GUIDANCE DOCUMENT. Mutual Recognition Procedure. RMS Day 68 Preliminary Assessment Report RMS Assessment Report

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1 GUIDANCE DOCUMENT Doc. Ref: CMDh/202/2005 Rev.5 October 2016 Mutual Recognition Procedure RMS Day 68 Preliminary Assessment Report RMS Assessment Report NON-CLINICAL AND CLINICAL ASSESSMENT OF A GENERIC APPLICATION Methotrexate 2.5 mg and 10 mg tablets METHOTREXATE IE/H/477/ /MR Applicant: Accord Healthcare Limited This template is aimed for generic applications. If, apart from bioequivalence studies, other (non)- clinical data have been submitted, the template should be supplemented with relevant headings from the general templates of assessment report for non-clinical and clinical data. Reference member state: IE <Start of the procedure:> Date of this report: Deadline for comments:

2 Table of content Page 1. INTRODUCTION NON-CLINICAL ASSESSMENT Critical evaluation of the Non-Clinical Points for Clarification CLINICAL ASSESSMENT Critical evaluation of the Clinical Overview and Summary PHARMACOVIGILANCE Pharmacovigilance system Risk management plan THE APPLICANT SHOULD ENSURE THAT INFORMATION WITHIN ANNEX 2 IS AMENDED SO THAT IT IS ALIGNED WITH THE UPDATED SMPC AND PIL PROPOSED BY THE CLINICAL ASSESSOR LIST OF QUESTIONS AS PROPOSED BY THE RMS...21

3 NON-CLINICAL AND CLINICAL ASSESSMENT Type of application: An abridged application, according to article 10.2(b) so called generic application Reference product used in the bioequivalence studies: Original product: 1. INTRODUCTION This mutual recognition application concerns a generic version of Methotrexate, under the trade names Methotrexate Tablets 2.5 mg and 10 mg. In this Assessment Report, the name Methotrexate is used. The originator product is Maxtrex 2.5 mg and 10 mg tablets first authorised in in Ireland on 18th July 1984 (PA236/14/7 & 8) by means of a full dossier to Carlo Erba Farmitalia. The Maxtrex 2.5 mg & 10 mg Tablets are not currently marketed on the IE market and this has been confirmed as for commercial reasons only. With IE as the Reference Member State in this Mutual Recognition Procedure, Accord Healthcare Limited is applying for the Marketing Authorisation for this product in the following member states: DK, ES, IT, FI, FR, NL, PL, MT, NO and RO. Methotrexate is a folate antagonist. Methotrexate inhibits dihydrofolate reductase (DHFR), the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate must be regenerated via the DHFR-catalyzed reaction in order to maintain the intracellular pool of tetrahydrofolate one-carbon derivatives for both thymidylate and purine nucleotide biosynthesis. The inhibition of DHFR by folate antagonists (methotrexate) results in a deficiency in the cellular pools of thymidylate and purines and thus in a decrease in nucleic acid synthesis. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. ATC Code: L01BA01 / L04AX03 Pharmacotherapeutic group: Antineoplastic and immunomodulating agents Methotrexate has been in clinical use since Methotrexate has been used to produce regression in a wide range of neoplastic conditions including acute leukaemias, non-hodgkin's lymphoma, soft-tissue and osteogenic sarcomas, and solid tumours particularly breast, lung, head and neck, bladder, cervical, ovarian, and testicular carcinoma. Methotrexate has also been used in the treatment of conditions requiring immunosuppressant treatment such as rheumatoid arthritis and psoriasis. The product is an uncoated immediate release tablet. This is a first wave Mutual Recognition Procedure for Methotrexate 2.5 mg tablets and Methotrexate 10 mg tablets. The legal basis of the application is under Article 10(1) of Directive 2001/83/EC, as amended. Methotrexate 2.5 mg and 10 mg tablets were first approved through a national procedure in Ireland on 01

