Azathioprin Doc Generici 50 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel - Azathioprin Doc Generici 50 mg Filmtabletten

PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Azathioprin Doc Generici 50 mg Filmtabeltten

Procedure-Number: DE/H/6746/001/DC

Active Substance:

Azathioprine

Dosage Form:

Film-coated tablet

Applicant:

Doc Generici S.r.l.

Publication:

10.10.2023

This module reflects the scientific discussion for the approval of the above-mentioned procedure. The procedure was finalised at 27.09.2023.

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

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Azathioprin Doc Generici 50 mg Filmtabletten
Name of the drug substance (INN name):	Azathioprine
Pharmaco-therapeutic group (ATC Code):	L04AX01
Pharmaceutical form(s) and strength(s):	Film-coated tablet 50 mg
Reference Number(s) for the Decentralised Procedure	DE/H/6746/001/DC
Reference Member State:	DE
Concerned Member States:	IT
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Applicant (name and address)	Doc Generici S.r.l. Via Filippo Turati 40 20121 Milan Italy
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	AqVida GmbH Kaiser-Wilhelm-Straße 89 20355 Hamburg Germany

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Azathioprin Doc Generici 50 mg Filmtabletten, in the treatment of

Azathioprine is indicated in immunosuppressive regimens as an adjunct to immunosuppressive agents that form the mainstay of treatment (basis immunosuppression).

Azathioprine is indicated in combination with other immunosuppressive agents for the prophylaxis of transplant rejection in patients receiving allogenic kidney, liver, heart, lung, or pancreas transplants.

Azathioprine is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and/ or procedures, which influence the immune response. Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids.

Azathioprine is indicated either alone or in combination with corticosteroids and/or other drugs and procedures in severe cases of the following diseases, in patients who are intolerant to steroids or who are dependent on steroids and in whom the therapeutic response is inadequate despite treatment with high doses of steroids:

severe active rheumatoid arthritis that cannot be kept under control by less toxic agents (disease modifying anti-rheumatic drugs, DMARDs)
severe or moderately severe inflammatory intestinal disease (Crohn’s disease or ulcerative colitis)
systemic lupus erythematosus
dermatomyositis
auto-immune chronic active hepatitis
polyarteritis nodosa
auto-immune haemolytic anaemia
chronic refractory idiopathic thrombocytopenic purpura

is approved.

II EXECUTIVE SUMMARY

II.1 Problem statement

N/A

II.2 About the product

Azathioprine 50 mg is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. The active drug is believed to be mercaptopurine. Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. Like other immunosuppressants, it suppresses the proliferation of T and B lymphocytes. By suppressing the immune system, it reduces the Azathioprin Doc Generici

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inflammation that accompanies immune reactions. It is used as an immunosuppressive in the treatment of multiple sclerosis and reduces new inflammatory lesions and relapse rates.

The therapeutic indications applied for are:

Azathioprine is indicated in immunosuppressive regimens as an adjunct to immunosuppressive agents that form the mainstay of treatment (basis immunosuppression).

severe active rheumatoid arthritis that cannot be kept under control by less toxic agents

(disease modifying anti-rheumatic drugs, DMARDs)

severe or moderately severe inflammatory intestinal disease (Crohn’s disease or ulcerative

colitis)

systemic lupus erythematosus
dermatomyositis
auto-immune chronic active hepatitis
polyarteritis nodosa
auto-immune haemolytic anaemia
chronic refractory idiopathic thrombocytopenic purpura
II.3 General comments on the submitted dossier

This decentralised application concerns a generic version of azathioprine, under the trade name Azathioprin Doc Generici 50 mg Filmtabletten. In this Assessment Report, the name Azathioprine 50 mg tablets is used.

The originator product is Imurek 50 mg Filmtabletten by Aspen Pharma Trading Limited, registered since 20.03.1992 and approved in Germany since 30.11.2004 (MA No: 6101735.00.00).

With DE as the Reference Member State in this Decentralized Procedure, Doc Generici S.r.l. applied for the Marketing Authorisation for Azathioprine 50 mg film coated tablet in CMS IT.

Similarity

Where a designated orphan medicinal product has been authorised for the condition, which covers the proposed therapeutic indication being applied for, and a period of market exclusivity is in force, applicants should provide a critical report addressing the possible similarity with the authorised orphan medicinal product and concluding on similarity or “non”-similarity.

In case of the indications for Azathioprine herewith applied Cablivi and Soliris were identified as approved Orphan drugs with overlapping indications. However, the applicant argues correctly that azathioprine is a small molecule which is structural and regarding the mechanism of action completely different and thus not similar to both products with respect to this two reasons.

After Response on Day 160 AR : an update was provided which inlcudes in addition Vyvgart and Enjaymo for additional similarity exercise. The RMS agrees with this argumentation and concludes that Azathioprine should be considered as non-similar neither with Soliris nor with Vyvgart, Cablivi or Enjaymo. Since the RMS needs a clear statement at each round until national approval that any similarity to orphan protected products in the EU remains missing, regular update of the similarity excersise during the whole procedure until finalisation of the nation phase of approval is required as a essential condition.

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. In relation to this, no inspection is deemed necessary.

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. In detail, the drug product manufacturer has been granted a GMP certificate issued by the German authority Behörde für Gesundheit und Verbraucherschutz located in Hamburg.

GMP active substance

Regarding the statement on GMP for the active substance, a satisfactory statement/declaration is provided from the manufacturer responsible for batch release situated in the EU (drug product manufacturer is located outside the Community).

GLP: The bioanalytical approach used in the pivotal BE trial 1 was performed under GLP conditions.

GCP:

The clinical study report states that all clinical work was conducted in compliance with GCP. The applicant provided a list of inspection by EU authorities.

III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Introduction

The chemical-pharmaceutical documentation in the dossier is of sufficient quality in view of the present European regulatory requirements.

Drug Substance

The active substance of Azathioprine 50 mg film-coated tablets is described in a Ph. Eur. monograph (07/2010:0369). The applicant has submitted two Certificates of Suitability of the European Pharmacopoeia, for the drug substance Azathioprine manufactured at the proposed manufacturing sites. Both the CEPs are

the valid versions according to the EDQM database. GMP statements on the active substance are provided in QP declarations which are considered satisfactory.

The control tests and specifications for the drug substance are adequately drawn up. Azathioprine is mainly controlled according to the tests specified in the Ph. Eur. monograph. Additional tests for residual solvents are stated on the CEPs, pertaining to pyridine and ethanol as well as to acetone, respectively. Moreover, the drug product manufacturer controls microbial purity and particle size distribution (micronization of the drug substance is required).

Regarding the container closure system and the re-test periods, reference to the CEPs is made. For the drug substance, the re-test period for Azathioprine is 5 years if stored in sealed double polyethylene or polypropylene bags placed in a sealed polyethylene drum. For the drug substance from the other active substance manufacturer, the re-test period for Azathioprine is 3 years if stored in double polyethylene bags placed in a fibre drum.

Drug Product

The drug product, Azathioprine 50 mg film-coated tablets, consists of pale yellow coloured, film coated, round, biconvex tablets, debossed with “AZ 50” on one side and a score line on the other side.

The drug product has been developed as generic medicinal product with respect to the innovator European reference product Imurek® 50 mg film-coated tablets from Aspen Pharma Trading Limited.

The development of the product has been described, the choice of excipients justified and their functions explained. The excipients of the tablet core are well-known, generally used for this kind of dosage form and of Ph. Eur. quality. Formulation and manufacturing process development has been sufficiently detailed. The selection of excipients has been justified appropriately based on comparability studies.

The development of the dissolution method has been described and justified. As the solubility of Azathioprine was demonstrated to be pH independent, the choice of purified water for routine control is acceptable.

Comparability of dissolution of test and reference products was demonstrated in three different media according to the BE Guideline. Moreover, dissolution data were provided in QC medium water. Similarity factors were calculated and proved to be above 50 in all media tested. Moreover, comparability of the recent test and reference products with the respective test and reference bio-batches (first BE study) has been investigated in QC medium and proved to be similar. The comparability of dissolution of the test product to the reference product may be deduced from this bridging approach from the quality point of view. In addition, the bio-batch of the reference product Imurek (second BE study) was compared with the test product Azathioprine 50 mg in the four mentioned dissolution media. Similarity factors were calculated and proved to be at or above 50 in all media tested.

The dissolution specification is acceptable in relation to the dissolution data provided from the bio-batch of the test product, being in accordance with the Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action (EMA/CHMP/CVMP/QWP/336031/2017). The discriminatory power of the dissolution method and batch-to-batch consistency were suitably demonstrated.

Manufacture of the drug product is considered a standard process, consisting of blending, wet granulation, sieving, tablet compression and coating. In-process controls performed are considered appropriate. Sufficient process validation was performed.

All excipients of the tablet core and the tablet coating are described in Ph. Eur. monographs and their quality complies with the respective requirements. Partly, additional specifications were set. The dye mixture is controlled according to an in-house specification. TSE declarations and residual solvent certificates have been provided.

The drug product specifications cover relevant parameters for this dosage form. The applied methods are in accordance with current technical and scientific requirements and have been adequately described. Validations of the analytical methods have been presented and are in accordance with the requirements of Azathioprin Doc Generici

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the relevant ICH guidelines. The stability indicating nature of the assay and purity methods has been verified. The test for microbial purity has also been verified.

Batch analyses have been presented, meeting specifications. An assessment of elemental impurities in the drug product in accordance with ICH Q3D has been provided and no further actions are necessary. Information on the reference standards is acceptable.

The proposed packs for Azathioprine 50 mg film-coated tablets are PVC/PVDC-Al blisters. The packaging materials are commonly used for oral preparations and the stability studies demonstrate that the containers do not interact physically or chemically with the drug product. Compliance with the relevant EU guidance and Ph. Eur. requirements is confirmed for the types of primary packaging material.

Stability data have been generated from several stability batches for up to 60 months during long-term stability testing. The conditions used in the stability studies are according to the ICH stability guideline. The drug product control tests and specifications are set adequately. Based on the submitted stability data, the proposed shelf life of 48 months can be granted. No storage restriction in relation to temperature will be necessary.

Photostability studies of the drug product are provided in accordance with EU guidance. Degradation was observed in the drug product in clear blisters, but no degradation was observed in the secondary pack, therefore, the applicant proposes the storage condition “Store in the original package in order to protect from light”.

Conclusion

The drug product is approvable as the remaining other concern in relation to the drug product was resolved.

III.2 Non clinical aspects

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

Environmental Risk Assessment (ERA)

Since Azathioprin Doc Generici 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.

Conclusion:

From a non-clinical point of view no objection are raised against approval of this product.

III.3 Clinical aspects

Demonstration of bioequivalence of the applied azathioprine with reference products is based only on trial, which compares a 100 mg test product with 2 × 50 mg of the reference product.

Although the relevant guideline recommends a single dose BE trial comparing 50 mg single dose of test against reference remains missing, an acceptable justification and bridging strategy for the provided approach was submitted during the response. Thus, trial 1 can be accepted for the demonstration of bioequivalence.

Bioequivalence of AZATHIOPRINE 100 MG, FILM-COATED TABLETS (Study code 1)

One open label, balanced, randomised, two treatment, two sequence, two period, two way crossover, singledose oral bioequivalence study 1 of Azathioprine tablets BP 100 mg (= AZATHIOPRINE 100 MG, FILMAzathioprin Doc Generici

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COATED TABLETS) and Imurek® of Aspen Pharma Trading (2×50 mg tablets), in normal, healthy, adult human subjects under fasting conditions is claimed for pivotal purposes in this application.

