SHORT COMMUNICATION
Generic Olanzapine Substitution in Patients With Schizophrenia: Assessment of Serum Concentrations and Therapeutic Response After Switching Domenico Italiano, MD, PhD,* Antonio Bruno, MD,† Vincenza Santoro, BSc,* Giulia Lanza, MD,† Maria Rosaria Muscatello, MD,† Rocco Zoccali, MD,† and Edoardo Spina, MD, PhD*
Background: Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switching to generic olanzapine in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response.
Methods: Preswitching and postswitching serum olanzapine concentrations were compared in schizophrenic outpatients who were switched from a chronic treatment with branded olanzapine to the same dose of its generic alternative. The Positive and Negative Syndrome Scale was concurrently administered to assess modifications in schizophrenia symptom control. Results: A total of 25 patients (13 women and 12 men, mean age 41.2 6 12.8 years) concluded the study. Mean olanzapine dose was 12.2 6 5.4 mg/d. The mean olanzapine serum concentrations decreased from 27.7 6 14.4 ng/mL during treatment with the branded formulation to 22.6 6 12.3 ng/mL after switching to the generic formulation (P , 0.01). The log-transformed ratio of generic/brand-name olanzapine serum concentration at steady state was 0.81 (90% confidence interval: 0.72–0.91). The total Positive and Negative Syndrome Scale scores did not significantly change after switching from branded to generic formulation (49.6 6 8.3 versus 48.6 6 9.5, P = 0.777). No patient exhibited disease relapse or required dose adjustment after switching. Conclusions: Significantly lower serum olanzapine concentrations were found after switching from branded to generic olanzapine. Although these modifications did not significantly impair schizophrenia symptoms control, it cannot be excluded that a longer exposure to lower olanzapine serum concentrations may result in relapse of schizophrenic symptoms. Generic substitution should be considered as an indication for therapeutic drug monitoring in psychiatry.
Received for publication December 27, 2014; accepted March 17, 2015. From the *Department of Clinical and Experimental Medicine; and †Section of Psychiatry, Department of Neurosciences, University of Messina, Italy. Dr E. Spina has participated in speakers and lectures supported by AstraZeneca, Bristol-Myers, Eli Lilly & Co, Janssen Pharmaceuticals, and Lundbeck. The remaining authors declare no conflict of interest. Correspondence: Edoardo Spina, MD, PhD, Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Via Consolare Valeria, 98125 Messina, Italy (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ther Drug Monit Volume 37, Number 6, December 2015
Key Words: generic substitution, therapeutic drug monitoring, antipsychotics, olanzapine (Ther Drug Monit 2015;37:827–830)
INTRODUCTION Generic drug substitution is a proposed solution to the problem of health care costs containment. Generic alternatives have the same formula as the brand-name drug but can be marketed at a lower price because their manufacturers are not influenced by the costs of the original registration studies. However, although generic formulations are less expensive than the corresponding brand-name drugs, it is debated if they are always as safe or effective.1 Controversies have sometimes arisen regarding generic substitution, and there is concern among some physicians and patients that brand-name drugs may be clinically superior to generic drugs. This issue is particularly relevant in some therapeutic areas such as psychiatry whose nature requires special consideration before switching a patient to a generic alternative.1 Indeed, when considering drugs with a narrow therapeutic index, such as most antipsychotics, even small changes in serum concentration may lead to loss of therapeutic effect or toxicity.2 Compared with the original medication, the generic drug must have the same amount and type of active ingredient, the same route of administration, and the same therapeutic effectiveness, as demonstrated by a bioequivalence study in healthy volunteers. Many second-generation antipsychotics currently in use are available as generic products. Nevertheless, in the last few years, several reports of loss of efficacy or adverse effects have been described after substitution of an originator antipsychotic drug with its generic alternative.3–6 To date, naturalistic studies comparing serum drug levels in patients treated with brand-name or generic antipsychotics in a standard clinical setting are lacking. Therefore, the aim of this study was to investigate whether the replacement of branded olanzapine with a generic alternative in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response.
