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Drug interactions affecting clozapine levels

  • Harvinder Singh (a1), William R. Dubin (a2) and Satinderpal Kaur (a3)
Abstract

Clozapine is used in combination with psychotropic medication and a wide variety of non-psychotropic medications. This article reviews the literature on clozapine drug interactions and the effect these have on serum level changes in clozapine. A total of 54 articles with a total of 109 individual case reports were obtained by manual and computerised literature search from January 1970 to May 2013. Psychotropic medications most likely to increase clozapine levels include: fluvoxamine, lamotrigine, aripiprazole and the discontinuation of levomepromazine and carbamazepine. Non-psychotropic medications associated with increase in clozapine levels include: erythromycin, ciprofloxacin, omeprazole, cimetidine, OCP containing ethinylestradiol, amiodarone, aluminum hydroxide and isoniazid. Rifampin and St John's wort resulted in low clozapine levels. Smoking cessation also increased clozapine levels. The role of routine clozapine monitoring in clinical practice requires further clarification. In the absence of recommendations for routine clozapine level monitoring, clinical judgment should always be used in addition to diagnostic testing. Clinicians must maintain increased clinical vigilance for adverse side effects when clozapine is combined with other medications.

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Copyright
Corresponding author
Correspondence to: Dr Harvinder Singh, Department of Psychiatry, Temple University Hospital, Episcopal Campus, MAB Building, 100 East Lehigh Avenue, Philadelphia, PA 19125, USA. E-mail: harvinder.singh@tuhs.temple.edu
References
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Abraham, G., Grunberg, B., Gratz, S. (2001) Possible interaction of clozapine and lisinopril. American Journal of Psychiatry. 158(6): 969.
Abu-Tair, F., Kopitz, J., Bergemann, N. (2006) Clozapine augmented with aripiprazole in 5 patients with schizophrenia. Journal of Clinical Psychopharmacology. 26(6): 669671.
Al Hadithy, A., Leeffers, E., Bruggeman, R. (2012) Clozapine levels might be affected by excessive cola consumption. Journal of Clinical Psychopharmacology. 32(5): 717719.
Allard, M., Légaré, N., Millaud, F. (2008) A possible case of clozapine interaction with aluminium hydroxide. Schizophrenia Research. 101(1–3): 346.
Andersson, T., Hassan-Aline, M., Hasselgren, G., Röhss, K. (2001) Drug interactions studies with esomeprazole, the (S)-isomer of omeprazole. Clinical Pharmacokinetics. 40(7): 523537.
Angelini, M.C., MacCormack-Gagnon, J., Dizio, S. (2009) Increase in plasma levels of clozapine after addition of isoniazid. Journal of Clinical Psychopharmacology. 29(2): 190191.
Armstrong, S.C., Stephans, J.R. (1997) Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage. Journal of Clinical Psychiatry. 58(11): 499.
Avari, J., Mahgoub, N., Alexopoulos, G.S. (2011) Adding aripiprazole to clozapine worsened delusions and hallucinations: a case report. Journal of Clinical Psychopharmacology. 31(4): 528531.
Batty, K.T., Davis, T.M., Ilett, K.F., Dusci, L.J., Langton, S.R. (1995) The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects. British Journal of Clinical Pharmacology. 39(3): 305311.
Bergemann, N., Kress, K.R., Frick, A., Kopitz, J. (2005) Amisulpride has no effect on plasma clozapine concentrations. Journal of Clinical Psychopharmacology. 25(5): 494497.
Bertilsson, L., Carrillo, J.A., Dahl, M.L., Llerena, A., Alm, C., Bondesson, U., Lindstrom, L., Rodriguez de la Rubia, I., Ramos, S., Benitez, J. (1994) Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. British Journal of Clinical Pharmacology. 38(5): 471473.
Brøsen, K. (1993) The pharmacogenetics of the selective serotonin reuptake inhibitors. The Clinical Investigator. 71(12): 10021009.
Brouwers, E.E., Söhne, M., Kuipers, S., van Gorp, E.C., Schellens, J.H., Koks, C.H., Beijnen, J.H., Huitema, A.D. (2009) Ciprofloxacin strongly inhibits clozapine metabolism: two case reports. Clinical Drug Investigation. 29(1): 5963.
