Opinion/ Commission. Notification. Decision. Issued 2 / affected 3 amended on

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1 Procedural steps taken and scientific information after the authorisation Application Scope Opinion/ Commission Product Summary number Notification Decision Information 1 issued on Issued 2 / affected 3 amended on II/0028 Extension of Indication to include the treatment of unresectable liposarcoma in adult patients who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease; as a consequence, sections 4.1, 4.2, 4.4, 4.5, 4.8, and 5.1 of the SmPC are updated with the PK, efficacy and safety information. The Package Leaflet and RMP are updated in accordance. In addition, the Marketing authorisation holder (MAH) 01/04/ /05/2016 SmPC and PL Please refer to the Scientific Discussion -H-C II Notifications are issued for type I variations and Article 61(3) notifications (unless part of a group including a type II variation or extension application or a worksharing application). Opinions are issued for all other procedures. 2 A Commission decision (CD) is issued for procedures that affect the terms of the marketing authorisation (e.g. summary of product characteristics, annex II, labelling, package leaflet). The CD is issued within two months of the opinion for variations falling under the scope of Article 23.1a(a) of Regulation (EU) No. 712/2012, or within one year for other procedures. 3 SmPC (Summary of Product Characteristics), Annex II, Labelling, PL (Package Leaflet). 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0) Facsimile +44 (0) Send a question via our website An agency of the European Union

2 took the opportunity to update the PI in line with the latest QRD template version 9.1. C.I.6.a - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one II/0029/G This was an application for a group of variations. 18/02/ /05/2016 SmPC and PL Update of section 4.4 of the SmPC to remove the information referring to the lack of data on safety and efficacy of eribulin in combination with anti- HER2 therapy. Moreover, the MAH deleted the black symbol and explanatory statements pertinent to the additional monitoring as has been removed from the list of the medicinal products subject to the additional monitoring. In addition, the MAH took the opportunity of this procedure to update the local representative contact of Romania in the PL. C.I.4 - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data C.I.4 - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data R/0027 Renewal of the marketing authorisation. 24/09/ /11/2015 SmPC, Labelling and PL Based on the review of the available information the CHMP is of the opinion that the quality, the safety and the efficacy of this medicinal product continues to be adequately and sufficiently demonstrated and therefore considers that the benefit/risk profile of continues to be favourable. The CHMP is of the opinion that the renewal can be granted EMA/437442/2016 Page 2/10

3 with unlimited validity. IA/0030 A.5.b - Administrative change - Change in the name and/or address of a manufacturer/importer of the finished product, including quality control sites (excluding manufacturer for batch release) 09/09/2015 n/a II/0024 B.I.a.2.b - Changes in the manufacturing process of the AS - Substantial change to the manufacturing process of the AS which may have a significant impact on the quality, safety or efficacy of the medicinal product 23/07/2015 n/a PSUSA/1254/ IA/0026 Periodic Safety Update EU Single assessment - ERIBULIN A.7 - Administrative change - Deletion of manufacturing sites 21/05/ /07/2015 SmPC and PL Please refer to PSUSA EPAR: Scientific conclusions and grounds recommending the variation to the terms of the marketing authorisation. 01/07/2015 n/a II/0023 Update of sections 4.2 and 5.2 of the SmPC to include further recommendations for patients with renal impairment based on data from Study 106. In addition, the MAH took the opportunity to implement minor editorial changes in the SmPC and to update the contact details of the local representatives in Belgium, Luxemburg and Poland in the Package Leaflet. C.I.4 - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data 25/06/ /11/2015 SmPC and PL Some patients with moderately or severely impaired renal function (creatinine clearance <50 ml/min) may have increased eribulin exposure and may need a reduction of the dose. For all patients with renal impairment, caution and close safety monitoring is advised. Increased eribulin exposure was seen in some patients with moderately or severely impaired renal function, with high between-subject variability. The pharmacokinetics of eribulin were evaluated in a Phase 1 study in patients with normal renal function (Creatinine clearance: 80 ml/min; n=7), moderate (30-50 ml/min; n=6) or severe (15-<30 ml/min; n=6) renal impairment. Creatinine clearance was estimated with the Cockroft-Gault formula. A 1.5-fold (90% CI: ) higher dose-normalised AUC(0-inf) was EMA/437442/2016 Page 3/10