MATERIALS AND METHODS Schizophrenic patients, of age older than 18 years, referring to the outpatient Unit of Psychiatry, University Polyclinic Messina, from October 2013 to September 2014,
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Ther Drug Monit Volume 37, Number 6, December 2015
Italiano et al
who were stabilized on chronic treatment with olanzapine, were considered for the enrollment in this study. Recent changes in drug treatment, including potentially interacting comedications, which may have prevented attainment of steady-state conditions of olanzapine, were exclusion criteria. Patients chronically treated with the originator brand of olanzapine (Zyprexa; Eli Lilly, Alcobendas, Madrid, Spain), who were switched to the same dose of a generic olanzapine formulation (olanzapine; Teva, Debrecen, Hungary), underwent 2 blood samples for the determination of serum concentration of olanzapine. The first assay was performed during the treatment with the branded olanzapine formulation, and the second at least 4 weeks after they had been switched to the generic olanzapine formulation. At the same time, the Positive and Negative Syndrome Scale (PANSS) was administered to patients by a trained psychiatrist to assess the severity of schizophrenia symptoms. Both blood samples were obtained before the intake of the morning dose and after 12 hours from the previous evening administration. The protocol was approved by a local ethics committee, and written informed consent was obtained from the patients or their relatives.
shown in Figure 1. The log-transformed ratio of generic/ brand-name olanzapine serum concentration at steady state was 0.81 (90% CI: 0.72–0.91). According to the PANSS total scores, patients might be considered as “mildly ill.”8 The total PANSS scores did not significantly change after switching from branded to generic formulation (49.6 6 8.3 versus 48.6 6 9.5, Z = 0.283, P = 0.777). No patient exhibited disease relapse after switching to generic olanzapine or required dose adjustment at 1-month follow-up. Switching to generic olanzapine was generally well tolerated with no new adverse effects reported.
DISCUSSION Findings from this study evidenced significantly lower serum olanzapine concentrations in patients switched from branded to generic olanzapine. However, these modifications did not seem to significantly impair schizophrenia symptoms
Drug Assays The steady-state serum concentrations of olanzapine were measured by high-performance liquid chromatography according to the method of D’Arrigo et al.7 The assay quantification limit was 5 ng/mL.
Statistical Analysis Descriptive statistics for the patient population are presented as mean 6 SDs. Serum concentrations of branded and generic olanzapine, as well as mean PANSS scores obtained before and after the switching, were compared by the Wilcoxon signed test with a level of 0.05 for statistical significance. Geometric mean ratios for olanzapine steadystate concentrations during treatment with branded or generic drug were also calculated. Multivariate repeated-measures analysis of variance was conducted to compare the logtransformed ratios of generic/brand-name olanzapine mean steady-state concentrations. Bioequivalence test rules were used to determine if 90% confidence interval (CI) of the geometric mean ratios was within the interval of 0.80–1.25.
RESULTS Overall, 28 patients fulfilling inclusion criteria were enrolled. A total of 25 patients (13 women and 12 men), mean age 41.2 6 12.8 (range 22–63) years concluded the study. Mean disease duration was 17.9 6 10.9 years (range 2–42), and mean olanzapine dose was 12.2 6 5.4 (range 5–20) mg/d. Smoking habits or comedications did not change during the observation period. The mean olanzapine serum concentration during treatment with the branded formulation was 27.7 6 14.4 ng/mL (range 6–61 ng/mL). After switching to the generic formulation, the mean olanzapine concentration significantly decreased (P , 0.01) to 22.6 6 12.3 ng/mL (range 5–56 ng/mL). Comparison between branded and generic serum olanzapine concentrations at steady state are
FIGURE 1. A, Steady-state serum olanzapine concentrations during treatment with branded or generic olanzapine. B, The PANSS total scores during treatment with branded or generic olanzapine.
