Drug products: Clozapine 2care4, Clozapine Accord, Clozapine Actavis, Clozapine Mylan, Clozapine Orifarm, Clozapine Rivopharm, Clozapine Sandoz, Froidir, Leponex, Leponex®
ATC code: N05AH02
Women display higher trough plasma concentrations of clozapine than men after administration of similar doses. However, the evidence regarding sex differences in efficacy and adverse effects during treatment with clozapine is inconclusive. Agranulocytosis has disproportionately affected women in the majority of identified studies, and certain metabolic adverse effects have been associated with sex-related incidence differences although the evidence is largely conflicting.
Pharmacokinetics and dosing
Clozapine is extensively metabolized in the liver, predominantly by the cytochrome P450 enzymes CYP1A2 and CYP3A4, with smaller contributions from CYP2C19 and CYP2D6 among other enzymes [1-3]. Women in clinical trials have generally displayed higher dose-adjusted plasma concentrations of clozapine and its active metabolite norclozapine than men [4-6]. The magnitude of reported sex differences has ranged between approximately 15-60% for clozapine and norclozapine depending on population and methodology . It is frequently suggested that this sex difference is derived primarily from a lower CYP1A2 activity in women, conferring a decreased clearance of clozapine [4-6]. However, several other factors may contribute, such as e.g. lower glomerular filtration rates, tubular secretion and hepatic blood flow in women on average, as well as sex differences in concomitant medications (e.g. oral contraceptives) and smoking which may influence the exposure of CYP1A2 metabolized drugs . Clinical trials with relevant sex analyses of clozapine plasma concentrations have generally relied predominantly on trough or random samples . This might theoretically exaggerate perceived sex differences in the total exposure of clozapine over the dosing interval; smaller fluctuations of clozapine concentrations during the dosing interval has been suggested in women compared to men, due to higher relative volumes of distribution for clozapine [7, 8]. Hence, sex differences in trough concentrations might be more pronounced than sex differences in e.g. mean plasma concentrations during the dosing interval [7, 8].No sex related dose adjustments are recommended by the manufacturer and no information regarding pharmacokinetic sex differences is provided in the summary of product characteristics .Therapeutic drug monitoring should be considered when prescribing clozapine, especially in the event of anticipated pharmacokinetic interactions, suspected toxicity or inadequate therapeutic effects in relation to administered doses.
No prospective, controlled trials examining sex differences in clozapine therapeutic efficacy have been identified. Observational data are conflicting, with some studies indicating a favorable treatment response rate in women compared to men [11-13], whereas others have indicated the opposite [14-16] or failed to demonstrate significant sex effects . Differences in patient populations, baseline conditions and evaluated endpoints between the different studies makes it difficult to perform meaningful comparisons. The authors of a systematic review published in 2019 concluded that although female sex is frequently associated with a more beneficial response to antipsychotics in schizophrenia, it is not yet clear whether this holds true for clozapine .
Several observational studies have indicated that women might be disproportionally affected by clozapine-induced neutropenia including agranulocytosis [19-22] and immunological sex differences have been proposed as a plausible explanation . According to the authors of a systematic review, available evidence suggests that metabolic adverse effects such as hypertension and dyslipidemia might be more common in men taking clozapine, whereas women may be more prone to gain weight and develop diabetes respectively . However, conflicting results have been reported [24-27]. Although female sex is generally considered an independent risk factor for drug induced QT-interval prolongation and development of Torsades de Pointes , reported sex differences for clozapine appear inconclusive in this respect .
