Emerging Drug List CANADIAN COORDINATING OFFICE for HEALTH ESCITALOPRAM TECHNOLOGY ASSESSMENT

Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH ESCITALOPRAM TECHNOLOGY ASSESSMENT

NO. 35 JANUARY 2003 Generic (Trade Name): Escitalopram (LexaproTM)

Manufacturer: Forest Laboratories, Inc.

Indication: For the treatment of major depressive disorders in adults.1

Current Regulatory Escitalopram was approved by the US FDA for the above indication in August 2002.2 It Status: was just recently launched in the US, according to the company's web site.3 It was launched in June 2002 in the UK under the trade name Cipralex by Lundbeck for both the treatment of depression and panic disorder.4 In Canada, escitalopram has been sub- mitted for review; no planned marketing date is available (Drug Information, Lundbeck Canada, Montreal: personal communication, 2002 Sep 30).

Description: Escitalopram is the S(+) enantiomer of the chiral compound citalopram. It is a selective serotonin reuptake inhibitor that exerts activity in both depressive and anxiety disorders. After oral administration of a single dose, maximal concentrations are reached within three to four hours. It is extensively metabolized via the liver, with eight percent excreted unchanged by the kidneys. After a 20 mg dose, the elimination half-life (of the parent compound) ranges from 22 to 27 hours.5

Current Treatment: Options for the treatment of depressive disorders are vast and include selective serotonin norepinephrine reuptake inhibitors (SNRI), norepinephrine dopamine reuptake inhibitors (NDRI), serotonin-2 antagonists/reuptake inhibitors (SARI), noradrenergic/specific serotoninergic antidepressants (NaSSA), reversible inhibitors of MAO-A (RIMA), irreversible monoamine oxidase inhibitors (MAOI), tricyclic antidepressants (TCA), and selective serotonin reuptake inhibitors (SSRIs). Escitalopram would be the sixth SSRI to be introduced to Canada, following fluoxetine (Prozac® - Lilly), fluvoxamine (Luvox® - Solvay Pharma), sertraline (ZoloftTM - Pfizer), paroxetine (Paxil® -GlaxoSmithKline) and citalopram (Celexa® - Lundbeck).6

Cost: In the US, the manufacturer states that the average wholesale price of Lexapro for a bottle of 100 tablets is $213.46 and $222.76 for the 10 and 20 mg strengths, respectively.1

Evidence: Wade et al. published the results of an eight-week double-blind trial, indicating that escitalopram 10 mg daily was statistically better than placebo in relieving symptoms of depression in outpatients.7

Montgomery and colleagues conducted an eight-week three armed study where patients (n=469) with major depressive disorder were randomized to receive either citalopram 20 mg daily, escitalopram 10 mg daily or placebo, with the objective of assessing efficacy and safety up to week four. The doses could be doubled after four to six weeks of

The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH ESCITALOPRAM TECHNOLOGY ASSESSMENT

treatment. At week four, the response to escitalopram was considered to be statistically significant when compared to placebo (p=0.002), which was not evident with citalopram (p=0.095). The authors conclude that the observations in the trial suggest escitalopram possesses a faster time to onset of efficacy. However the trial was not specifically designed to assess this parameter, nor were the active arms compared with each other, rather with placebo.8

Burke et al. examined the efficacy and safety of escitalopram over eight weeks in outpatients (n=491) with major depressive disorder. Patients were randomized to one of four arms: escitalopram 10 mg or 20 mg, citalopram 40 mg or placebo daily. At the end of the study, all active treatment arms produced a statistically superior response on assessed efficacy outcome measurements as compared to placebo (p<0.05). No statistically significant difference in response rate was noted between the three active treatment arms.9

Wade et al. reported that patients showed continued improvement with long-term use of escitalopram 10-20 mg, based on data gathered during an open label, 52-week extension study.10

A recent abstract presented at the ECJP Congress in October 2002 reported the results of a randomized, double-blind eight week trial where escitalopram (10 to 20 mg/day) was found to be as effective as venlafaxine XR (75 to 150 mg/day) in those with major depressive disorder.11 There is some evidence available in abstract format that escitalopram is statistically superior to placebo in social anxiety disorder and panic disorder.12,13 Its use in generalized anxiety disorder has also been evaluated.14 Further information on abstracts presented at various conferences, including pooled data and subanalyses, can be retrieved from the company's website at http://www.lundbeck.com/investor/pipeline/ clinicaldata/default.asp.