The applicant clarified that study 1 has been conducted as per the approved protocol in compliance with the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects, 64th World Medical Association – General Assembly, Fortaleza, Brazil, October 2013), Good Clinical Practice (International Council for Harmonisation – E6 (R2) Guidelines, Current Step 4 version dated 9 November 2016) and all other pertinent regulatory requirements of Schedule Y(Amendments in 2005, 2013, 2014, 2015, 2016 and 2017 Central Drugs Standards Control Organization, India), CDSCO Guidelines for Bioavailability & Bioequivalence Studies Mar 2005, Indian Council of Medical Research (Ethical Guidelines for Biomedical Research on Human Participants, 2017), Guidance on the Investigation of Bioequivalence, CHMP – EMA (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr**, Jan 2010), ethical requirements of Directive 2001/20/EC and other applicable regulatory requirements.

As recommended by the relevant EMA guideline, the primary objective of this study was to assess whether the test product is bioequivalent to the reference product based on the evaluation of Cmax, and AUC0-t of azathioprine. The secondary objectives of the present study include: Descriptive statistics for pharmacokinetic parameters – AUC0-∞, tmax, t1/2, Kel (apparent first–order terminal elimination rate constant), NKel (the number of points of the terminal log-linear phase used to estimate the Kel), Kel-lower (lower limit on time for values to be included in the calculation of Kel), Kel-upper (upper limit on time for values to be included in the calculation of Kel), AUCratio and residual area [percentage of AUC0-∞ due to extrapolation from last time point to infinity calculated using formula {(AUC0-∞ – AUC0-t) / AUC0-∞}x100]; furthermore, an assessment of the safety and tolerability of the test product and the reference product was performed.

The main inclusion criteria were: Normal, healthy, adult, human subjects 18 to 45 years (both inclusive) of age with a body mass index in the range of 18.50–29.90 kg/m2 (both inclusive) and judged to be healthy on the basis of medical and medication history, a pre-study physical examination and 12-lead electrocardiogram and clinical laboratory tests performed within 21 days prior to first check-in.

After pre-study examinations and verification of compliance with inclusion and exclusion criteria, subjects were checked-in to ensure fasting of at least 10.00 hours prior dosing in each study period. All subjects were fasted overnight for at least 10.00 hours prior to dosing during each study period. Following an overnight fast of at least 10.00 hours, subjects were then administered one tablet (1×100 mg azathioprine) of the test product or two tablets (2×50 mg azathioprine) of the reference product with 240 □ 2 ml of drinking water orally at ambient temperature in an upright sitting position as per a randomisation schedule. A total of 22 blood samples were collected during each study period. Prior to each sample collection, 0.5 ml of isotonic saline mixed blood was discarded and cannula patency was maintained by flushing 0.5 ml of isotonic saline after each sample collection. 5.0 ml of blood was withdrawn at pre-dose (within 2.00 hour prior to dosing), and 00.08, 00.17, 00.33, 00.50, 00.67, 00.83, 01.00, 01.25, 01.50, 01.75, 02.00, 02.50, 03.00, 03.50, 04.00, 05.00, 06.00, 07.00, 08.00, 12.00 and 16.00 hours post dose in pre-labelled vacutainers containing K3EDTA as an anticoagulant during each study period. Subjects were checked out at 24.00 hours post-dose during each study period. The duration of subject participation was 17 days including a wash-out period of 14 days between consecutive study periods. Total blood loss for a subject during the study did not exceed 267.00 ml (for male subjects).

The primary pharmacokinetic parameters (Cmax and AUC0-t) and secondary pharmacokinetic parameters (AUC0-∞, tmax, t1/2, Kel, NKel, Kel-lower, Kel-upper, AUCratio and residual area) for azathioprine were calculated using plasma concentration data by the non-compartmental model of Phoenix® WinNonlin® Software (Version 8.1). The statistical analysis was performed on pharmacokinetic parameters using Statistical Analysis Software SAS®. Consistent with Schuirmann’s two one-sided tests procedure for bioequivalence, ANOVA was performed on natural log-transformed pharmacokinetic parameters Cmax and AUC0-t for azathioprine. The non-parametric analysis of tmax was performed on untransformed data using the Wilcoxon signed-rank test.

