SHORT COMMUNICATION
The Comparison of Brand-Name and Generic Formulations of Venlafaxine: A Therapeutic Drug Monitoring Analysis Stefan Unterecker, MD, Florian Proft, Dipl.Biol, Dr Peter Riederer, Martin Lauer, MD, Jürgen Deckert, MD, and Bruno Pfuhlmann, MD
Objective: Venlafaxine (VEN) is a widely used antidepressant drug,
suggest variability of serum concentrations and thus could endanger safety and efficacy of drug use.
which is available in both brand-name and generic formulations. Bioequivalence studies indicate some pharmacokinetic variability. However, naturalistic therapeutic drug monitoring studies of different generic formulations are lacking.
Key Words: venlafaxine, comparison of generic and brand-name formulations, therapeutic drug monitoring
Methods: In 2010, inpatients of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, were treated with either slow-release brand-name VEN (Trevilor) or slow-release generic VEN (Venlafaxin Hexal) depending on the respective inpatient ward. Routine therapeutic drug monitoring analyses of both groups were compared after matching samples regarding dose of VEN, gender, age, smoking habits, and evaluation of co-medication. Results: Both groups did not differ in mean values of VEN, O-desmethyl-VEN (ODV), VEN + ODV serum concentrations, and ODV/VEN ratio. No difference in dose-corrected serum concentrations between generic and brand-name VEN was revealed for males, females, smokers, or nonsmokers. In both groups, Spearman Rho correlation between VEN dose and VEN + ODV serum concentration was moderate but significant (P , 0.001; generic: r = 0.554; brand name: r = 0.668). Within the generic subgroup, females had a significantly higher dose-corrected serum concentration of VEN (U test, P , 0.05), whereas within brand name, no gender influence was detected. Spearman Rho correlation of age and dose-corrected ODV (P , 0.05) and VEN + ODV (P , 0.05) was significant only in the generic group. In the brandname sample, smokers had significantly lower dose-corrected serum concentrations of ODV (U test, P , 0.01) and VEN + ODV (P , 0.01). In the generic group, smoking habit was without any influence. Discussion: No differences in serum concentrations in dependence of either VEN formulations suggest a safe and efficient treatment of patients using the evaluated generic VEN. However, differences within one formulation regarding gender, age, and smoking status Received for publication March 18, 2013; accepted August 26, 2013. From the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Germany. S. Unterecker has received travel and accommodation expenses from Astra Zeneca, Pfizer, and Janssen. P. Riederer has received an honorarium from Merz-Pharmaceuticals GmbH. J. Deckert has received speaker’s honoraria from Janssen, Bristol-Myers Squibb, Wyeth, Lundbeck, Astra Zeneca, and Pfizer and grant support from Medice. B. Pfuhlmann has received speaker’s honoraria from Astra Zeneca, Janssen, and Pfizer. The authors have not received funding for this work from any organization. Correspondence: Stefan Unterecker, MD, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Füchsleinstrasse 15, D-97080 Würzburg, Germany (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
Ther Drug Monit Volume 36, Number 2, April 2014
(Ther Drug Monit 2014;36:269–272)
INTRODUCTION The antidepressant drug venlafaxine (VEN) acts by inhibiting the reuptake of serotonin and norepinephrine.1,2 VEN has been available in both brand-name and generic formulations for several years. Generic formulations are merchandized as therapeutically equivalent and less expensive alternatives to brand-name medications. Whereas health-care and pharmacy costs were found to be lower in patients receiving a generic instead of brand-name antidepressant drug with no difference in likelihood of therapy discontinuation in both patient samples,3 switching to a less expensive generic medication may lead to higher costs because of a higher risk of emergency department visits and hospitalizations.4 The process of approval of generic drugs is not as comprehensive as that of brand-name medication5 because marketing of generics does not require large clinical trials but only bioequivalence studies.6 The criteria of bioavailability in bioequivalence studies are area under the plasma concentration–time curve, maximum plasma concentration, and time to peak concentration. The bioequivalence criteria are fulfilled if area under the plasma concentration– time curve and relative mean measured maximum plasma concentration of the test drug compared with the reference drug fall within a range from 80% to 125%,7 allowing for some pharmacokinetic variability.8 Even if some studies examining the bioavailability and bioequivalence of different VEN formulations in varying doses in fasted and fed states altogether revealed comparable results,9–11 other authors described relapses, worsening of clinical outcomes, and occurrence of new adverse effects after switching from one antidepressant formulation to another.7,12–15 In some studies, different formulations were associated with a significant difference in serum concentrations, although the same doses of 2 antidepressant formulations were administered.8,16 As naturalistic studies are lacking and because of interindividual variations of pharmacokinetic parameters with potential influence on bioavailability, such as gender, age, smoking habits,17,18 or alterations of drug metabolism by genetic polymorphisms, comparisons of brand-name– and generic-treated patients in a standard clinical setting can be highly informative.
