534mg & 801mg, with the following indication:
<Invented name> is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF)
is approved.
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, Rontis Hellas Medical and Pharmaceutical Products S.A. is applying for the Marketing Authorisations of “Pirfenidone beta /Rontis 267 mg, 534 mg, 801 mg film-coated tablets” in MT.
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.
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.
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 (India) complied with the ethical standards of Directive 2001/20/EC. During the assessment, no relevant concerns were identified about the compliance with GCP or related regulatory and ethical standards.
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. The drug substance manufacturers are holding a Certificate of Suitability respectively.
No re-test period is mentioned on the Certificates of the manufacturers. The Applicant has provided stability studies from the two suppliers.
For the drug substance coming from the Lupin source, a re-test period of two years is mentioned on the CEP.
Drug Product
The drug product is a film coated tablet containing Pirfenidone as active 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. Up to 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.
Information on reference standards used has been provided.
The shelf life of 24 months without any precaution advice is acceptable for the batches packed in the proposed blisters and in HDPE bottles.
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.
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 and 801 mg film-coated tablets weredeveloped as a generic medicinal product with reference to the brand leader Esbriet® 267 mg, 534 mg and 801 mg film-coated tablet, Roche Registrations GmbH.
A bioequivalence study was conducted by Veeda Clinical Research Pvt. Ltd., Shivalik Plaza, Near I.I.M, Ambawadi, Ahmedabad, India, between August 18, and 25, 2020, 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 62 male subjects 18 to 45 years of age received either test or reference product in randomised order under fed conditions. 52 subjects completed the study per protocol and were analysed for pharmacokinetics. Study periods were separated by a washout of at least 5 days. Primary variables for the assessment of bioequivalence were AUC0-t and Cmax, 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 30000.000 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 = 52
| Pharmacokinetic parameter | 4Arithmetic Means (±SD) | |
| Test product | Reference Product | |
| AUC(O-t)1 | 49018.358 ± 17290.3570 | 50545.258 ± 19142.3324 |
| AUC(O-oo)2 | 49437.550 ± 17439.9999 | 51026.780 ± 19274.7764 |
| Cmax | 10350.696 ±2564.0929 | 11495.468 ±3374.1399 |
| Tmax3 | 1.500 (0.25–4.50) | 1.750 (0.50–4.50) |
2.7.1.Table 7: Pharmacokinetic data for Pirfenidone in 20-VLN-0191
*AUC (0–7211) can be reported instead of AUC(O-t), in studies with a sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products.
2AUC (0-oo) does not need to be reported when AUC(0–72h) is reported instead of AUC (0-t).
3Median (Min, Max)
4Aritlunetic Means (±SD) may be substituted by Geometric Mean (±CV%)
Table 2: Geometric means of the primary equivalence parameters and assessment of bioequivalence
| Pharmacokinetic parameter | Geometric Mean Ratio Test. Ref | Confidence Intervals | CVW |
| AUC2(0-t) | 99.29 | 94.31% – 104.52% | 15.68 |
| Cmax | 91.87 | 85.05% – 99.24% | 23.73 |
2.7.1.Table 9: Bioequivalence evaluation of Pirfenidone in 20-VIN-0191
Data from this study demonstrated that the test and the reference products were well tolerated. Total eleven (11) adverse events were reported by ten (10) subjects during the study. AEs were about equally distributed among the test and the reference product. No death and serious adverse event reported during entire course of the study.
Summary
The Applicant has submitted a bioequivalence study to compare Pirfenidone 801 mg film-coated tablets with Esbriet 801 mg film-coated tablets. The procedures followed for a fed study are in line with the bioequivalence guideline. Bioequivalence has been shown for the 801 mg tablet under fed conditions. The manufacturing process of Pirfenidone 267 mg, 534 mg and 801 mg film-coated tablets is the same and the ratio of excipients to the amount of active substance is the same for all strengths. Further, a comparable in vitro dissolution profile was shown for the different strength tablets under the three requested conditions. Dissolution of the 801 mg and 267 / 534 mg strength is comparable, as the conditions mentioned in the BE guideline appendix I were met. Finally, the AUC and Cmax for Pirfenidone is considered linear over the relevant dose range. Therefore, a biowaiver for additional strengths 267 and 534 mg, based on the BE data for the 801 mg strength, is considered acceptable.
Pharmacodynamics N/A
N/A
N/A
Medicinal product subject to medical prescription.
Bridging Report:
Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006).
The Applicant submitted a Bridging Report for Pirfenidone Rontis 267 mg, 534 mg, 801 mg, film-coated tablets (henceforth referred to as the Daughter PL) because it is very similar to PL for Esbriet 267 mg, 534 mg, 801 mg, film-coated tablets in content, key safty massages and similar to the Parent PL in design and layout for Etoricoxib 30 mg, 60 mg, 90 mg, 120 mg, film-coated tablets (henceforth referred to as the two Parent PLs). The bridging study of the Daughter PL was performed by Creative Pharma Solution on 2020–01–12. The specification of both the Daughter PL proposed for bridging and the Parent PL (Esbriet film-coated tablets) are identical in content and key safty messages.
The specification of the design and layout of both the Daughter PL proposed for bridging and the Parent PL (Etoricoxib film-coated) are very similar. Differences between the Daughter and Parent PLs (Pirfenodone Rontis and Esbriet film-coated tablets) are presented with analysis and evidence which
show that these differences have little material impact on readability. Summarized, the bridging study shows that the Daughter PL is strongly similar to the Parent PLs.
Therefore the PL for Pirfenidone Rontis requires no separate user testing according the ‘QuestionAnswer-Document’ Consultation with target patient groups for the Package Leaflet, published on the HMA-website.
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.
The MAA 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
| Summary of safety concerns | |
| Important identified risks | □ Photosensitivity reaction and rash □ Drug-induced liver injury □ Gastrointestinal symptoms |
| Important potential risks | □ Severe skin reactions □ Risk of medication error in patients transferring between capsules and tablets |
| Missing information | □ QT prolongation □ Underlying specific cardiac events |
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed. Guided questionnaires for the assessment of drug-induced liver injury are included.
Risk minimisation measures
Additional risk minimisation activities in the form of safety checklists for liver function and photosensitivity are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan (version no 0.4, sign off date 15/02/22) is considered acceptable. However, the applicant is requested to include either the QPPV signature or the oversight declaration on the RMP submitted with the closing sequence.
After approval 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.
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.