4 July 2016, (PA1390/116/ ). Methotrexate 2.5 mg and 10 mg tablets are a generic of the reference product Maxtrex 2.5 mg and 10 mg tablets licenced to Pharmacia in Ireland and first authorised in in Ireland on 18th July 1984 (PA236/14/7 & 8) by means of a full dossier to Carlo Erba Farmitalia. The medicinal products to which bioequivalence has been demonstrated compare methotrexate 2.5mg and 10mg tablets of Cipla Ltd., India with the products Maxtrex 2.5mg tablet containing methotrexate 2.5mg and Maxtrex 10mg tablet containing methotrexate 10mg of Pharmacia Limited, UK respectively. The products used in the bioequivalence studies have been supported previously by the Maxtrex 2.5 mg and 10 mg tablets licensed to Pharmacia in Ireland on 18th July 1984 (PA236/14/7 & 8) dossier as the European Reference Product. During the national MA application it was highlighted with the MAH that the product information is not in line with recently approved SmPCs for oral methotrexate authorised through the DCP procedure. The MAH has committed to updating the product information for Methotrexate 2.5mg & 10mg during this MRP procedure. In order to facilitate the update of the current MA and to harmonise product information across EU methotrexate products, the RMS proposes that the SmPCs from the procedures FI/H/0667/ and UK/11/5635/ /DC are used to harmonise the core clinical and pre-clinical sections of the SmPC. The Applicant has agreed to this approach as part of the Day 60 responses. Of note, there was a switch of RMS from FI/H/667/01-02 DCP to the current UK/H/3956/01-02 MR. 2. NON-CLINICAL ASSESSMENT 2.1. Critical evaluation of the Non-Clinical Points for Clarification Question 1: The non-clinical overview has been written by Dr. Siddart Chachad but a CV has not been provided therefore the expert s affiliation is unknown and it cannot be determined whether the non-clinical expert is suitably qualified. Please provided a CV for the nonclinical expert. Summary of the Applicant s Response An updated overview has been provided signed by Dr. Anirban Thakur and a CV included which details that he is suitably qualified as a non-clinical expert. Conclusion Issue resolved Question 2 The non-clinical expert mentioned in module is Ashish Shedage who is also mentioned on the cover of the Non-Clinical Overview, whereas on the first page of the Non- Clinical Overview the name Siddarth Chachad appears. The name of the non-clinical expert should be clarified. Summary of the Applicant s Response An updated overview has been provided signed by Dr. Anirban Thakur and a CV included which details that he is suitably qualified as a non-clinical expert. Conclusion

5 Issue resolved Question 3 Data regarding mechanisms of resistance to methotrexate should be included in the Non- Clinical Overview. Summary of the Applicant s Response An updated overview has been provided which included a section detailing the mechanisms of resistance to methotrexate. Conclusion Issue resolved 3. CLINICAL ASSESSMENT 3.1. Critical evaluation of the Clinical Overview and Summary Potential serious risk to public health: 1. The proposed SPC is in line with the reference product Maxtrex 2.5mg and 10mg. During the national MA application it was highlighted with the MAH that the product information is not in line with recently approved SmPCs for oral methotrexate authorised through the DCP procedure. The MAH has committed to updating the product information for Methotrexate 2.5mg & 10mg during this MRP procedure. In order to facilitate the update of the current MA and to harmonise product information across EU methotrexate products, the RMS proposes that the SmPCs from the procedures FI/H/0667/ and UK/11/5635/ /DC are used to harmonise the core clinical sections of the SmPC. Member states, are asked to comment on the acceptability of the proposal and or to provide additional comments. The applicant is also requested to comment on this proposal. In line with RMS recommendations, SmPC is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates. Further, warning statement in section 4.2 of SmPC adopted from procedure no. UK/H/5635/ /DC is made bold and boxed to address FR and NL agency s comment. Assessor s comment: Issue not fully resolved. The MAH has agreed to the harmonisation of the product information (PI) as per the recommendation of the RMS. The majority of CMSs support this recommendation, DK, NL, PL, RO and ES (no comment from FI, NO and MT). DK and ES have advocated to upgrade the recommendation for harmonisation to a Potential serious risk to public health. The RMS support this as harmonisation will lead to improved safety measures and indications and posology in line with more current practice.

6 FR and IT have requested further supporting data in order to implement harmonisation of the FI/H/0667/ and UK/11/5635/ /DC PI, therefore the issue remains unresolved as a Potential serious risk to public health. Please see responses to numbers 2 and 17 below, for further information. The harmonisation of the product information with the SmPCs from the procedures FI/H/0667/ and UK/11/5635/ /DC has provided more up to date product information. In addition, harmonisation of the PI with FI/H/0667/ and UK/11/5635/ /DC PI has resolved additional other concerns raised by the RMS and CMSs regarding: -warnings relating to once weekly administration -QRD updates -removal of instructions regarding parenteral administration -incorrect indications on the labelling -harmonisation of indications between the 2.5mg and 10mg formulations -updated ADRs consistent with the safety profile of more recently approved methotrexate products. These are discussed in more detail in the remaining AR. 2. France was not involved in the procedure UK/H/5635/1-2/DC and could not accept the amendments of the product information without any scientific justification. The scientific data and the documents of the End of Procedure should be provided. (CMS: FR) We request RMS (IE) to kindly provide the requested documentation to French Authority. Assessor s comment: Issue not resolved. The RMS plan to contact the RMSs for both the UK/H/5635/01-02/DC and FI/H/0667/ procedures for end of procedure documents and any further supporting documents. As highlighted by FR with thanks, there was a switch of RMS from FI/H/667/01-02 DCP to UK/H/3956/01-02 MR following the end of procedure and therefore the UK will be contacted for both procedures. The applicant is also requested to update their clinical overview/expert literature review to support the proposed indications and posology set out in the UK/H/5635/01-02/DC procedure. The clinical overview should contain supporting evidence for the proposed updates to the reference product indications and posology. This also applies for the update to the indication for acute lymphoblastic leukaemia, see Point for consideration number 7 below. To note FR was a CMS in the FI/H/0667/ and the data for this procedure is therefore available to FR. The RMS will however also forward any correspondence with the UK RMS regarding UK/H/5635/01-02/DC and FI/H/0667/ to both FR and IT to assist with their assessment.