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Ther Drug Monit Volume 37, Number 6, December 2015
Generic Substitution and Olanzapine Concentrations
control. In fact, the total PANSS scores obtained during treatment with branded or generic olanzapine did not exhibit significant differences. Furthermore, no patient presented clinical worsening of schizophrenic symptoms or required dose augmentation. Nevertheless, only short-term modifications in olanzapine serum concentration after switching have been evaluated, therefore it cannot be excluded that a longer exposure to lower steady-state serum concentrations of olanzapine may result in later relapse of schizophrenic symptoms. To the best of our knowledge, this pilot study is the first in investigating differences in serum concentrations during treatment with branded olanzapine or its generic alternative, in a naturalistic setting. Two previous anecdotal studies reported relevant side effect or therapeutic failure after generic olanzapine substitution.6,9 Goldberg9 described a case of akathisia after switching from brand-name to generic preparation of olanzapine in a 33-year-old man with a diagnosis of bipolar affective disorder, which resolved on reverting back to the brand-name preparation. More recently, Samuel et al6 reported a case of a 14-year-old boy with an acute clinical deterioration within 48 hours when changed to generic olanzapine followed by subsequent return to a previous stable mental state. Also, this effect subsided on reverting from generic to brand-name olanzapine. Araszkiewicz et al10 retrospectively reviewed the charts of 85 patients with schizophrenia who had been prescribed branded or generic olanzapine. Patients remaining on branded olanzapine, or switched to a generic, or initially prescribed a generic were considered. The average dose, frequency of outpatient visits, side effects, and rates of relapses were similar for the 3 groups. The 25 patients switched to the generic did not show significant changes in their dosage or an increase in relapses after substitution. It has been suggested that drugs acting on the central nervous system may be more prone to significant changes when switching from brand to generic compared with other medication categories.11 Many hypothesize these responses to be related to differences in bioavailability and other pharmacokinetic variables between the 2 formulations in favor of brand-name versus generic.2,11,12 According to drug regulatory agencies, the bioequivalence of a generic drug is decreed when 90% CIs for the ratios of the generic to the reference compound for the area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) fall within a 0.80–1.25 range.2,13 This should be demonstrated by a standardized, single-dose cross-over pharmacokinetic study that is conducted in 24–36 healthy volunteers. Based on these criteria, if 2 formulations are bioequivalent, they are assumed to be similarly effective and safe. Therefore, manufacturers of generic drugs are not required to conduct large clinical studies to demonstrate safety and effectiveness, which contributes greatly to the lower cost of generic products. Rather, they are only required to demonstrate that their formulations are pharmacokinetically similar to the brand-name product. However, there is a growing body of evidences to suggest that despite meeting regulatory agencies’ criteria for bioequivalence and thus therapeutic equivalence, the response to a generic formulation can exhibit important clinical differences compared with the response to a brand-name one.
Therefore, some clinicians have raised concerns that interchangeability may not translate to therapeutic equivalence in clinical practice.14,15 In psychiatry, several case reports and studies reported relapses or exacerbations of psychotic disorders after generic substitution of clozapine.3,4,16 However, many other studies did not find significant modifications after switching.17–22 Importantly, a prospective, randomized cross-over study performed to evaluate steady-state pharmacokinetics and tolerability of generic versus branded clozapine in schizophrenic patients found significant differences in the primary pharmacokinetic parameters for bioequivalence of the 2 formulations in almost 40% of patients. Indeed, despite comparable mean plasma concentration–time curves, in many patients exclusively the 90% CI for the mean log-transformed AUC ratio lied between 80% and 125%, whereas the 90% CI for the mean log-transformed Cmax did not.23 Such intraindividual differences raise the issue of average bioequivalence versus individual bioequivalence and the implication for interchangeability of different generic formulations.24 Some pharmacokinetic studies do not prove the bioequivalence of generic antipsychotics. For example, a study, comparing the pharmacokinetics of a generic oral solution of risperidone with that of a brand solution in 32 healthy volunteers, demonstrated that the 90% CIs for the mean ratios were not within the acceptable range of 80%–125%.25 Because of the naturalistic setting of our study, we were not able to determine the AUC and Cmax values at steady state in our patients. However, when comparing the steady-state concentrations of branded and generic olanzapine, we observed that the lower 90% CI for their ratio fell out of the 80%–125% range. These data, along with the above-reported cases, raise doubts about clinical and therapeutic equivalence of generic versus branded antipsychotics. Even if in our patients no clinical worsening was observed after switching, the lower mean serum olanzapine concentrations during generic treatment can be of concern. Indeed, although pharmacokinetic variations resulting after switching are not significant in most cases, they can become important with drugs with a narrow therapeutic index or nonlinear kinetics.2 Under these circumstances, even small changes in serum concentration may lead to loss of therapeutic effect or even