26 November 2020 EMA/640861/2020 Veterinary Medicines Division Committee for Medicinal Products for Veterinary Use CVMP assessment report for NexGard Combo (EMEA/V/C/005094/0000) INN: esafoxolaner / eprinomectin / praziquantel Assessment report as adopted by the CVMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Introduction ................................................................................................ 4 Scientific advice.......................................................................................................... 5 MUMS/limited market status ........................................................................................ 5 Part 1 - Administrative particulars .............................................................. 5 Detailed description of the pharmacovigilance system ..................................................... 5 Manufacturing authorisations and inspection status ......................................................... 5 Overall conclusions on administrative particulars ............................................................ 6 Part 2 - Quality ........................................................................................... 6 Composition ............................................................................................................... 6 Containers ................................................................................................................. 6 Development pharmaceutics ........................................................................................ 6 Method of manufacture ............................................................................................... 7 Control of starting materials ......................................................................................... 7 Active substance ........................................................................................................ 7 Excipients ................................................................................................................ 10 Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies ...................................................................................................... 11 Control tests on the finished product ........................................................................... 11 Stability................................................................................................................... 11 Overall conclusions on quality .................................................................................... 12 Part 3 – Safety .......................................................................................... 12 Safety documentation ............................................................................................... 12 Pharmacodynamics ................................................................................................... 12 Pharmacokinetics ...................................................................................................... 13 Toxicological studies ................................................................................................. 13 Single dose toxicity ................................................................................................... 14 Repeat dose toxicity .................................................................................................. 14 Tolerance in the target species of animal ..................................................................... 15 Reproductive toxicity ................................................................................................. 16 Genotoxicity ............................................................................................................. 17 Carcinogenicity ......................................................................................................... 17 Studies of other effects ............................................................................................. 17 Excipients ................................................................................................................ 18 User safety .............................................................................................................. 18 Environmental risk assessment .................................................................................. 20 Residues documentation ............................................................................................ 20 Overall conclusions on the safety documentation .......................................................... 20 Part 4 – Efficacy ........................................................................................ 21 Pharmacodynamics ................................................................................................... 22 Development of resistance ......................................................................................... 23 Pharmacokinetics ...................................................................................................... 24 Justification of fixed combination ................................................................................ 25 Dose justification/ determination / finding studies ......................................................... 25 CVMP assessment report for NexGard Combo (EMEA/V/C/005094/0000) EMA/640861/2020 Page 2/46 Dose confirmation studies .......................................................................................... 25 Target animal tolerance ............................................................................................. 31 Clinical field trials ..................................................................................................... 35 Overall conclusion on efficacy ..................................................................................... 40 Part 5 – Benefit-risk assessment .............................................................. 42 Introduction ............................................................................................................. 42 Benefit assessment ................................................................................................... 42 Direct therapeutic benefit .......................................................................................... 42 Additional benefits .................................................................................................... 43 Risk assessment ....................................................................................................... 43 Risk management or mitigation measures ................................................................... 44 Evaluation of the benefit-risk balance .......................................................................... 44 Conclusion ............................................................................................................... 46 CVMP assessment report for NexGard Combo (EMEA/V/C/005094/0000) EMA/640861/2020 Page 3/46 Introduction On 5 November 2020, the CVMP adopted an opinion and CVMP assessment report. On 06 January 2021, the European Commission adopted a Commission Decision granting the marketing authorisation for NexGard Combo. On 21 May 2019, an application for a marketing authorisation to the European Medicines Agency (The Agency) for NexGard Combo was submitted, through the centralised procedure under Article 3(2)(a) of Regulation (EC) No 726/2004 (optional scope). The initial applicant for the product was Merial; however, due to a company merger, the applicant changed during the procedure to Boehringer Ingelheim Vetmedica GmbH. The eligibility to the centralised procedure was agreed upon by the CVMP on 20 July 2018 as NexGard Combo contains a combination of active substances (esafoxolaner, eprinomectin and praziquantel), one of which (esafoxolaner) was not authorised as a veterinary medicinal product in the Union on the date of entry into force of Regulation (EC) No 726/2004. At the time of submission, the applicant applied for the following indications: “For cats with, or at risk from mixed infestations by cestodes, nematodes and ectoparasites. The veterinary medicinal product is exclusively indicated when all three groups are targeted at the same time. Ectoparasites: Treatment and prevention of infestations by fleas (Ctenocephalides felis). One treatment prevents further infestations for at least one month. Prevention of environmental flea contamination by preventing egg laying for over a month. The product can be used as part of a treatment strategy for the control of flea allergy dermatitis (FAD). Treatment and prevention of infestations by ticks (Rhipicephalus sanguineus, Ixodes ricinus, Ixodes scapularis, Amblyomma americanum). One treatment prevents further infestations for at least one month. Treatment of ear mange (Otodectes cynotis). Gastro-intestinal cestodes: Treatment of infestations with tapeworms (Dipylidium caninum, Taenia taeniaeformis, Echinococcus multilocularis, Joyeuxiella pasqualei (adult), and Joyeuxiella fuhrmanni