Reproductive health issues
Use of combined hormonal contraceptives containing ethinylestradiol has been associated with an increased exposure to clozapine [9, 10]. Regarding other drug interaction aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner). Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2020-08-21
- Leponex (klozapin). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-09-22, cited 2020-08-25]
- Krivoy A, Gaughran F, Weizman A, Breen G, MacCabe JH. Gene polymorphisms potentially related to the pharmacokinetics of clozapine: a systematic review. Int Clin Psychopharmacol. 2016;31(4):179-84. PubMed
- Eiermann B, Engel G, Johansson I, Zanger UM, Bertilsson L. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol. 1997;44(5):439-46. PubMed
- Albitar O, Harun SN, Zainal H, Ibrahim B, Sheikh Ghadzi SM. Population Pharmacokinetics of Clozapine: A Systematic Review. Biomed Res Int. 2020;2020:9872936. PubMed
- Mayerova M, Ustohal L, Jarkovsky J, Pivnicka J, Kasparek T, Ceskova E. Influence of dose, gender, and cigarette smoking on clozapine plasma concentrations. Neuropsychiatr Dis Treat. 2018;14:1535-1543. PubMed
- Aichhorn W, Whitworth AB, Weiss EM, Marksteiner J. Second-generation antipsychotics: is there evidence for sex differences in pharmacokinetic and adverse effect profiles?. Drug Saf. 2006;29(7):587-98. PubMed
- Ng W, Uchida H, Ismail Z, Mamo DC, Rajji TK, Remington G et al. Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study. Ther Drug Monit. 2009;31(3):360-6. PubMed
- Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24(1):70-8. PubMed
- Janusmed Interactions. Stockholm: Region Stockholm. 2020 [updated 2020-08-19, cited 2020-08-26.] länk
- Stockley’s Drug Interactions. London: Royal Pharmaceutical Society. 2020 [updated 2020-08-11, cited 2020-08-26.] länk
- Usall J, Suarez D, Haro JM, SOHO Study Group. Gender differences in response to antipsychotic treatment in outpatients with schizophrenia. Psychiatry Res. 2007;153:225-31. PubMed
- Ciapparelli A, Ducci F, Carmassi C, Carlini M, Paggini R, Catena M et al. Predictors of response in a sample of treatment-resistant psychotic patients on clozapine. Eur Arch Psychiatry Clin Neurosci. 2004;254(5):343-6. PubMed
- Umbricht DS, Wirshing WC, Wirshing DA, McMeniman M, Schooler NR, Marder SR et al. Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia. J Clin Psychiatry. 2002;63(5):420-4. PubMed
- Nielsen J, Nielsen RE, Correll CU. Predictors of Clozapine Response in Patients With Treatment-Refractory Schizophrenia. J Clin Psychiatry. 2012;32(5):678-83. PubMed
- Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, Howard A et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry. 1994;151(12):1744-52. PubMed
- Szymanski S, Lieberman J, Pollack S, Kane JM, Safferman A, Munne R et al. Gender differences in neuroleptic nonresponsive clozapine-treated schizophrenics. Biol Psychiatry. 1996;39(4):249-54. PubMed
- Perry PJ, Miller DD, Arndt SV, Cadoret RJ. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry. 1991;148(2):231-5. PubMed
- Alberich S, Fernández-Sevillano J, González-Ortega I, Usall J, Sáenz M, González-Fraile E et al. A systematic review of sex-based differences in effectiveness and adverse effects of clozapine. Psychiatry Res. 2019;280:112506. PubMed
- Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162-7. PubMed
- Balda MV, Garay OU, Papale RM, Bignone I, Bologna VG, Brandolini A et al. Clozapine-associated neutropenia and agranulocytosis in Argentina (2007-2012). Int Clin Psychopharmacol. 2015;30(2):109-14. PubMed
- Hollingworth SA, Winckel K, Saiepour N, Wheeler AJ, Myles N, Siskind D. Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014. Psychopharmacology (Berl). 2018;235(7):1915-1921. PubMed
- Atkin K, Kendall F, Gould D, Freeman H, Liberman J, O'Sullivan D. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry. 1996;169(4):483-8. PubMed
- Seeman MV. Men and women respond differently to antipsychotic drugs. Neuropharmacology. 2020;163:107631. PubMed
- Covell NH, Weissman EM, Essock SM. Weight gain with clozapine compared to first generation antipsychotic medications. Schizophr Bull. 2004;30(2):229-40. PubMed
- Lau SL, Muir C, Assur Y, Beach R, Tran B, Bartrop R et al. Predicting Weight Gain in Patients Treated With Clozapine: The Role of Sex, Body Mass Index, and Smoking. J Clin Psychopharmacol. 2016;36(2):120-4. PubMed
- Wu RR, Zhao JP, Zhai JG, Guo XF, Guo WB. Sex difference in effects of typical and atypical antipsychotics on glucose-insulin homeostasis and lipid metabolism in first-episode schizophrenia. J Clin Psychopharmacol. 2007;27:374-9. PubMed
- Meltzer HY, Perry E, Jayathilake K. Clozapine-induced weight gain predicts improvement in psychopathology. Schizophr Res. 2003;59(1):19-27. PubMed
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- Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk
Reviewed by: Diana Rydberg, Carl-Olav Stiller
Approved by: Karin Schenck-Gustafsson