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MATERIALS AND METHODS In 2010, patients in the Department of Psychiatry, Psychosomatics, and Psychotherapy of the University Hospital of Würzburg received slow-release brand-name (Trevilor, Wyeth) or slow-release generic (Venlafaxin Hexal) formulations of VEN depending on the respective inpatient ward in which the treatment was given. If antidepressant therapy with VEN was chosen, dosage was individually titrated according to clinical efficacy and adverse effects. As part of routine clinical practice, therapeutic drug monitoring (TDM) was performed during antidepressant therapy for different indications, such as lack of response, control of adherence, suspected drug interaction, or occurrence of adverse effects. In case of multiple determinations of VEN in one patient, only the last determination was included to avoid multiple inclusion of the same individual. In a second step, serum concentration determinations, in which the ratio of metabolite to parent compound was ,1 and .5.2, were excluded to prevent confounding effects by poor, intermediate, and ultrarapid metabolizers.19,20 To examine a potential influence of the formulation of VEN and to compare brand-name VEN with generic VEN regarding influence of gender, age, smoking habits, and dose on VEN/O-desmethyl-VEN (ODV) serum concentration, the 2 groups were matched patient by patient. The psychopharmacological co-medication was completely recorded on the request form for TDM, and an influence on CYP2D6 and CYP3A4 activities could be excluded.
Statistical Analysis Samples were compared regarding dose-corrected serum concentrations of VEN, ODV, and the sum of both and the ratio of ODV/VEN with U tests. Spearman Rho correlations between serum concentrations of VEN + ODV and VEN dose on the one hand and dose-corrected serum concentrations of VEN, ODV, and VEN + ODV and the ratio of ODV/VEN and age on the other hand were evaluated.
Determination of VEN and ODV In the TDM laboratory of the Psychiatric University Hospital of Würzburg, VEN serum concentrations were determined by an isocratic reversed-phase high-performance liquid chromatography method.18 The laboratory participates in an external quality control program (Cardiff Bioanalytical Services, The Cardiff Medical Center, Cardiff, United Kingdom) with monthly analyzed control samples. The quality control program was operated without rejection of submitted values.
RESULTS Sample Characteristics In total, 348 TDM analyses of VEN were performed in 178 patients: 110 patients (58 females and 52 males) were treated with slow-release brand-name VEN and 68 patients with generic slow-release VEN (40 females and 28 males). Mean age in the generic sample was 38.4 years (SD 14.5, range 18–73) versus 47.3 years (SD 17.0, range 18–88) in the brandname sample. Sufficient information on smoking habits in the generic sample was available in 62 patients, 25 of whom were smokers and 37 nonsmokers. In the brand-name sample,
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information about smoking habit was available in 93 cases (32 smokers and 61 nonsmokers). The mean daily doses were 209.2 mg (SD 85.1, range 37.5–375) in the generic and 240.5 mg (SD 96.0, range 75–600) in the brand-name samples. In the latter, the mean serum concentration of the sum VEN + ODV was 375.5 ng/mL (SD 214.6, range 56–1443), in contrast to 320.4 ng/mL (SD 161.0, range 26–717) in the generic sample. By including every patient only once, 170 serum concentrations were excluded. After matching patients one by one regarding daily dose, age, gender, and smoking status and excluding patients with ODV/VEN ratio ,1 and .5.2, 35 patients remained in both matched groups with 22 females and 13 males each. Regarding smoking habits, an exact matching was not possible. In the generic sample, the ratio of nonsmokers to smokers was 18:16, whereas in the brand-name sample, it was 14:14 with missing data in 1 versus 7 cases. The matched samples did not significantly differ regarding mean age [37.8 6 13.1 (19–68) versus 37.8 6 13.2 (19–66) years] or mean VEN dose [212.1 6 83.8 (37.5–375) versus 226.1 6 104.7 (75–450) mg]. Both groups did not differ in the mean values of VEN, ODV, and VEN + ODV serum concentrations, dose-corrected serum concentrations, or in the ODV/VEN ratio (Table 1). In subgroup comparisons within males, females, smokers, and nonsmokers, no significant differences in dose-corrected serum concentrations between generic and brand-name formulations were found. The Spearman Rho correlation between VEN dose and serum concentration of VEN + ODV was significant in both groups (P , 0.001), and the correlation coefficient reached a similar magnitude (generic: r = 0.554; brand name: r = 0.668). Whereas within the generic subgroup, females showed a significantly higher dose-corrected serum concentration of VEN (U test, P , 0.05) and a trend toward higher dosecorrected serum concentration in VEN + ODV (P , 0.10) (Table 2), in the brand-name group, there was no gender difference in dose-corrected serum concentrations and ODV/VEN ratio. In contrast to a significant Spearman Rho correlation between age and dose-corrected ODV (r = 0.413, P , 0.05) and VEN + ODV (r = 0.396, P , 0.05) concentrations in the generic group, in the brand-name sample, no such correlation could be found. In the generic group, no difference between smokers and nonsmokers in dose-corrected serum concentrations and a trend of higher ODV/VEN ratio in smokers (P , 0.10) could be detected, whereas within the brand-name sample, smokers had significantly lower dose-corrected serum concentrations of ODV (0.712 6 0.158 versus 1.155 6 0.428 ng/mL per milligram, U test, P , 0.01) and VEN + ODV (1.069 6 0.235 versus 1.675 6 0.647 ng/mL per milligram, U test, P , 0.01) with a trend toward lower dose-corrected serum concentrations of VEN (P , 0.10) and no difference in the ODV/VEN ratio.