7 The RMS maintains the proposal to harmonise the product information with UK/H/5635/01-02/DC based on: - the precedence set in the UK/H/5635/01-02/DC procedure which implemented the FI/H/0667/ PI based solely on the principle to harmonise the PI with the most up to date MTX PI available - the legal basis of this application, under Article 10(1) of Directive 2001/83/EC, as amended. - all indications are maintained from the European reference product Maxtrex 2.5 mg and 10 mg (Carlo Erba Farmitalia), harmonisation has however updated these indications and posology with the most recent, widely accepted clinical practice which is also reflected in the majority of existing MTX product information of each MS. - further supporting evidence has been requested from the Applicant for the indication of acute lymphoblastic leukaemia to support the indication better. As currently proposed, the indication and posology is in line with other current licenced MTX products. - the harmonisation has improved safety warnings, a priority given the errors of prescribing and administration of MTX and the toxicity profile. - the agreement of the applicant and CMSs DK, NL, PL, RO and ES to implement harmonisation and the upgrading of the harmonisation to a Potential serious risk to public health. 3. Due to several fatal cases after accidental overdoses (daily intake instead of weekly intake), the applicant should warn patients of risks of medicinal errors and adapt the product information accordingly. (CMS: FR) Product information should take into account, in particular, the following comments in order to ensure the safety: - A red box with wording of warning should appear on the Labelling and the Package Leaflet We have noted agency s concern. We would like to inform agency that product information has been harmonised in line with recommendations from RMS (IE) and RMP is amended accordingly. Adapted product information contains suitable warning statement in section 4.2 of SmPC and at the start/section 3 of PIL to inform health care professionals and patients regarding toxicity hazards associated with the use of methotrexate respectively. Proposed updates: SmPC section 4.2 This medicine should be taken once a week. Do not exceed the weekly dose of this medicine due to toxicity hazards in psoriasis and rheumatoid arthritis. The prescriber may specify the day of intake on the prescription. At the start of PIL Do not exceed the weekly dose of this medicine due to toxicity hazards. PIL section 3 Take Methotrexate Tablets once a week.

8 Patients with rheumatoid arthritis or psoriasis will usually take their tablets orally once a week on the same day each week. Do not take tablets more often than your doctor has told you to. Daily administration can lead to serious toxic effects. Take the tablets with a glass of water whilst sitting upright or standing. Assessor s comment: Issue resolved. The warnings to the SmPC and PL adequately address the safety risk and are in line with other methotrexate products and the PhVWP in December 2011 for oral Methotrexate (Doc. Ref.: CMDh/PhVWP/043/2012 January 2012). The FR comment also included other safety measures relating to labelling which will be addressed for France during national phase of procedure. Points for consideration: Clinical Overview related: 4. There were no reported adverse events during the 11-VIN-075 bioequivalence study for the 2.5mg product. This would be unusual given the toxicity associated with MTX, can the MAH comment? Studies by Gilani et al showed the frequency of adverse effects attributed to low dose (10 mg/week) methotrexate for 3 months in rheumatoid arthritis patients. The study indicates that the adverse event experienced due to methotrexate is associated with long term administration and dose above 2.5 mg. In the present two-way crossover bioequivalence study, a single dose of 2.5 mg was administered to healthy subjects in both the periods with a washout of 07 days between the dosing periods. Since the dose as well as frequency of methotrexate was low in the present study, Cipla did not observe any adverse effects in the study. Assessor s comment: Query adequately addressed. Issue resolved Points for consideration RMS: SmPC related: 5. The MAH is requested to clarify the absence of the indication for RA in the 10mg formulation? It is proposed to include RA as an indication for both formulations in line with FI/H/0667/ and UK/11/5635/001. In line with RMS recommendations, SmPC is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates and proposed rheumatoid arthritis indication for 10 mg strength as well.

9 Assessor s comment: Issue resolved, pending harmonisation with the FI/H/0667/ and UK/11/5635/ /DC PI. 6. There are two ATC Level 5 Codes for methotrexate: L01BA01 methotrexate and L04AX03 methotrexate. The ATC code that is more correct for oral formulations is L04AX. This was noted by the MAH and communicated to the HPRA following national authorisation. The MAH is asked to confirm that this will be corrected as part of this MRP? We have acknowledged agency s comment. ATC code for oral formulation has already been amended in submitted eaf and cover letter during MRP sequence circulation (ectd seq. no. 0007) and now it has been included in revised SmPC. Assessor s comment: Issue resolved 7. The currently proposed indications for paediatric haem/oncology are not included in the SmPCs of FI/H/0667/ and UK/11/5635/001 however this indication is relevant to current paediatric haem/oncology practice. The Applicant is requested to update the haem/oncology posology & indications in line with clinical guidance & best practice for its use in these indications. We have noted agency s comment. We would like to inform agency that indication related to oncology have been incorporated in line with recent SmPC/PIL approved in Ireland (Methotrexate Orion 2.5/10 mg Tablets, MA No. PA1327/019/ , MAH: Orion Corporation, Finland). We request agency s acceptance for the same. Assessor s comment: Issue not resolved. The applicant has proposed an indication in Section 4.1: Cytostatic: Maintenance therapy in acute lymphoblastic leukemia. And the revised proposed posology in Section 4.2: Cytostatic Oral administration of methotrexate at doses of up to 30 mg/m2 is possible but higher doses should be administrated parenterally. Paediatric population Methotrexate 15 mg/m2 should be given orally once weekly for maintenance of drug-induced remissions.

