Odnos originala i generike i međusobna zamenljivost generičkih lekova/the relation between original and generic medicines and.

Transcription

1 Odnos originala i generike i međusobna zamenljivost generičkih lekova/the relation between original and generic medicines and mutual interchangeability of generic medicines Prof. Dr. Slobodan M. Janković, Fakultet medicinskihnaukauniverzitetau Kragujevcu, KliničkicentarKragujevac/Faculty of Medical Sciences, University of Kragujevac, Clinical Centre Kragujevac

2 Definition of generic drugs products which have the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. Guideline on the Investigation of Bioequivalence, Committee for Medicinal Products for Human Use, European Medicines Agency, 2010/01/WC , available at: ntific_guideline/2010/01/wc pdf, accessed for the last time on September the 16th,2014.

3 Conditions for marketing authorization of generic drugs Bioequivalence study on healthy adult males showing that 90% -confidence intervals of ratios between area under the plasma concentration/time curve (AUC), maximal plasma concentration and time to maximal plasma concentration of generic and original drug after their administration by the same route are somewhere between 80 and 125%. More stringent conditions for drugs with narrow therapeutic index or narrow therapeutic window whose 90% -confidence intervals of AUC ratios with original drugs should fall within much narrower limits between 90 and %

4 Key parameters Концентрација лека (мг/л) Drug concentration (mg/l) Cmax Cmax/2 Ke= 0.693/Т 1/2 Површина испод криве (ПИК) Area under the curve (AUC) Време (часови) Time (hours) Tmax

5 Problems with bioequivalence concept bioequivalence studies are performed in standardized conditions, in healthy volunteers and while they are fasting. brand-name and generic drugs could be bioequivalent under fasting conditions, but not after a meal (e.g. case of nifedipinebefore and after a high-fat meal); bioavailability of a drug might not be the same in healthy young males and elderly patients with much co-morbidity Wonnemann M, Schug B, Schmücker K, Brendel E, van Zwieten PA, BlumeH. Significant food interactions observed with a nifedipinemodified-release formulation marketed in the European Union. Int J Clin Pharmacol Ther 2006; 44(1):

6 Definition of a narrow therapeutic index drug the ratio between its the least toxic and the least effective concentration is less than twofold» Le CorreP. Bioequivalence and generics of index drugs» with narrow therapeutic margins. Presse Med 2010;39(2):

7 List of narrow therapeutic index drugs not yet official Anticonvulsants Antiarrythmics(quinidine, procainamide, disopyramide, and amiodarone) Oral anticoagulants (warfarin in the first place) Lithium Cardiotonic glycosides Theophylline Cyclosporine

8 Comparison of efficacy and safety of original and generic drugs Even in the case of narrow therapeutic index drugs efficacy and safety are not significantly different KesselheimAS, Stedman MR, BubrickEJ, et al. Seizure outcomes following the use of generic versusbrand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 2010;70(5): TalatiR, ScholleJM, PhungOP, et al. Efficacy and safety of innovator versus generic drugs inpatients with epilepsy: a systematic review. Pharmacotherapy 2012;32(4):

9 Problem of switching Switching from original to generic drug or from one to another generic during an ongoing therapy is frequently accompanied with loss of a disease control

10 Examples of unfavorable consequences of switching A study on 975 switched from original to generic warfarin showed decrease of INR for 4.2% and increase in warfarin dose for 26.5%. HalkinH, Shapiro J, KurnikD, Loebstein R, ShalevV, KokiaE. Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther 2003; 74: A study on 32patients showed that switching from original to generic amiodaronewas followed by recurrence of arrhythmias. Three patients died. ReiffelJA, Kowey PR. Generic antiarrhythmicsare not therapeutically equivalent for the treatment of tachyarrhythmias. Am J Cardiol 2000; 85:

11 Examples of unfavorable consequences of switching the patients who change an anti-convulsant use higher doses and either more frequently visit their doctors or are more often hospitalized KesselheimAS, Stedman MR, BubrickEJ, et al. Seizure outcomes following the use of generic versusbrand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs 2010;70(5): TalatiR, ScholleJM, PhungOP, et al. Efficacy and safety of innovator versus generic drugs inpatients with epilepsy: a systematic review. Pharmacotherapy 2012;32(4):

12 Examples of unfavorable consequences of switching The case/control study on 9110 patients who switched from original to a generic anticonvulsanthas shown that the switching was associated with increased risk of a seizure-related event (adjusted odds ratio 1.27)» Hansen RN, Nguyen HP, Sullivan SD. Bioequivalent antiepileptic drug switching and the risk of seizure-related events. Epilepsy Res 2013;106(1-2): There is higher risk of an epilepsy-related event among patients who switched from original to generic anti-convulsantin comparison to those who did not (odds ratio 1.57).» Hansen RN, Campbell JD, Sullivan SD. Association between antiepileptic drugswitching and epilepsy-related events. Epilepsy Behav 2009;15(4):481-5.

13 Need to change bioequivalence studies bioequivalent anti-convulsantsshow significant differences in pharmacokinetic parameters which are not routinely used for bioequivalence testing Yamada M, Welty TE. Generic substitution of antiepileptic drugs: a systematic review of prospective and retrospective studies. Ann Pharmacother 2011;45(11):

14 Scaled-average bioequivalence testing Even with different lots of the same brand-name anticonvulsantsome individuals show high variability of plasma concentrations; At first intra-individual variability of study subjects in regard to bioavailability of the reference drug should be established, and then it should be shown that intraindividual variability with the generic product will not go out of these limits. With this approach the bioequivalence studies are carried out in three periods on the same subjects (the reference product is administered twice, and the test product once), and the bioequivalence criteria are then scaled to observed variability of the reference product.» 1Bialer M, MidhaKK. Generic products of antiepileptic drugs: a perspective onbioequivalence and interchangeability. Epilepsia 2010;51(6):

15 Proposal for new design of bioequivalence studies Multiple point measurements during the steady-state and estimates of time spent in the therapeutic range are necessary, since only with such data we could make reliable reconstruction of plasma concentration course during the dose interval and estimate true degree of the effect.» JankovicSM, IgnjatovicRistic D. Is bioavailability altered in generic versus brand anticonvulsants? Expert OpinDrug Metab Toxicol 2015; 11(3):

16 Recommendation for the time being If a physician and his/her patient decide to use a generic drug as more affordable treatment option, they should do this from the beginning, choosing drug whose presence on the market is stable. Switching from brand-name to generic drug or from one to another generic product should be avoided. However, if switching is inevitable, it should be done with due care and precautions, in order to minimize possibility of injuries or other adverse consequences of temporary loss of a disease control.» JankovicSM, IgnjatovicRisticD. Is bioavailability altered in generic versus brand anticonvulsants? Expert Opin Drug Metab Toxicol 2015; 11(3):