Evaluation of pharmaceutical concerns in Germany: frequency and potential reasons

Keywords: Drugs, Generic, Drug Substitution, Medication Adherence, Medication Errors, Patient Safety, Germany


Background: Generic substitution can have unintended consequences. In Germany, brand name to generic or generic to generic switching is mainly driven by rebate contracts. Frequent switching may raise concerns about bio- and therapeutic equivalence. Expected patient confusion may result in compromised medication adherence or new onset of other drug-related problems. Since 2008, pharmacists are allowed to deviate from rebate contracts by denying substitution due to pharmaceutical concerns on an individual basis.

Objectives: To explore the frequency of documented pharmaceutical concerns in Germany between July 2011 and December 2013 and to identify the medicines most frequently related to pharmaceutical concerns in 2013.

Methods: We analyzed documented pharmaceutical concerns in all prescribed drugs at the expense of any statutory health insurance company requiring pharmacies’ generic substitution according to rebate contracts.

Results: Since July 2011, the frequency of documented pharmaceutical concerns in relation to prescribed drug products with rebate contracts requiring substitution increased consistently and doubled between July 2011 and July 2013. Overall in 2013, the trend of the two previous years continued and reached approximately 1.5%. The most affected drugs/drug classes were thyroid hormones (in particular combinations with iodide; 15.9%) followed by ondansetron (12.5%), and levothyroxine (11.3%). For all drugs/drug classes under investigation, product-, patient- or disease-related aspects could be identified which are potential reasons to deny substitution and to document pharmaceutical concerns.

Conclusions: Although there is no electronic recording of the specific reasons for pharmaceutical concerns in claims data, our analyses support the assumption that pharmacists make use of this instrument based on individual clinical decisions and as required by contract. Pharmaceutical concerns are, therefore, an important instrument for pharmacies to refuse generic substitution. They are considered to prevent compromised medication safety and to assure pharmacotherapy effectiveness in a generic substitution environment driven by low drug prizes above all.


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1. Saverno K, Gothe H, Schuessel K, Biskupiak J, Schulz M, Siebert U, Brixner D. Consideration of international generic distribution policies on patient outcomes in the United States and Germany. Pharmazie. 2014;69(3):238-240. doi: 10.1691/ph.2014.3786

2. Schwabe U, Paffrath D (eds.). Arzneiverordnungs-Report 2015. Springer: Heidelberg, Germany.

3. Fischer KE, Stargardt T. The diffusion of generics after patent expiry in Germany. Eur J Health Econ. 2015 Nov 16. [ahead of print] doi:10.1007/s10198-015-0744-3

4. Simoens S. The Portuguese generic medicines market: a policy analysis. Pharm Pract (Granada). 2009;7(2):74-80.

5. Dylst P, Vulto A, Simoens S. How can pharmacist remuneration systems in Europe contribute to generic medicine dispensing? Pharm Pract (Granada). 2012;10(1):3-8.

6. Bate R, Mathur A, Lever HM, Thakur D, Graedon J, Cooperman T, Mason P, Fox ER. Generics Substitution, Bioequivalence Standards, and International Oversight: Complex Issues Facing the FDA. Trends Pharmacol Sci. 2016;37(3):184-191. doi: 10.1016/j.tips.2015.11.005

7. Toklu HZ, Dülger GA, Hıdıroğlu S, Akici A, Yetim A, Gannemoğlu HM, Güneş H. Knowledge and attitudes of the pharmacists, prescribers and patients towards generic drug use in Istanbul - Turkey. Pharm Pract (Granada). 2012;10(4):199-206.

8. Hoffmann, F, Glaeske, G, Pfannkuche, MS. Einfluss von Rabattverträgen auf die Aut-idem-Nutzung [The effect of introducing rebate contracts to promote generic drug substitution, on doctors’ prescribing practices]. Dtsch Arztebl Int. 2009;106(48):783-788. doi: 10.3238/arztebl.2009.0783

9. Hoffmann, F, Windt, R, Glaeske, G. Umsetzung der Aut-idem-Regelung vor und nach Einführung der Rabattverträge [Implementation of "aut idem" before and after introduction of rebate contracts]. Dtsch Med Wochenschr. 2010;135(15):739-744. doi: 10.1055/s-0030-1251926

10. Goebel R, Griese N, Schulz M. Pharmazeutische Bedenken. Tipps für die Praxis. [Pharmaceutical Concerns – tips for practice]. Pharm Ztg. 2008;153(38):3612-3614.

11. Griese N, Goebel R, Schulz M. Rabattverträge. Pharmazeutische Bedenken bei Phenprocoumon? [Rebate contracts. Pharmaceutical concerns affecting phenprocoumon?]. Pharm Ztg. 2010;155(15):1410-1411.

12. Czeche-Wimmer, S, Damer, S. Substitution von Fertigarzneimitteln [Generic substitution]. Govi-Verlag Pharmazeutischer Verlag GmbH, Eschborn 2014.