Brownlowe, K., Sola, C. (2008) Clozapine toxicity in smoking cessation and with ciprofloxacin. Psychosomatics. 49(2): 176.
Bugamelli, F., Madrioli, R., Kenndler, E., Bartoletti, C., Boncompagni, G., Raggi, M.A. (2007) Possible levomepromazine-clozapine interaction: two case reports. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 31(2): 567570.
Calabrese, J.R., Gajwani, P. (2000) Lamotrigine and clozapine for bipolar disorder. American Journal of Psychiatry. 157(9): 1523.
Carrillo, J.A., Herraiz, A.G., Ramos, S.I., Benitez, J. (1998) Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. Journal of Clinical Psychopharmacology. 18(4): 311316.
Centorrino, F., Baldessarini, R.J., Kando, J., Frankenburg, F.R., Volpicelli, S.A., Puopolo, P.R., Flood, J.G. (1994) Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. American Journal of Psychiatry. 151(1): 123125.
Chan, J., Sweeting, M. (2007) Review: combination therapy with non-clozapine atypical antipsychotic medication: a review of current evidence. Journal of Psychopharmacology. 21(6): 657664.
Chong, S.A., Tan, C.H., Lee, H.S. (1997) Worsening of psychosis with clozapine and selective serotonin reuptake inhibitor combination: two case reports. Journal of Clinical Psychopharmacology. 17(1): 6869.
Cohen, L.G., Chesley, S., Eugenio, L., Flood, J.G., Fisch, J., Goff, D.C. (1996) Erythromycin-induced clozapine toxic reaction. Archives of Internal Medicine. 156(6): 675677.
Conca, A., Beraus, W., König, P., Waschgler, R. (2000) A case of pharmacokinetic interference in comedication of clozapine and valproic acid. Pharmacopsychiatry. 33(6): 234235.
Cooper, T.B. (1996) Clozapine plasma level monitoring: current status. Psychiatric Quarterly. 67(4): 297311.
Couchman, L., Bowskill, S.V.J., Handley, S., Patel, M.X., Flanagan, R.J. (2013) Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: data from a therapeutic drug monitoring service, 1994–2010. Early Intervention in Psychiatry. 7(2): 122130.
Darling, P., Huthwaite, M.A. (2011) Infection-associated clozapine toxicity. Clinical Schizophrenia & Related Psychoses. 5(3): 159160.
de Leon, J., Diaz, F.J. (2003) Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 27(6): 10591063.
Dequardo, J.R. (2002) Modafinil-associated clozapine toxicity. American Journal of Psychiatry. 159(7): 12431244.
Dequardo, J.R., Roberts, M. (1996) Elevated clozapine levels after fluvoxamine initiation. American Journal of Psychiatry. 153(6): 840841.
Derenne, J.L., Baldessarini, R.J. (2005) Clozapine toxicity associated with smoking cessation: case report. American Journal of Therapeutics. 12(5): 469471.
DuMortier, G., Lochu, A., Colen de Melo, P., Ghribi, O., Roche-Rabreau, D., DeGrassat, K., Desce, J.M. (1996) Elevated clozapine plasma concentrations after fluvoxamine initiation. American Journal of Psychiatry. 153(5): 738739.
Egger, C., Muehlbacher, M., Grohmann, R., Stuppaeck, C. (2010) Clozapine intoxication in a patient with lamotrigine-induced rash. Pharmacopsychiatry. 43(1): 3536.
Eiermann, B., Engel, G., Johansson, I., Zanger, U.M., Bertilsson, L. (1997) The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. British Journal of Clinical Pharmacology. 44(5): 439446.
Farde, L., Nordström, A.-L., Wiesel, F.-A., Pauli, S., Halldin, C., Sedvall, G. (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Archives of General Psychiatry. 49(7): 538544.
Ferslew, K.E., Hagardorn, A.N., Harlan, G.C., McCormick, W.F. (1998) A fatal drug interaction between clozapine and fluoxetine. Journal of forensic sciences. 43(5): 10821085.
