ESCITALOPRAM

128196-01-0 ESCITALOPRAM

Escitalopram (also known under various trade names) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition. The similarity between escitalopram and citalopram has led to accusations of “evergreening“, an accusation that Lundbeck has rejected.[1]

Escitalopram has FDA approval for the treatment of major depressive disorder and generalized anxiety disorder in adults.[2]

Off-label uses

Escitalopram is sometimes prescribed off-label for the treatment of other conditions: social anxiety disorder,[3] panic disorder[4]and obsessive-compulsive disorder.[5] There is some evidence favouring escitalopram over the antidepressants citalopram andfluoxetine in the first two weeks of major depression.[6] Concerns of sponsorship bias with the studies are however noted.[6] In another review escitalopram and sertraline had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.[7]

Efficacy

There is some controversy over selective publishing of SSRI clinical trials.[8] A meta-analysis analyzing published as well as unpublished trials found placebos to be similarly effective to SSRIs in treating mild depression, although SSRIs were more effective than placebo in more severe cases, with the magnitude of SSRI superiority increasing with increasing depression severity.[9]

A series of randomized, double-blind trials have found Escitalopram to be more efficacious and have fewer adverse effects than Citalopram.[10][11][12][13] Meta-analysis show a “small” but statistically significant improvement in effect strength [14][15] and some dispute these findings.[16]

Pharmacology

Cipralex brand escitalopram 10mg package and tablet sheet

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest affinity for the human serotonin transporter (SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram has been claimed to be a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.[42] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,[43] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter.[44] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.

History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.[45] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of “evergreening“[46] (also called “lifecycle management”[47])– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound of theracemic mixture citalopram, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram’s launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.[48]On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.[49]

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.[50] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

Brand names

Escitalopram is sold under the following brand names:

• Animaxen (Colombia)
• Anxiset-E (India)
• Cipralex
• Escital (Nigeria)
• Citalin
• Citram (Croatia)
• Ecytara (Slovenia)
• Elicea
• Entact (Greece)
• Escitalopram Actavis (Finland)
• Escitil (Czech Republic)
• Esitalo (Australia)
• Esopram, by Actavis (Iceland)
• Esto (Israel)
• Escitalopram Teva (Israel)
• Exodus (Brazil)
• Lexam
• Lexamil (South Africa)
• Lexapro
• Losita (Bangladesh)
• Nexito
• Reposil (Chile)
• Selectra (Russia)
• Selpram (Pakistan)
• Seroplex
• Sipralexa (Belgium)

