As part of the PRAC (Pharmacovigilance Risk Assessment Committee) meeting of 3-6 September 2018, European Medicines Agency (EMA) examined the problem of Post-SSRI/SNRI Sexual Dysfunction for the first time. Agenda - PRAC draft agenda of meeting 3-6 september 2018 (page 16)
4.2. New signals detected from other sources
Applicant(s): Eli Lilly Nederland B.V. (Ariclaim, Cymbalta, Duloxetine Lilly, Xeristar, Yentreve), Generics UK Limited (Duloxetine Mylan), H. Lundbeck A/S (Brintellix), Zentiva k.s. (Duloxetine Zentiva), various
PRAC Rapporteur: To be appointed
Scope: Signal of persistent sexual dysfunction after drug withdrawal
Action: For adoption of PRAC recommendation
EPITT 19277 – New signal
On October 26, 2018 the minutes of the meeting are published, available here (pages 19 and 20): Minutes of the PRAC meeting 3-6 September 2018
4.2. New signals detected from other sources
4.2.1. Clomipramine (NAP);
Serotonin and noradrenaline reuptake inhibitors (SNRI)5 : desvenlafaxine (NAP); duloxetine - ARICLAIM (CAP), CYMBALTA (CAP), DULOXETINE LILLY (CAP), DULOXETINE MYLAN (CAP), DULOXETINE ZENTIVA (CAP), XERISTAR (CAP), YENTREVE (CAP); milnacipran (NAP); venlafaxine (NAP);
Selective serotonin reuptake inhibitors (SSRI)6 : citalopram (NAP); escitalopram (NAP); fluoxetine (NAP); fluvoxamine (NAP); paroxetine (NAP); sertraline (NAP); Vortioxetine – BRINTELLIX (CAP)
Applicant(s): Eli Lilly Nederland B.V. (Cymbalta, Duloxetine Lilly, Xeristar, Yentreve), Generics UK Limited (Duloxetine Mylan), H. Lundbeck A/S (Brintellix), Zentiva k.s. (Duloxetine Zentiva), various
PRAC Rapporteur: Menno van der Elst
Scope: Signal of persistent sexual dysfunction after drug withdrawal
EPITT 19277 – New signal
Background
Clomipramine is a non-selective monoamine reuptake inhibitor indicated, among others, for the treatment of major depressive disorder. Desvenlafaxine, duloxetine, milnacipran and venlafaxine are serotonin and noradrenaline reuptake inhibitors (SNRIs) indicated, among others, for the treatment of major depressive disorder. Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline are selective serotonin reuptake inhibitors (SSRIs) indicated, among others, for the treatment of major depressive disorder. Brintellix is a centrally authorised product containing vortioxetine, a psychoanaleptic antidepressant. It is indicated for the treatment of major depressive disorders in adults.
Cymbalta and Yentreve, centrally authorised medicines containing duloxetine, are estimated to have been used by approximately 91,636,000 patients worldwide (all indications) in the period from first authorisations in 2004 to 2017. Milnacipran capsule for major depressive episodes7 is estimated to have been used by more than 8,611,639 patients (corresponding to 15,296,991 patients-months) worldwide in the period from first authorisation in 1966 to 2018. Escitalopram (all indication) is estimated8 to have been used by approximately 402,748,747 patients worldwide in the period from first authorisation in 2001 to 2016. The exposure for fluvoxamine (all indications) is estimated9 to have been approximately 1,560,498 patient treatment years worldwide in the period from first authorisation in 1983 to 2017. Paroxetine (all indications) is estimated10 to have been used by more than 400 million patients worldwide in the period from first authorisation in 1990 to 2017. The exposure to sertraline (all indications) is estimated11 to have been approximately 146,798,100 patientyears worldwide in the period from first authorisation in 1990 to 2017. The exposure for
Brintellix (vortioxetine) is estimated to have been approximately 2,429,103 patient-years worldwide in the period from first authorisation in 2013 to 2017. The exposure for fluoxetine (all indications) is estimated to have been approximately 121,620,000 patient-years worldwide in the period from first authorisation in 1986 to 2017.