Finley, P., Warner, D. (1994) Potential impact of valproic acid therapy on clozapine disposition. Biological Psychiatry. 36(7): 487488.
Freeman, D.J., Oyewumi, L.K. (1997) Will routine therapeutic drug monitoring have a place in clozapine therapy? Clinical Pharmacokinetics. 32(2): 93100.
Frick, A., Kopitz, J., Bergemann, N. (2003) Omeprazole reduces clozapine plasma concentrations: a case report. Pharmacopsychiatry. 36(3): 121123.
Fuchs, D.C. (1994) Clozapine treatment of bipolar disorder in a young adolescent. Journal of the American Academy of Child and Adolescent Psychiatry. 33(9): 12991302.
Funderburg, L.G., Vertrees, J.E., True, J.E., Miller, A.L. (1994) Seizure following addition of erythromycin to clozapine treatment. American Journal of Psychiatry. 151(12): 18401841.
Gabbay, V., O'Dowd, M.A., Mamamtavrishvili, M., Asnis, G.M. (2002) Clozapine and oral contraceptives: a possible drug interaction. Journal of Clinical Psychopharmacology. 22(6): 621622.
Granfors, M.T., Backman, J.T., Laitila, J., Neuvonen, P.J. (2005) Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A. Clinical Pharmacology & Therapeutics. 78(4): 400411.
Haack, M.-J., Bak, M.L.F.J., Beurskens, R., Maes, M., Stolk, L.M.L., Delespaul, P.A.E.G. (2003) Toxic rise of clozapine plasma concentrations in relation to inflammation. European Neuropsychopharmacology. 13(5): 381385.
Hals, P.A., Dahl, S.G. (1994) Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat. Pharmacology & Toxicology. 75(5): 255260.
Haring, C., Meise, U., Humpel, C., Saria, A., Fleischhacker, W.W., Hinterhuber, H. (1989) Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology. 99: S38S40.
Heeringa, M., Beurskens, R., Shouten, W., Verduijn, M.M. (1999) Elevated plasma levels of clozapine after concomitant use of fluvoxamine. Pharmacy World & Science. 21(5): 243244.
Hiemke, C., Weigman, H., Härtter, S., Dahmen, N., Wetzel, H., Müller, H. (1994) Elevated levels of clozapine in serum after addition of fluvoxamine. Journal of Clinical Psychopharmacology. 14(4): 279280.
Hiemke, C., Dragicevic, A., Gründer, G., Hätter, S., Sachse, J., Vernaleken, I., Müller, M.J. (2004) Therapeutic monitoring of new antipsychotic drugs. Therapeutic Drug Monitoring. 26(2): 156160.
Huang, F., Lasseter, K.C., Janssens, L., Verhaeghe, T., Lau, H., Zhao, Q. (2002) Pharmacokinetic and safety assessments of galantamine and risperidone after the two drugs are administered alone and together. Journal of Clinical Pharmacology. 42(12): 13411351.
Jain, S., Chawla, J.M., Theethira, T.G., Strassnig, M., Chengappa, K.N.R. (2008) Changes in cigarette consumption in psychiatric patients: impact on side-effects or the efficacy of clozapine and olanzapine. Acta Neuropsychiatrica. 20(6): 324326.
Jecel, J., Michel, T.M., Gutknecht, L., Schmidt, D., Pfuhlmann, B., Jabs, B.E. (2005) Toxic clozapine serum levels during acute urinary tract infection: a case report. European Journal of Clinical Pharmacology. 60(12): 909910.
Jerling, M., Lindström, L., Bondesson, U., Bertilsson, L. (1994) Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Therapeutic Drug Monitoring. 16(4): 368374.
Kapur, S., Zipursky, R.B., Remington, G. (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. American Journal of Psychiatry. 156(2): 286293.
Khan, A.Y., Preskorn, S.H. (2005) Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. Journal of Psychiatric Practice. 11(5): 289301.
Koponen, H.J., Leinonen, E., Lepola, U. (1996) Fluvoxamine increases the clozapine serum levels significantly. European neuropsychopharmacology. 6(1): 6971.