References

1. ^ a b c NHS pays millions of pounds more than it needs to for drugs, The Independent. Retrieved 05/10/2011.
2. ^ “Escitalopram Oxalate”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
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4. ^ Stahl, SM; Gergel, I; Li, D (2003). “Escitalopram in the treatment of panic disorder: A randomized, double-blind, placebo-controlled trial”. The Journal of clinical psychiatry 64(11): 1322–7. PMID 14658946.
5. ^ Stein, DJ; Andersen, EW; Tonnoir, B; Fineberg, N (2007). “Escitalopram in obsessive-compulsive disorder: A randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study”. Current medical research and opinion 23 (4): 701–11. doi:10.1185/030079907X178838. PMID 17407626.
6. ^ a b Cipriani, A; Santilli C; Furukawa TA; Signoretti A; Nakagawa A; McGuire H; Churchill R; Barbui C (2009 April 15). “Escitalopram versus other antidepressant agents for depression”. In Cipriani, Andrea. Cochrane database of systematic reviews(2): CD006532. doi:10.1002/14651858.CD006532.pub2. PMID 19370639. CD006532.
7. ^ Cipriani, A; Furukawa TA; Salanti G; Geddes JR; Higgins JP; Churchill R; Watanabe N; Nakagawa A; Omori IM; McGuire H; Tansella M; Barbui C (2009 February 28). “Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis”. Lancet 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342.
8. ^ Ioannidis JP (2008). “Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?”. Philos Ethics Humanit Med 3: 14.doi:10.1186/1747-5341-3-14. PMC 2412901. PMID 18505564.
9. ^ Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J (January 2010). “Antidepressant drug effects and depression severity: a patient-level meta-analysis”. JAMA 303 (1): 47–53. doi:10.1001/jama.2009.1943.PMID 20051569.
10. ^ Ou, JJ; Xun, GL; Wu, RR; Li, LH; Fang, MS; Zhang, HG; Xie, SP; Shi, JG; Du, B; Yuan, XQ; Zhao, JP (2011 Feb). “Efficacy and safety of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, randomized, double-blind, flexible-dose study.”. Psychopharmacology 213 (2-3): 639–46. doi:10.1007/s00213-010-1822-y. PMID 20340011. |accessdate= requires |url= (help)
11. ^ Yevtushenko, VY; Belous, AI; Yevtushenko, YG; Gusinin, SE; Buzik, OJ; Agibalova, TV (2007 Nov). “Efficacy and tolerability of escitalopram versus citalopram in major depressive disorder: a 6-week, multicenter, prospective, randomized, double-blind, active-controlled study in adult outpatients.”. Clinical therapeutics 29 (11): 2319–32.PMID 18158074.
12. ^ Colonna, L; Andersen, HF; Reines, EH (2005 Oct). “A randomized, double-blind, 24-week study of escitalopram (10 mg/day) versus citalopram (20 mg/day) in primary care patients with major depressive disorder.”. Current medical research and opinion 21(10): 1659–68. PMID 16238906.
13. ^ Moore, N; Verdoux, H; Fantino, B (2005 May). “Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder.”. International clinical psychopharmacology 20 (3): 131–7. PMID 15812262.
14. ^ Montgomery, Stuart; Hansen, Thomas; Kasper, Siegfried (28 September 2010). “Efficacy of escitalopram compared to citalopram: a meta-analysis”. The International Journal of Neuropsychopharmacology 14 (02): 261–268.doi:10.1017/S146114571000115X. PMID 20875220.
15. ^ Gorman, JM; Korotzer, A; Su, G (2002 Apr). “Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials.”. CNS spectrums 7 (4 Suppl 1): 40–4. PMID 15131492.
16. ^ Trkulja, V (2010 Feb). “Is escitalopram really relevantly superior to citalopram in treatment of major depressive disorder? A meta-analysis of head-to-head randomized trials.”. Croatian medical journal 51 (1): 61–73. PMID 20162747.
17. ^ “Citalopram and escitalopram: QT interval prolongation—new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings”.Medicines and Healthcare products Regulatory Agency. December 2011. Retrieved March 5, 2013.
18. ^ Van Gorp, Freek; Whyte, Ian M.; Isbister, Geoffrey K. (2009). “Clinical and ECG Effects of Escitalopram Overdose”. Annals of Emergency Medicine 54 (3): 404–8.doi:10.1016/j.annemergmed.2009.04.016. PMID 19556032.
19. ^ FDA Center for Drug Evaluation and Research (2001). “Review and evaluation of clinical data for application 21-323″. Retrieved 2009-12-03.
20. ^ Bolton JM, Sareen J, Reiss JP (2006). “Genital anesthesia persisting six years after sertraline discontinuation”. J Sex Marital Ther 32 (4): 327–30.doi:10.1080/00926230600666410. PMID 16709553.
21. ^ Clayton A, Keller A, McGarvey EL (2006). “Burden of phase-specific sexual dysfunction with SSRIs”. Journal of Affective Disorders 91 (1): 27–32.doi:10.1016/j.jad.2005.12.007. PMID 16430968.
22. ^ Lexapro prescribing information
23. ^ Csoka AB, Bahrick AS, Mehtonen O-P (2008). “Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs)”. J Sex Med. 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.x. PMID 18173768.
24. ^ Baldwin DS, Reines EH, Guiton C, Weiller E (2007). “Escitalopram therapy for major depression and anxiety disorders”. Ann Pharmacother 41 (10): 1583–92.doi:10.1345/aph.1K089. PMID 17848424.
25. ^ Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM (2007). “Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder”. Curr Med Res Opin 23 (6): 1303–18.doi:10.1185/030079907X188107. PMID 17559729.