DISCUSSION In this study, the serum concentrations of VEN and its main metabolite ODV were evaluated in patient samples treated with brand-name or generic formulations of slowrelease VEN under naturalistic conditions. The authors found Ó 2014 Lippincott Williams & Wilkins
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Comparison of Brand-Name and Generic Venlafaxine
TABLE 1. Comparison of Serum Concentrations of VEN and ODV and ODV/VEN Ratio With Respect to Generic and Brand-Name VEN Treatment by U Test Mean 6 SD (Range) Generic VEN Serum concentration of VEN (ng/mL) Serum concentration of ODV (ng/mL) Serum concentration of VEN + ODV (ng/mL) Dose-corrected serum concentration of VEN (ng/mL per milligram per day) Dose-corrected serum concentration of ODV (ng/mL per milligram per day) Dose-corrected serum concentration of VEN + ODV (ng/mL per milligram per day) ODV/VEN ratio
comparable serum concentrations of VEN, ODV, and VEN + ODV and the ODV/VEN ratio after matching samples, which was also the case in the subgroup analyses of dose-corrected serum concentrations in males, females, smokers, and nonsmokers. The evaluated generic and brand-name VEN are therefore comparable regarding dose-corrected serum concentrations under naturalistic clinical conditions. Only analyses within subgroups revealed some significant differences: In generic-treated patients, age significantly correlated with serum concentrations of ODV and VEN + ODV, whereas in the brand-name group, smokers had significantly lower dose-corrected serum concentrations of ODV and VEN + ODV. Moreover, a difference between females and males regarding dose-corrected serum concentration of VEN was only found in the generic, but not in the brand-name, group. The present study did not evaluate comparability of the generic and brand-name VEN by differences of tolerability or efficacy. Because of the retrospective nature of the study, it can only provide explorative results. In addition, an influence of co-medication cannot be ruled out, although psychopharmacological co-medication was evaluated to exclude cases of CYP2D6 or CYP3A4 inhibition. Because bioequivalence studies are generally performed in smaller homogeneous samples of male, healthy volunteers, the advantage of a study in a naturalistic setting despite its heterogeneity is the evaluation of the relevance of possible differences for everyday clinical practice.21 This includes the evaluation of pharmacokinetic parameters, such as gender, age, and smoking habits,17,18 which are often ignored. The matching procedure in the present study together with the exclusion of multiple determinations was important to make the groups comparable but, inevitably, resulted in a considerable decrease of sample size. In contrast to bioequivalence studies, which measure serum or plasma concentrations in the hours after dosing,
95.6 202.2 297.8 0.481 1.000 1.481 2.304
6 6 6 6 6 6 6
52.0 (10–235) 104.2 (16–476) 148.8 (26–711) 0.272 (0.10–1.23) 0.447 (0.21–2.48) 0.685 (0.35–3.71) 0.774 (1.11–4.23)
P
Brand-Name VEN 93.6 190.5 284.1 0.418 0.898 1.316 2.409
6 6 6 6 6 6 6
61.7 (13–236) 98.0 (43–524) 152.1 (56–760) 0.230 (0.15–1.29) 0.378 (0.30–1.87) 0.553 (0.59–2.76) 0.979 (1.03–5.20)
0.626 0.782 0.622 0.301 0.247 0.211 0.747
this study has a more clinical focus evaluating serum concentrations under steady state conditions. This might be one reason for the lack of any difference in VEN, ODV, and VEN + ODV serum concentrations between brand-name and generic formulations in contrast to the study of Chenu et al.8 The different pattern of influence of gender, age, and smoking habits on serum concentrations in generic and brand-name VEN corresponds with unequivocal results regarding these variables in different studies.17,18,22,23 As it was discussed in the context of pharmacokinetic profiles of different VEN formulations,8 a variation in galenic formulation may also cause differences regarding the influence of gender, age, or smoking habits on dose-corrected serum concentrations of VEN and ODV. Possibly, variable galenic formulation can lead to gender- or age-related differences in the absorption of the same drug, but up to now, there is no clear evidence for such effects in various studies.24,25 Although switch studies suggest differences between brand-name and generic versions of psychotropic drugs regarding efficacy or adverse events7,12–15 and although variation of bioequivalence of the same compound in dependence of the respective manufacturer is a long-known problem,26 there still is a lack of studies comparing different generics with brand-name medication, which would involve higher number of patients under steady state conditions.6 Because switching from one generic drug to another one with a 80% to 125% bioequivalence to the brand-name drug might lead to a more than 50% increase or a more than one-third decrease of serum concentration,8 this represents a clear-cut indication for TDM.