toxicity. Moreover, the delicate balance achieved in polypharmacy may be disrupted by a formulation change in medications that may induce or inhibit hepatic drug-metabolizing enzymes, such as antidepressants,26 anticonvulsants,27 and most antipsychotics. Therefore, switching from a branded preparation to a generic form (and vice versa) should be considered as an indication for measuring plasma concentration of medications in psychiatry.28,29 Particular attention is needed when switching from 1 generic drug to another one. Indeed, although both generics fulfill the 80%–125% bioequivalence to the brand-name drug, substitution might result in a more than 50% increase or a more than one-third decrease of drug serum concentration. Larger pharmacokinetic studies performed on real clinical populations are warranted to determine the bioequivalence and the therapeutic equivalence of generic olanzapine versus branded. Indeed, studies currently performed to establish bioequivalence are usually small cross-over trials conducted
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in healthy volunteers, mostly young men, nonsmokers, and not taking other medications. Therefore, data from bioequivalence studies do not take into account the possibility of variation because of gender, age, environmental factors, and medical illness.13,27,30,31 Furthermore, single doses do not reproduce real-life situations as target plasma concentrations are unlikely to be reached. Ideally, bioequivalence and pharmacokinetic studies should be performed in both patients and healthy controls32 and should involve therapeutic doses administered over a given time period as opposed to single-dose administration. 1. Carbon M, Correll CU. Rational use of generic psychotropic drugs. CNS Drugs. 2013;27:353–365. 2. Borgherini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25:1578–1592. 3. Kluznik JC, Walbek NH, Farnsworth MG, et al. Clinical effects of a randomized switch of patients from clozaril to generic clozapine. J Clin Psychiatry. 2001;62(suppl 5):14–17. 4. Mofsen R, Balter J. Case reports of the reemergence of psychotic symptoms after conversion from brand-name clozapine to a generic formulation. Clin Ther. 2001;23:1720–1731. 5. Oluboka O, Stewart S, Landry S, et al. Does therapeutic equivalence follow bioequivalence? A randomized trial to assess clinical effects after switching from Clozaril to generic clozapine (gen-clozapine). J Clin Pharmacol. 2010;50:531–535. 6. Samuel R, Attard A, Kyriakopoulos M. Mental state deterioration after switching from brand-name to generic olanzapine in an adolescent with bipolar affective disorder, autism and intellectual disability: a case study. BMC Psychiatry. 2013;13:244. 7. D’Arrigo C, Migliardi G, Santoro V, et al. Determination of olanzapine in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection. Ther Drug Monit. 2006;28:599–602. 8. Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res. 2005;79:231–238. 9. Goldberg J: A case of akathisia after switching from branded to generic high-dose olanzapine. J Clin Psychiatry. 2012;73:497. 10. Araszkiewicz AA, Szabert K, Godman B, et al. Generic olanzapine: health authority opportunity or nightmare? Expert Rev Pharmacoecon Outcomes Res. 2008;8:549–555. 11. Desmarais JE, Beauclair L, Margolese HC. Switching from brand-name to generic psychotropic medications: a literature review. CNS Neurosci Ther. 2011;17:750–760. 12. Margolese HC, Wolf Y, Desmarais JE, et al. Loss of response after switching from brand name to generic formulations. Three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol. 2010;25:180–182.
13. Blier P. Generic substitution for psychotropic drugs. CNS Spectr. 2009; 14:1–7. 14. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003;25:2875–2890. 15. Nuss P, Taylor D, De Hert M, et al. The generic alternative in schizophrenia: opportunity or threat? CNS Drugs. 2004;18:769–775. 16. Alvarez CA, Mascarenas C, Timmerman I. Increasing psychosis in a patient switched from Clozaril to generic clozapine. Am J Psychiatry. 2006;163:746. 17. Sajbel TA, Carter GW, Wiley RB. Converting patients from brand-name clozapine to generic clozapine. Ann Pharmacother. 2001;35:281–284. 18. Stoner SC, Lea JW, Dubisar B, et al. A program to convert patients from trade name to generic clozapine. Pharmacotherapy. 2003;23:806–810. 19. Makela EH, Cutlip WD, Stevenson JM, et al. Branded versus generic clozapine for treatment of schizophrenia. Ann Pharmacother. 2003;37: 350–353. 20. Healy DJ, Taylor S, Godman M, et al. Clinical equivalence of generic clozapine. Comm Ment Health J. 2005;41:393–398. 21. Alessi-Severini S, Honcharik PL, Simpson KD, et al. Evaluation of an interchangeability switch in patients treated with clozapine: a retrospective review. J Clin Psychiatry. 2006;67:1047–1054. 22. Paton C. Generic clozapine: Outcomes after switching formulations. Br J Psychiatry. 2006;189:184–185. 23. Lam YW, Ereshefsky L, Toney GB, et al. Branded versus generic clozapine: bioavailability comparison and interchangeability issues. J Clin Psychiatry. 2001;62(suppl 5):18–22. 24. Yim DS. Simulation of the AUC changes after generic substitution in patients. J Korean Med Sci. 2009;24:7–12. 25. van Os S, Relleke M, Piniella PM. Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets. Int J Clin Pharmacol Ther. 2007;45:293–299. 26. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30:1206–1227. 27. Crawford P, Feely M, Guberman A, et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006;15:165–176. 28. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195–235. 29. Unterecker S, Proft F, Riederer P, et al. The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis. Ther Drug Monit. 2014;36:269–272. 30. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet. 2002;41:329–342. 31. Shi S, Morike K, Klotz U. The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol. 2008;64:183–199. 32. Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psychiatry. 2001;62(suppl l 5):10–13.
