Export

ATC codes: N06AB03
EMLc
Indication
Depressive disorders ICD11 code: 6A9Z
INN
Fluoxetine
Medicine type
Chemical agent
List type
Core (EML)
Complementary (EMLc)
Formulations
Oral > Solid: 20 mg (as hydrochloride)
EML status history
First added in 2007 (TRS 946)
Changed in 2007 (TRS 950)
Changed in 2019 (TRS 1021)
Sex
All
Age
Also recommended for children
Age restriction
> 8 years
Therapeutic equivalence
Medicines within the same pharmacological class can be used
Therapeutic equivalence limitations for EMLc
The square box does not apply for the listing of fluoxetine on the EMLc.
Patent information
Patents have expired in most jurisdictions
Wikipedia
DrugBank
Expert Committee recommendation
The Committee recommended the addition of a square box symbol to the current listing of fluoxetine on the core list of the EML for treatment of depressive disorders. The Committee noted that medicines within the pharmacological class of selective serotonin reuptake inhibitors all have demonstrated efficacy, but can differ in terms of pharmacokinetics, adverse events and drug-interaction profiles. The availability of different SSRIs as essential medicines may be beneficial at country level to expand therapeutic alternatives for patients and support better procurement. As a consequence of the recommendation for the square box with fluoxetine, the Committee did not recommend the separate addition of escitalopram to the core list of the EML. Escitalopram, and other SSRIs should be considered therapeutically equivalent alternatives to fluoxetine for selection at national level.
Background
Two applications regarding the listing of selective serotonin reuptake inhibitors (SSRIs) were received: Application 1: requested the inclusion of escitalopram on the core list of the EML for the treatment of adults with major depressive disorder. Application 2: requested the addition of a square box symbol to the current listing of fluoxetine on the core list of the EML for treatment of depressive disorders. Fluoxetine was added to the core list of the EML in 2007. The Committee considered that the available evidence supported the public health need, comparable effectiveness and generally more favourable tolerability of fluoxetine compared to amitriptyline. A square box was not recommended as the Committee felt there may be significant within-class differences among SSRIs in relation to safety (1).
Public health relevance
The public health relevance of depressive disorders is well established and has been previously accepted by the Committee. However, the global burden of disease due to depressive disorders is increasing over time. In 2017, depressive disorders were estimated to affect over 260 million people globally, including 160 million with major depressive disorder. According to the Global Burden of Disease Study 2017, depressive disorders were responsible for over 43 million disability-adjusted life years (DALYs) annually, accounting for 1.7% of total estimated DALYs due to any disease. Depressive disorders were also responsible for over 43 million years lived with disability (YLD), accounting for 5.0% of the total YLD globally (2).
Benefits
Both applications presented the findings of a 2018 systematic review and network meta-analysis (NMA) of 522 randomized controlled trials (RCTs) involving 117 477 participants, which evaluated the comparative efficacy and tolerability of 21 antidepressant medicines compared to each other and to placebo for the treatment of depression in adults (3). Compared to placebo, all SSRIs were associated with statistically significantly greater response rates. The greatest response rate seen was for paroxetine (odds ratio (OR) 1.75, 95%CI 1.61 to 1.90). With regard to acceptability, as measured by dropout rates, all SSRIs except for fluvoxamine showed an advantage over placebo, however this was only statistically significant for fluoxetine (OR 0.88, 95%CI 0.80 to 0.96). In comparisons between SSRIs, there was moderate level GRADE evidence of statically significant superior efficacy of escitalopram compared to citalopram, fluoxetine, and fluvoxamine, and of paroxetine compared to fluoxetine. Other comparisons were not statistically significant. The findings of a 2009 Cochrane systematic review of 22 RCTs comparing escitalopram to other antidepressants were largely consistent with the 2018 NMA (4). In six studies (1823 participants) that compared response rates between escitalopram and citalopram, there was a statistically significant difference in favour of escitalopram (OR 0.67, 95%CI 0.50 to 0.89, p=0.006), also found in remission rates (OR 0.57, 95%CI 0.36 to 0.90, p=0.02). Three studies (783 participants) that directly compared escitalopram and fluoxetine did not find a statistically significant difference in response or remission rates but did find escitalopram to be more efficacious than fluoxetine in reduction of depressive symptoms from baseline (SMD −0.17, 95%CI −0.32 to −0.03, p=0.02). Two studies (784 participants) that compared escitalopram to paroxetine, and two studies (489 participants) that compared escitalopram to sertraline, did not find any statistically significant differences for any of the above parameters.
