The impact of chiral switch on drug labeling in Turkey: indication, posology, and adverse effects

Abstract

Objective: Chiral switch, which involves replacing racemic drugs to market them as pure enantiomers, is presumed to improve efficacy and safety. Data on how chiral switch-related changes are represented in summary of product characteristics (SmPC) is scarce. We aimed to compare the indication, posology, and safety expressions in SmPCs of racemates and their pure enantiomers. Materials and Methods: We examined SmPCs of nine drug pairs (racemate/pure enantiomer) that underwent chiral switching among top 100 utilized active substances throughout Turkey. We evaluated the expressions in “indications”, “posology”, and “adverse effects” (AE) subheadings. Daily doses were examined based on “Defined Daily Dose” (DDD) metric. Results: We detected indication differences in four drug pairs, including absence of “peptic ulcer” in dexlansoprazole and “prevention of depression relapses” in escitalopram. DDDs of pure enantiomers decreased in most of the pairs. Recommended daily doses of esomeprazole and dexibuprofen per DDD were lower than their racemates. Cautions about use in renal and/or hepatic insufficiency varied in three pairs. AE expressions differed in seven drug pairs, mainly citalopram/escitalopram. Conclusion: This study demonstrated few indication differences in SmPCs of the drug pairs frequently used in Turkey and underwent chiral switching. However, dose reductions and distinctions in safety expressions were remarkable.

Keywords

• Chirality
• Chiral switch
• Pure enantiomer
• Racemate
• Summary of product characteristics
• Health policy

References

1. Hancu G, Modroiu A. Chiral switch: between therapeutical benefit and marketing strategy. Pharmaceuticals (Basel) 2022;15:240. doi: 10.3390/ph15020240.
2. Tucker GT. Chiral switches. Lancet 2000;355:1085-7. doi: 10.1016/S0140-6736(00)02047-X.
3. McConathy J, Owens MJ. Stereochemistry in drug action. Prim Care Companion J Clin Psychiatry 2003;5:70-3. doi: 10.4088/pcc.v05n0202.
4. Bahar A, Kırmızı Sönmez Nİ, Vızdıklar C, Aydın V, Akıcı A. The concept of chirality and its association with drug safety: traditional review. J Lit Pharm Sci 2022;11:77-85. doi: 10.5336. pharmsci.2022-88233.
5. Caner H, Groner E, Levy L, Agranat I. Trends in the development of chiral drugs. Drug Discov Today 2004;9:105- 10. doi: 10.1016/s1359-6446(03)02904-0.
6. Lin GQ, Zhang JG, Cheng JF. Overview of chirality and chiral drugs. In: Lin GQ, Zhang JG, Cheng JF. (Eds). Chiral drugs: chemistry and biological action. Hoboken, NY: John Wiley & Sons, Inc., 2011:3-28. doi: 10.1002/978.111.8075647.ch1.
7. Aydin V, Bahar A, Vizdiklar C, Akici A. The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis. Br J Clin Pharmacol. 2023;89:290-8. doi: 10.1111/bcp.15486.
8. Abram M, Jakubiec M, Kaminski K. Chirality as an important factor forthe development of new antiepileptic drugs.Chem Med Chem 2019;20:1744-61. doi: 10.1002/cmdc.201900367.