10 This is supported by the recent approval of this indication in the generic Orion 2.5/10 mg Tablets, (MA No. PA1327/019/ , MAH: Orion Corporation, Finland), through the DCP procedure SE/H/1442/01-02/DC. The existing indication of acute leukaemias in the reference product for this MRP, Maxtrex Tablets is also supportive of this indication. The retention of the indication for acute lymphoblastic leukaemia (ALL) is, in general, advocated by the RMS in order to avoid a restriction of use in the paediatric population. However the applicant has not provided sufficient supportive data to justify the indication and the posology chosen for their product. A clinical overview/expert report supplying a literature review and rationale for indication and posology chosen is requested from the MAH in order to maintain the indication as proposed at D The proposed common renewal date is the 30/06/2021 which is in line with the national renewal date as recommended by CMDh/004/2005/Rev.14 February Is the applicant in agreement with the proposed date of 30/06/2021? We agree with agency s proposal of having common renewal date as 30/06/2021 in line with the national renewal date. Assessor s comment: Issue resolved Points for consideration, SmPC related: from CMSs: 9. The RMS proposes that the SmPCs from the procedures FI/H/0667/ and UK/11/5635/ /DC are used to harmonise the core clinical and non-clinical sections of the SmPC. This is generally agreed. More specifically: The posology contains the sentence A test dose of 5-10 mg parentally is recommended, which erroneously seems to refer to a parenteral administration. This should be corrected. Moreover, the proposed dose is not in line with a recently approved product Methotrexaat Sandoz. (CMS: NL) In line with RMS recommendations, SmPC is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates and reference of parenteral administration is removed. Assessor s comment: Issue resolved, pending harmonisation with the FI/H/0667/ and UK/11/5635/ /DC PI.

11 10. The proposed update of section 4.2 for Rheumatoid Arthritis is not totally agreed. It is proposed to change the maximum dose: The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of mg. Argumentation: Regarding posology, it is noted that in the EULAR treatment recommendations the maximum recommended dose of MTX is higher: MTX should be rapidly escalated, usually to mg/week, orally or subcutaneously administered, with folic acid supplementation, and the maximal MTX dose, if tolerated, should be sustained for about 8 12 weeks to judge the MTX treatment response. In the posology for Psoriasis, the proposed maximum dose in this SPC also is 25 mg once weekly. (CMS: NL) In line with RMS recommendations, SmPC is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates. Additionally, we have amended total weekly dose (25mg) as per agency s recommendation. Assessor s comment: Issue resolved. The amendment to the maximum weekly dose in rheumatoid arthritis is also agreed by the RMS as proposed by NL as in line with EULAR treatment recommendations. This recommendation is well recognised in practice and the RMS agrees to the amended total weekly dose (25mg) of rheumatoid arthritis. 11. The proposed update of section 4.1 for Psoriasis is not totally agreed with. A slightly different text is proposed: Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis. could be replaced by: Moderate to severe plaque psoriasis in adults who are candidates for systemic therapy, and for the treatment of active psoriatic arthritis in adult patients. Argumentation: Although the original proposal above is in agreement with before mentioned FI and UK procedures, this is not completely in line with the EDF treatment recommendations for Psoriasis in which MTX is recommended for induction and long term treatment. Because of the potential risk of phototherapy and PUVA of skin cancer, there is hesitation to suggest that these therapies should be tried before MTX, which has an acceptable safety profile. Moreover, there may be local differences in the treatment arsenal and clinical guidance, and therefore, a more general wording without specific examples of the line of treatment is preferred. This is also reflected in the more general indication as described in the SPC of Cosentyx - EMEA/H/C/ and above it is proposed to follow that indication for Psoriasis. (CMS: NL) In line with RMS recommendations, SmPC is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates. Further, harmonised wording for psoriasis is also supported by product information approved through centralised procedure EMEA/H/C/ dated wherein similar text is proposed. (Ref: Jylamvo 2 mg/ml oral solution, MAH: Therakind Ltd, United Kingdom). Therefore, we would like to keep the text as such in line with RMS recommendations. We request agency s acceptance for the same.

12 Assessor s comment: Issue not resolved The RMS considers both points and is in favour of amending the indication harmonised with the UK and FI procedures. Considering the EDF treatment recommendations, the indication for methotrexate is not completely clear as to what grade of psoriasis should be managed with MTX, although it is recommended for induction treatment. The NICE guidance and AAD give more specific guidance in this respect. The NICE guidance recommends MTX in- any type of psoriasis if it cannot be controlled with topical therapy and it has a significant impact on physical, psychological or social wellbeing and one or more of the following apply: psoriasis is extensive (for example, more than 10% of body surface area affected or a PASI score of more than 10) or psoriasis is localised and associated with significant functional impairment and/or high levels of distress (for example severe nail disease or involvement at high-impact sites) or phototherapy has been ineffective, cannot be used or has resulted in rapid relapse (rapid relapse is defined as greater than 50% of baseline disease severity within 3 months). American Academy of Dermatology- MTX Indication: Severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy. The RMS does agree with NL s point regarding there may be local differences in the treatment arsenal and clinical guidance, and therefore, a more general wording without specific examples of the line of treatment is preferred. Which is supported by NICE, AAD and EDF guidance and proposes the amendment to the indication: Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis. Conventional therapy can therefore imply 1 st line management such as topical treatment and corticosteroid treatment as well as PUVA and systemic therapy giving a more generalised indication. See Quest 12 for full proposed indication. 12. For Psoriatic arthritis, treatment with MTX is recommended as first-line treatment immediately after NSAIDs and glucocorticosteroids according to the EULAR treatment guidelines. Therefore, it is proposed to describe the indication as active psoriatic arthritis, rather than severe psoriatic arthritis. (CMS: NL) We request agency to kindly refer response to Q.12 provided above. Assessor s comment: Issue not resolved. The RMS does not advocate a strict first-line indication as there are varying practices locally and many recommendations relate to a 1 st line indication only with more complex psoriasis presentations. Severity and choice of therapy is also based on a number of factors for psoriasis including response/duration/site/type and patient perception (as worded by the NICE guidance significant impact on physical, psychological or social wellbeing ). The replacement of the word severe is agreed however and the active description more representative of current guidelines. In conjunction with the wording recommended in the above Quest 11 the proposed indication maintains a more generalised indication while not limiting to 1 st or 2 nd line therapy. The proposed indication-full text:

13 Severe Active forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis. Can the MAH and CMSs in particular NL please comment? 13. The proposed warning in section 4.4: The Patients should be informed clearly that in the treatment of psoriasis and rheumatoid arthritis the administration is in most cases once weekly. Patients should be aware of the importance of adhering to the once weekly intakes and that wrong daily administration can result in severe toxic reactions. The prescriber may specify the day of intake on the prescription. is repetitive with the warning in section 4.2 which is agreed because of its importance. It may be considered to place the warning in section 4.2 in a box. Apparently by accident, this warning appears twice in the proposed section 4.4 (see warning number 8 in row). (CMS: NL) We would like to inform agency that proposed wordings are included in line with RMS recommendations and suggested procedure (UK/H/5635/ /DC) for harmonisation of product information. Further, text proposed in section 4.2 and section 4.4 of SmPC are according to the wordings agreed by the PhVWP in December 2011 for oral Methotrexate (Doc. Ref.: CMDh/PhVWP/043/2012 January 2012) and hence same is retained to comply with PhVWP recommendations. In line with agency s recommendation, we have placed the warning statement of section 4.2 in a box. We request agency s acceptance for the same. Assessor s comment: Issue resolved. The comments from NL are supported by the RMS and are considered to have been adequately addressed by the MAH. 14. It is proposed to delete the warning in section 4.4: For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.. Argumentation: it reflects a former description of the indication (4.1) but is not in agreement to it. (CMS: NL) The applicant maintains this text in the SmPC with the justification of harmonisation with the proposed FI and UK DCP product information. Assessor s comment: Issue not resolved. The RMS supports NL comments and requests the applicant to delete text. This is repetition, furthermore biopsy is not recommended as routine in clinical guidance and for the most up to date recommendations regarding diagnosis, and clinicians should refer to current clinical guidance rather than this Section of the SmPC. The MAH is requested to submit an amended SmPC to reflect the deletion.

14 15. It is proposed to add the use of concomitant folic acid in the treatment of Rheumatoid Arthritis to the respective precaution: Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate. In the treatment of Rheumatoid Arthritis, suppletion with folic acid is recommended when patients are treated with methotrexate. There is evidence to suggest that adverse events are prevented. Argumentation: this is in line with the EULAR treatment recommendations for RA and brings the possible positive effects of folic acid suppletion under attention. (CMS: NL) We have acknowledged agency s comment and amended section 4.4 and 4.5 of SmPC with suggested wordings. Assessor s comment: RMS supports the NL comment, the update has been added to Section 4.4 and 4.5 by the MAH. Issue resolved 16. Section 4.8: Undesirable effects should appear in a table format. (CMS: FR) We have acknowledged agency s comment and presented undesirable effects in tabular format. Assessor s comment: RMS supports the FR comment, update added to Section 4.8. Issue resolved 17. Clinical information proposed on the SPC and PL, such as therapeutic indications and posology are not in line with those approved for the IT reference METHOTREXATE by Pfizer.In order to harmonise the product information, the RMS proposes that the SmPCs from the procedures FI/H/0667/ and UK/11/5635/ /DC are used to harmonise the core clinical and non-clinical sections of the SmPC. Unfortunately IT didn t act as CMS in both the above mentioned procedures, therefore clinical evidences (clinical studies, evaluation reports for the a.m. procedures) should be submitted in order to support the proposed therapeutic indications and dosage scheme. (CMS: IT) We have noted agency s comment and would request RMS (IE) to kindly provide the requested documentation. Assessor s comment: Issue not resolved. The RMS plan to contact the RMSs for both the UK/H/5635/01-02/DC and FI/H/0667/ procedures for end of procedure documents and any further supporting documents. As highlighted by FR with thanks, there was a switch of RMS from FI/H/667/01-02 DCP to UK/H/3956/01-02 MR following the end of procedure and therefore the UK will be contacted for both procedures. The applicant is also requested to update their clinical overview/expert literature review to support the proposed indications and posology set out in the UK/H/5635/01-02/DC procedure.