4 observed in patients with moderate and severe renal impairment. IB/0025 B.II.e.5.a.2 - Change in pack size of the finished product - Change in the number of units (e.g. tablets, ampoules, etc.) in a pack - Change outside the range of the currently approved pack sizes 13/04/ /07/2015 SmPC and Labelling II/0021 B.II.e.5.c - Change in pack size of the finished product - Change in the fill weight/fill volume of sterile multidose (or single-dose, partial use) parenteral medicinal products, including biological/immunological medicinal products 26/02/ /07/2015 SmPC, Labelling and PL IA/0020 B.I.a.3.a - Change in batch size (including batch size ranges) of AS or intermediate - Up to 10-fold increase compared to the originally approved batch size 01/12/2014 n/a IA/0019 B.I.a.1.f - Change in the manufacturer of AS or of a starting material/reagent/intermediate for AS - Changes to quality control testing arrangements for the AS -replacement or addition of a site where batch control/testing takes place 30/07/2014 n/a II/0011 Extension of Indication to include the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. As a consequence, sections 4.1, 4.5, 4.8, 5.1 of the SmPC were updated. The Package Leaflet is updated in accordance. 22/05/ /06/2014 SmPC and PL Please refer to the Scientific Discussion EMEA/H/C/002084/II/0011. EMA/437442/2016 Page 4/10

5 C.I.6.a - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one PSUV/0018 Periodic Safety Update 13/06/2014 n/a PRAC Recommendation - maintenance IA/0017 B.I.b.2.a - Change in test procedure for AS or starting material/reagent/intermediate - Minor changes to an approved test procedure 27/02/2014 n/a IA/0015 A.7 - Administrative change - Deletion of manufacturing sites 18/12/2013 n/a II/0014 IA/0016 Update of sections 4.2, 4.5 and 5.2 of the SmPC in order to reflect the results of studies investigating the use of eribulin in patients with renal impairment, interactions with Pgp inhibitors and whether eribulin is a substrate of hepatic transporters, as requested by PRAC/CHMP further to the review of FUMs 009, 010, 011 and 013. C.I.3.b - Change(s) in the SPC, Labelling or PL intended to implement the outcome of a procedure concerning PSUR or PASS or the outcome of the assessment done under A 45/46 - Change(s) with new additional data submitted by the MAH B.II.e.6.b - Change in any part of the (primary) packaging material not in contact with the finished product formulation - Change that does not affect the product information 18/12/ /06/2014 SmPC Analyses performed across Phase I studies show that patients with severely impaired renal function may require a reduction of dose however the optimal dose remains to be established. In patients with mild to moderate renal impairment, caution and close safety monitoring is advised without recommendation for specific dose adjustments. Eribulin is mainly eliminated through biliary excretion. In vivo studies submitted by the MAH show that eribulin exposure (AUC and Cmax) was not affected by Pgp inhibitors. In addition, on the basis of in vitro studies, it was concluded thateribulin is not a Pgp inhibitor and is not considered as a substrate for OCT1. As a consequence, sections 4.2, 4.5 and 5.2 of the SmPC were updated to reflect new information. 13/12/2013 n/a EMA/437442/2016 Page 5/10

6 IG/0345 C.I.8.a - Introduction of or changes to a summary of Pharmacovigilance system - Changes in QPPV (including contact details) and/or changes in the PSMF location 03/09/2013 n/a N/0012 Minor change in labelling or package leaflet not connected with the SPC (Art Notification) 07/08/ /11/2013 PL II/0009 Update of section 4.8 of the SmPC in order to update 25/04/ /11/2013 SmPC, Annex Further to the review of the company safety database with the safety information to include disseminated II and PL a data lock point of 14th November 2012, the MAH intravascular coagulation (DIC) as an adverse drug identified 4 case reports of DIC. While a direct causal reaction further to the PRAC review of PSUR 3. relationship cannot be established at this point in time, In addition, the MAH took the opportunity to update there is enough circumstantial evidence to conclude that a the list of local representatives in the Package causal relationship between eribulin and DIC is at least a Leaflet. reasonable possibility. Section 4.8 of the SmPC was Furthermore, the MAH proposed this opportunity to updated to include DIC as a rare event. bring the PI in line with the latest QRD template version 9.0. C.I.3.b - Implementation of change(s) requested following the assessment of an USR, class labelling, a PSUR, RMP, FUM/SO, data submitted under Article 45/46, or amendments to reflect a Core SPC - Change(s) with new additional data submitted by the MAH IAIN/0010 C.I.z - Changes (Safety/Efficacy) of Human and 27/03/2013 n/a Veterinary Medicinal Products - Other variation IB/0008/G This was an application for a group of variations. 22/11/2012 n/a B.I.a.1.z - Change in the manufacturer of AS or of a starting material/reagent/intermediate for AS - Other EMA/437442/2016 Page 6/10

