Value and Actuality of the Prescription Information for Therapeutic Drug Monitoring of Psychopharmaceuticals: A Comparison with the Medico-Scientific Evidence

Abstract

Therapeutic drug monitoring (TDM) of psychopharmaceuticals, i.e., the assay of plasma concentrations, is a practical therapeutic application of pharmacokinetic principles in psychiatry. The prescription information (summary of product characteristics, SPC) is provided by pharmaceutical companies according to the requirements of regulatory authorities. The present study investigated the degree of agreement of German SPCs for 48 psychopharmaceuticals with the existing medico-scientific evidence in the area of TDM. For this aim, an empirical summary score of SPC content related to TDM (SPCC_TDM) was calculated and compared with the level of recommendation of TDM (LOR) of the AGNP-TDM expert group consensus guidelines. Considerable disagreement was found between the information on TDM in SPCs and existing medico-scientific evidence, e.g., in the case of antidepressant and antipsychotic drugs. Even for well studied compounds, such as amitriptyline and clozapine, insufficient information on TDM is included in German SPCs. Small differences existed in the TDM-related information in SPCs of generic drugs with, however, much variance between Germany, Austria and Switzerland. Generally, it must be concluded that deficits exist in the preparation of German SPCs for psychopharmaceutical drugs with respect to empirical pharmacokinetic data, i.e., TDM-relevant information. It is recommended that SPCs of psychopharmaceuticals should be improved in terms of TDM-related information and that target plasma concentrations be adjusted according to the guidelines of the AGNP-TDM expert group. A higher level of good pharmacokinetic practice may be thus achieved.

Key words

therapeutic drug monitoring - prescription information - pharmacovigilance - amitriptyline - haloperidol