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REFERENCES
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Generic Olanzapine Substitution in Patients With Schizophrenia: Assessment of Serum Concentrations and Therapeutic Response After Switching Domenico Italiano, MD, PhD,* Antonio Bruno, MD,† Vincenza Santoro, BSc,* Giulia Lanza, MD,† Maria Rosaria Muscatello, MD,† Rocco Zoccali, MD,† and Edoardo Spina, MD, PhD*
Background: Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switching to generic olanzapine in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response.
Methods: Preswitching and postswitching serum olanzapine concentrations were compared in schizophrenic outpatients who were switched from a chronic treatment with branded olanzapine to the same dose of its generic alternative. The Positive and Negative Syndrome Scale was concurrently administered to assess modifications in schizophrenia symptom control. Results: A total of 25 patients (13 women and 12 men, mean age 41.2 6 12.8 years) concluded the study. Mean olanzapine dose was 12.2 6 5.4 mg/d. The mean olanzapine serum concentrations decreased from 27.7 6 14.4 ng/mL during treatment with the branded formulation to 22.6 6 12.3 ng/mL after switching to the generic formulation (P , 0.01). The log-transformed ratio of generic/brand-name olanzapine serum concentration at steady state was 0.81 (90% confidence interval: 0.72–0.91). The total Positive and Negative Syndrome Scale scores did not significantly change after switching from branded to generic formulation (49.6 6 8.3 versus 48.6 6 9.5, P = 0.777). No patient exhibited disease relapse or required dose adjustment after switching. Conclusions: Significantly lower serum olanzapine concentrations were found after switching from branded to generic olanzapine. Although these modifications did not significantly impair schizophrenia symptoms control, it cannot be excluded that a longer exposure to lower olanzapine serum concentrations may result in relapse of schizophrenic symptoms. Generic substitution should be considered as an indication for therapeutic drug monitoring in psychiatry.
Received for publication December 27, 2014; accepted March 17, 2015. From the *Department of Clinical and Experimental Medicine; and †Section of Psychiatry, Department of Neurosciences, University of Messina, Italy. Dr E. Spina has participated in speakers and lectures supported by AstraZeneca, Bristol-Myers, Eli Lilly & Co, Janssen Pharmaceuticals, and Lundbeck. The remaining authors declare no conflict of interest. Correspondence: Edoardo Spina, MD, PhD, Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Via Consolare Valeria, 98125 Messina, Italy (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ther Drug Monit Volume 37, Number 6, December 2015
Key Words: generic substitution, therapeutic drug monitoring, antipsychotics, olanzapine (Ther Drug Monit 2015;37:827–830)
INTRODUCTION Generic drug substitution is a proposed solution to the problem of health care costs containment. Generic alternatives have the same formula as the brand-name drug but can be marketed at a lower price because their manufacturers are not influenced by the costs of the original registration studies. However, although generic formulations are less expensive than the corresponding brand-name drugs, it is debated if they are always as safe or effective.1 Controversies have sometimes arisen regarding generic substitution, and there is concern among some physicians and patients that brand-name drugs may be clinically superior to generic drugs. This issue is particularly relevant in some therapeutic areas such as psychiatry whose nature requires special consideration before switching a patient to a generic alternative.1 Indeed, when considering drugs with a narrow therapeutic index, such as most antipsychotics, even small changes in serum concentration may lead to loss of therapeutic effect or toxicity.2 Compared with the original medication, the generic drug must have the same amount and type of active ingredient, the same route of administration, and the same therapeutic effectiveness, as demonstrated by a bioequivalence study in healthy volunteers. Many second-generation antipsychotics currently in use are available as generic products. Nevertheless, in the last few years, several reports of loss of efficacy or adverse effects have been described after substitution of an originator antipsychotic drug with its generic alternative.3–6 To date, naturalistic studies comparing serum drug levels in patients treated with brand-name or generic antipsychotics in a standard clinical setting are lacking. Therefore, the aim of this study was to investigate whether the replacement of branded olanzapine with a generic alternative in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response.