Kossen, M., Selten, J.P., Kahn, R.S. (2001) Elevated clozapine plasma level with lamotrigine. American Journal of Psychiatry. 158(11): 1930.
Kuo, F.-J., Lane, H.-Y., Chang, W.-H. (1998) Extrapyramidal symptoms after addition of fluvoxamine to clozapine. Journal of Clinical Psychopharmacology. 18(6): 483484.
Lehman, A.F., Lieberman, J.A., Dixon, L.B., McGlashan, T.H., Miller, A.L., Perkins, D.O., Kreyenbuhl, J. (2010) Practice guideline for the treatment of patients with schizophrenia, 2nd edition. American Psychiatric Association Steering Committee on Practice Guidelines. DOI: 10.1176/appi.books.9780890423363.45859
Lieberman, J.A., Safferman, A.Z. (1992) Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatric Quarterly. 63: 5170.
Liu, H.C., Chang, W.H., Wei, F.C., Lin, S.K., Jann, M.W. (1996) Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients. Therapeutic Drug Monitoring. 18(2): 200207.
Longo, L.P., Salzman, C. (1995) Valporic acid effects on serum concentrations of clozapine and norclozapine. American Journal of Psychiatry. 152(4): 650.
Martínez, C., Albet, C., Agúndez, J.A., Herrero, E., Carrillo, J.A., Márquez, M., Benítez, J., Ortiz, J.A. (1999) Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists. Clinical Pharmacology & Therapeutics. 65(4): 369376.
McCarthy, R.H. (1994) Seizures following smoking cessation in a clozapine responder. Pharmacopsychiatry. 27(5): 210211.
Meyer, J.M. (2001) Individual changes in clozapine levels after smoking cessation: results and a predictive model. Journal of Clinical Psychopharmacology. 21: 569574.
Miller, D.D. (1981) Effect of phenytoin on plasma clozapine concentrations in two patients. Journal of Clinical Psychiatry. 52(1): 2325.
Mitchell, P.B. (2000) Therapeutic drug monitoring of psychotropic medications. British Journal of Clinical Pharmacology. 49(4): 303312.
Müller, T., Becker, T., Fritze, J. (1998) Neuroleptic malignant syndrome after clozapine plus carbamazepine. Lancet. 332(8626): 1500.
Murray, M. (1992) P450 enzymes. Inhibition mechanisms, genetic regulation and effects of liver disease. Clinical Pharmacokinetics. 23(2): 132146.
Nebel, A., Schneider, B.J., Baker, R.K., Kroll, D.J. (1999) Potential metabolic interaction between St. John's wort and theophylline. Annals of Pharmacotherapy. 33(4): 502.
Nielsen, J., Correll, C.U., Manu, P., Kane, J.M. (2013) Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? Journal of Clinical Psychiatry. 74(6): 603613.
Ohyama, K., Nakajima, M., Suzuki, M., Shimada, N., Yamazaki, H., Yokoi, T. (2000) Inhibitory effects of amiodarone and its N-demethylated metabolite on human cytochrome P450 activities: prediction of in-vivo drug interactions. British Journal of Clinical Pharmacology. 49: 244253.
Perry, P.J., Bever, K.A., Arndt, S., Combs, M.D. (1998) Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biological Psychiatry. 44(8): 733738.
Pinninti, N.R., de Leon, J. (1997) Interaction of sertraline with clozapine. Journal of Clincial Psychopharmacology. 17(2): 119120.
Préterre, P. (1995) Blood clozapine level and therapeutic adjustment. Encephale. 21(spec. no 3): 5357 [in French].
Raaska, K., Raitasuo, V., Arstila, M., Neuvonen, P. (2002) Bacterial pneumonia can increase serum concentration of clozapine. European Journal of Pharmacology. 58(5): 321322.
Raitasuo, V., Lehtovaara, R., Huttunen, M. (1993) Carbamazepine and plasma levels of clozapine. American Journal of Psychiatry. 150(1): 169.
Remington, G., Agid, O., Foussias, G., Ferguson, L., McDonald, K., Powell, V. (2013) Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Psychopharmacology. 225(3): 505518.