Criteria for bioequivalence were that the test product was considered bioequivalent to the reference product, if 90% CIs for ratio (test/reference) of geometric least square means based on log transformed primary pharmacokinetic parameters Cmax and AUC0-t fell within acceptable bioequivalence limits of 80.00% to 125.00% for azathioprine.

Safety monitoring including of adverse events, serious adverse events if any, intercurrent illness and laboratory assessments (performed during entire course of the study) were completed. Adverse events were evaluated based on frequency, severity grades, system specific and causality.

In conclusion, it is agreed that BE trial 1 was designed and performed fully in accordance with the recommendations as outlined in the GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE [Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr]. No product specific guideline for Azathioprin seems currently available in the EU.

A total of 54 subjects were planned and enrolled in the study. Samples of 54 subjects were analysed and data of these 54 subjects were considered for assessment of pharmacokinetic parameters whereas data of 53 subjects were considered for statistical analysis. Subject number 33 did not report to the facility for check in activity at the start of period II due to personal reasons.

Analytical methods

Azathioprine in K3EDTA human plasma is analysed by a validated LC-MS/MS method over a working range from 0.40 ng/mL to 125.23 ng/mL. This concentration is suitable.

The maximum storage time between first sample collection and last analysis is 23 days at – 70ºC°C. This period is covered by the long-term stability of 50 days at –70°C.

The applicant provided an acceptable GLP statement.

In conclusion, the bioanalytical method used in this trial seems to be adequate and with sufficient validity. The performance of the study sample analysis was apparently adequate with sufficient in –study validity. The performance / results of ISR testing is acceptable. The bioanalytical part of the dossier is acceptable, there are no further questions. The detailed bio-analytical assessment report is located in the non-clinical and clinical part of this AR.

The results of the pharmacokinetic assessment based on plasma concentration data of azathioprine are summarised below in Table 1 and 2 below.

Table 1: Mean pharmacokinetic parameters of azathioprine (n = 53 evaluated subjects) (test product A = AZATHIOPRINE 100 MG, FILM-COATED TABLETS; reference product B = Imurek® (taken from Rane 2019)

Pharmacokinetic parameters (units)	Mean ±SD (CV %)
Pharmacokinetic parameters (units)	Test Product (A)	Reference Product (B)
CmM (ng/mL)	34.51 ± 13.05 (37.82)	33.03 ± 10.39(31.45)
AUCo.t (hr.ng/mL)	42.64 ± 11.30(26.50)	43.08 ± 12.13(28.15)
AUCo.ilir(hr.ng/mL)	43.98 ± 11.67 (26.53)	44.01 ± 12.18(27.68/
T„„(hr)	0.83 (0.33 –4.00)	0.83 (0.33 – 5.00)
Kd (I-1)	1.22 ± 0.54 (44.38)	1.47 ± 0.58(39.77/
NKd	5.53 ±2.83 (51.24)	4.68 ± 2.46 (52.48)
^elJowert^O	2.33 ± 1.15(49.09)	2.52 ± 1.15(45.58/
Kd upper(hr)	4.73 ± 1.27(26.93)	4.51± 1.30 (28.92)
ti/2 (hr)	0.70 ±0.35 (49.83)	0.57 ± 0.32 (55.04/
AUC Ratio (%)	97.08 ±4.09 (4.21)	98.01 ± 1.68(1.71/
Residual area (%)	2.92 ± 4.09(139.97)	1.99 ± 1.68(84.31/

* = Median (Range) is provided; # = n = 52: (no value of Kel, Kel-lower, Kel-upper, t1/2, AUC0-«, AUCratio and residual area were reported for subject number 24 (Imurek®) in period I, as this subject did not exhibit a terminal log-linear phase in the concentrations versus time profile).