MATERIALS AND METHODS Schizophrenic patients, of age older than 18 years, referring to the outpatient Unit of Psychiatry, University Polyclinic Messina, from October 2013 to September 2014,
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Ther Drug Monit Volume 37, Number 6, December 2015
Italiano et al
who were stabilized on chronic treatment with olanzapine, were considered for the enrollment in this study. Recent changes in drug treatment, including potentially interacting comedications, which may have prevented attainment of steady-state conditions of olanzapine, were exclusion criteria. Patients chronically treated with the originator brand of olanzapine (Zyprexa; Eli Lilly, Alcobendas, Madrid, Spain), who were switched to the same dose of a generic olanzapine formulation (olanzapine; Teva, Debrecen, Hungary), underwent 2 blood samples for the determination of serum concentration of olanzapine. The first assay was performed during the treatment with the branded olanzapine formulation, and the second at least 4 weeks after they had been switched to the generic olanzapine formulation. At the same time, the Positive and Negative Syndrome Scale (PANSS) was administered to patients by a trained psychiatrist to assess the severity of schizophrenia symptoms. Both blood samples were obtained before the intake of the morning dose and after 12 hours from the previous evening administration. The protocol was approved by a local ethics committee, and written informed consent was obtained from the patients or their relatives.
shown in Figure 1. The log-transformed ratio of generic/ brand-name olanzapine serum concentration at steady state was 0.81 (90% CI: 0.72–0.91). According to the PANSS total scores, patients might be considered as “mildly ill.”8 The total PANSS scores did not significantly change after switching from branded to generic formulation (49.6 6 8.3 versus 48.6 6 9.5, Z = 0.283, P = 0.777). No patient exhibited disease relapse after switching to generic olanzapine or required dose adjustment at 1-month follow-up. Switching to generic olanzapine was generally well tolerated with no new adverse effects reported.
DISCUSSION Findings from this study evidenced significantly lower serum olanzapine concentrations in patients switched from branded to generic olanzapine. However, these modifications did not seem to significantly impair schizophrenia symptoms
Drug Assays The steady-state serum concentrations of olanzapine were measured by high-performance liquid chromatography according to the method of D’Arrigo et al.7 The assay quantification limit was 5 ng/mL.
Statistical Analysis Descriptive statistics for the patient population are presented as mean 6 SDs. Serum concentrations of branded and generic olanzapine, as well as mean PANSS scores obtained before and after the switching, were compared by the Wilcoxon signed test with a level of 0.05 for statistical significance. Geometric mean ratios for olanzapine steadystate concentrations during treatment with branded or generic drug were also calculated. Multivariate repeated-measures analysis of variance was conducted to compare the logtransformed ratios of generic/brand-name olanzapine mean steady-state concentrations. Bioequivalence test rules were used to determine if 90% confidence interval (CI) of the geometric mean ratios was within the interval of 0.80–1.25.
RESULTS Overall, 28 patients fulfilling inclusion criteria were enrolled. A total of 25 patients (13 women and 12 men), mean age 41.2 6 12.8 (range 22–63) years concluded the study. Mean disease duration was 17.9 6 10.9 years (range 2–42), and mean olanzapine dose was 12.2 6 5.4 (range 5–20) mg/d. Smoking habits or comedications did not change during the observation period. The mean olanzapine serum concentration during treatment with the branded formulation was 27.7 6 14.4 ng/mL (range 6–61 ng/mL). After switching to the generic formulation, the mean olanzapine concentration significantly decreased (P , 0.01) to 22.6 6 12.3 ng/mL (range 5–56 ng/mL). Comparison between branded and generic serum olanzapine concentrations at steady state are
FIGURE 1. A, Steady-state serum olanzapine concentrations during treatment with branded or generic olanzapine. B, The PANSS total scores during treatment with branded or generic olanzapine.
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Ther Drug Monit Volume 37, Number 6, December 2015
Generic Substitution and Olanzapine Concentrations
control. In fact, the total PANSS scores obtained during treatment with branded or generic olanzapine did not exhibit significant differences. Furthermore, no patient presented clinical worsening of schizophrenic symptoms or required dose augmentation. Nevertheless, only short-term modifications in olanzapine serum concentration after switching have been evaluated, therefore it cannot be excluded that a longer exposure to lower steady-state serum concentrations of olanzapine may result in later relapse of schizophrenic symptoms. To the best of our knowledge, this pilot study is the first in investigating differences in serum concentrations during treatment with branded olanzapine or its generic alternative, in a naturalistic setting. Two previous anecdotal studies reported relevant side effect or therapeutic failure after generic olanzapine substitution.6,9 Goldberg9 described a case of akathisia after switching from brand-name to generic preparation of olanzapine in a 33-year-old man with