Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssuspension - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension
Name of the drug substance (INN name):	Azacitidine
Pharmaco-therapeutic group (ATC Code):	L01BC07
Pharmaceutical form(s) and strength(s):	Powder for suspension for injection
Reference Number(s) for the Decentralised Procedure	DE/H/6756/001/DC
Reference Member State:	DE
Concerned Member States:	PL and RO
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Marketing Authorisation Holder (name and address)	Onko Pharmaceuticals Bulgaria Ltd EOOD Ul.gramada 18 1680 Sofia Bulgaria
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	WESSLING GmbH Oststraße 7 48341 Altenberge Germany Wessling Hungary Kft. Anonymus u. 6 1045 Budapest Hungary Wessling GmbH Johann-Krane-Weg 42 48149 Muenster Germany

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension in the treatment of

Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation (HSCT) with:

• - intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International

Prognostic Scoring System (IPSS),

• - chronic myelomonocytic leukaemia (CMML) with 10 – 29 % marrow blasts without

myeloproliferative disorder,

• - acute myeloid leukaemia (AML) with 20 – 30 % blasts and multi-lineage dysplasia, according

to World Health Organisation (WHO) classification,

• - AML with > 30 % marrow blasts according to the WHO classification.

is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

Not applicable (generic application).

• II.2 About the product

Pharmacotherapeutic group: Antineoplastic agents, pyrimidine analogues; ATC code: L01BC07

Azacitidine is a pyrimidine analogue and is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA. DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer- suppressing functions to cancer cells. The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.

The claimed indications, recommendation for use and posology of Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension are identical to the reference product Vidaza:

Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation (HSCT) with:

• – intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International

Prognostic Scoring System (IPSS),

• – chronic myelomonocytic leukaemia (CMML) with 10 – 29 % marrow blasts without

myeloproliferative disorder,

• – acute myeloid leukaemia (AML) with 20 – 30 % blasts and multi-lineage dysplasia, according

to World Health Organisation (WHO) classification,

• – AML with > 30 % marrow blasts according to the WHO classification.

Posology

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m² of body surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle).

It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continued as long as the patient continues to benefit or until disease progression.

Patients should be monitored for haematologic response/toxicity and renal toxicities (see section 4.4); a delay in starting the next cycle or a dose reduction as described below may be necessary.

• II.3 General comments on the submitted dossier

This application for marketing authorisation, via the decentralised procedure with DE as RMS, concerns the generic medicinal product Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension.

The following CMS are involved in this procedure: PL and RO.

The product applied for is submitted as a generic application according to article 10.1 of Directive 2001/83/EC, referring to Vidaza 25 mg/mL powder for suspension for injection (Celgene Europe B.V., MA number EU/1/08/488/001) as reference product. Vidaza has been registered in the EEA since 17.12.2008.

The applicant did not conduct an in vivo bioequivalence study and applied for a biowaiver based on comparative in vitro testing.

The applicant states that the proposed Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension has an identical qualitative and quantitative composition in terms of active substance and same pharmaceutical form as the reference product, with similar excipients.

Comparative dissolution data for Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension vs. Vidaza 25 mg/ml powder for suspension as per the recommendation cited in the FDA ‘Draft Guidance on Azacitidine (FDA, published in 2017)’ were provided. The samples were analysed for impurity profile, physico-chemical characteristics, particle morphology and particle diameter and in-vitro release.

No scientific advice has been provided.

A risk management plan is submitted with this application.

Currently authorised orphan medicinal products

• in acute myeloid leukemia (AML):

• 1. Dacogen (Decitabine), Janssen-Cilag International NV

• 2. Daurismo (Glasdegib maleate), Pfizer Europe MA EEIG

• 3. Mylotarg (Gemtuzumab ozogamicin), Pfizer Europe MA EEIG

• 4. Rydapt (Midostaurin), Novartis Europharm Limited

• 5. Vyxeos (daunorubicin, cytarabine, liposomal formulation), Jazz Pharmaceuticals Ireland

Ltd.

• 6. Xospata (Gilteritinib), Astellas Pharma Europe B.V.

• in myelodysplatic syndromes (MDS)

• 7. Reblozyl (Luspatercept), Celgene Europe B.V.

Similarity assessment is performed during the registration procedure. It is currently concluded that Azacitidine is considered not similar (as defined in Article 3 of Commission Regulation (EC) No. 847/2000) to these products.

• 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.

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

GCP

Not applicable.

• 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 drug substance Azacitidine is assessed in ASMF worksharing procedure. The ASMF is acceptable. The synthesis has been adequately described and the control of the synthesis and the quality of the starting materials, intermediate product and active substance is appropriate.

Starting materials are defined in line with ICH Q11. Potential carry-over of impurities has adequately been evaluated.

A re-test period of 60 months at 2 – 8°C has been established.

Drug Product

The composition of the drug product is satisfactorily described.

The drug substance is shortly described in the dossier.

The excipients used are standard and commonly used in the pharmaceutical industry. Their chose as diluent and stability aid have been justified.

Azacitidine exhibits polymorphism. As the active substance is dissolved in water during the manufacturing process, the original form and particle size distribution are not critical.

The pharmaceutical development section provided is acceptable.