26. ^ Davidson JR, Bose A, Wang Q (2005). “Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder”. J Clin Psychiatry 66 (11): 1441–6.doi:10.4088/JCP.v66n1115. PMID 16420082.
27. ^ Kasper S, Lemming OM, de Swart H (2006). “Escitalopram in the long-term treatment of major depressive disorder in elderly patients”. Neuropsychobiology 54 (3): 152–9. doi:10.1159/000098650. PMID 17230032.
28. ^ Guerdjikova, AI; McElroy SL, Kotwal R, et al. (January 2008). “High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial”. Human Psychopharmacology: Clinical and Experimental23 (1): 1–11. doi:10.1002/hup.899. PMID 18058852.
29. ^ Levenson M, Holland C. “Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)”. Retrieved 2007-05-13.
30. ^ Stone MB, Jones ML (2006-11-17). “Clinical Review: Relationship Between Antidepressant Drugs and Suicidality in Adults” (PDF). Overview for December 13 Meeting of Pharmacological Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22.
31. ^ Levenson M; Holland C (2006-11-17). “Statistical Evaluation of Suicidality in Adults Treated with Antidepressants” (PDF). Overview for December 13 Meeting of Pharmacological Drugs Advisory Committee (PDAC). FDA. pp. 75–140. Retrieved 2007-09-22.
32. ^ Gunnell D, Saperia J, Ashby D (2005). “Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomized controlled trials submitted to the MHRA’s safety review”. BMJ330 (7488): 385. doi:10.1136/bmj.330.7488.385. PMC 549105. PMID 15718537.
33. ^ Khan A, Schwartz K (2007). “Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports”. Ann Clin Psychiatry 19 (1): 31–6.doi:10.1080/10401230601163550. PMID 17453659.
34. ^ Budur, Kumar; Hutzler, Jeffrey (June 2004). “Severe suicidal ideation with escitalopram (Lexapro): a case report”. Primary Care Psychiatry 9 (2): 67–68.doi:10.1185/135525704125004222.
35. ^ Karch, Amy (2006). 2006 Lippincott’s Nursing Drug Guide. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins. ISBN 1-58255-436-6.
36. ^ Malling, D.; Poulsen, M.; Søgaard, B. (2005). “The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects”. British Journal of Clinical Pharmacology 60 (3): 287–290. doi:10.1111/j.1365-2125.2005.02423.x.PMC 1884771. PMID 16120067. edit
37. ^ “Lexapro – Warnings”. RxList. 12/08/2004. Retrieved 2006-10-22.
38. ^ Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, for the National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007;356:2684–92.
39. ^ van Gorp F, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram overdose. Ann. Emer. Med. 54: 404-408, 2009.
40. ^ Haupt D. Determination of citalopram enantiomers in human plasma by liquid chromatographic separation on a Chiral-AGP column. J. Chrom. B 685: 299-305, 1996.
41. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 552-553.
42. ^ For an overview of supporting data, see Sánchez C, Bøgesø KP, Ebert B, Reines EH, Braestrup C (2004). “Escitalopram versus citalopram: the surprising role of the R-enantiomer”. Psychopharmacology (Berl.) 174 (2): 163–76. doi:10.1007/s00213-004-1865-z. PMID 15160261.
43. ^ Chen F, Larsen MB, Sánchez C, Wiborg O (2005). “The (S)-enantiomer of (R,S)-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors”.European Neuropsychopharmacology 15 (2): 193–198.doi:10.1016/j.euroneuro.2004.08.008. PMID 15695064.
44. ^ Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, Sánchez C, Haddjeri N (2007). “Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies”. The International Journal of Neuropsychopharmacology 10 (1): 31–40. doi:10.1017/S1461145705006462. PMID 16448580.
45. ^ “2000 Annual Report. p 28 and 33″ (PDF). Lundbeck. 2000. Retrieved 2007-04-07.
46. ^ “”New drugs from old”. Presented at the Medical Journal Club, Morriston Hospital, by Scott Pegler, pharmacist at the National Health Service, UK, on November 20, 2006.” (PPT). Retrieved 2007-04-07.
47. ^ “New drugs from old”. Drug and Therapeutics Bulletin (BMJ Publishing Group Ltd.)44 (10): 73–77. 2006. doi:10.1136/dtb.2006.441073. PMID 17067118.
48. ^ Miranda Hitti. “FDA OKs Generic Depression Drug – Generic Version of Lexapro Gets Green Light”. WebMD. Retrieved 2007-10-10.
49. ^ Marie-Eve Laforte (2006-07-14). “US court upholds Lexapro patent”. FirstWord. Retrieved 2007-10-10.
50. ^ “Forest Laboratories Receives Patent Term Extension for Lexapro” (Press release). PRNewswire-FirstCall. 2006-03-02. Retrieved 2009-01-19.
51. ^ Harris, “A Drug Maker’s Playbook Reveals a Marketing Strategy”
52. ^ Lexapro Fiscal 2004 Marketing Plan
53. ^ “Forest Laboratories: A Tale of Two Whistleblowers” article by Alison Frankel inThe American Lawyer February 27, 2009
54. ^ United States of America v. Forest Laboratories Full text of the federal complaint filed in the US District Court for the district of Massachusetts
55. ^ “Drug Maker Is Accused of Fraud” article by Barry Meier and Benedict Carey inThe New York Times February 25, 2009
56. ^ “Forest Laboratories, Inc. Provides Statement in Response to Complaint Filed by U.S. Government” Forest press-release. February 26, 2009.