a diagnosis of bipolar affective disorder, which resolved on reverting back to the brand-name preparation. More recently, Samuel et al6 reported a case of a 14-year-old boy with an acute clinical deterioration within 48 hours when changed to generic olanzapine followed by subsequent return to a previous stable mental state. Also, this effect subsided on reverting from generic to brand-name olanzapine. Araszkiewicz et al10 retrospectively reviewed the charts of 85 patients with schizophrenia who had been prescribed branded or generic olanzapine. Patients remaining on branded olanzapine, or switched to a generic, or initially prescribed a generic were considered. The average dose, frequency of outpatient visits, side effects, and rates of relapses were similar for the 3 groups. The 25 patients switched to the generic did not show significant changes in their dosage or an increase in relapses after substitution. It has been suggested that drugs acting on the central nervous system may be more prone to significant changes when switching from brand to generic compared with other medication categories.11 Many hypothesize these responses to be related to differences in bioavailability and other pharmacokinetic variables between the 2 formulations in favor of brand-name versus generic.2,11,12 According to drug regulatory agencies, the bioequivalence of a generic drug is decreed when 90% CIs for the ratios of the generic to the reference compound for the area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax) fall within a 0.80–1.25 range.2,13 This should be demonstrated by a standardized, single-dose cross-over pharmacokinetic study that is conducted in 24–36 healthy volunteers. Based on these criteria, if 2 formulations are bioequivalent, they are assumed to be similarly effective and safe. Therefore, manufacturers of generic drugs are not required to conduct large clinical studies to demonstrate safety and effectiveness, which contributes greatly to the lower cost of generic products. Rather, they are only required to demonstrate that their formulations are pharmacokinetically similar to the brand-name product. However, there is a growing body of evidences to suggest that despite meeting regulatory agencies’ criteria for bioequivalence and thus therapeutic equivalence, the response to a generic formulation can exhibit important clinical differences compared with the response to a brand-name one.
Therefore, some clinicians have raised concerns that interchangeability may not translate to therapeutic equivalence in clinical practice.14,15 In psychiatry, several case reports and studies reported relapses or exacerbations of psychotic disorders after generic substitution of clozapine.3,4,16 However, many other studies did not find significant modifications after switching.17–22 Importantly, a prospective, randomized cross-over study performed to evaluate steady-state pharmacokinetics and tolerability of generic versus branded clozapine in schizophrenic patients found significant differences in the primary pharmacokinetic parameters for bioequivalence of the 2 formulations in almost 40% of patients. Indeed, despite comparable mean plasma concentration–time curves, in many patients exclusively the 90% CI for the mean log-transformed AUC ratio lied between 80% and 125%, whereas the 90% CI for the mean log-transformed Cmax did not.23 Such intraindividual differences raise the issue of average bioequivalence versus individual bioequivalence and the implication for interchangeability of different generic formulations.24 Some pharmacokinetic studies do not prove the bioequivalence of generic antipsychotics. For example, a study, comparing the pharmacokinetics of a generic oral solution of risperidone with that of a brand solution in 32 healthy volunteers, demonstrated that the 90% CIs for the mean ratios were not within the acceptable range of 80%–125%.25 Because of the naturalistic setting of our study, we were not able to determine the AUC and Cmax values at steady state in our patients. However, when comparing the steady-state concentrations of branded and generic olanzapine, we observed that the lower 90% CI for their ratio fell out of the 80%–125% range. These data, along with the above-reported cases, raise doubts about clinical and therapeutic equivalence of generic versus branded antipsychotics. Even if in our patients no clinical worsening was observed after switching, the lower mean serum olanzapine concentrations during generic treatment can be of concern. Indeed, although pharmacokinetic variations resulting after switching are not significant in most cases, they can become important with drugs with a narrow therapeutic index or nonlinear kinetics.2 Under these circumstances, even small changes in serum concentration may lead to loss of therapeutic effect or even toxicity. Moreover, the delicate balance achieved in polypharmacy may be disrupted by a formulation change in medications that may induce or inhibit hepatic drug-metabolizing enzymes, such as antidepressants,26 anticonvulsants,27 and most antipsychotics. Therefore, switching from a branded preparation to a generic form (and vice versa) should be considered as an indication for measuring plasma concentration of medications in psychiatry.28,29 Particular attention is needed when switching from 1 generic drug to another one. Indeed, although both generics fulfill the 80%–125% bioequivalence to the brand-name drug, substitution might result in a more than 50% increase or a more than one-third decrease of drug serum concentration. Larger pharmacokinetic studies performed on real clinical populations are warranted to determine the bioequivalence and the therapeutic equivalence of generic olanzapine versus branded. Indeed, studies currently performed to establish bioequivalence are usually small cross-over trials conducted