The formulation of the proposed product is acceptable and is qualitatively in line with the composition of the reference product.

Comparative impurity and assay profile results for the test and reference product have been provided.

Based on above results it was concluded that biowaiver for a generic azacitidine powder for suspension for injection product is acceptable. A test method for particle morphology has been provided.

The proposed manufacturing method has been justified and is acceptable.

The manufacturing process is well developed.

The container closure system and its associated components have been sufficiently characterized. The suitability of the container closure system for its intended use of packaging Azacitidine Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension drug product could be shown.

The development studies and the stability studies further support the compatibility of the container closure system with the proposed Azacitidine Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension drug product.

The results from antimicrobial effectiveness testing summarized support the label statement that reconstituted final drug solution can be stored for 8 h at 25°C.

Sterility test and the test for bacterial endotoxins are implemented in the drug product specification.

To assure method sensitivity in line with the Guideline on sterilisation of the medicinal product, active substance, excipient and primary container, the control limit for the pre-filtration bioburden should reflect a sample size of 100 ml (NMT 10 CFU/100 ml) unless otherwise justified.

Reconstitution stability studies have been conducted with 20–25°C Water for Injection (25 mg/ml). Results are found well within acceptance criteria.

Details of the manufacturing, packaging, testing and batch release sites have been provided. Satisfactory supporting GMP and MA certificates have been provided.

The batch formulae provided is acceptable and in line with the composition proposed.

The manufacturing process needs an overage of 3% drug substance, the stability performance of the formulation do not require the use of an overage.

The manufacturing process is described including conditions/pa­rameters and equipment used.

Details on the filtration steps included in the manufacturing process have been provided, which are satisfactory. Both pre and post filtration integrity testing will take place.

Details of the conditions for sterilisation of vials, rubber stoppers and seals have been indicated and are acceptable.

Satisfactory information has also been provided on the lyophilisation process.

The IPC’s performed on a routine basis have been adequately indicated and have been included in the flow diagram.

The process validation data provided for three commercial batches indicate a robust and reproducible manufacturing process.

Satisfactory process validation data has been provided, including data from media fill runs in support of validation for aseptic filling.

The excipients are of pharmacopoeial grade.

The release and shelf life specifications presented cover relevant parameters for this dosage form and are suitable to control the quality of the drug product.

Analytical methods used have been described in detail, including the principle of the method, the equipment parameters, the sample and standard preparation, the calculation formula, and a System Suitability Test.

The applied methods are in accordance with current technical and scientific requirements.

The validation data provided are in accordance with the requirements of the relevant ICH guidelines.

Satisfactory batch analyses have been presented. The batch analyses data together with the results obtained from the validation of the manufacturing process, stability testing confirm consistency and uniformity of the product based on the parameters tested and indicate the reproducibility of the manufacturing process for the drug product.

The degradation impurities have been sufficiently characterized.

An Elemental Impurities Risk Assessment performed by the proposed Drug Product Manufacturer, in line with the guideline ICH Q3D – Guideline “For Elemental Impurities” has been presented.

A risk evaluation regarding nitrosamines impurities has been conducted.

The specification of the drug product has been sufficiently justified.

The reference standards proposed and documentation provided is satisfactory, and includes specifications and certificates of analysis.

The container closure system proposed is acceptable and satisfactory supporting documentation has been provided. The provided specifications and information for the proposed container closure systems are considered as sufficient.

The stability data presented has been conducted in line with CHMP guidance.

Stability data is available for 24 months of long term (25°C) and 6 months of accelerated (40°C) storage. Stability studies at long-term conditions are ongoing.

A shelf-life of 30 months has been proposed based on 6 month accelerated and 24 months long term stability data. The proposed shelf-life is acceptable.

Photo stability studies in line with ICH guidance have shown the product is photo-stable. The proposed packaging and the proposed storage condition: “This medicinal product does not require any special storage conditions.” is acceptable. Sufficient information on the chemical -physical stability of the reconstituted solution has been provided.

The commitment to place one commercial batch on long-term stability per year is acceptable.

The proposed SmPC has been assessed with regard to chemical-pharmaceutical aspects.

The proposed SmPC is in line with the SmPC of the reference product with regard to chemicalpharma­ceutical aspects.

• III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of azacitidine are well known. As azacitidine 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. The applicant provided an updated NC-OV with information about impurities and residual solvents found in drug substance/drug product to be in accordance to the Notice to Applicants, volume 2B, incorporating the Common Technical Document. (May 2008) as requested by RO.

Environmental Risk Assessment (ERA)

Since Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssus­pension 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

The pharmaceutical form of the medicinal product applied for is powder for suspension for injection.

No bioequivalence studies were submitted.

The applicant applied for a biowaiver based on in vitro studies, comparing the medicinal product applied for and the reference product with respect to impurity profile, physico-chemical characteristics, particle morphology and particle diameter and in-vitro release.

The biowaiver request is assessed in the Quality part of this AR.

Summary Pharmacovigilance system

The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/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/similar products 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.

After approval the MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the dossier 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.

Common renewal date

The common renewal date is 12.10.2026.

Legal status

Medicinal product subject to medical prescription.

User Testing

The user testing is accepted.

• IV. BENEFIT RISK ASSESSMENT