• “A Drug Maker’s Playbook Reveals a Marketing Strategy” article in The New York Times by Gardiner Harris, September 1, 2009

• Royal Pharmaceutical Society of Great Britain (September 2009). British National Formulary (BNF 58). UK: BMJ Group and RPS Publishing. ISBN 978-0-85369-778-7.

• U.S. National Library of Medicine: Drug Information Portal — Escitalopram
• Lexapro (Forest Laboratories) Official Lexapro homepage
• Cipralex (Lundbeck) Official Cipralex homepage
• Pharmacological information Lexapro
• Cipla Medpro Official Cipla Medpro homepage

http://www.sciencedirect.com/science/article/pii/S0040402011015249

http://www.sciencedirect.com/science/article/pii/S0040402011015249

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Philadelphia, PA (Scicasts) – A study reported by Elsevier and published in Vaccine could provide hope for new live-attenuated malaria vaccine. This study suggests that genetically engineered malaria parasites that are stunted through precise gene deletions (genetically attenuated parasites, or "GAP") could be used as a vaccine that protects against malaria infection
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Stem cells « New Drug Approvals:

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Guidance on Medicinal Product Registration in Singapore

Singapore Drug Registration Information and Guidelines

Guidance on Medicinal Product Registration in Singapore

Announcement - Revision to Guidance on Medicinal Product Registration in Singapore (Mar 2012)

Guidance on Medicinal Product Registration in Singapore (Effective 1 April 2011)

• Complete Guidance Document (includes all appendices) 
• Main Guidance Document only (without appendices)

