Public Assessment Report Scientific discussion Granon (Acetylcysteine) DK/H/2352/001-002/MR Date: 25-06-2015 This module reflects the scientific discussion for the approval of Granon. The procedure was finalised at April 21 st 2015. For information on changes after this date please refer to the module Update.
I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Granon effervescent tablets 200 mg and 600 mg from Takeda Pharma A/S. The product is indicated for: 200 mg tablets: Secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus in adults, adolescents and children from 6 years of age. 600 mg tablets: Secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus in adults. A comprehensive description of the indications and posology is given in the SmPC. This Mutual recognition procedure concerns a generic application claiming essential similarity with the reference product Mucomyst effervescent tablets 200 mg, Meda A/S, Denmark, MA no. 10802, which has been granted marketing authorisation in Denmark on 24.09.1982. II. QUALITY ASPECTS II.1 Introduction The finished product of 200 mg effervescent tablet is round, white with faultless surface. Each effervescent tablet contains 16.7% of the active substance. The finished product of 600 mg effervescent tablet: is round, white with faultless surface and break mark on one side. The tablet can be divided into equal doses. Each effervescent tablet contains 30.8% of the active substance. The drug product of both strengths are to be marketed in polyethylene tubes closed with polyethylene stoppers with desiccant. Pack sizes: 200 mg: 20 tablets 600 mg: 10 tablets Not all pack sizes may be marketed. Compliance with Good Manufacturing Practice The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorization. II.2 Drug Substance International Non-proprietary Name (INN): Acetylcysteine Chemical name(s): (2R)-2-acetamido-3-sulfanylpropanoic acid or Acetylcysteinum, N-Acetyl-Lcysteine or (R)-Acetylamino-3-mercapto-propionic acid. PAR Scientific discussion 2/6
Structure: Acetylcysteine is a White or almost white, crystalline powder or colourless crystals. The active substance acetylcysteine is manufactured by Moehs Iberica, S.L and PharmaZell GmbH and both manufacturers have obtained a CEP. The proposed specifications for impurities in the active substance are in accordance with EU/ICH guidelines. The specifications comply with the Ph. Eur. monograph for acetylcysteine. The analytical methods used for the active substance is satisfactorily described and are in accordance with Ph. Eur. monograph for acetylcysteine. Packaging materials have been approved in relation to the issued CEP s. II.3 Medicinal Product The finished product of 200 mg and 600 mg, effervescent tablet are formulated with well-known excipients. The formulation of the 200 mg and 600 mg effervescent tablets is not proportional. The pharmaceutical development work is acceptable and in accordance with relevant EU guidelines. Justifications for the choice of manufacturing process and packaging material have been satisfactorily described. No dissolution test are performed. However, a disintegration time test is considered adequate for the drug product, as the active substance is freely soluble in water. The manufacturing process has been satisfactorily described and validated in accordance with the EU guidelines. The manufacturing process is conventional using standard techniques. Excipients comply with Ph. Eur. except for the lemon AU flavour. The only excipient derived from animal source is lactose. It is confirmed that the preparation of lactose is in accordance with the EU regulations. The proposed limits on degradation products are justified according to relevant EU/ICH guidelines and Ph. Eur. The analytical methods used for the active substance is satisfactorily described and validated in accordance with the relevant EU/ICH guidelines. The description and choice of container closure system is in accordance with relevant EU guidelines. The studies have been carried out according to relevant EU/ICH stability guidelines, including inuse studies. 3 batches per strengths have been stored for up to 36 months at ICH conditions. No significant changes are observed in the investigated parameters. Currently the approved shelf-life is 3 years with the specific storage warning Store in the original container to protect from moisture. II.4 Discussion on chemical, pharmaceutical and biological aspects From a quality point of view the benefit risk is considered positive. PAR Scientific discussion 3/6