Rowland, M., Tozer, T.N. (1995) Clinical Pharmacokinetics: Concepts and applications, 3rd edition. Baltimore: Williams and Wilkins, 601 pp.
Sambhi, R.S., Puri, R., Jones, G. (2007) Interaction of clozapine and ciprofloxacin: a case report. European Journal of Clinical Pharmacology. 63(9): 895896.
Sandson, N.B., Cozza, K.L., Armstrong, S.C., Eckermann, G., Fischer, B.A., Phillips, B. (2007) Clozapine case series. Psychosomatics. 48(2): 170175.
Siewert, E., Bort, R., Kluge, R., Heinrich, P.C., Castell, J., Jover, R. (2000) Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent. Hepatology. 32(1): 4955.
Spina, E., Avenoso, A., Salemi, M., Facciolá, G.E., Scordo, M.G., Ancione, M., Madia, A. (2000) Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline. Pharmacopsychiatry. 33(6): 213217.
Stevens, J.R., Freudenreich, O., Stern, T.A. (2008) Elevated clozapine serum level after treatment with amiodarone. Psychosomatics. 49(3): 255257.
Szymanski, S., Lieberman, J.A., Picou, D., Masiar, S., Cooper, T. (1991) A case report of cimetidine-induced clozapine toxicity. Journal of Clinical Psychiatry. 52(1): 2122.
Taylor, D., Ellison, Z., Ementon, S.L., Wickham, H., Murray, R. (1998) Co-administration of citalopram and clozapine: effect on plasma clozapine levels. International Clinical Psychopharmacology. 13(1): 1921.
Taylor, D., Paton, C., Kapur, S. (2009) The Maudsley Prescribing Guidelines, 10th edition. London: Informa Healthcare.
Tyson, S.C., Devane, C.L., Risch, S.C. (1995) Pharmacokinetic interaction between risperidone and clozapine. American Journal of Psychiatry. 152(9): 14011402.
Uges, D.R., Boom, K., Wentjex, G.D., Versteege, J. DR (2000) Therapeutic drug monitoring of clozapine: an unexpected outcome. Therapeutic Drug Monitoring. 22(3): 323324.
Vailleau, J.L., Jeanny, B., Chomard, P., Vincent, R. (1996) Importance of determining clozapine plasma level in follow-up of schizophrenic patients. Encephale. 22(2): 103109. [in French].
Vainer, J.L., Chouinard, G. (1994) Interaction between caffeine and clozapine. Journal of Clinical Psychopharmacology. 14(4): 284285.
Van Strater, A.C., Bogers, J.P. (2012) Interaction of St John's wort (Hypericum perforatum) with clozapine. International Clinical Psychopharmacology. 27(2): 121124.
VanderZwaag, C., McGee, M., McEvoy, J.P., Freudenreich, O., Wilson, W.H., Cooper, T.B. (1996) Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. American Journal of Psychiatry. 153(12): 15791584.
Wagner, S., Varet-Legros, M.G., Fabre, C., Montastruc, J.L., Bagheri, H. (2011) Confounding factors for variation of clozapine plasma levels: drug interactions with proton pump inhibitor or infectious etiologies? European Journal of Clinical Pharmacology. 67(5): 533534.
Wetzel, H., Anghelescu, I., Szegedi, A., Wiesner, J., Weigmann, H., Hartter, S., Hiemke, C. (1998) Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. Journal of Clinical Psychopharmacology. 18(1): 29.
Wynn, G.H., Oesterheld, J.R., Cozza, K.L., Armstrong, S.C. (2009) Clinical manual of drug interaction principles for medical practice. Washington, DC: American Psychiatric Publishing Inc., 608 pp.
Yusufi, B., Mukherjee, S., Flanagan, R., Paton, C., Dunn, G., Page, E., Barnes, T.R.E. (2007) Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration. International Clinical Psychopharmacology. 22(4): 238243.
Zullino, F.F., Delessert, D., Eap, C.B., Preisiq, M., Baumann, P. (2002) Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. International Clinical Psychopharmacology. 17(3): 141143.
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