CONCLUSIONS From the present study, the differences in serum concentrations of parent compound and metabolite between
TABLE 2. Comparison of Dose-Corrected Serum Concentrations of VEN and ODV and ODV/VEN Ratio in Female and Male Generic VEN–Treated Patients by U Tests Mean 6 SD (Range) Females (n = 22) Dose-corrected serum concentration of VEN (ng/mL per milligram per day) Dose-corrected serum concentration of ODV (ng/mL per milligram per day) Dose-corrected serum concentration of VEN + ODV (ng/mL per milligram per day) ODV/VEN ratio
Ó 2014 Lippincott Williams & Wilkins
0.553 1.090 1.644 2.171
6 6 6 6
0.302 0.487 0.753 0.780
Males (n = 13)
P
6 6 6 6
0.041 0.106 0.073 0.511
0.356 0.847 1.204 2.530
0.151 0.332 0.453 0.737
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the evaluated generic and brand-name VEN formulations are marginal, but factors such as gender, age, and smoking habit may influence dose-corrected serum concentrations depending on the respective generic or brand-name formulation. Hence, different results in different generic formulations of VEN cannot be ruled out and highlight the need for TDM. ACKNOWLEDGMENTS The authors gratefully acknowledge the staff of the TDM laboratory of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, R. Burger, M. Burger, R. Schreiner, and M. Weyer. REFERENCES 1. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs. 1995;49:280–294. 2. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry. 2000;57:503–509. 3. Vlahiotis A, Devine ST, Eichholz J, et al. Discontinuation rates and health care costs in adult patients starting generic versus brand SSRI or SNRI antidepressants in commercial health plans. J Manag Care Pharm. 2011;17:123–132. 4. Wu EQ, Yu AP, Lauzon V, et al. Economic impact of therapeutic substitution of a brand selective serotonin reuptake inhibitor with an alternative generic selective serotonin reuptake inhibitor in patients with major depressive disorder. Ann Pharmacother. 2011;45:1169–1170. 5. Desmarais JE, Beauclair L, Margolese HC. Switching from brand-name to generic psychotropic medications: a literature review. CNS Neurosci Ther. 2011;17:750–760. 6. Borgherini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25:1578–1592. 7. Van Ameringen M, Mancini C, Patterson B, et al. Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series. J Psychopharmacol. 2007;21:472–476. 8. Chenu F, Batten LA, Zernig G, et al. Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study. J Clin Psychiatry. 2009;70:958–966. 9. Rajasekhar D, Kumar IJ, Venkateswarlu P. Rapid high-performance liquid chromatography-tandem mass spectrometry method for simultaneous measurement of venlafaxine and O-desmethylvenlafaxine in human plasma and its application in comparative bioavailability study. Biomed Chromatogr. 2009;23:1300–1307. 10. Wright CW, Aikman MS, Werts E, et al. Bioequivalence of single and multiple doses of venlafaxine extended-release tablets and capsules in the
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19. 20. 21. 22. 23. 24. 25. 26.
fasted and fed states: four open-label, randomized crossover trials in healthy volunteers. Clin Ther. 2009;31:2722–2734. Homero de Souza Filho J, Bonifacio FN, Bedor DC, et al. Relative bioavailability of two formulations of venlafaxine extended-release 75-mg capsules in healthy Brazilian male volunteers: a single-dose, randomizedsequence, open-label, two-period crossover study in the fasting and fed states. Clin Ther. 2010;32:2088–2096. Bakish D, Miller C, Hooper C, et al. A double-blind, crossover study comparing generic and brand fluoxetine in the treatment of major depressive disorder. Int J Neuropsychopharmacol. 2000;3:S234–S235. Albrecht J, Adler RH. Therapeutic inadequacy in spite of bioequivalency on replacing FluctineÒ with FluocimÒ. Swiss Med Wkly. 2001;131:84. Yu BP, Chong YS, Maguire GA. Is generic fluoxetine effective? J Affect Disord. 2004;81:185–186. 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. Dubovsky SL. Severe nortriptyline intoxication due to change from a generic to a trade preparation. J Nerv Ment Dis. 1987;175:115–117. Reis M, Lundmark J, Björk H, et al. Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting. Ther Drug Monit. 2002;24:545–553. Unterecker S, Hiemke C, Greiner C, et al. The effect of age, sex, smoking and co-medication on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions. Pharmacopsychiatry. 2012;45:229–235. Hiemke C, Baumann P, Bergemann N, et al. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry. 2011;44:195–235. Shams MEE, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther. 2006;31:493–502. Bengtsson F. Therapeutic drug monitoring of psychotropic drugs. TDM “nouveau”. Ther Drug Monit. 2006;26:145–151. Klamerus KJ, Parker VD, Rudolph RL, et al. Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics. Pharmacotherapy. 1996;16:915–923. Reis M, Aamo T, Spigset O, et al. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit. 2009;31:42–56. Del Carmen Carrasco-Portugal M, Flores-Murrieta FJ. Gender differences in the pharmacokinetics of oral drugs. Pharmacol Pharm. 2011; 2:31–41. Schwartz JB. The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther. 2007;82: 87–96. Ostroff RB, Docherty JP. Tricyclics, bioequivalence, and clinical response. Am J Psychiatry. 1978;135:1560–1561.