9. [9] FDA’s policy statement for the development of new stereoisomeric drugs. Chirality 1992;4:338-40. doi: 10.1002/ chir.530040513.
10. Smith SW. Chiral toxicology: it’s the same thing...only different. Toxicol Sci 2009;110:4-30. doi: 10.1093/toxsci/kfp097.
11. Gellad WF, Choi P, Mizah M, Good CB, Kesselheim AS. Assessing the chiral switch: approval and use of singleenantiomer drugs, 2001 to 2011. Am J Manag Care 2014;20: e90-e97.
12. Long AS, Zhang AD, Meyer CE, Egilman AC, Ross JS, Wallach JD. Evaluation of trials comparing singleenantiomer drugs to their racemic precursors: a systematic review. JAMA Netw Open 2021;4: e215731. doi: 10.1001/ jamanetworkopen.2021.5731.
13. Republic of Turkey Official Gazette. Regulation on the registration of medicinal products for human use. 19.01.2015, no: 25705, Ankara.
14. IQVIA Turkey web site. https://www.iqvia.com/tr-tr/ locations/turkey (accessed on 29 April 2022).
15. Turkish Medicines and Medical Devices Agency. SmPC/ PIL list. https://www.titck.gov.tr/kubkt (accessed on 18 April2022).
16. WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2022. Oslo, Norway, 2021.
17. Arguello B, Salgado TM, Fernandez-Llimos F. Assessing the information in the summaries of product characteristics for the use of medicines in pregnancy and lactation. Br J Clin Pharmacol. 2015;79(3):537-544. doi: 10.1111/bcp.12515.
18. Bayram D, Aydın V, Akıcı A. investigation of warnings regarding driving and machine use in summary of product characteristics and patient information leaflets of drugs frequently used in psychiatry. GMJ 2020; 31:38-43. doi: 10.12996/gmj.2020.10.
19. United Nations, Department of Economic and Social Affairs, Sustainable Development. https://sdgs.un.org/goals#icons (accessed on 19 December 2022).
20. UN General Assembly (2015) Resolution Adopted by the General Assembly on 25 September 2015. Transforming our world: the 2030 agenda for sustainable development. https:// www.un.org/en/development/desa/population/migration/ generalassembly/docs/globalcompact/A_RES_70_1_E.pdf (accessed on 19 December 2022)
21. Hershcovici T, Jha LK, Fass R. Dexlansoprazole MR: a review. Ann Med 2011;43:366-74. doi: 10.3109/07853.890.2011.554429.
22. Zhou Q, Yan XF, Pan WS, Zeng S. Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors? World J Gastroenterol 2008;14:2617-9. doi: 10.3748/wjg.14.2617.
23. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol 2008;64:935-51. doi: 10.1007/s00228.008.0538-y.
24. Asghar W, Pittman E, Jamali F. Comparative efficacy of esomeprazole and omeprazole: Racemate to single enantiomer switch. DARU J Pharm Sci 2015; 23:50. doi: 10.1186/ s40199.015.0133-6.
25. Savarino V, Di Mario F, Scarpignato C. Proton pump inhibitors in GORD: An overview of their pharmacology, efficacy and safety. Pharmacol Res 2009;59:135-53. doi: 10.1016/j. phrs.2008.09.016.
26. Wu DC, Kuo CH, Tsay FW, Hsu WH, Chen A, Hsu PI. A pilot randomized controlled study of dexlansoprazole MR-based triple therapy for helicobacter pylori infection. Medicine (Baltimore) 2016;95:e2698. doi: 10.1097/ MD.000.000.0000002698.
27. Kuo CJ, Chen CW, Le PH, et al. Efficacy of dexlansoprazolebased triple therapy for Helicobacter pylori infections. Therap Adv Gastroenterol 2019; 12:175.628.4819870960. doi: 10.1177/175.628.4819870960.
28. Peura DA, Metz DC, Dabholkar AH, Paris MM, Yu P, Atkinson SN. Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience. Aliment Pharmacol Ther 2009;30:1010-21. doi: 10.1111/j.1365- 2036.2009.04137.x.
29. Calcaterra A, D’Acquarica I. The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds. J Pharm Biomed Anal 2018; 147:323-40. doi: 10.1016/j. jpba.2017.07.008.
