PL/H/0353/001-003/R/001

Mutual Recognition Procedure Renewal Final Renewal Assessment Report Milukante Montelukastum PL/H/0353/001-003/R/001 Marketing Authorisation Holder: Adamed Sp. z o.o. Date: 2015-01-14 Time table Renewal Procedure Start Date 2014-12-08 Date of Preliminary Renewal Assessment 2014-12-18 Report (PRAR) Deadline for Comments by CMS (day 55) -

Deadline for CMS to advise acceptance/nonacceptance of decision (day 85) Proposed common renewal date - This renewal is unlimited, when it is approved. Table of content 1. Introduction...3 2. Summary of authorities comments and MAH s response...5 3. Conclusions...8 2

ADMINISTRATIVE INFORMATION Name of the medicinal product(s) in the RMS INN (or common name) of the active substance(s) Pharmaco-therapeutic group (ATC code) Pharmaceutical form(s) and strength(s) Reference Number for the Renewal Procedure Reference Member State Member States concerned Names and addresses of manufacturer(s) dosage form(s) Milukante Monteluk astum R03DC03 Chewable tablets, 4 mg, 5 mg, film-coated tablets, 10 mg PL/H/0353/001-003/R/001 PL none AET Laboratories Ltd. Survey No. 42 Gaddapotharam, Kazipally Ind. Area, Medak Dist., Hyderbad 502 319 (AP), Indie Takeda Pharma Sp. z o. o. ul. Księstwa Litewskiego 12, 99-420 Łyszkowice Names and addresses of manufacturer(s) responsible for batch release in the EEA Pharmacare plc Beitunia Industrial Zone, P.O. Box 677 Ramallah, Palestyna ADAMED Sp. z o. o. ul. Pieńków 149 05-152 Czosnków Takeda Pharma Sp. z o. o. ul. Księstwa Litewskiego 12 99-420 Łyszkowice HBM Pharma s.r.o. Sklabinská 30 03680 Martin Słowacja Pabianickie Zakłady Farmaceutyczne Polfa S.A., ul. Marszałka Józefa Piłsudskiego 5 95-200 Pabianice In the Re fe re nce Me mbe r State : Marketing authorisation holder's name and address ADAMED Sp. z o. o. ul. Pieńków 149 05-152 Czosnków Date of first marketing authorisation 07-11-2008 3

14978, 14976, 14977 RMS contact person Names of the assessors Name : Ane ta Jamka Tel: 22 49 21 593 Email: aneta.jamka@urpl.gov.pl Quality: Name (s ): Kamila Gaje ws ka Tel: (22) 49 21 522 Email: kamila.gajewska@urpl.gov.pl PI: Name (s ): Katarzyna Chrobak Tel: 22 49 21 436 Email: katarzyna.chrobak@urpl.gov.pl Clinical (e fficacy): Name (s ): Ewa Nowakows ka-radziwonka Tel: (22) 49 21 422 Email: ewa.nowakowska@urpl.gov.pl Clinical (s afe ty): Name (s ): Katarzyna Ziółkows ka Tel: (22) 49 21 305 Email: katarzyna.ziolkowska@urpl.gov.pl 4

1. Introduction Medicinal product Milukante contains montelukast sodium as an active ingredient. Montelukast is an oral leukotriene receptor antagonist. Milukante 4 mg and 5 mg chewable tablet is indicated: In the treatment of asthma as add-on therapy in those patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom as-needed short-acting ß-agonists provide inadequate clinical control of asthma. As alternative treatment option to low-dose inhaled corticosteroids for 2 to 14 year old patients with mild persistent asthma who do not have a recent history of serious asthma attacks that required oral corticosteroid use, and who have demonstrated that they are not capable of using inhaled corticosteroids. In the prophylaxis of asthma in which the predominant component is exercise - induced bronchoconstriction. Milukante 10 mg film-coated tablets is indicated: In the treatment of asthma as add-on therapy in those patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom as-needed short-acting ß-agonists provide inadequate clinical control of asthma. In those asthmatic patients older than 15 years old in whom Milukante is indicated in asthma, Milukante can also provide symptomatic relief of seasonal allergic rhinitis. In the prophylaxis of asthma in which the predominant component is exercise - induced bronchoconstriction. 2. Summary of authorities comments and MAH s response 1) CMS comment: Efficacy The Applicant should confirm that there were no reports on lack of efficacy of the medicinal product Milukante. Niniejszym firma Adamed Sp.z.o.o.oświadcza, iż w okresie od 07 listopada 2008 do 31 października 2014 roku nie odnotowała żadnego przypadku braku skuteczności produktów leczniczych : Milukante 4 mg, tabletki do rozgryzania i żucia, numer pozwolenia 14978 Milukante 5 mg, tabletki do rozgryzania i żucia, numer pozwolenia 14976 Milukante 10 mg, tabletki powlekane, numer pozwolenia 14977 5

