This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.

Citation: Kirilochev OO, Dorfman IP, Umerova AR, Bataeva SE (2019) Potential drug-drug interactions in the psychiatric hospital: Frequency analysis. Research Results in Pharmacology 5(4): 1-6. https://doi. AbstractIntroduction: Drug-drug interactions are an important clinical problem in pharmacotherapy. This study is focused on different types of drugs used in a psychiatric hospital. Materials and methods:The pharmacoepidemiological study included the analysis of medical records of 500 psychiatric inpatients. The patients were divided into 2 groups: under 65 and over 65 years of age. All the drug prescriptions were analyzed to identify the combinations of drugs that can induce drug-drug interactions and determine their clinical significance.Results and discussion: Over 77% of hospitalized patients were administered drug combinations that could induce drug-drug interactions, most of which were of moderate clinical significance. A reliable association was found between the patient's age, the clinical significance of drug-drug interactions, and the pharmacotherapy structure. The most common irrational drug combinations were identified.Conclusion: Timely analysis of drug prescriptions for potential drug-drug interactions can enhance the safety of pharmacotherapy and decrease the risk of adverse drug reactions in the psychiatric inpatient setting. Keywordsadverse drug reactions, drug-drug interactions, pharmacotherapy safety. Copyright Kirilochev OO et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Research Results in Pharmacology 5(4): 1-6 UDC: 615.065

Purpose/BackgroundA recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis.MethodsHere, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions.Findings/ResultsStudies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year.Implications/ConclusionsThe interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

The results substantiate the need to continue drug safety monitoring in the Astrakhan region. We plan to further improve the software for ADR analysis.