15 The clinical overview should contain the most up to date source of supporting evidence for the proposed indications and posology for the UK/H/5635/01-02/DC. This also applies for the indication for acute lymphoblastic leukaemia, see Point for consideration number 7 below. To note FR was a CMS in the FI/H/0667/ and the data for this procedure is therefore available to FR. The RMS will however also forward any correspondence with the UK RMS of UK/H/5635/01-02/DC and FI/H/0667/ to both FR and IT to assist with their assessment. The RMS maintains the proposal to harmonise the product information with UK/H/5635/01-02/DC based on: - the precedence set in the UK/H/5635/01-02/DC procedure which implemented the FI/H/0667/ PI based solely on the principle to harmonise the PI with the most up to date MTX PI available - the legal basis of this application, under Article 10(1) of Directive 2001/83/EC, as amended. - all indications are maintained from the European reference product Maxtrex 2.5 mg and 10 mg (Carlo Erba Farmitalia), harmonisation has however updated these indications and posology with the most recent, widely accepted clinical practice which is also reflected in the majority of existing MTX product information of each MS. - further supporting evidence has been requested from the Applicant for the indication of acute lymphoblastic leukaemia to support the indication better. As currently proposed, the indication and posology is in line with other current licenced MTX products. - the harmonisation has improved safety warnings, a priority given the errors of prescribing and administration of MTX and the toxicity profile. - the agreement of the applicant and CMSs DK, NL, PL, RO and ES to implement harmonisation and the upgrading of the harmonisation to a Potential serious risk to public health. Points for consideration: PL related: 18. As with the proposed SPC, the PIL is in line with the reference product Maxtrex. It is also proposed that the PIL is updated in the current MA to facilitate harmonisation of information across EU methotrexate products. The RMS proposes that FI/H/0667/ and UK/11/5635/ /DC is used as a basis for the core clinical sections. Member states and the applicant, are asked to comment on the acceptability of the proposal. In line with RMS recommendations, PIL is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates. Assessor s comment: Issue not resolved- as for the SmPC. See Questions 1, 2 and 17 above. 19. Section 3. How to take Methotrexate Tablets As the tablet is not intended to be divided into equal doses, according to QRD annotated template, one of those sentences should be added : <The score line is only there to help you break the tablet if you have difficulty swallowing it whole.> <The score line is not intended for breaking the tablet.> (CMS: FR)

16 We have acknowledged agency s comment and amended PIL section 3 to include appropriate statement in line with QRD recommendations. Assessor s comment: Issue resolved Points for consideration: Labelling related: 20. The attached labelling text is considered acceptable. To note, instruction regarding rheumatoid arthritis is included on the 10mg packaging but is not an indication in the currently proposed 10mg SPC. This is considered acceptable if the SPC is updated in line with FI/H/0667/ and UK/11/5635/ /DC, as proposed, to include an indication for rheumatoid arthritis. In line with RMS recommendations, SmPC is revised to harmonise the product information with suggested procedure (UK/H/5635/ /DC) along with recommended QRD updates. Rheumatoid arthritis indication is proposed for 10 mg strength as well. Assessor s comment: Issue resolved, pending harmonisation with the FI/H/0667/ and UK/11/5635/ /DC PI. 4. PHARMACOVIGILANCE 4.1. 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 Points for consideration: RMP related 1. Part 1 of the RMP will require substantial revision in order to ensure that it is aligned with the product information which has been proposed by the clinical assessor, particularly in terms of the sections pertaining to the indications and posology and route of administration. Applicant s response: We have acknowledged agency s comment and have revised the RMP accordingly.