Following some ongoing procedures, where some EU Member States have reviewed information on persistent sexual dysfunction for SSRIs and SNRIs, including spontaneous data in EudraVigilance (EV), recent literature and a petition from a group of professors, psychiatrists and related healthcare professionals (HCPs) concerning persistent sexual disorders with SSRIs and SNRIs, where authors refer to literature cases of genital anaesthesia, persistent genital arousal disorder (PGAD) and post-SSRI sexual dysfunctions (PSSD) and postulate changes in product information, risk minimisation measures taken by MAHs and communication to both HCPs and patients, a signal of persistent sexual dysfunction after drug withdrawal was identified by EMA. The Netherlands confirmed that the signal needed initial analysis and prioritisation by the PRAC.
Discussion
Having considered the available data, including a publication in the International Journal of Risk & Safety in Medicine by Healy D. et al.12 and 574 case reports retrieved for duloxetine in EV with relevant MedDRA HLT13, the PRAC concluded that the signal merits further investigation.
The PRAC appointed Menno van der Elst as Rapporteur for the signal.
Summary of recommendation(s)
• The Lead Member States (LMS)/Rapporteurs for the concerned active substances will review the literature referenced in the above-mentioned petition received by the Agency. In addition, EMA will perform literature reviews, EV data analysis and will explore the feasibility for a pharmacoepidemiological study. Finally, EMA in collaboration with the LMS/Rapporteurs will elaborate on appropriate case definitions for the sexual dysfunction disorders adverse drug reactions (ADRs), using read codes and MedDRA terms, to facilitate further assessments.
• A 30-day timetable was recommended for the assessment of this review leading to a further PRAC recommendation.
5 Indicated in the treatment of major depressive disorder (MDD)
6 Indicated in the treatment of major depressive disorder (MDD)
7 Ixel. Joncia, Dalcipran, Tivanyl, Savella, Toledomin, Milnacipran Pierre Fabre
8 By H. Lundbeck A/S
9 By Mylan
10 By GlaxoSmithKline Research & development
11 By Pfizer
12 Healy D, Le Noury J, Mangin D. Enduring Sexual Dysfunction after Treatment with Antidepressants, 5α-Reductase Inhibitors and Isotretinoin: 300 Cases. Int. J. Risk. Saf. Med. 2018. doi:10.3233/JRS-180744
13 Medical dictionary for regulatory activities – High level term
On December 20, 2018 the minutes of the 29-31 october PRAC meeting are published, available here (pages 15 and 16): Minutes of the PRAC meeting 29-31 october 2018.
4.3. Signals follow-up and prioritisation
4.3.1. Clomipramine (NAP);
Serotonin and noradrenaline reuptake inhibitors (SNRI): desvenlafaxine (NAP);
duloxetine - CYMBALTA (CAP), DULOXETINE LILLY (CAP), DULOXETINE MYLAN
(CAP), DULOXETINE ZENTIVA (CAP), XERISTAR (CAP), YENTREVE (CAP);
milnacipran (NAP); venlafaxine (NAP);
Selective serotonin reuptake inhibitors (SSRI): citalopram (NAP); escitalopram
(NAP); fluoxetine (NAP); fluvoxamine (NAP); paroxetine (NAP); sertraline (NAP);
Vortioxetine – BRINTELLIX (CAP)
Applicant(s): Eli Lilly Nederland B.V. (Cymbalta, Duloxetine Lilly, Xeristar, Yentreve),
Generics UK Limited (Duloxetine Mylan), H. Lundbeck A/S (Brintellix), Zentiva k.s.
(Duloxetine Zentiva), various
PRAC Rapporteur: Liana Gross-Martirosyan
Scope: Signal of persistent sexual dysfunction after drug withdrawal
EPITT 19277 – Follow-up to September 2018
Background
For background information, see PRAC minutes September 2018.
Following the further investigation performed on the signal of persistent sexual dysfunction after drug withdrawal by the Lead Member States (LMS) and EMA, the consolidated review was assessed by the Rapporteur.
Discussion
Having considered the available evidence, the PRAC agreed that the MAHs should provide a cumulative review of the signal of persistent sexual dysfunction. This cumulative review should include data from all sources including non-clinical data, clinical data (e.g. withdrawal trials if available), spontaneous post-marketing cases as well as any relevant literature that was not yet evaluated in the assessment report. The review of any non-clinical data should include a discussion on the relevance for humans. To allow a meaningful assessment of post-marketing spontaneous data, the MAHs of originator-containing products are requested to include in the cumulative review only the cases that contain sufficient clinical details for causality assessment. Furthermore, the MAHs should discuss the most frequently reported symptoms of sexual dysfunction in descending order, provide the percentage of cases with each of the reported indications for each substance with which the treatment was initiated,
provide the median duration of treatment with the considered substance (with interquartile range), the median duration of persistence of sexual dysfunction (with interquartile range), determine if there is any correlation between the dosage of a considered substance and the duration of persistence of sexual dysfunction, determine if there is any correlation between the indication for which treatment was initiated with the considered substance and the duration of persistence of sexual dysfunction after discontinuation, determine if there is any correlation between the duration of treatment with the considered substance and the duration of persistence of sexual dysfunction after discontinuation.