Ó 2014 Lippincott Williams & Wilkins
The Comparison of Brand-Name and Generic Formulations of Venlafaxine: A Therapeutic Drug Monitoring Analysis Stefan Unterecker, MD, Florian Proft, Dipl.Biol, Dr Peter Riederer, Martin Lauer, MD, Jürgen Deckert, MD, and Bruno Pfuhlmann, MD
Objective: Venlafaxine (VEN) is a widely used antidepressant drug,
suggest variability of serum concentrations and thus could endanger safety and efficacy of drug use.
which is available in both brand-name and generic formulations. Bioequivalence studies indicate some pharmacokinetic variability. However, naturalistic therapeutic drug monitoring studies of different generic formulations are lacking.
Key Words: venlafaxine, comparison of generic and brand-name formulations, therapeutic drug monitoring
Methods: In 2010, inpatients of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, were treated with either slow-release brand-name VEN (Trevilor) or slow-release generic VEN (Venlafaxin Hexal) depending on the respective inpatient ward. Routine therapeutic drug monitoring analyses of both groups were compared after matching samples regarding dose of VEN, gender, age, smoking habits, and evaluation of co-medication. Results: Both groups did not differ in mean values of VEN, O-desmethyl-VEN (ODV), VEN + ODV serum concentrations, and ODV/VEN ratio. No difference in dose-corrected serum concentrations between generic and brand-name VEN was revealed for males, females, smokers, or nonsmokers. In both groups, Spearman Rho correlation between VEN dose and VEN + ODV serum concentration was moderate but significant (P , 0.001; generic: r = 0.554; brand name: r = 0.668). Within the generic subgroup, females had a significantly higher dose-corrected serum concentration of VEN (U test, P , 0.05), whereas within brand name, no gender influence was detected. Spearman Rho correlation of age and dose-corrected ODV (P , 0.05) and VEN + ODV (P , 0.05) was significant only in the generic group. In the brandname sample, smokers had significantly lower dose-corrected serum concentrations of ODV (U test, P , 0.01) and VEN + ODV (P , 0.01). In the generic group, smoking habit was without any influence. Discussion: No differences in serum concentrations in dependence of either VEN formulations suggest a safe and efficient treatment of patients using the evaluated generic VEN. However, differences within one formulation regarding gender, age, and smoking status Received for publication March 18, 2013; accepted August 26, 2013. From the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Germany. S. Unterecker has received travel and accommodation expenses from Astra Zeneca, Pfizer, and Janssen. P. Riederer has received an honorarium from Merz-Pharmaceuticals GmbH. J. Deckert has received speaker’s honoraria from Janssen, Bristol-Myers Squibb, Wyeth, Lundbeck, Astra Zeneca, and Pfizer and grant support from Medice. B. Pfuhlmann has received speaker’s honoraria from Astra Zeneca, Janssen, and Pfizer. The authors have not received funding for this work from any organization. Correspondence: Stefan Unterecker, MD, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Füchsleinstrasse 15, D-97080 Würzburg, Germany (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
Ther Drug Monit Volume 36, Number 2, April 2014
(Ther Drug Monit 2014;36:269–272)
INTRODUCTION The antidepressant drug venlafaxine (VEN) acts by inhibiting the reuptake of serotonin and norepinephrine.1,2 VEN has been available in both brand-name and generic formulations for several years. Generic formulations are merchandized as therapeutically equivalent and less expensive alternatives to brand-name medications. Whereas health-care and pharmacy costs were found to be lower in patients receiving a generic instead of brand-name antidepressant drug with no difference in likelihood of therapy discontinuation in both patient samples,3 switching to a less expensive generic medication may lead to higher costs because of a higher risk of emergency department visits and hospitalizations.4 The process of approval of generic drugs is not as comprehensive as that of brand-name medication5 because marketing of generics does not require large clinical trials but only bioequivalence studies.6 The criteria of bioavailability in bioequivalence studies are area under the plasma concentration–time curve, maximum plasma concentration, and time to peak concentration. The bioequivalence criteria are fulfilled if area under the plasma concentration– time curve and relative mean measured maximum plasma concentration of the test drug compared with the reference drug fall within a range from 80% to 125%,7 allowing for some pharmacokinetic variability.8 Even if some studies examining the bioavailability and bioequivalence of different VEN formulations in varying doses in fasted and fed states altogether revealed comparable results,9–11 other authors described relapses, worsening of clinical outcomes, and occurrence of new adverse effects after switching from one antidepressant formulation to another.7,12–15 In some studies, different formulations were associated with a significant difference in serum concentrations, although the same doses of 2 antidepressant formulations were administered.8,16 As naturalistic studies are lacking and because of interindividual variations of pharmacokinetic parameters with potential influence on bioavailability, such as gender, age, smoking habits,17,18 or alterations of drug metabolism by genetic polymorphisms, comparisons of brand-name– and generic-treated patients in a standard clinical setting can be highly informative.