17 Assessor's comment: The Applicant has updated Part I of the RMP in line with the revised product information submitted within this round. However, the proposed SmPC requires further revision, particularly section 4.1, therapeutic indications, as per comments received from the RMS and NL. Therefore this section of the RMP will require further revision to ensure that it is aligned with the product information agreed within this procedure. The Applicant should also ensure that the most recent version of the RMP is specified within the section titled Current RMP versions under evaluation. It is suggested that the Applicant provides these amendments at the next regulatory opportunity. Issue partly resolved. 2. The Applicant is requested to revise the summary of safety concerns to more accurately reflect the important and identified risks that could have an impact on the risk-benefit balance of the product or have implications for public health. The summary of safety concerns outlined below is recommended by the RMS. If the Applicant wishes to diverge from this proposal, a thorough scientific justification should be provided. Summary of safety concerns Important identified risks Hepatic impairment/hepatotoxicity; Renal impairment; Immunosuppression/Immunotoxicity; Gastrointestinal toxicity; Pulmonary toxicity; Haematotoxicity; Teratogenicity Important potential risks Infertility; Use in elderly patients; Progressive multifocal leukoencephalopathy; Medication errors; Missing information Use in paediatric population for non-neoplastic indications It is suggested that Progressive multifocal leukoencephalopathy (PML) should be included as an important potential risk. A signal concerning risk of PML in association with methotrexate was reviewed at PRAC in September The signal was triggered following review of case reports indicating a possible causal association between methotrexate and development of PML. Following review of the available data, the PRAC concluded that the evidence was not strong enough to substantiate a causal association but the risk of PML should remain under close monitoring as an important safety concern. The Applicant should ensure that the remaining sections of the RMP are updated so that they are in line with any revisions made to the summary of safety concerns. Applicant s response: We have acknowledged agency s comment and have revised the RMP accordingly.

18 Assessor's comment: The Applicant has revised the summary of safety concerns as requested. Issue resolved. 3. Within the tables in section III.1 which provides an overview of each safety concern, the Applicant has specified the following under the heading areas requiring conformation or further investigation : Stability of the reporting frequency relative to exposure and to evaluate risk factors. Given that the safety profile of Methotrexate is well established it is considered that the safety concerns for methotrexate, as specified within the summary of safety concerns are well characterised. Therefore the Applicant is requested to amend this section so that the text under this section specifies none as opposed to stability of the reporting frequency relative to exposure and to evaluate risks. Applicant s response: We have acknowledged agency s comment and have revised the RMP accordingly. Assessor's comment: The Applicant has revised section III.I of the RMP as requested. Issue resolved. 4. The Applicant is requested to amend Part V: Risk Minimisation measures to reflect the revised summary of safety concerns proposed by the RMS. The Applicant is requested to amend Part V of the RMP, particularly section V.I in which a description of the routine risk minimisation measures including the proposed text within the SmPC are presented for each of the proposed safety concerns, in order to ensure that it is aligned with the updated SmPC and PIL proposed by the clinical assessor. Within the description of the other routine risk minimisation measures pertaining to the important potential risk of medication errors in section V.I, the Applicant should provide an overview of the differences between the two strengths of the methotrexate tablet in terms of physical attributes (e.g. size, colour, shape etc.) which would ensure that they are clearly distinguishable. In addition, differences in terms of the outer packaging pertaining to each of the different strengths, which clearly facilitates clear distinction between the two, should also be outlined. Applicant s response: We have acknowledged agency s comment and have revised the RMP accordingly. Assessor's comment: Within the description of the routine risk minimisation measures for each of the respective safety concerns, the Applicant has provided a description of the relevant proposed text within the SmPC. However, the Applicant has not provided an overview of the proposed text within the PIL. The Applicant is therefore requested to amend this section of the RMP accordingly. Within the description of the routine risk minimisation measures pertaining to the safety concerns, the Applicant should provide a synopsis of the relevant text within the SmPC and PIL as opposed to quoting the exact text within the SmPC/PIL for each of the respective safety concerns. Within the description of the routine risk minimisation measures for the important identified risk of hepatotoxicity the Applicant is requested to remove reference to information regarding the drugdrug interaction between methotrexate and oral antibiotics/phenytoin. The Applicant is requested to refer to text within section 4.5 of the proposed SmPC which outlines that concomitant

19 administration with other potentially hepatotoxic medications should be avoided and that in the event of concomitant administration of methotrexate with either retinoids/azathioprine special caution should be exercised. The Applicant is also requested to include the following PT from section 4.8 of the proposed SmPC within the description of the routine risk minimisation measures for the important identified risk of hepatotoxicity, Elevated transaminase. Within the description of the important identified risk of renal impairment the Applicant is requested to refer to text within section 4.5 of the proposed SmPC concerning the potential for enhancement of nephrotoxicity with concomitant administration of high dose methotrexate in combination with potentially nephrotoxic chemotherapeutic agents. In addition the Applicant should also specify that concomitant administration with other potentially nephrotoxic medications should be avoided. Within the description of the important identified risk of immunosuppression/immunotoxicity the Applicant should refer to text in section 4.4 of the proposed SmPC concerning the potential for reactivation of inactive chronic infections. The Applicant is requested to remove the following from the description of the routine risk minimisation measures for the important identified risk of gastrointestinal toxicity: since changes may occur without previous signs of gastrointestinal toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. Within the description of the important identified risk of pulmonary toxicity the Applicant is requested to refer to text within section 4.4 of the proposed SmPC which specifies that prior to initiation of therapy, a chest X-ray is recommended and pleural effusions and ascites should be drained. Within the description of the important identified risk of haematotoxicity, the Applicant is requested to refer to text within section 4.5 which outlines that concomitant administration of NSAIDs and high-dose methotrexate may result in haematological toxicity. The Applicant is requested to remove the following PTs from the description of the routine risk minimisation measures for the important potential risk of infertility: vaginal bleeding and gynaecomastia. The Applicant should also ensure that the following PT is included within the description of the routine risk minimisation measures for the important potential risk of infertility: Impotence. The Applicant is requested to correct a typo within the description of the important potential risk of PML (i.e. the MAH has referred to the important potential risk of medication errors as opposed to PML within the sub-section titled objective of the risk minimisation measure on page 53 of the RMP). The Applicant is requested to provide a description of the differences of the outer packaging pertaining to each of the two different strengths which facilitates clear distinction within the description of the other routine risk minimisation measures for the important potential risk of medication errors. The Applicant is requested to amend Table V.3, Summary table of risk minimisation measures, so that it is aligned with amendments outlined above. Given that the product information has not been