30. Barbanoj MJ, Antonijoan RM, Gich I. Clinical pharmacokinetics of dexketoprofen. Clin Pharmacokinet 2001;40:245-62. doi: 10.2165/00003.088.200140040-00002.
31. Metz DC, Vakily M, Dixit T, Mulford D. Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy. Aliment Pharmacol Ther 2009;29:928-37. doi: 10.1111/j.1365- 2036.2009.03984.x.
32. Hao H, Wang G, Sun J. Enantioselective pharmacokinetics of ibuprofen and involved mechanisms. Drug Metab Rev 2005;37:215-34. doi: 10.1081/dmr-200047999.
33. Phleps W. Overview on clinical data of dexibuprofen. Clin Rheumatol 2001;20 Suppl 1: S15-S21. doi: 10.1007/ BF03342663.
34. Zamani O, Böttcher E, Rieger JD, et al. Comparison of safety, efficacy and tolerability of dexibuprofen and ibuprofen in the treatment of osteoarthritis of the hip or knee. Wien Klin Wochenschr 2014;126:368-75. doi: 10.1007/s00508.014.0544-2.
35. Yoon JS, Jeong DC, Oh JW, et al. The effects and safety of dexibuprofen compared with ibuprofen in febrile children caused by upper respiratory tract infection. Br J Clin Pharmacol 2008;66:854 60. doi: 10.1111/j.1365- 2125.2008.03271.x.
36. Gaskell H, Derry S, Wiffen PJ, Moore RA. Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults. Cochrane Database Syst Rev 2017;5:CD007355. doi: 10.1002/14651858.CD007355.pub3.
37. Culpepper L. Escitalopram: A new SSRI for the treatment of depression in primary care. Prim Care Companion J Clin Psychiatry 2002;4:209-214. doi: 10.4088/pcc.v04n0601.
38. Leonard B, Taylor D. Escitalopram—translating molecular properties into clinical benefit: reviewing the evidence in major depression. J Psychopharmacol 2010;24:1143-52. doi: 10.1177/026.988.1109349835.
39. Lenze EJ, Mulsant BH, Shear MK, et al. Efficacy and tolerability of citalopram in the treatment of late-life anxiety disorders: results from an 8-week randomized, placebo-controlled trial. Am J Psychiatry 2005;162:146-50. doi: 10.1176/appi. ajp.162.1.146.
40. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M; Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles anxieux and McGill University, Antony MM, Bouchard S, Brunet A, Flament M, Grigoriadis S, Mendlowitz S, O’Connor K, Rabheru K, Richter PM, Robichaud M, Walker JR. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry 2014;14 Suppl 1(Suppl 1): S1. doi: 10.1186/1471-244X-14-S1-S1.
41. Mansfield P, Henry D, Tonkin A. Single-enantiomer drugs: elegant science, disappointing effects. Clin Pharmacokinet 2004;43:287-90. doi: 10.2165/00003.088.200443050-00002.
42. Tillement JP, Testa B, Brée F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists. Biochem Pharmacol 2003;66:1123-26. doi: 10.1016/s0006- 2952(03)00558-6.
43. Pollock M, Sinha IP, Hartling L, Rowe BH, Schreiber S, Fernandes RM. Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews. Allergy 2017;72:183-200. doi: 10.1111/all.13039.
44. Liu F, Qiu M, Zhai SD. Tolerability and effectiveness of (S)-amlodipine compared with racemic amlodipine in hypertension: a systematic review and meta-analysis. Curr Ther Res Clin Exp 2010;71:1-29. doi: 10.1016/j. curtheres.2010.02.005.
45. Galappatthy P, Waniganayake YC, Sabeer MI, Wijethunga TJ, Galappatthy GK, Ekanayaka RA. Leg edema with (S)-amlodipine vs conventional amlodipine given in triple therapy for hypertension: a randomized double blind controlled clinical trial. BMC Cardiovasc Disord 2016;16:168. doi: 10.1186/s12872.016.0350-z.
46. Dalal J, Mohan JC, Iyengar SS, et al. S-Amlodipine: an isomer with difference-time to shift from racemic amlodipine. Int J Hypertens 2018; 2018:8681792. doi: 10.1155/2018/8681792.