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MATERIALS AND METHODS In 2010, patients in the Department of Psychiatry, Psychosomatics, and Psychotherapy of the University Hospital of Würzburg received slow-release brand-name (Trevilor, Wyeth) or slow-release generic (Venlafaxin Hexal) formulations of VEN depending on the respective inpatient ward in which the treatment was given. If antidepressant therapy with VEN was chosen, dosage was individually titrated according to clinical efficacy and adverse effects. As part of routine clinical practice, therapeutic drug monitoring (TDM) was performed during antidepressant therapy for different indications, such as lack of response, control of adherence, suspected drug interaction, or occurrence of adverse effects. In case of multiple determinations of VEN in one patient, only the last determination was included to avoid multiple inclusion of the same individual. In a second step, serum concentration determinations, in which the ratio of metabolite to parent compound was ,1 and .5.2, were excluded to prevent confounding effects by poor, intermediate, and ultrarapid metabolizers.19,20 To examine a potential influence of the formulation of VEN and to compare brand-name VEN with generic VEN regarding influence of gender, age, smoking habits, and dose on VEN/O-desmethyl-VEN (ODV) serum concentration, the 2 groups were matched patient by patient. The psychopharmacological co-medication was completely recorded on the request form for TDM, and an influence on CYP2D6 and CYP3A4 activities could be excluded.
Statistical Analysis Samples were compared regarding dose-corrected serum concentrations of VEN, ODV, and the sum of both and the ratio of ODV/VEN with U tests. Spearman Rho correlations between serum concentrations of VEN + ODV and VEN dose on the one hand and dose-corrected serum concentrations of VEN, ODV, and VEN + ODV and the ratio of ODV/VEN and age on the other hand were evaluated.
Determination of VEN and ODV In the TDM laboratory of the Psychiatric University Hospital of Würzburg, VEN serum concentrations were determined by an isocratic reversed-phase high-performance liquid chromatography method.18 The laboratory participates in an external quality control program (Cardiff Bioanalytical Services, The Cardiff Medical Center, Cardiff, United Kingdom) with monthly analyzed control samples. The quality control program was operated without rejection of submitted values.