20 finalised for this procedure, this section of the RMP may require further revision to ensure that it is alligned with the final version of the product informaiton which has been agreed at the end of this procedure. It is suggested that the Applicant provides these amendments to the RMP at the next regulatory opportunity. Issue partly resolved. 5. The Applicant is requested to amend Part VI of the RMP to reflect the revised summary of safety concerns proposed by the RMS and the comments related to the risk minimisation measures as outlined above. The Applicant is requested to amend section VI.2.1 (i.e. Overview of disease epidemiology ) and VI.2.2 (i.e. Summary of treatment benefits ) in order to ensure that the indications are aligned with those proposed by the clinical assessor. The Applicant is requested to delete the following statement within section VI.2.2 (i.e. Summary of Treatment Benefits): As per the literature published by To H and colleagues, methotrexate (MTX) is the most important drug for treating rheumatoid arthritis dosing at bedtime improve the arthritis symptoms. The Applicant is requested to amend section VI.2.4 (i.e. Summary of Safety Concerns) so that it is aligned with the revised summary of safety concerns proposed by the RMS. Applicant s response: We have acknowledged agency s comment and have revised the RMP accordingly. Assessor's comment: The Applicant is requested to amend the content of table VI.I.4, Summary table of risk minimisation measures, so that it is aligned with the amendments requested for part V of the RMP as outlined above. Within section VI.2.I (i.e. Overview of disease epidemiology ) the Applicant has referred to Non- Hodgkin s lymphoma (NHL). Given that this is not an indication as per the proposed product information, the Applicant is requested to amend the section of the RMP accordingly. In addition the Applicant should ensure that references are provided for any definitive information regarding epidemiology that has been provided within this section of the RMP. The Applicant should ensure that language suitable for a lay reader is utilised in section VI.2.4, Summary of safety concerns. For example, the Applicant should use alternative terms for PML, leukoencephalopathy and encephalopathy which are more appropriate for lay readers. It is suggested that the Applicant provides these amendments to the RMP at the next regulatory opportunity. Issue partly resolved. 6. The applicant should ensure that information within Annex 2 is amended so that it is aligned with the updated SmPC and PIL proposed by the clinical assessor. Applicant s response: We have acknowledged agency s comment and have revised the RMP accordingly. Assessor's comment: The Applicant has updated Annex 2 of the RMP. However, given that the product information has not been finalised yet, this section of the RMP will require further revision. Issue resolved. Member State comments concerning the RMP

21 The following comment was received from a Member state regarding the RMP: Due to several fatal cases after accidental overdoses (daily intake instead of weekly intake), the Applicant should warn patients of risks of medicinal errors and adopt the product information accordingly. The RMP should clearly analyze and take into account this serious risk (Module 1.8) Product information should take into account, in particular, the following comments in order to ensure the safety; A red box with wording of warning should appear on the labelling and package Leaflet The days of the week should appear on the Labelling so that the patient could mention the day of treatment; Only pack sizes of a unit dose blister as containers could be accepted in France MAH response: We have noted agency s concern. We would like to inform the agency that PI has been harmonized in line with recommendations from RMS (IE) and RMP is amended accordingly. Adapted product information contains suitable warning statement in section 4.2 of the SmPC and at the start/section 3 of the PIL to inform healthcare professionals and patients regarding toxicity hazards associated with the use of methotrexate respectively. We have acknowledged the authority s comments and herewith we confirm that all three labelling comment (red box warning, days of the weeks and unit dose blister container) will be addressed for France during the national stage of the procedure. Assessor's comment: The SmPC proposed by the MAH contains a boxed warning in section 4.2. The Applicant has outlined that the issues raised by the MS will be addressed during the national stage of the procedure. Issue resolved. 5. LIST OF QUESTIONS AS PROPOSED BY THE RMS Non-clinical aspects Major Objections Other concerns Clinical aspects Potential serious risk to public health: 1. The proposed SPC is in line with the reference product Maxtrex 2.5mg and 10mg. During the national MA application it was highlighted with the MAH that the product information is not in line with recently approved SmPCs for oral methotrexate authorised through the DCP