Banu BAYAR, Ali ALKAN, Hakkı GÜRSÖZ, Emine Nur ÖZDAMAR, Ahmet AKICI

A nationwide evaluation of off-label drug utilization in Turkey

Background/aim: Off-label drug use (OLDU) is under the control of the Turkish Medicines and Medical Devices Agency (TMMDA) in Turkey. It was aimed to investigate demographic and medical features of patients with OLDU applications in Turkey. Materials and methods: A total of 4426 electronic OLDU application records of the TMMDA were evaluated retrospectively. Information regarding patients demographic characteristics, diagnoses, requested drugs, institutions, and specialties of the physicians were evaluated. Results: OLDU applications were mostly made by rheumatologists (21.5%) and 95.2% of them were approved by the TMMDA. The mean age of the patients was 35 years and 54.4% of them were female. Off-label drugs were mostly prescribed for patients aged 18 64 years (62.1%) and were most frequently prescribed by physicians from university medical centers (81.0%). Systemic lupus erythematosus (10.1%) was the most common diagnosis. Mycophenolate (16.1%) and rituximab (10.1%) were the most frequently prescribed off-label drugs. There were differences regarding some characteristics of patients and their physicians among most frequently prescribed off-label drugs (P < 0.05). Conclusion: It is noteworthy that OLDU applications showed demographical and institutional differences. It is expected that this study will provide important contributions to physicians working in the relevant area with respect to treatment alternatives of diseases with treatment challenges.