Agreed. 2) CMS comment: Efficacy Application Form for Milukante 5 mg should be corrected in point Qualitative and quantitative composition in terms of the active substance(s) and the excipient(s) Application Form for Milukante 5 mg has been corrected. Accepted. 3) CMS comment: Efficacy Clinical Expert Statement should be updated. Due to new pharmacovigilance legislation safety renewal dossier should contain Addendum to Clinical Overview no Clinical Expert Statement is proposed. The Applicant submits the Addendum to the Clinical Overview. Agreed 4) CMS comment: Efficacy List of follow up measures/post authorisation commitments should be submitted. The Applicant submits along with the Responses to the PRAR the post authorisation commitmence. Please find attached the updated follow up measures (included in additional data) and the required stability studies of film-coated tablets (included in Module 3.2.P.8.3). Agreed 5) RMS comment: Addendum to the Clinical Overview MAH is requested to submit Addendum to the Clinical Overview, which should be prepared based on data collected since the granting marketing authorisations for Milukante up to this time. Moreover, the Clinical Expert, who will prepare addendum should: Confirm that no new clinical (or pre-clinical data in the absence of non-clinical overview) are available which changes or results in a new benefit/risk evaluation. Where there are new pre- 6

clinical data the MAH should submit a non-clinical expert report as appropriate. Confirm that the product can be safely renewed at the end of a 5- year period, or any action recommended or initiated should be specified and justified. Confirm that the authorities have been kept informed of any additional data significant for the assessment of the benefit/risk balance of the product concerned. Confirm that the product information is up to date with current scientific knowledge including the conclusions of assessments and recommendations made publicly available on the European medicines web-portal. MAH has submitted Addendum to the Clinical Overview which is the summary of the safety data received by the Pharmacovigilance Department of Adamed from worldwide sources during the report period, i.e. from 07.11.2008 to 31.10.2014. Clinical Expert, who has prepared addendum, confirms above mentioned issues in Clinical Expert Statement (Appendix II) enclosed to Addendum to the Clinical Overview. Accepted 6) RMS comment: RMP Please note: The RMP (Code: RMP/MON/02 dated 20-NOV-2013) enclosed to renewal dossier hasn t been assessed. If MAH wishes to update the dossiers of medicinal products Milukante should submit variation after the end of renewal procedure. MAH has submitted statement on RMP that declare to submit RMP of medicinal product Milukante, chewable tablets 4 mg and 5 mg and film-coated tablets 10 mg via variation after the end of renewal procedure. Agreed 7) RMS comment: next PSUR The next PSUR should be submitted after 3 years. (EURD list EMA/630645/2012 Rev.25, dated 1 December 2014). The following safety issues should be monitored: a cumulative overview of suicide case, including fatal cases and also non-fatal suicide attempts and intention overdoses and other relevant cases, frequency of psychiatric ADRs in children versus in adults, depression and suicidality in pediatric patients, psychosis, diabetes mellitus, monitoring of Churg- Strauss syndrome (CSS) should be widened, not be limited to CSS cases strictly matching the ACR criteria but wider entity including AGA and other relevant reported events involving eosinophilic infiltrates, Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), visual impairment, including vision disorders, ocular 7

motility disorders (SMQ) drug interactions (including those with clarithromycin and fluconazole). A statement regarding the above mentioned issues is expected MAH has submitted statement on PSUR that MAH will be continue to submit PSURs in accordance with the EURD list and that above mentioned issues will be monitored as part of the routine Pharmacovigilance activities for the above mentioned medicinal product. Agreed 8) RMS comment: SPC SPC Milukante should be amended in line with SPC of the reference medicinal product. I, the undersigned, Izabela Skowrońska-Krzak hereby declare to submit the amended SPC of medicinal product Milukante, Montelukast, chewable tablets 4 mg and 5 mg and film-coated tablets 10 mg in line with the SPC of reference medicinal product via variation within three months after the end of renewal procedure. Accepted 3. OVERALL CONCLUSION AND BENEFIT -RISK ASSESSMENT The RMS is of the opinion that the renewal can be granted with unlimited validity. 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. Hence, MAH should continue to submit PSURs in accordance with the EUDR list. Next PSUR will be submitted no later than 28.10.2015 with DLP 30.07.2015. 4. Conclusions All the issues are resolved. The renewal may be granted for an unlimited period. 8

Marketing authorisation holders shall continuously check the European medicines web - portal for the DLP and frequency of submission of the next PSUR. The MAH should continue to submit PSURs in accordance with the EUDR list. Next PSUR will be submitted no later than 28.10.2015 with DLP 30.07.2015. 9