Table 2: Bioequivalence assessment of azathioprine, Ln-transformed data (n = 53) (taken from Rane 2019)

Parameter	Geometric Least-Squares Means'		Test-to-Ref Ratio2	ISCV%3	90% Confidence Interval Limits4		Power (%)
Parameter	Test	Reference	Test-to-Ref Ratio2	ISCV%3	Lower	Upper	Power (%)
LnCmax (ng/mL)	32.43	31.40	103.26	26.68	94.81	112.46	98.93
LnAUCw (hr.ng/mL)	41.19	41.52	99.21	11.73	95.50	103.05	100.00

Clinical safety

Safety Results:

The test product and the reference product were safe and well tolerated by the subjects under fasting condition.
No adverse events (AEs) were reported during this study period I and period II.
No AE was reported during post study safety assessments of the study.
There were no SAE reported in this study and no unresolved safety concerns with either test product or reference product

Pharmacokinetic conclusion:

The results presented for the absorption of azathioprine in terms of 90% confidence intervals for ratio (test/reference) of geometric least square means based on log transformed primary PK parameter Cmax and AUC0-t were found within the acceptable BE limits of 80.00% to 125.00% for the parent drug Azathioprine Azathioprin Doc Generici

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as required. Hence, the results based on Azathioprine data demonstrated that the test product Azathioprine tablets BP 100 mg was found bioequivalent to the reference product Imurek (Azathioprine / 2 Tablets of 50 mg) of Aspen Pharma Trading in normal, healthy, adult, human subjects under fasting conditions.

However, the 100 mg dose strength is not applied in this procedure and this trial does not investigate the test product under discussion (50 mg azathioprine from the same manufacturer). During response on D70 Assessment the applicant clarified that BE Trial FARMOVS 05/2001 is no longer claimed as pivotal in this application and is no longer included in the dossier.

Thus, further discussion of BE has to focus on the results of the pivotal BE trial 1 only.

A 50 mg Film-coated tablet of Azathioprine is here applied. For this situation, the relevant EMA BE guideline document recommends clearly a direct comparison of a single 50 mg dose strength for demonstration of bioequivalence. This study remains missing and the applicant clarified that such a trial is not planned to be submitted during this procedure.

This is based on the following argumentation: The pivotal BE trial 1 was designed to demonstrate bioequivalence of a 100 mg dose strength and the applicant clarified that this strategy was intended to consider also potential approval of lower dose strengths (25, 50 and 75 mg) via biowaiver approach for dose strengths below the highest dose of 100 mg. Since the 100 dose strength of the reference product is not available, it is inevitable to test two 50 mg tablet of the reference against two tablet of the test product.

Since BE trial 1 was successful in principle to demonstrate bioequivalence for the referred DCP application DE/H/6466/001–002/DC, BfArM approved the 100 mg dose strength based on trial 1 and a 75 mg dose strength based on fulfilment of the biowaiver conditions:

The pharmacokinetics of the product has to be proven to be linear in the requested dose range
The applied dose strengths were manufactured by the same manufacturer via the same process
The qualitative composition of the different strengths is the same and the composition of the strengths are quantitatively proportional,
Bioequivalence must have been proven for the highest dose strength for sensitivity purposes.
The in vitro dissolution profiles of the applied lower dose strength(s) in physiologic pHs have to be comparable to the highest dose strength for which BE has been shown.

The applicant now propose a bridging strategy based on the argument that bioequivalence was shown for the 100 mg dose strength in an approach using two 50 mg tablets test versus two 50 mg tablets reference. As the same two 50 mg tablets were used to demonstrate bioequivalence for the 100mg dose against two 50 mg tablets of the reference and the comparability of dissolution of the test product to the reference product may be deduced, a biowaiver approach should be possible in the Assessor’s view. Moreover, the both other criteria (“dose strength were manufactured by the same manufacturer via the same process” / “qualitative composition of the different strengths is the same and the composition of the strengths are quantitatively proportional”) are inherent also fulfilled.