Appendices

1.      Target Processing Timelines
2A.    Application Checklist for NDA & GDA (ICH CTD) (Feb 2012)
2B.    Application Checklist for MAV (ICH CTD)
3A.    Application Checklist for NDA & GDA (ACTD) (Feb 2012)
3B.    Application Checklist for MAV (ACTD)
4.      Flowchart on Translation of Non-English Documents
5.      Guideline on Submission for Non-Prescription Medicinal Products
6.      Points to Consider for Singapore Labelling
7.      Patent Declaration Form
8.      Singapore Quality Overall Summary for Chemical Drugs
9.      Singapore Quality Overall Summary for Biologics
10.    Guideline on the Registration of Human Plasma-derived Medicinal Products
11.    Guideline on the Registration of Human Medicinal Products Containing Materials of Animal Origin
12.    Product Interchangeability and Biowaiver Request for Chemical Generic Drug Applications
12A. Quick Reference for Acceptability of Bioequivalence Study
13.    Guideline on Submission under CECA Scheme
14.    MIV Filing and Submission Inquiry Form
15.    Guideline on MIV Applications for Chemical Drugs
16.    Guideline on MIV Applications for Biologics
17.    Guidance on Registration of Similar Biological Products in Singapore

Template Downloads (MS Word format)

Appendices

 

2A.     Application Checklist for NDA & GDA (ICH CTD) (Feb 2012)2B.     Application Checklist for MAV (ICH CTD)
3A.     Application Checklist for NDA & GDA (ACTD) (Feb 2012)3B.     Application Checklist for MAV (ACTD)
7.       Patent Declaration Form
8.       Singapore Quality Overall Summary for Chemical Drugs
9.       Singapore Quality Overall Summary for Biologics
10.     Checklist for Registration of Human Plasma-derived Medicinal Products
11.     Checklist for Registration of Human Medicinal Products Containing Materials of Animal Origin
12A.  Quick Reference for Acceptability of Bioequivalence Study
14.     MIV Filing and Submission Inquiry Form
15.     Part B Checklist for MIV-1 Applicaitons for Chemical Drugs 
           Part C Checklist for MIV-2 Applications for Chemical Drugs
16.     Part B Checklist for MIV-1 Applications for Biologics
           Part C Checklist for MIV-2 Applications for Biologics
           Part D Checklist for Plasma MAster File Variations for Biologics

Guidance on Registration of Similar Biological Products in Singapore

• Guidance on Registration of Similar Biological Products in Singapore

Other Application / Submission Guidelines

• Guideline for Renewal of Product Licence
• Guideline for Application to Transfer Product Licence
• Guideline on Submission of Notification to Import Medicinal Products for Re-Export
• Guideline on Submission of Application for a Licence to Import a Medicinal Product on Consignment Basis
• Guideline to Apply for Approval to Import an Unregistered Medicinal Product for Use on Named-Patient Basis

ASEAN Registration of Pharmaceuticals for Human Use

ASEAN Common Technical Dossier (ACTD)

• Organisation of the Dossier
• Glossary used for the ACTD and ACTR
• Part II: Quality
• Part III: Nonclinical Document
• Part IV: Clinical Document
• ACTD Clinical Check List for Product Classification

ASEAN Common Technical Requirements (ACTR)

• ASEAN Variation Guidelines (draft) [NEW]
• ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration (includes all annexes)
• ASEAN Guideline on Submission of Manufacturing Process Validation Data for Drug Registration (Main Guide; without all annexes)
  • Annex A1 Guidance on Process Validation Scheme for Solid Oral Dosage Products
  • Annex A2 Guidance on Process Validation Scheme for Aseptically Processed Products
  • Annex A3 Guidance on Process Validation Scheme for Terminally Sterilised Products
  • Annex B Table of Content of Process Validation Documentation
  • Annex C Guidance for Quality By Design as an Alternative Approach to Process Validation (DRAFT)
  • Annex D Glossary
• ASEAN Guideline for the Conduct of Bioavailability and Bioequivalence Studies
• ASEAN Guideline on Stability Study of Drug Product 
• ASEAN Guideline for Validation of Analytical Procedures
• ASEAN Guideline on Process Validation Q&A
• ASEAN Guideline on Analytical Validation Q&A

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