RESULTS Sample Characteristics In total, 348 TDM analyses of VEN were performed in 178 patients: 110 patients (58 females and 52 males) were treated with slow-release brand-name VEN and 68 patients with generic slow-release VEN (40 females and 28 males). Mean age in the generic sample was 38.4 years (SD 14.5, range 18–73) versus 47.3 years (SD 17.0, range 18–88) in the brandname sample. Sufficient information on smoking habits in the generic sample was available in 62 patients, 25 of whom were smokers and 37 nonsmokers. In the brand-name sample,
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information about smoking habit was available in 93 cases (32 smokers and 61 nonsmokers). The mean daily doses were 209.2 mg (SD 85.1, range 37.5–375) in the generic and 240.5 mg (SD 96.0, range 75–600) in the brand-name samples. In the latter, the mean serum concentration of the sum VEN + ODV was 375.5 ng/mL (SD 214.6, range 56–1443), in contrast to 320.4 ng/mL (SD 161.0, range 26–717) in the generic sample. By including every patient only once, 170 serum concentrations were excluded. After matching patients one by one regarding daily dose, age, gender, and smoking status and excluding patients with ODV/VEN ratio ,1 and .5.2, 35 patients remained in both matched groups with 22 females and 13 males each. Regarding smoking habits, an exact matching was not possible. In the generic sample, the ratio of nonsmokers to smokers was 18:16, whereas in the brand-name sample, it was 14:14 with missing data in 1 versus 7 cases. The matched samples did not significantly differ regarding mean age [37.8 6 13.1 (19–68) versus 37.8 6 13.2 (19–66) years] or mean VEN dose [212.1 6 83.8 (37.5–375) versus 226.1 6 104.7 (75–450) mg]. Both groups did not differ in the mean values of VEN, ODV, and VEN + ODV serum concentrations, dose-corrected serum concentrations, or in the ODV/VEN ratio (Table 1). In subgroup comparisons within males, females, smokers, and nonsmokers, no significant differences in dose-corrected serum concentrations between generic and brand-name formulations were found. The Spearman Rho correlation between VEN dose and serum concentration of VEN + ODV was significant in both groups (P , 0.001), and the correlation coefficient reached a similar magnitude (generic: r = 0.554; brand name: r = 0.668). Whereas within the generic subgroup, females showed a significantly higher dose-corrected serum concentration of VEN (U test, P , 0.05) and a trend toward higher dosecorrected serum concentration in VEN + ODV (P , 0.10) (Table 2), in the brand-name group, there was no gender difference in dose-corrected serum concentrations and ODV/VEN ratio. In contrast to a significant Spearman Rho correlation between age and dose-corrected ODV (r = 0.413, P , 0.05) and VEN + ODV (r = 0.396, P , 0.05) concentrations in the generic group, in the brand-name sample, no such correlation could be found. In the generic group, no difference between smokers and nonsmokers in dose-corrected serum concentrations and a trend of higher ODV/VEN ratio in smokers (P , 0.10) could be detected, whereas within the brand-name sample, smokers had significantly lower dose-corrected serum concentrations of ODV (0.712 6 0.158 versus 1.155 6 0.428 ng/mL per milligram, U test, P , 0.01) and VEN + ODV (1.069 6 0.235 versus 1.675 6 0.647 ng/mL per milligram, U test, P , 0.01) with a trend toward lower dose-corrected serum concentrations of VEN (P , 0.10) and no difference in the ODV/VEN ratio.
DISCUSSION In this study, the serum concentrations of VEN and its main metabolite ODV were evaluated in patient samples treated with brand-name or generic formulations of slowrelease VEN under naturalistic conditions. The authors found Ó 2014 Lippincott Williams & Wilkins
Ther Drug Monit Volume 36, Number 2, April 2014
Comparison of Brand-Name and Generic Venlafaxine
TABLE 1. Comparison of Serum Concentrations of VEN and ODV and ODV/VEN Ratio With Respect to Generic and Brand-Name VEN Treatment by U Test Mean 6 SD (Range) Generic VEN Serum concentration of VEN (ng/mL) Serum concentration of ODV (ng/mL) Serum concentration of VEN + ODV (ng/mL) Dose-corrected serum concentration of VEN (ng/mL per milligram per day) Dose-corrected serum concentration of ODV (ng/mL per milligram per day) Dose-corrected serum concentration of VEN + ODV (ng/mL per milligram per day) ODV/VEN ratio
comparable serum concentrations of VEN, ODV, and VEN + ODV and the ODV/VEN ratio after matching samples, which was also the case in the subgroup analyses of dose-corrected serum concentrations in males, females, smokers, and nonsmokers. The evaluated generic and brand-name VEN are therefore comparable regarding dose-corrected serum concentrations under naturalistic clinical conditions. Only analyses within subgroups revealed some significant differences: In generic-treated patients, age significantly correlated with serum concentrations of ODV and VEN + ODV, whereas in the brand-name group, smokers had significantly lower dose-corrected serum concentrations of ODV and VEN + ODV. Moreover, a difference between females and males regarding dose-corrected serum concentration of VEN was only found in the generic, but not in the brand-name, group. The present study did not evaluate comparability of the generic and brand-name VEN by differences of tolerability or efficacy. Because of the retrospective nature of the study, it can only provide explorative results. In addition, an influence of co-medication cannot be ruled out, although psychopharmacological co-medication was evaluated to exclude cases of CYP2D6 or CYP3A4 inhibition. Because bioequivalence studies are generally performed in smaller homogeneous samples of male, healthy volunteers, the advantage of a study in a naturalistic setting despite its heterogeneity is the evaluation of the relevance of possible differences for everyday clinical practice.21 This includes the evaluation of pharmacokinetic parameters, such as gender, age, and smoking habits,17,18 which are often ignored. The matching procedure in the present study together with the exclusion of multiple determinations was important to make the groups comparable but, inevitably, resulted in a considerable decrease of sample size. In contrast to bioequivalence studies, which measure serum or plasma concentrations in the hours after dosing,