Harms
In the above-mentioned Cochrane review, 14 RCTs compared escitalopram to another SSRI (4). Escitalopram did not have significantly different rates of mild to severe adverse events than citalopram (n = 1802 in six RCTs), fluoxetine (n = 804 in four RCTs), or paroxetine (n = 784 in two RCTs). Also, there was no significant difference in serious adverse events for escitalopram compared to sertraline (n = 483 in 2 RCTs); however, escitalopram had a decreased incidence of diarrhoea. Overall, escitalopram and other SSRIs had similar rates of agitation, anxiety, constipation, diarrhoea, dry mouth, hypotension, insomnia, nausea, urinary complaints, drowsiness, vomiting, deaths, suicide, suicidality and other adverse events. With respect to acceptability as measured by dropout rates, in the abovementioned NMA, escitalopram was associated with moderate level GRADE evidence of superiority compared to fluvoxamine. There were no other statistically significant differences between SSRIs with regard to acceptability (3). A 2006 meta-analysis using patient-level data from published and unpublished clinical trials based on mandatory reporting by pharmaceutical companies assessed the risk of suicidality (ideation or worse) amongst antidepressants (5, 6). Half of the treatment indications were related to depression, with the remaining 50% for other psychiatric or non-psychiatric indications. Among SSRI, considering only data for adults with psychiatric diagnoses, suicidality risk was found to be lowest for sertraline and fluoxetine (low quality evidence). Suicidality risk was greatest for citalopram and escitalopram although the differences did not reach statistical significance (very low-quality evidence). A 2014 meta-analysis examined the association between SSRI antidepressants and QTc (corrected QT) prolongation (7). Citalopram and escitalopram were associated with the greatest amount of QTc prolongation, while sertraline was associated with the least. Fluvoxamine was associated with shortened QTc. Results for fluoxetine and paroxetine were not statistically significant. With regard to sexual dysfunction, escitalopram and paroxetine have been associated with a higher risk of sexual dysfunction than fluoxetine. Pairwise comparisons of other SSRIs have not shown statistically significant differences (8). The pharmacokinetic properties of individual SSRIs differ considerably. Considering potential for drug–drug interactions, many SSRIs are inhibitors of cytochrome P450 enzymes and may interact with other drugs that are metabolized by these enzymes. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine is a potent inhibitor of CYP1A2. Fluoxetine and fluvoxamine are also moderate inhibitors of CYP2C19. Citalopram, escitalopram and sertraline are considered to have the lowest potential for CYP enzyme-mediated interactions (9). Fluoxetine has a half-life of one to four days and an active metabolite (norfluoxetine) with a half-life of seven to fifteen days. The half-lives of the other SSRIs are considerably shorter. Therefore, fluoxetine will take longer to reach steady-state concentrations and will remain in the body for longer following discontinuation of therapy. As a result, adverse reactions and drug-interactions with fluoxetine may persist for some time following cessation of treatment (10). Paroxetine has the shortest half-life among the SSRIs (one day) and has been found to have a higher potential for withdrawal symptoms following discontinuation (11).
Cost / cost effectiveness
SSRIs vary in price globally, but are generally inexpensive, with multiple generic brands available. Cost-effectiveness analyses in different settings have shown SSRIs to be cost-effective interventions (18–27).
WHO guidelines
The WHO Mental Health Gap Action Programme (mhGAP) Guidelines make the following recommendations in relation to antidepressants for treatment of adults with depression (12): – Antidepressants should not be considered for the initial treatment of adults with mild depressive episode. (Strength of recommendation: Conditional; Quality of evidence: Low); – Tricyclic antidepressants or fluoxetine should be considered in adults with moderate to severe depressive episode/disorder. (Strength of recommendation: Conditional; Quality of evidence: Low); – If drug treatment is required in older people, tricyclic antidepressants should be avoided if possible. (Strength of recommendation: Conditional; Quality of evidence: Low); – If drug treatment is required in women with depressive episode who are planning a pregnancy or are pregnant or breastfeeding, tricyclic antidepressants or fluoxetine should be considered. (Strength of recommendation: Conditional; Quality of evidence: Low). SSRIs are also recommended as first-line treatment choices in numerous international guidelines (13–17). The choice of individual SSRI should be made after taking into consideration the differing safety and tolerability profiles, pharmacokinetic and pharmacodynamic factors, price and individual patient factors and patient preferences.
Availability
SSRIs are widely available globally, with off-patent generic formulations available.
Other considerations
Letter of support for escitalopram application from the Ministry for Health and Welfare, National Centre for Mental Health, Republic of Korea: “More than one SSRI should be considered as essential drugs. It is an important point that patients may respond to specific SSRIs differently and it is difficult to predict which agent will be the most effective for each patient.”