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in healthy volunteers, mostly young men, nonsmokers, and not taking other medications. Therefore, data from bioequivalence studies do not take into account the possibility of variation because of gender, age, environmental factors, and medical illness.13,27,30,31 Furthermore, single doses do not reproduce real-life situations as target plasma concentrations are unlikely to be reached. Ideally, bioequivalence and pharmacokinetic studies should be performed in both patients and healthy controls32 and should involve therapeutic doses administered over a given time period as opposed to single-dose administration. 1. Carbon M, Correll CU. Rational use of generic psychotropic drugs. CNS Drugs. 2013;27:353–365. 2. Borgherini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25:1578–1592. 3. Kluznik JC, Walbek NH, Farnsworth MG, et al. Clinical effects of a randomized switch of patients from clozaril to generic clozapine. J Clin Psychiatry. 2001;62(suppl 5):14–17. 4. Mofsen R, Balter J. Case reports of the reemergence of psychotic symptoms after conversion from brand-name clozapine to a generic formulation. Clin Ther. 2001;23:1720–1731. 5. Oluboka O, Stewart S, Landry S, et al. Does therapeutic equivalence follow bioequivalence? A randomized trial to assess clinical effects after switching from Clozaril to generic clozapine (gen-clozapine). J Clin Pharmacol. 2010;50:531–535. 6. Samuel R, Attard A, Kyriakopoulos M. Mental state deterioration after switching from brand-name to generic olanzapine in an adolescent with bipolar affective disorder, autism and intellectual disability: a case study. BMC Psychiatry. 2013;13:244. 7. D’Arrigo C, Migliardi G, Santoro V, et al. Determination of olanzapine in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection. Ther Drug Monit. 2006;28:599–602. 8. Leucht S, Kane JM, Kissling W, et al. What does the PANSS mean? Schizophr Res. 2005;79:231–238. 9. Goldberg J: A case of akathisia after switching from branded to generic high-dose olanzapine. J Clin Psychiatry. 2012;73:497. 10. Araszkiewicz AA, Szabert K, Godman B, et al. Generic olanzapine: health authority opportunity or nightmare? Expert Rev Pharmacoecon Outcomes Res. 2008;8:549–555. 11. Desmarais JE, Beauclair L, Margolese HC. Switching from brand-name to generic psychotropic medications: a literature review. CNS Neurosci Ther. 2011;17:750–760. 12. Margolese HC, Wolf Y, Desmarais JE, et al. Loss of response after switching from brand name to generic formulations. Three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol. 2010;25:180–182.
13. Blier P. Generic substitution for psychotropic drugs. CNS Spectr. 2009; 14:1–7. 14. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003;25:2875–2890. 15. Nuss P, Taylor D, De Hert M, et al. The generic alternative in schizophrenia: opportunity or threat? CNS Drugs. 2004;18:769–775. 16. Alvarez CA, Mascarenas C, Timmerman I. Increasing psychosis in a patient switched from Clozaril to generic clozapine. Am J Psychiatry. 2006;163:746. 17. Sajbel TA, Carter GW, Wiley RB. Converting patients from brand-name clozapine to generic clozapine. Ann Pharmacother. 2001;35:281–284. 18. Stoner SC, Lea JW, Dubisar B, et al. A program to convert patients from trade name to generic clozapine. Pharmacotherapy. 2003;23:806–810. 19. Makela EH, Cutlip WD, Stevenson JM, et al. Branded versus generic clozapine for treatment of schizophrenia. Ann Pharmacother. 2003;37: 350–353. 20. Healy DJ, Taylor S, Godman M, et al. Clinical equivalence of generic clozapine. Comm Ment Health J. 2005;41:393–398. 21. Alessi-Severini S, Honcharik PL, Simpson KD, et al. Evaluation of an interchangeability switch in patients treated with clozapine: a retrospective review. J Clin Psychiatry. 2006;67:1047–1054. 22. Paton C. Generic clozapine: Outcomes after switching formulations. Br J Psychiatry. 2006;189:184–185. 23. Lam YW, Ereshefsky L, Toney GB, et al. Branded versus generic clozapine: bioavailability comparison and interchangeability issues. J Clin Psychiatry. 2001;62(suppl 5):18–22. 24. Yim DS. Simulation of the AUC changes after generic substitution in patients. J Korean Med Sci. 2009;24:7–12. 25. van Os S, Relleke M, Piniella PM. Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets. Int J Clin Pharmacol Ther. 2007;45:293–299. 26. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30:1206–1227. 27. Crawford P, Feely M, Guberman A, et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006;15:165–176. 28. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195–235. 29. Unterecker S, Proft F, Riederer P, et al. The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis. Ther Drug Monit. 2014;36:269–272. 30. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet. 2002;41:329–342. 31. Shi S, Morike K, Klotz U. The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol. 2008;64:183–199. 32. Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psychiatry. 2001;62(suppl l 5):10–13.
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