Although this sort of circular reasoning appears to foil the mentioned guideline recommended testing of a 50 mg Tablet against a 50 mg Tablet, in this difficult situation, the approach seems acceptable in the RMS’s view. In particular, since the clarification provided from the literature in the response, in the dose range between 25 mg and 100 mg dose linearity can be concluded, while in higher doses than 100 mg non-linearity appears to be likely.

Pharmacodynamics

N/A

Efficacy and Safety:

N/A

Conclusion:

From a Clinical point of view no objection are longer raised against approval of this product.

Summary Pharmacovigilance system

The Applicant has submitted a signed Summary of the Applicant'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 Azathioprine Doc Generici 50 mg Filmtabletten DE/H/6746/001/DC.

Safety specification

Important identified risks

Myelosuppression
Neoplasms
Interaction with xanthine oxidase inhibitors

(e.g. Allopurinol, Febuxostat)

Important potential risks

Rhabdomyolysis
Progressive multifocal leucoencephalo-

pathy (PML)

Use in pregnant women
Inosine triphosphate pyrophosphatase

(ITPA) deficiency

Hepatotoxicity

Missing information

Use for the treatment of juvenile chronic arthritis, systemic lupus erythematosus, dermatomyositis, and polyarteritis nodosa in children and adolescents < 18 years
Use in elderly
Mutagenicity

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed. The Applicant stated that DOC Generici S.r.l. has established an effective pharmacovigilance system to collect, collate and evaluate individual case safety reports obtained through spontaneous reporting systems, identified from the worldwide scientific literature or received from competent authorities. Individual case safety reports are followed up to ensure that all relevant information is captured. Cumulative safety information are regularly reviewed during signal detection processes. There are no routine pharmacovigilance activities beyond adverse reactions reporting and signal detection.

Plans for post-authorisation efficacy studies

The applicant states that no post-authorisation efficacy studies have been planned.

Risk minimisation measures

The applicant states that routine risk minimisation measures are sufficient to manage the safety concerns of the medicinal product.

Table Part V.1: Description of routine risk minimisation measures by safety concern

Safety concern	Routine risk minimisation activities
Myelosuppression	SmPC sections 4.4, 4.8
Neoplasms	SmPC sections 4.4, 4.8
Interaction with xanthine oxidase inhibitors (e.g. allopurinol, febuxostat)	SmPC section 4.5
Rhabdomyolysis	Currently available data do not support the need for risk minimisation measures.
Progressive multifocal leucoencephalopathy	Currently available data do not support the need for risk minimisation measures.
Use in pregnant women	SmPC section 4.6
Inosine triphosphate pyrophosphatase (ITPA) deficiency	SmPC section 5.2
Hepatotoxicity	SmPC sections 4.4
Use for the treatment of juvenile chronic arthritis, systemic lupus erythematosus, dermatomyositis and polyarteritis nodosa in children and adolescents < 18 years	SmPC section 4.2
Use in elderly patients	SmPC section 4.2
Mutagenicity	SmPC section 4.4

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.

Azathioprin Doc Generici

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Common Renewal Date

The common renewal date is 27.09 2028.

Legal Status

Medicinal product subject to medical prescription.

User Testing

The applicant submitted a readability study.

The results of the first round showed that 100% of participants were able to find the correct information (locating was very easy in 90.0% of the cases) and 100% of participants were able to understand the information (it was very easy to understand in 98.9% of the cases).

Also, 100% of the answers given by the participants were correct. The results of the second round showed that 100% of participants were able to find the correct information (locating was very easy in 90% of the cases) and 100% of participants were able to understand the information (it was very easy to understand in 98.4% of the cases). Also, 100% of the answers given by the participants were correct. The overall results obtained show that 100% of the participants located and understood the information in the leaflet and that 100% of the answers were correct. Also, the results indicate that the leaflet is readable, that the key safety messages are understood and that the participants can act accordingly.

Since the acceptance criteria established in the protocol to perform the readability test are met, it is concluded that the applied leaflet fulfils the readability testing criteria established in the current legislation.

IV BENEFIT RISK ASSESSMENT