95.6 202.2 297.8 0.481 1.000 1.481 2.304
6 6 6 6 6 6 6
52.0 (10–235) 104.2 (16–476) 148.8 (26–711) 0.272 (0.10–1.23) 0.447 (0.21–2.48) 0.685 (0.35–3.71) 0.774 (1.11–4.23)
P
Brand-Name VEN 93.6 190.5 284.1 0.418 0.898 1.316 2.409
6 6 6 6 6 6 6
61.7 (13–236) 98.0 (43–524) 152.1 (56–760) 0.230 (0.15–1.29) 0.378 (0.30–1.87) 0.553 (0.59–2.76) 0.979 (1.03–5.20)
0.626 0.782 0.622 0.301 0.247 0.211 0.747
this study has a more clinical focus evaluating serum concentrations under steady state conditions. This might be one reason for the lack of any difference in VEN, ODV, and VEN + ODV serum concentrations between brand-name and generic formulations in contrast to the study of Chenu et al.8 The different pattern of influence of gender, age, and smoking habits on serum concentrations in generic and brand-name VEN corresponds with unequivocal results regarding these variables in different studies.17,18,22,23 As it was discussed in the context of pharmacokinetic profiles of different VEN formulations,8 a variation in galenic formulation may also cause differences regarding the influence of gender, age, or smoking habits on dose-corrected serum concentrations of VEN and ODV. Possibly, variable galenic formulation can lead to gender- or age-related differences in the absorption of the same drug, but up to now, there is no clear evidence for such effects in various studies.24,25 Although switch studies suggest differences between brand-name and generic versions of psychotropic drugs regarding efficacy or adverse events7,12–15 and although variation of bioequivalence of the same compound in dependence of the respective manufacturer is a long-known problem,26 there still is a lack of studies comparing different generics with brand-name medication, which would involve higher number of patients under steady state conditions.6 Because switching from one generic drug to another one with a 80% to 125% bioequivalence to the brand-name drug might lead to a more than 50% increase or a more than one-third decrease of serum concentration,8 this represents a clear-cut indication for TDM.
CONCLUSIONS From the present study, the differences in serum concentrations of parent compound and metabolite between
TABLE 2. Comparison of Dose-Corrected Serum Concentrations of VEN and ODV and ODV/VEN Ratio in Female and Male Generic VEN–Treated Patients by U Tests Mean 6 SD (Range) Females (n = 22) Dose-corrected serum concentration of VEN (ng/mL per milligram per day) Dose-corrected serum concentration of ODV (ng/mL per milligram per day) Dose-corrected serum concentration of VEN + ODV (ng/mL per milligram per day) ODV/VEN ratio
Ó 2014 Lippincott Williams & Wilkins
0.553 1.090 1.644 2.171
6 6 6 6
0.302 0.487 0.753 0.780
Males (n = 13)
P
6 6 6 6
0.041 0.106 0.073 0.511
0.356 0.847 1.204 2.530
0.151 0.332 0.453 0.737
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Unterecker et al
the evaluated generic and brand-name VEN formulations are marginal, but factors such as gender, age, and smoking habit may influence dose-corrected serum concentrations depending on the respective generic or brand-name formulation. Hence, different results in different generic formulations of VEN cannot be ruled out and highlight the need for TDM. ACKNOWLEDGMENTS The authors gratefully acknowledge the staff of the TDM laboratory of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, R. Burger, M. Burger, R. Schreiner, and M. Weyer. REFERENCES 1. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs. 1995;49:280–294. 2. Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry. 2000;57:503–509. 3. Vlahiotis A, Devine ST, Eichholz J, et al. Discontinuation rates and health care costs in adult patients starting generic versus brand SSRI or SNRI antidepressants in commercial health plans. J Manag Care Pharm. 2011;17:123–132. 4. Wu EQ, Yu AP, Lauzon V, et al. Economic impact of therapeutic substitution of a brand selective serotonin reuptake inhibitor with an alternative generic selective serotonin reuptake inhibitor in patients with major depressive disorder. Ann Pharmacother. 2011;45:1169–1170. 5. Desmarais JE, Beauclair L, Margolese HC. Switching from brand-name to generic psychotropic medications: a literature review. CNS Neurosci Ther. 2011;17:750–760. 6. Borgherini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25:1578–1592. 7. Van Ameringen M, Mancini C, Patterson B, et al. Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series. J Psychopharmacol. 2007;21:472–476. 8. Chenu F, Batten LA, Zernig G, et al. Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study. J Clin Psychiatry. 2009;70:958–966. 9. Rajasekhar D, Kumar IJ, Venkateswarlu P. Rapid high-performance liquid chromatography-tandem mass spectrometry method for simultaneous measurement of venlafaxine and O-desmethylvenlafaxine in human plasma and its application in comparative bioavailability study. Biomed Chromatogr. 2009;23:1300–1307. 10. Wright CW, Aikman MS, Werts E, et al. Bioequivalence of single and multiple doses of venlafaxine extended-release tablets and capsules in the
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