References

• 1 Bauer M, Whybrow PC, Angst J, Versiani M, Möller HJ. World Federation of Societies of Biological Psychiatry: Task Force on Treatment Guidelines for Unipolar Depressive Disorders . World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, Part 1: Acute and continuation treatment of major depressive disorder.  World J Biol Psychiat. 2002;  3 5-43
• 2 Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G. AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.  Pharmacopsychiatry. 2004;  37 243-265
• 3 Baumann P, Hiemke C, Ulrich S, Eckermann G, Kuss HJ, Laux G, Müller-Oerlinghausen BM, Rao ML, Riederer P, Zernig G. Le dosage plasmatique des médicaments psychotropes à des fins thérapeutiques: recommandations du groupe d’experts AGNP-TDM.  Rev Med Suisse. 2006;  2 1413-1426
• 4 Baumann P, Hiemke C, Ulrich S, Gaertner I, Rao ML, Eckermann G, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Riederer P, Zernig G. Therapeutic drug monitoring of psychotropic drugs: An outline of the AGNP-TDM expert group consensus guideline.  Ther Drug Monit. 2004;  26 167-170
• 5 BfArM . 2006;  http://www.bfarm.de/cln_043/nn_424574/DE/Arzneimittel/mufag/ mufagDb/mufagdb-node.html_nnn=true
• 6 Bergk V, Haefeli WE, Gasse C, Brenner H, Martin-Facklam M. Information deficits in the summary of product characteristics preclude an optimal management of drug interactions: a comparison with evidence from the literature.  Eur J Clin Pharmacol. 2005;  61 327-235
• 7 European Commission (EC) . Notice to Applicants: A guideline on summary of product characteristics.  http://ec.europa.eu/enterprise/pharmaceuticals/ eudralex/vol-2/c/spcguidrev1-oct2005.pdf , Sept 2006; 
• 8 European Medicines Agency (EMEA) . Note for guidance on dose response information to support drug registration (CPMP/ICH/378/95).  http://www.emea.europa.eu/pdfs/human/ich/037895en.pdf , Sept 2006; 
• 9 Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Moller HJ. WFSBP Task Force on Treatment Guidelines for Schizophrenia . World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: long-term treatment of schizophrenia.  World J Biol Psychiat. 2006;  7 5-40
• 10 Gebran N, Al Haidari K. Assessment of prescribing information for generic drugs manufactured in the Middle East and marketed in Saudi Arabia.  Ann Saudi Med. 2006;  26 192-199
• 11 Gex-Fabry M, Balant-Gorgia AE, Balant LP. Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions.  Drug Saf. 2001;  24 947-959
• 12 Gilles M, Deuschle M, Kellner S, Shams M, Krumm B, Härtter S, Heuser I, Hiemke C. Paroxetine serum concentrations in depressed patients and response to treatment.  Pharmacopsychiatry. 2005;  38 118-121
• 13 Gräfe KA. Fachinformation: veraltet, ungenau oder fehlerhaft.  Pharmazeutische Zeitung. 2006;  3 222
• 14 Grasmäder K, Verwohlt PL, Kuhn KU, Frahnert C, Hiemke C, Dragicevic A, von Widdern O, Zobel A, Maier W, Rao ML. Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.  Pharmacopsychiatry. 2005;  38 113-117
• 15 Hiemke C, Baumann P, Laux G, Kuss HJ. Therapeutisches Drug Monitoring in der Psychiatrie.  Psychopharmakotherapie. 2005;  12 166-182
• 16 Leinonen E, Lillsunde P, Laukkanen V, Ylitalo P. Effects of carbamazepine on serum antidepressant concentrations in psychiatric patients.  J Clin Psychopharmacol. 1991;  11 313-318
• 17 Müller MJ, Regenbogen B, Sachse J, Eich FX, Härtter S, Hiemke C. Gender aspects in the clinical treatment of schizophrenic inpatients with amisulpride: a therapeutic drug monitoring study.  Pharmacopsychiat. 2006;  39 41-46
• 18 Perry PJ, Zeilmann C, Arndt S. Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specificity as a predictor of response.  J Clin Psychopharmacol. 1994;  14 230-240
• 19 Perry PJ, Lund BC, Sanger T, Beasley C. Olanzapine plasma concentrations and clinical response: acute phase results of the North American olanzapine trial.  J Clin Psychopharmacol. 2001;  21 14-20
• 20 Reggi V, Balocco-Mattavelli R, Bonati M, Breton I, Figueras A. et al . Prescribing information in 26 countries: a comparative study.  Eur J Clin Pharmacol. 2003;  59 263-270
• 21 Riederer P, Laux G. Therapeutic drug monitoring of psychotropics: report of a consensus conference.  Pharmacopsychiat. 1992;  25 271-272
• 22 SRZ 2006: FachInfo . , Fachinformationsverzeichnis Deutschland, Ausgabe 2006/1-CD-Version, Satz-Rechen-Zentrum Berlin, Bessemerstraße 83-91, D-12103 Berlin
• 23 Steinmetz KL, Coley KC, Pollock BG. Assessment of geriatric information on the drug label for commonly prescribed drugs in older people.  J Am Geriatr Soc. 2005;  53 891-894
• 24 Ulrich S, Läuter J. A comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression.  Clin Pharmacokin. 2002;  41 853-876
• 25 Ulrich S, Schroeder I, Partscht G, Baumann P. Therapeutisches Drug Monitoring von psychotropen Pharmaka: Eine allgemeine Einführung.  Psychopharmakotherapie. 2000;  7 2-14
• 26 Ulrich S, Wolf R, Staedt J. Serum level of clozapine and relapse.  Ther Drug Monit. 2003;  25 252-255
• 27 Ulrich S, Wurthmann C, Brosz M, Meyer FP. The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia: A review.  Clin Pharmacokin. 1998;  34 227-263
• 28 Van der Zwaag C, McGee M, McEvoy JP, Freudenreich O, Wilson WH, Cooper TB. Response of patients with treatment refractory schizophrenia to clozapine within three serum level ranges.  Am J Psychiat. 1996;  153 1579-1584
• 29 Van Putten T, Marder SR, Wirshing WC, Aravagiri M, Chabert N. Neuroleptic plasma levels.  Schizophr Bull. 1991;  17 197-216
• 30 Zineh I, Pebanco GD, Aquilante CL, Gerhard T, Beitelshees AL, Beasley BN, Hartzema AG. Discordance between availability of pharmacogenetics studies and pharmacogenetics-based prescribing information for the top 200 drugs.  Ann Pharmacother. 2006;  40 639-644

1 Other members of the AGNP-TDM expert group N. Bergemann, Heidelberg; M. Dobmeier, Cham; G. Eckermann, Kaufbeuren; M. Gerlach, Würzburg; E. Haen, Regensburg; E. Jaquenoud-Sirot, Königsfelden; M. Köhnke, Rostock; H. J. Kuss, München; T. Messer, Augsburg; B. Pfuhlmann, Würzburg; M. L. Rao, Bonn; B. Schoppek, Haar, M. Schwarz, München

Correspondence