PDF

___

1. Epstein RS, Huang SM. The many sides of off-label prescribing. Clin Pharmacol Ther 2012; 91: 755-758.
2. Wittich CM, Burkle CM, Lanier WL. Ten common questions (and their answers) about off-label drug use. Mayo Clin Proc 2012; 87: 982-990.
3. Lat I, Micek S, Janzen J, Cohen H, Olsen K, Haas C. Off-label medication use in adult critical care patients. J Crit Care 2011; 26: 89-94.
4. Herring C, McManus A, Weeks A. Off-label prescribing during pregnancy in the UK: an analysis of 18,000 prescriptions in Liverpool Womens Hospital. Int J Pharm Pract 2010; 18: 226- 229.
5. Roila F, Ballatori E, Labianca R, De Braud F, Borgonovo K, Martelli O, Gallo C, Tinazzi A, Perrone F; Italian Medical Oncology Association (AIOM). Off-label prescription of antineoplastic drugs: an Italian prospective, observational, multicenter survey. Tumori 2009; 95: 647-651.
6. Poole SG, Dooley MJ. Off-label prescribing in oncology. Support Care Cancer 2004; 12: 302-305.
7. Santos DB, Clavenna A, Bonati M, Coelho HL. Off-label and unlicensed drug utilization in hospitalized children in Fortaleza, Brazil. Eur J Clin Pharmacol 2008; 64: 1111-1118.
8. Morales-Carpi C, Estan L, Rubio E, Lurbe E, Morales-Olivas FJ. Drug utilization and off-label drug use among Spanish emergency room paediatric patients. Eur J Clin Pharmacol 2010; 66: 315-320.
9. Khdour MR, Hallak HO, Alayasa KSA, AlShahed QN, Hawwa AF, McElnay JC. Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine. Int J Clin Pharm 2011; 33: 650-655.
10. Mühlbauer B, Janhsen K, Pichler J, Schoettler P. Off-label use of prescription drugs in childhood and adolescence an analysis of prescription patterns in Germany. Dtsch Arztebl Int 2009; 106: 25-31.
11. Bavdekar SB, Sadawarte PA, Gogtay NJ, Jain SS, Jadhav S. Offlabel drug use in a pediatric intensive care unit. Indian J Pediatr 2009; 76: 1113-1118.
12. Lindell-Osuagwu L, Korhonen MJ, Saano S, Helin-Tanninen M, Naaranlahti T, Kokki H. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther 2009; 34: 277- 287.
13. Olsson J, Kimland E, Pettersson S, Odlind V. Paediatric drug use with focus on off-label prescriptions in Swedish outpatient carea nationwide study. Acta Pædiatr 2011; 100: 1272-1275.
14. Lass J, Kaar R, Jogi K, Varendi H, Metsvaht T, Lutsar I. Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol 2011; 67: 1263-1271.
15. Oguz SS, Kanmaz HG, Dilmen U. Off-label and unlicensed drug use in neonatal intensive care units in Turkey: the old-inn study. Int J Clin Pharm 2012; 34: 136-141.
16. Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol 2002; 54: 665-670.
17. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006; 166: 1021-1026.
18. Stafford RS. Regulating off-label drug use-rethinking the role of the FDA. New Engl J Med 2008; 358: 1427-1429.
19. Kockaya G, Polat M, Vural IM, Akbulat A, Dedeoglu BD, Akar H, Kerman S. Off-label and unlicensed oncology medicine use in Turkey: a retrospective analysis of computer records of the Turkish Ministry of Health. J Pharm Health Serv Res 2011; 2: 53-57.
20. Koçkaya G, Tanyeri P, Vural İM, Akbulat A, Akar H, Artiran G, Tokaç M, Kerman S. Off-label and unlicensed endocrinology medicine use in Turkey: a retrospective analysis of computer records in the Turkish Ministry of Health. Yeditepe Medical Journal 2012; 6: 491-498.
21. Chiche L, Jourde N, Ulmann C, Mancini J, Darque A, Bardin N, Dicostanzo MP, Thomas G, Harle JR, Vienne J et al. Seasonal variations of systemic lupus erythematosus flares in southern France. Eur J Intern Med 2012; 23: 250-254.
22. Iuliano G. Multiple sclerosis: long time modifications of seasonal differences in the frequency of clinical attacks. Neurol Sci 2012; 33: 999-1003.
23. Hames A, Wynne HA. Unlicensed and off-label drug use in elderly people. Age Ageing 2001; 30: 530-531.
24. Kamble P, Sherer J, Chen H, Aparasu R. Off-label use of second generation antipsychotic agents among elderly nursing home residents. Psychiatr Serv 2010; 61: 130-136.
25. Zhan C, Sangl J, Bierman AS, Miller MR, Friedman B, Wickizer SW, Meyer GS. Potentially inappropriate medication use in the community-dwelling elderly: findings from the 1996 Medical Expenditure Panel Survey. J Am Med Assoc 2001; 286: 2823- 2829.
26. Chen YF, Dewey ME, Avery AJ. Self-reported medication use for older people in England and Wales. J Clin Pharm Ther 2001; 26: 129-140.
27. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006; 15: 308-318.
28. Koutsouraki E, Costa V, Baloyannis S. Epidemiology of multiple sclerosis in Europe: a review. Int Rev Psychiatry 2010; 22: 2-13.
29. Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. Clev Clin J Med 2003; 70: S2-S8.
30. Bertsias GK, Salmon JE, Boumpas DT. Therapeutic opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade. Ann Rheum Dis 2010; 69: 1603-1611.
31. Looney RJ, Anolik J, Sanz I. B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells. Lupus 2004; 13: 381-390.
32. Gottenberg J, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, Larroche C, Soubrier M, Bouillet L, Dougados M et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 2005; 64: 913-920.
33. Carr DR, Heffernan MP. Off-label uses of rituximab in dermatology. Dermatol Ther 2007; 20: 277-287.
34. Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 2006; 6: 859-866.
35. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2673-2677.
36. Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus A systematic review of off-label use in 188 cases. Lupus 2009; 18: 767-776.
37. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus the randomized, doubleblind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010; 62: 222-233.
38. Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis the lupus nephritis assessment with rituximab study. Arthritis Rheum 2012; 64: 1215-1226.
39. Butterly SJ, Pillans P, Horn B, Miles R, Sturtevant J. Off-label use of rituximab in a tertiary Queensland hospital. Intern Med J 2010; 40: 443-452.
40. Alba P, Karim BY, Hunt BJ. Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 2003; 12: 633-635.
41. Sahin A. Mycophenolatemofetil in the treatment of systemic lupus erythematosus. Eurasian J Med 2009; 41: 180-185.
42. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Noordegraaf AV, Beghetti M et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2015; 46: 903-975
43. Beghetti M. Paediatric pulmonary hypertension: monitoring progress and identifying unmet needs. Eur Respir Rev 2009; 18: 18-23.
44. Schafer JA, Gunderson BW, Gleason PP. Price increases and new drugs drive increased expenditures for multiple sclerosis. J Manag Care Pharm 2010; 16: 713-717.