13. Ghate SR, Biskupiak JE, Ye X, Hagan M, Kwong WJ, Fox ES, Brixner D. Hemorrhagic and thrombotic events associated with generic substitution of warfarin in patients with atrial fibrillation: a retrospective analysis. Ann Pharmacother. 2011;45(6):701-712. doi: 10.1345/aph.1P593

14. Haines ST. Substituting warfarin products: what's the source of the problem? Ann Pharmacother. 2011;45(6):807-809. doi: 10.1345/aph.1Q063

15. A.T.I. Arzneimittelinformation Berlin. Therapieempfehlung zum Austausch von Levothyroxin-Präparaten [Recommendations when substituting levothyroxine]. Arznei-Telegramm 2013;44(6):51-52.

16. Gemeinsamer Bundesausschuss: Tragende Gründe zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie (AM-RL): Abschnitt M und Anlage VII – Hinweise zur Austauschbarkeit von Darreichungsformen (aut idem) gemäß §129 Absatz 1a SGB V: Bestimmung von Arzneimitteln, deren Ersetzung durch ein wirkstoffgleiches Arzneimittel ausgeschlossen ist (1. Tranche) vom 18. September 2014: https://www.g-ba.de/downloads/40-268-2952/2014-09-18_AM-RL-VII_AbschnittM_Substitutionsausschluss_TrG.pdf (accessed 18 April 2016).

17. Hämmerlein A, Müller U, Schulz M. Pharmacist-led intervention study to improve inhalation technique in asthma and COPD patients. J Eval Clin Pract. 2011;17(1):61-70. doi: 10.1111/j.1365-2753.2010.01369.x

18. Basheti IA, Hamadi SA, Reddel HK. Inter-professional education unveiling significant association between asthma knowledge and inhaler technique. Pharm Pract (Granada). 2016;14(1):713. doi: 10.18549/PharmPract.2016.01.713

19. Ärztliches Zentrum für Qualität in der Medizin (ÄZQ), Nationale VersorgungsLeitlinie (NVL) Asthma, 2nd ed: http://www.asthma.versorgungsleitlinien.de/ (accessed 17 April 2016).

20. Atif M, Azeem M, Sarwar MR. Potential problems and recommendations regarding substitution of generic antiepileptic drugs: a systematic review of literature. SpringerPlus. 2016;5:182. doi: 10.1186/s40064-016-1824-2

21. Sabaté E. Adherence to long-term therapies: evidence for action. World Health Organization, Geneva 2003.

22. Fikenzer K, Knoll A, Fischer D, Schulz M, Böhm M, Laufs U. Chronische Herzinsuffizienz: Teufelskreis aus geringer Einnahmetreue von Medikamenten und kardialer Dekompensation [Poor medication adherence and worsening heart failure - a vicious circle]. Dtsch Med Wochenschr. 2014;139(47):2390-2394. doi: 10.1055/s-0034-1387391

23. Hakonsen H, Eilertsen M, Borge H, Toverud EL. Generic substitution: additional challenge for adherence in hypertensive patients? Curr Med Res Opin. 2009;25(10):2515-2521. doi: 10.1185/03007990903192223

24. Shrank WH, Hoang T, Ettner SL, Glassman PA, Nair K, DeLapp D, Dirstine J, Avorn J, Asch SM. The implications of choice: prescribing generic or preferred pharmaceuticals improves medication adherence for chronic conditions. Arch Intern Med. 2006;166(3):332-337.

25. Shrank WH, Liberman JN, Fischer MA, Avorn J, Kilabuk E, Chang A, Kesselheim AS, Brennan TA, Choudry NK. The consequences of requesting “dispense as written”. Am J Med. 2011;124(4):309-317. doi: 10.1016/j.amjmed.2010.11.020

26. Ude M, Schuessel K, Quinzler R, Leuner K, Müller WE, Schulz M. Generic switch after ramipril patent expiry is not associated with decreased pharmacy refill compliance: a retrospective study using the DAPI database. J Hypertens. 2011;29(9):1837-1845. doi: 10.1097/HJH.0b013e32834942be

27. Mano Y, Fukushima S, Kuroda H, Ohshima H, Kato Y, Ohuchi K, Maezawa K, Momose Y, Ikeda S, Asahi M. Adherence to changing from brand-name to generic atorvastatin in newly treated patients: a retrospective cohort study using health insurance claims. J Pharm Health Care Sci. 2015;1:12. doi: 10.1186/s40780-015-0013-8

28. Laufs U, Böhm M, Kroemer HK, Schüssel K, Griese N, Schulz M. Strategien zur Verbesserung der Einnahmetreue von Medikamenten [Strategies to improve medication adherence]. Dtsch Med Wochenschr. 2011;136(31-32):1616-1621. doi: 10.1055/s-0031-1281566

29. Krueger K, Botermann L, Schorr SG, Griese-Mammen N, Laufs U, Schulz M. Age-related medication adherence in patients with chronic heart failure: A systematic literature review. Int J Cardiol. 2015;184:728-735. doi: 10.1016/j.ijcard.2015.03.042

30. Schulz M, Krueger K, Schuessel K, Friedland K, Laufs U, Müller WE, Ude M. Medication adherence and persistence according to different antihypertensive drug classes: a retrospective cohort study of 255,500 patients. Int J Cardiol. 2016;220:668-676. doi: 10.1016/j.ijcard.2016.06.263
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