III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of Acetylcysteine are well known. As Acetylcysteine 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. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Granon 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 Discussion on the non-clinical aspects From a non-clinical point of view the benefit risk is considered positive. IV. CLINICAL ASPECTS IV.1 Introduction No specific clinical studies have been performed, as the application is submitted in accordance with Article 10(1) and 10(3) of Directive 2001/83/EC as amended. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. Overview based on literature review is, thus, appropriate. IV.2 Pharmacokinetics According to CPMP/EWP/QWP/1401/98 Rev1/Corr** bioequivalence studies may be waived if the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved aqueous solution. Granon 200 mg has the same qualitative and quantitative composition with regard to the active substance as the reference medicinal product (Mucomyst 200 mg). Granon 600 mg has the same qualitative composition as the reference medicinal product with regard to the active substance but deviates regarding the quantitative composition. Therefore, supplementary information is given for Mucolysin 600 mg (the supportive medicinal product). The applicant has presented data/justification showing that: 1) the product is fully dissolved in 100ml water before dosing (assay 100% at 5min time point in deionized water). The specification the reconstituted tablet should be colourless, clear and without particles. The SPC sec 4.2 states: Administration: The effervescent tablets are dissolved in ½ glass of water. The solution obtained after dissolving the effervescent tablet in water is clear, colourless and without particles and 2) the active substance from effervescent tablets comply with all GL Annex III conditions for solubility over ph range (ph 1.0, ph 4.5, ph 6.8, ph 3.24 (pka)) (highest dose (600mg) in 250ml media) and 3) the levels of sorbitol and mannitol in the formulation, are considered below level which may have effect on GI motility/permeability and thereby absorption of the active substance (discussion on published literature presented). The applied product dosage form is the same as the product referred to and since the Drug Product is an oral solution at time of administration. Therefore, a biowaiver is acceptable according to Guideline requirements, as additional justification and discussion on excipients (and their amount) used in the formulation, have been discussed and their influence on Drug Substance bioavailability has been presented. PAR Scientific discussion 4/6
IV.3 Risk Management Plan and Pharmacovigilance system RMP 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 Granon. The following summary list of safety concerns with no additional pharmacovigilance measures or risk minimisation measures has been agreed: Summary of safety concerns Important identified risks Anaphylactic reactions and anaphylactic shock Important potential risks Stevens-Johnson syndrome and Lyell syndrome Missing information None RMP version 1.0, signed 13 th March 2015 with data lock point of 25 th November 2013 is acceptable. Summary of Pharmacovigilance System Masterfile (PSMF) The applicant has provided a summary of PSMF in which proof is provided that the applicant has at his disposal a qualified person responsible for pharmacovigilance. Information about the Member States in which the qualified person resides and carries out his/her tasks and the contact details of the qualified person is also included. A statement signed by the applicant to the effect that the applicant has the necessary means to fulfill the tasks and responsibilities listed in Title IX of Directive 2001/83/EC as amended has been provided together with a reference to the location where the pharmacovigilance system master file for the medicinal product is kept. IV.4 Discussion on the clinical aspects From a clinical point of view the benefit risk is considered positive. V. PRODUCT INFORMATION SmPC and Package leaflet The content of the SmPC and package leaflet approved during the mutual recognition procedure is in accordance with that accepted for the reference product nationally in RMS and CMS. User consultation and bridging report Granon 600 mg The package leaflet (PL) for Granon 600 mg effervescent tablets has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PL was Danish. The results show that the PL meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. Granon 200 mg A user consultation with target patient groups on the package leaflet for Granon 200 mg effervescent tablets has been performed on the basis of a bridging report making reference to Granon 600 mg effervescent tablets. The bridging report submitted by the applicant has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Granon effervescent tablets 200 mg and 600 mg have a proven chemical-pharmaceutical quality and is a generic form of Mucomyst effervescent tablets 200 mg. Meda A/S. PAR Scientific discussion 5/6
Mucomyst is a well-known medicinal product with an established favourable efficacy and safety profile. The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with the texts for Mucomyst approved nationally in RMS and CMS. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Granon with the reference product, and have therefore granted a marketing authorisation. The Mutual recoignition procedure was finished on April 21, 2015. 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. The common renewal date will be 14-05-2018 based on the approval date in RMS. PAR Scientific discussion 6/6