Serotonin reuptake inhibitors and persistent sexual dysfunction after discontinued CONFIDENTIAL treatment Medicines Adverse Reactions Committee Meeting date 12/09/2019 Agenda item 3.2.2 Title Serotonin reuptake inhibitors and persistent sexual dysfunction after discontinued treatment Submitted by Medsafe Pharmacovigilance Paper type For advice Team Active ingredient Product name Sponsor SSRIs Citalopram Cipramil Pharmacy Retailing (New Zealand) Limited t/a Healthcare Logistics Citalopram PSM Healthcare Limited t/a API Consumer Brands Escitalopram Escitalopram Air Flow Products Limited Lexapro Pharmacy Retailing (New Zealand) Limited t/a Healthcare Logistics Loxalate Mylan New Zealand Limited Fluoxetine Arrow-Fluoxetine Teva Pharma (New Zealand) Limited Arrow-Fluoxetine Dispersible Teva Pharma (New Zealand) Limited Fluoxetine-AFT AFT Pharmaceuticals Limited Prozac 20 Eli Lily and Company (New Zealand) Limited Paroxetine Apo-Paroxetine Apotex New Zealand Limited Aropax GlaxoSmithKline (New Zealand) Limited Loxamine Mylan New Zealand Limited Sertraline Arrow-Sertraline Teva Pharma (New Zealand) Limited Setrona Douglas Pharmaceuticals Limited Zoloft Pfizer New Zealand Limited SNRIs Venlafaxine Arrow-Venlafaxine Teva Pharma (New Zealand) Limited Efexor-XR Pfizer New Zealand Limited Enlafax-XR Mylan New Zealand Limited PHARMAC Products funded by PHARMAC and on the Hospital Medicines List (in bold) funding Previous MARC None meetings International EMA action PRAC meeting on 13-16 May 2019 – Having considered the available evidence from EudraVigilance, literature, social media and cumulative reviews provided by Marketing Authorisation Holders, product information for SSRIs and SNRIs should be amended to include information on persistent sexual dysfunction after drug withdrawal1. Prescriber Update Sexual dysfunction associated with antidepressants and antipsychotics – March 20152. Classification Prescription medicine Medicines Adverse Reactions Committee: 12 September 2019 Page 1 of 29 Serotonin reuptake inhibitors and persistent sexual dysfunction after discontinued CONFIDENTIAL treatment Table of Contents 1 PURPOSE ................................................................................................................................................................................................. 4 2 BACKGROUND ...................................................................................................................................................................................... 4 2.1 RxISK study and petition ....................................................................................................................................................... 4 2.2 Serotonin reuptake inhibitors .............................................................................................................................................. 5 2.2.1 Selective serotonin reuptake inhibitors (SSRIs) ....................................................................................................... 5 2.2.2 Serotonin and noradrenalin reuptake inhibitors (SNRIs) .................................................................................... 5 2.3 Persistent sexual dysfunction .............................................................................................................................................. 6 2.4 Data sheets ................................................................................................................................................................................. 6 2.4.1 New Zealand ......................................................................................................................................................................... 6 3 SCIENTIFIC INFORMATION .............................................................................................................................................................. 9 3.1 Published literature.................................................................................................................................................................. 9 3.1.1 Bala et al (2018)32 ................................................................................................................................................................ 9 3.1.2 Coskuner et al (2017)33 .................................................................................................................................................... 10 3.1.3 Reisman (2017)34................................................................................................................................................................ 11 3.2 International ................................................................ 12 3.2.1 .......................................................................................................... 12 3.2.2 ............................................................................................................ 12 3.2.3 ................................................................................................................................................. 14 3.2.4 ......................................................... 14 3.2.5 ............................................................................................ 15 3.2.6 .................................................................................................................................................................... 16 3.3 Further action from the FDA, EMA and MHRA ........................................................................................................... 16 3.3.1 EMA ......................................................................................................................................................................................... 16 3.4 Company reports .................................................................................................................................................................... 17 3.4.1 GlaxoSmithKline (New Zealand) Limited – Aropax (paroxetine) (Annexe 1).............................................. 17 3.4.2 Lundbeck on behalf of Pharmacy Retailing (New Zealand) Limited trading as Healthcare Logistics – Cipramil (citalopram) (Annexe 2) ............................................................................................................................................. 18 3.4.3 Pfizer New Zealand Limited – Zoloft (sertraline) (Annexe 3) ........................................................................... 19 3.5 CARM data (Annexe 5) ......................................................................................................................................................... 22 3.6 ADIS Insight35 ........................................................................................................................................................................... 23 4 DISCUSSION AND CONCLUSIONS ............................................................................................................................................. 26 5 ADVICE SOUGHT ............................................................................................................................................................................... 27 6 ANNEXES .............................................................................................................................................................................................. 27 7 REFERENCES ........................................................................................................................................................................................ 27 Medicines Adverse Reactions Committee: 12 September 2019 Page 3 of 29 Serotonin reuptake inhibitors and persistent sexual dysfunction after discontinued CONFIDENTIAL treatment 1 PURPOSE In May 2018, Medsafe received an email from RxISK highlighting a study they had recently published in the International Journal of Risk and Safety in Medicine regarding persistent sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin4. A petition was also attached which has been submitted to the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Medicines and Healthcare products Regulatory Agency (MHRA), requesting changes to product information5. The purpose of this paper is to review the risk of persistent sexual dysfunction after discontinued treatment with serotonin reuptake inhibitors (SRIs). 2 BACKGROUND 2.1 RxISK study and petition The objective of the RxISK study was to investigate clinical reports of post-selective serotonin reuptake inhibitors (SSRI) sexual dysfunction, post-finasteride syndrome and persisting sexual dysfunction following antidepressants, 5α-reductase inhibitors and isotretinoin4. RxISK.org is an independent drug safety website set up by the authors and colleagues, offering an adverse event reporting facility which began collecting data on all drugs and all adverse events in 20124. Data from RxISK was used to establish the clinical features, demographic details and clinical trajectories of syndromes of persistent sexual difficulties following three superficially different treatment modalities4. The study reported on 300 cases of persisting sexual dysfunction from 37 countries following 14 different drugs comprised of serotonin reuptake inhibiting antidepressants, 5α-reductase inhibitors and isotretinoin4. While reports