The EMA will provide an analysis of data available in EudraVigilance including reporting trend analysis.
Summary of recommendation(s)
• The MAHs Eli Lilly for Cymbalta (duloxetine) and fluoxetine-containing product,
Lundbeck for citalopram-containing product, escitalopram-containing product and
Brintellix (vortioxetine), Mylan for fluvoxamine-containing product, Pfizer for sertraline-and desvenlafaxine-containing products, GSK for paroxetine-containing product, Almirall for venlafaxine-containing product, and Pierre-Fabre for milnacipram-containing product as well as Alfasigma for clomipramine-containing product should submit to EMA, within 60 days, a cumulative review of the signal of persistent sexual dysfunction, including data from all sources including non-clinical data, clinical data (e.g. withdrawal trials if available), and spontaneous post-marketing cases as well as any relevant literature not yet evaluated in the assessment report.
• Based on all the requested analyses, the MAHs are requested to evaluate and discuss the causality assessment of the post-marketing spontaneous reports on a cumulative
level. Furthermore, the MAHs are requested to discuss the relationship between
depression and sexual dysfunction as well as provide the available data regarding the prevalence of the most commonly reported symptoms (from the MAHs’ cumulative analyses) in the general population. In addition, the MAHs are requested to discuss the possible mechanisms which may underlie the persistent sexual dysfunction events in humans. Based on all available data and analyses, the MAHs should discuss the need for any potential amendment to the product information and/or risk management plan.
• A 90-day timetable was recommended for the assessment of this review leading to a
further PRAC recommendation.
PRAC RECOMMENDATION PUBLISHED ON 11 JUNE 2019
1.3. Serotonin and noradrenaline reuptake inhibitors (SNRI) (4); selective serotonin reuptake inhibitors (SSRI) (5, 6) – Persistent sexual dysfunction after drug withdrawal
Authorisation procedure Centralised and non-centralised
EPITT No19277
PRAC rapporteur(s) Liana Gross-Martirosyan(NL)
Date of adoption 16 May 2019
Recommendation
Having considered the available evidence from EudraVigilance, literature, social media and cumulative reviews provided by MAHs for duloxetine, fluoxetine (Eli Lilly), citalopram, vortioxetine, escitalopram (Lundbeck), fluvoxamine (Mylan), sertraline, desvenlafaxine (Pfizer), paroxetine (GSK), venlafaxine (Almirall), milnacipram (Pierre Fabre) and clomipramine (Alfasigma) the PRAC has agreed that all MAHs of products containing citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline (Selective serotonin reuptake inhibitors (SSRIs)) and all MAHs of products containing duloxetine, venlafaxine, desvenlafaxine, milnacipram (Serotonin–norepinephrine reuptake inhibitors (SNRIs)) should submit a variation within 2 months (6), to amend the product information as described below (new text underlined):
Summary of product characteristics
4.4. Special warnings and precautions for use
Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.
Package leaflet
2. What you need to know before you take [Invented name]
Warnings and precautions
Medicines like [Invented name] (so called SSRIs/SNRIs) may cause symptoms of sexual dysfunction (see section 4). In some cases, these symptoms have continued after stopping treatment.
(4) Desvenlafaxine; duloxetine; milnacipran; venlafaxine
(5) Citalopram; escitalopram; fluoxetine; fluvoxamine; paroxetine; sertraline
(6 ) Clomipramine and vortioxetine were part of the signal assessment but are not concerned by the recommendation to update the product information.
MEDIA:
https://rxisk.org/ema-acknowledges-persistent-sexual-dysfunction-after-ssris-snris/
https://www.dailymail.co.uk/health/article-7125745/How-depression-pills-wreck-sex-life.html
https://www.psychologytoday.com/us/blog/side-effects/201906/post-ssri-sexual-dysfunction-recognized-medical-condition