7 variation B.I.a.1.z - Change in the manufacturer of AS or of a starting material/reagent/intermediate for AS - Other variation B.I.a.1.z - Change in the manufacturer of AS or of a starting material/reagent/intermediate for AS - Other variation B.I.a.1.f - Change in the manufacturer of AS or of a starting material/reagent/intermediate for AS - Changes to quality control testing arrangements for the AS -replacement or addition of a site where batch control/testing takes place II/0006 Update of section 4.5 of the SmPC in order to reflect 15/11/ /11/2013 SmPC, Annex Following the review of a drug-drug interaction study new data regarding concomitant use with inhibiting II, Labelling investigating the effect of concomitant use of rifampicin and inducing substances. Furthermore, the PI is and PL and eribulin versus eribulin alone, the MAH has updated being brought in line with the latest QRD template section 4.5 of the SmPC to reflect new data on inhibiting version 8.1. and inducing substances. C.I.4 - Variations related to significant modifications of the SPC due in particular to new quality, preclinical, clinical or pharmacovigilance data IB/0007 B.I.d.1.a.4 - Stability of AS - Change in the re-test 08/08/2012 n/a period/storage period - Extension or introduction of a re-test period/storage period supported by real time data II/0005 Update of sections 2, 4.2, 4.9, 5.1, 5.2, 5.3 and 6.3 of the SmPC to clarify the expression of the strength and dosage of to be administered to patients. This update has been triggered by concerns of potential risk of overdose related to the confusion 19/04/ /05/2012 SmPC, Labelling and PL Following reports of potential risk of overdose related to the confusion between the use of eribulin base for the expression of the strength and dose in the EU compared to the use of the salt (mesilate) in a number of other countries and in the scientific literature, the MAH was EMA/437442/2016 Page 7/10

8 between the use of eribulin base for the expression of the strength and dose in the EU compared to the use of the salt (mesilate) in a number of other countries and in the scientific literature. The Labelling and Package Leaflet have been updated accordingly. In addition, the MAH took the opportunity of this variation to make a minor amendment to section 4.8 of the SmPC, to correct the spelling of the salt and to update the list of local representatives in the Package Leaflet. requested to amend the product information (PI) to express eribulin strength and dose consistently using the eribulin base and to avoid altogether the expression of these based on the eribulin mesilate salt throughout the PI. C.I.3.b - Implementation of change(s) requested following the assessment of an USR, class labelling, a PSUR, RMP, FUM/SO, data submitted under Article 45/46, or amendments to reflect a Core SPC - Change(s) with new additional data submitted by the MAH II/0004 Update of section 4.8 Undesirable effects of the SmPC in order to include pancreatitis as requested by the CHMP following the assessment of the 1st PSUR. The Package Leaflet was updated in accordance. In addition, the text and format of the table of undesirable effects in section 4.8 of the SmPC has been changed to include the uncommon and rare events into the one table. Finally the MA date and numbers have been added to sections 8 and 9 of the SmPC. 15/03/ /04/2012 SmPC and PL In the 1st PSUR of, two cases of pancreatitis were reported, one of which fulfilling the criteria for a very likely/certain drug reaction. As an outcome of the PSUR assessment, the CHMP requested the MAH to add pancreatitis in section 4.8 Undesirable effects. The Package leaflet was updated in accordance. The table of undesirable effects in section 4.8 of the SmPC was reformatted to include the uncommon and rare events already present in the section. C.I.3.b - Implementation of change(s) requested following the assessment of an USR, class labelling, a PSUR, RMP, FUM/SO, data submitted under Article 45/46, or amendments to reflect a Core SPC - EMA/437442/2016 Page 8/10

9 Change(s) with new additional data submitted by the MAH II/0003/G This was an application for a group of variations. 16/02/ /02/2012 Addition of manufacturing, quality control and testing sites for the finished product. Minor differences in the manufacturing process at the new manufacturing site. B.II.b.2.a - Change to batch release arrangements and quality control testing of the FP - Replacement or addition of a site where batch control/testing takes place B.II.b.3.z - Change in the manufacturing process of the finished product - Other variation B.II.b.1.d - Replacement or addition of a manufacturing site for the FP - Site which requires an initial or product specific inspection B.II.b.2.a - Change to batch release arrangements and quality control testing of the FP - Replacement or addition of a site where batch control/testing takes place B.II.b.2.a - Change to batch release arrangements and quality control testing of the FP - Replacement or addition of a site where batch control/testing takes place B.II.b.2.a - Change to batch release arrangements and quality control testing of the FP - Replacement or addition of a site where batch control/testing takes place IA/0002 A.5.b - Administrative change - Change in the name 22/09/2011 n/a EMA/437442/2016 Page 9/10

10 and/or address of a manufacturer of the finished product, including quality control sites (excluding manufacturer for batch release) IB/0001 B.I.b.1.c - Change in the specification parameters and/or limits of an AS, starting material/intermediate/reagent - Addition of a new specification parameter to the specification with its corresponding test method 09/09/2011 n/a EMA/437442/2016 Page 10/10