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2007 (including the 15th Model List of Essential Medicines) (WHO Technical Report Series No. 946). Geneva: World Health Organization; 2007. Available from https://apps.who.int/iris/bitstream/handle/10665/43745/WHO_TRS_946_eng.pdf, accessed 30 October 2019. 2. GBD Results Tool | GHDx. 2018. Seattle: Institute for Health Metrics and Evaluation, University of Washington; 2018. Available from http://ghdx.healthdata.org/gbd-results-tool, accessed 29 September 2019. 3. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–66. 4. Cipriani A, Santilli C, Furukawa TA, Signoretti A, Nakagawa A, McGuire H et al. Escitalopram versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2009(2):CD006532. 5. Stone M, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ. 2009;339:b2880. 6. Laughren TP. Memorandum: Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research. 2006. Available from http://dixitciencia.com/wp-content/uploads/2006-4272b1-01-FDA.pdf, accessed 29 September 2019. 7. Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014; 75(5):e441–9. 8. Reichenpfader U, Gartlehner G, Morgan LC, Greenblatt A, Nussbaumer B, Hansen RA et al. Sexual dysfunction associated with second-generation antidepressants in patients with major depressive disorder: results from a systematic review with network meta-analysis. Drug Saf. 2014;37(1):19–31. 9. Hirsch M, Birnbaum RJ. Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects Internet]. Waltham, MA: UpToDate; 2018. Available from https://www.uptodate.com/contents/selective-serotonin-reuptake-inhibitors-pharmacology-administration-and-side effects,accessed 29 September 2019. 10. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85(1):11–28. 11. Fava GA, Gatti A, Belaise C, Guidi J, Offidani E. Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. Psychother Psychosom. 2015;84(2):72–81. 12. Antidepressants (Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors) in treatment of adults with depression. mhGAP Evidence Resource Center. Geneva: World Health Organization, 2012. Available from https://www.who.int/mental_health/mhgap/evidence/depression/q1/en/, accessed 29 September 2019. 13. Depression in adults: recognition and management. Clinical guideline [CG90]. October 2009. Last updated April 2018. London: National Institute for Health and Care Excellence; 2018. Available from http://www.nice.org.uk/guidance/CG90, accessed 29 September 2019. 14. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540–60. 15. Gelenberg AJ, Marlene Freeman CP, Markowitz JC et al. Practice guideline for the treatment of patients with major depressive disorder; Third Edition. Washington, DC: American Psychiatric Association; 2010. Available from http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx, accessed 29 September 2019. 16. Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12):1087–206. 17. Emsley R, Flisher AJ, Grobler G, Seedat S, Szabo CP. The South African Society of Psychiatrists (SASOP) Treatment Guidlelines for Psychiatric Disorders. S Afr J Psychiatr. 2013;19(3). 18. Khoo AL, Zhou HJ, Teng M, Lin L, Zhao YJ, Soh LB et al. Network Meta-Analysis and Cost-Effectiveness Analysis of New Generation Antidepressants. CNS drugs. 2015;29(8):695–712. 19. Kaplan C, Zhang Y. Assessing the comparative-effectiveness of antidepressants commonly prescribed for depression in the US Medicare population. J Ment Health Policy Econ. 2012;15(4):171–8. 20. Mencacci C, Aguglia E, Biggio G, Cappellari L, Di Sciascio G, Fagiolini A et al. C-QUALITY: cost and quality-of-life pharmacoeconomic analysis of antidepressants in major depressive disorder in Italy. Adv Ther. 2013;30(7):697–712. 21. Mencacci C, Di Sciascio G, Katz P, Ripellino C. Cost-effectiveness evaluation of escitalopram in major depressive disorder in Italy. ClinicoEconomics and outcomes research : CEOR. 2013;5:87–99. 22. Mencacci C, Aguglia E, Biggio G, Cappellari L, Di Sciascio G, Fagiolini A et al. C-QUALITY: cost and quality-of-life pharmacoeconomic analysis of antidepressants used in major depressive disorder in the regional Italian settings of Veneto and Sardinia. ClinicoEconomics and outcomes research:CEOR. 2013;5:611–21. 23. Nuijten MJ, Brignone M, Marteau F, den Boer JA, Hoencamp E. Cost-effectiveness of escitalopram in major depressive disorder in the Dutch health care setting. Clin Ther. 2012;34(6):1364–78. 24. Sorensen J, Stage KB, Damsbo N, Le Lay A, Hemels ME. A Danish cost-effectiveness model of escitalopram in comparison with citalopram and venlafaxine as first-line treatments for major depressive disorder in primary care. Nord J Psychiatry. 2007;61(2):100–8. 25. Armstrong EP, Skrepnek GH, Haim Erder M. Cost-utility comparison of escitalopram and sertraline in the treatment of major depressive disorder. Curr Med Res Opin. 2007;23(2):251–8. 26. Malone DC. A budget-impact and cost-effectiveness model for second-line treatment of major depression. J Manag Care Pharm. 2007;13(6 Suppl A):S8-18. 27. Kongsakon R, Bunchapattanasakda C. The treatment of major depressive disorders (MDD) in Thailand using escitalopram compared to fluoxetine and venlafaxine: a pharmacoeconomic evaluation. J Med Assoc Thai. 2008;91(7):1117–28.