Adverse Effects: In the clinical trial by Burke et al., escitalopram was reported to be well-tolerated. Adverse effects reported in 10% or more of patients and more prevalent than in the control arm, included nausea, diarrhea, insomnia, dry mouth and ejaculatory disorder. The rate of treatment-emergent adverse effects were considered significantly different from placebo for the escitalopram 20 mg daily group (p<0.01), but this was not evident with the lower 10 mg daily dose.7

Commentary: Information available to date suggests that citalopram's S-enantiomer, escitalopram, is a well-tolerated, efficacious antidepressant of the SSRI class which may also have applica- tion in anxiety disorders. However, concrete data is lacking demonstrating the benefits of this new antidepressant over others currently marketed, including the racemic parent. A recent report examining differences between single enantiomers and racemates echoes similar concerns about perceived differences that may not be realized clinically.15

References: 1. O'Mara NB. Escitalopram (Lexapro). Pharm Lett [serial online] 2002:180906. 2. Market news for the US. Inpharma 2002;1352:18. 3. Lexapro™ is now available in pharmacies nationwide for the treatment of depressive disorder [press release]. New York: Forest Laboratories; 2002 Sep 5. Available: http://www.frx.com/servlet/financial.displayDoc?doc_id=09-05-2002/0001794727. 4. EU market news. Inpharma 2002;1345:18. 5. Klasco RK, editor. DRUGDEX® System. Greenwood Village (CO): MICROMEDEX; 2002 Dec. 6. Bezchlibnyk-Butler KZ, Jeffries JJ, editors. Clinical handbook of psychotropic drugs. 11th ed. Toronto: Hogrefe & Huber Publishers; 2001. 7. Wade AG, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002;17(3):95-102. 8. Montgomery SA, Loft H, Sanchez C, Reines EH, Papp M. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2002;88(5):282-6. 9. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002;63(4):331-6. 10. Wade A, Despiegel N, Reines E. Depression in primary care patients: improvement during long-term escitalpram treatment [poster]. 15th European College of Neuropsychopharmacology Congress; 2002 Oct 5-9; Barcelona. Poster no P.1.156. Available: http://www.lundbeck.com/investor/Pipeline/ ClinicalData/Depression in Primary Care Patients Improvement During Long-term Escitalopram Treatment.pdf (accessed 2002 Dec 9). 11. Montgomery SA, Huusom AKT, Bothmer J. Escitalopram is at least as effective as venlafaxine XR in the treatment of depression and is better tolerated [poster]. 15th European College of Neuropsychopharmacology Congress; 2002 Oct 5-9; Barcelona. Poster no P.1.206. Available: http://www.lundbeck.com/investor/ Pipeline/ClinicalData/Escitalopram Is at Least as Effective as Venlafaxine XR in the Treatment of Depression and Is Better Tolerated.pdf (accessed 2002 Dec 9). 12. Stahl S, Gergel I, Li D. Escitalopram in the treatment of panic disorder. 155th Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia. Poster no 485. Available: http://www.lundbeck.com/investor/Pipeline/ClinicalData/APA 2002 - Escitalopram in the treatment of panic disorder.pdf (accessed 2002 Dec 9). 13. Kasper S, Loft H, Smith JR. Escitalopram is efficacious and well tolerated in the treatment of social anxiety disorder. 155th Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia. Poster no 491. Available: http://www.lundbeck.com/investor/Pipeline/ClinicalData/APA 2002 - Escitalopram is efficacious and well tolerated in the treatment of SAD.pdf (accessed 2002 Dec 9) 14. Davidson J, Bose A, Su G. Escitalopram in the treatment of generalized anxiety disorder [abstract]. 22nd Annual Conference of the Anxiety Disorders Association of America; 2002 March 21-4; Austin (TX). Available: http://www.lundbeck.com/investor/Pipeline/ClinicalData/ Escitalopram in the treatment of Generalized Anxiety Disorder.PDF (accessed 2002 Dec 9). 15. Do single stereoisomer drugs provide value? Ther Lett 2002;45:1-4. Available: http://www.ti.ubc.ca/pages/letter45.htm (accessed 6 Dec 2002).

This series highlights medical technologies that are not yet in widespread use in Canada and that may have a significant impact on health care. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada. These summaries have not been externally peer reviewed.

ISSN 1496-8398 (online only)

The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca)