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INTRODUCTION. Documents on the pharmacovigilance system of the marketing authorisation holder (MAH), including the Pharmacovigilance System Master File (PSMF) and the PSMF-based summary of the pharmacovigilance system (SPS), are a mandatory component of the registration dossier for a medicinal product. Applicants must submit and update these documents in strict accordance with the legislation of the Eurasian Economic Union (EAEU). Systematisation of the requirements for drafting and submitting documents on the pharmacovigilance system will help applicants streamline the documentation process.AIM. This study aimed to analyse the requirements for submitting either the PSMF or the SPS, depending on the EAEU marketing authorisation procedure, and to describe typical errors made by applicants when submitting these documents.DISCUSSION. The content of dossier documents on the pharmacovigilance system is regulated by the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union (Decision No. 87 of the Council of the Eurasian Economic Commission (EEC) dated 3 November 2016), and their submission is governed by the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use (EEC Council Decision No. 78 dated 3 November 2016). MAHs are required to keep documents on the pharmacovigilance system and the corresponding registration dossiers up to date. This article summarises the specific requirements for submitting either the PSMF or the SPS, depending on the EAEU marketing authorisation procedure. Additionally, this article highlights typical errors made by MAHs when preparing documents on the pharmacovigilance system. According to the EAEU Rules of Good Pharmacovigilance Practice, the first application submitted for marketing authorisation of a medicinal product in the EAEU should include the PSMF, and subsequent applications should include the SPS as part of the registration dossier. Changes to the pharmacovigilance documents should be made in accordance with the classifier (EEC Council Decision No. 78 dated 3 November 2016).CONCLUSIONS. This analysis of the requirements for the PSMF or the SPS as part of various marketing authorisation procedures will facilitate compliance with the requirements of the EAEU legislative acts and ensure correct submission of necessary documents on the pharmacovigilance system by applicants. In addition, regulatory authorities will make fewer requests to submit missing information and grant more marketing authorisations.

The development of international regulatory practices and the accumulation of new experience in pharmacovigi­lance prompted the need to amend the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union (EAEU GVP Guideline), first adopted in 2016.The aim of the study was to review, from a regulatory expert’s perspective, the changes to the structure and presentation of the pharmacovigilance system master file (PSMF) introduced with the amendment of the EAEU GVP Guideline effective since December 6, 2022.The authors compared the requirements for the PSMF outlined in the new edition of the EAEU GVP Guideline adopted by Decision No.81 of the Council of the Eurasian Economic Commission of 19.06.2022 “On Amendments to the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union” with the requirements described in the previous version of this document.The structure and content of Module III, Pharmacovigilance System Master File, have been significantly amended in the new version of the EAEU GVP Guideline; this will require marketing authorisation holders (MAHs) to revise the PSMFs describing pharmacovigilance system data. The most significant editorial changes have been made to the paragraphs concerning the PSMF format, the pharmacovigilance quality system, and the presentation of information in the Annexes. The amendment has strengthened the control of records and documentation related to the pharmacovigilance system. Electronic PSMFs are acceptable; electronic book-marking and searchable text make working with the PSMF more convenient for representatives of MAHs and experts of regulatory authorities. Aligning of the PSMF with the requirements of the new edition of the EAEU GVP Guideline will contribute to improving the pharmacovigilance system operation and performance.

Adverse drug reactions (ADRs) are recorded throughout the lifecycle of a medicinal product. In the post-marketing period, new ADRs are primarily identified via drug safety signals. In order to assess a signal and establish causality between an adverse drug reaction and a suspected medicinal product, it is necessary to evaluate the signal strength and quality.The aim of the study was to analyse the information submitted to Russian regulatory authorities by a patient and check it for a potential causal association of acute tubulointerstitial nephritis (ATIN) with the use of ceftriaxone and with the patient’s principal diagnosis, Lyme disease.Materials and methods: the authors analysed the patient’s submission received by the Ministry of Health of the Russian Federation in 2022 with a complaint that the treatment of Lyme disease with ceftriaxone had caused ATIN. The probability of a causal relationship between the medicinal product and the ADR was evaluated using the Naranjo algorithm.Results: according to the review of literature and the spontaneous reports collected in Pharmacovigilance 2.0, the database in the Automated Information System of the Russian Federal Service for Surveillance in Healthcare, both ceftriaxone and the underlying condition (Lyme disease) may cause renal abnormalities. Ceftriaxone is potentially nephrotoxic; it mainly affects the tubular system of the kidneys. Borreliosis may cause kidney damage as well; such damage manifests clinically as rapidly progressing and fatal damage to the glomeruli.Conclusions: the probability of a causal relationship between the development of ATIN in the complainant and the use of ceftriaxone was categorised as “possible”. However, the information available did not allow for establishing a definite relationship between kidney damage and the use of the medicinal product. Further monitoring of similar cases is necessary to minimise the risks of developing this pathology during treatment with ceftriaxone.

The experts of the Scientific Centre for Expert Evaluation of Medicinal Products analysed administrative decisions of foreign regulatory authorities on the recalls of antibacterial and antiprotozoal medicinal products and/or the need for labelling updates due to changes in the safety profile. The analysis revealed 16 decisions containing information on the following medicines registered in Russia: ertapenem, сeftriaxone, cefazolin, аmoxicillin, сefoperazone+sulbactam, piperacillin+tazobactam, сlindamycin, teicoplanin, rifampin, co-trimoxazole, hydroxychloroquine.

Since 1 January 2021 the authorisation of medicines in the Russian Federation has to be performed according to the Eurasian Economic Union (EAEU) procedure. The Pharmacovigilance System Master File (PSMF) is the main document describing the pharmacovigilance system of the marketing authorisation holder (MAH) or its authorised representative. The aim of the study was to analyse noncompliances with the EAEU requirements, which were revealed during PSMF assessment.Materials and methods: the authors analysed 687 pharmacovigilance documents included in registration dossiers that were submitted for assessment from 1 January to 30 June, 2021. Results: the authors identified and systematised the main noncompliances with the EAEU requirements in terms of presentation, content, completeness of each PSMF section. They analysed the frequency of noncompliances in PSMFs and identified the most frequent flaws of MAHs’ pharmacovigilance systems.Conclusions: the authors give recommendations for elimination of significant noncompliances identified during PSMF assessment, which may include: timely updating, maintenance, and revision of the documents in accordance with changes in legislation and any other significant changes, regular training of pharmacovigilance staff, etc. The results of this review will be useful for MAHs as the main participants of the marketing authorisation process who are directly involved in the pharmacovigilance system management at the pre- and post-authorisation stages, and will help them prevent potential mistakes when drawing up pharmacovigilance system documents.

The introduction into clinical practice of immune checkpoint inhibitors that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1), has improved the prognosis of patients with malignant neoplasms of diff erent localisation. The antitumour eff ect of immune checkpoint inhibitors is based on blocking CTLA-4 and PD-1/PD-L1 signaling pathways and enhancing lymphocyte antitumour activity. However, inhibition of immune checkpoints may lead to dysregulation of immune responses and appearance of a new type of adverse reactions resulting from changes in the activity of immunocompetent cells. The aim of the study was to analyse adverse reactions associated with the use of immune checkpoint inhibitors. It was demonstrated that the structure of immune-mediated adverse reactions varied depending on the class of immune checkpoint inhibitors. The incidence of immune-mediated adverse reactions was higher with CTLA-4 inhibitors as compared with PD-1/PD-L1 inhibitors, and increased signifi cantly in the case of combination therapy. The treatment with CTLA-4 inhibitors most often resulted in skin reactions (rash, itching), gastrointestinal tract reactions (diarrhea, colitis), and endocrine gland problems (hypophysitis). The treatment with PD-1 inhibitors most often led to respiratory disorders (pneumonitis), and in some cases to gastrointestinal disorders (diarrhea, colitis), skin reactions (rash, itching), and endocrine gland problems (hypothyroidism), but they were less common. The treatment with PD-L1 inhibitors was associated with the development of pneumonitis. The development of immune-mediated adverse reactions may require discontinuation of treatment and administration of immunosuppressants, therefore early diagnosis and timely treatment of complications are important prerequisites for successful antitumour therapy. Further study of the mechanisms of immune-mediated adverse reaction development will optimise antitumour therapy with immune checkpoint inhibitors.

Experts of the Department for Evaluation of Medicinal Products’ Safety of the Scientific Centre for Expert Evaluation of Medicinal Products analysed administrative decisions of foreign regulatory authorities on limiting the use of some medicinal products and/or the need to introduce changes in patient information leaflets due to changes in the medicines’ safety profiles. The analysis helped to identify 16 administrative decisions that contain information on the following medicines registered in Russia: duloxetine, sertraline, paroxetine, сitalopram, desvenlafaxine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, venlafaxine, vortioxetine, mirtazapine, risperidone, clozapine, aripiprazole, quetiapine, olanzapine, lacosamide, gabapentin, pregabalin.

In the 1960s, following the Thalidomide Disaster, the World Health Organization (WHO) initiated the development of an international drug safety monitoring programme. The objectives of this WHO programme are to improve the quality and safety of pharmaceuticals, and to support public health programmes by providing information for effective assessment of the risk-benefit ratio of medicinal products. The paper outlines the main focus areas of the programme and the mechanism of interaction between the countries involved. It summarises the functions of the WHO Collaborating Centre for International Drug Monitoring located in Uppsala, namely, accumulation and assessment of data on efficacy, inefficacy and risks of medicinal products, which are communicated by the participating countries, and provision of reliable and coherent data to specialists. The paper provides a review of online resources and methods used by VigiBase — global database of adverse drug reactions — that make it possible to search and analyse the data statistically. It describes the functions of the national monitoring centres located in different regions, and their interaction with the WHO. The dissemination of objective and reliable medical information throughout the world, promotion of pharmacovigilance as a science, creation of international partnerships and pooling of expertise from different countries allow for a significant improvement in the safety of pharmacotherapy.

Efficacy, safety and biotransformation features of any drug are fully revealed during widely using. Therefore, postmarketing studies of the pharmacological properties of drugs are an integral component of pharmacovigilance. The aim of this study was to evaluate the nature and frequency of drugs adverse reactions that have been reported in the post-marketing period, as well as a review of measures taken by foreign regulatory authorities to ensure the safety of use of these drugs. The results of monitoring the drug safety in the post-marketing period used in clinical practice during various time intervals are presented: from several years (atelizumab, daclizumab) to several decades (valproate, retinoids). The review included data from decisions of regulatory authorities, published in 2018. Recommendations from foreign sources on the rational use of drugs, ways to increase the benefit/risk ratio of adverse reactions when using drugs from different therapeutic groups and/or the need for changes in the instructions on their medical use due to changes in the safety profile are considered. These recommendations will be helpful to healthcare professionals, as well as persons authorized for pharmacovigilance by pharmaceutical companies. Particularly, this information may be of interest to rheumatologists, oncologists, neurologists, psychiatrists, as well as other physicians who use atezolizumab, tocilisumab, daclizumab, pomalidomide, valproate sodium and valproic acid, retinoids, clarithromycin, cotrimaxozol, cefalexine, hydroxycarbamide, ritonavir.

Abstract. Detection and analysis of drug safety signals in children is a mandatory part of pharmacovigilance. The criteria for evaluating signals of adverse effects were considered. Spontaneous reports databases as a source for detecting signaling information about adverse reactions, including in children were used. More than 17.5 million cases of adverse reactions identified in WHO global database of individual case safety reports — VigiBase which was detected since 1968 in 120 countries — members of the WHO Drug Treatment Control Program. Of these, 1.5 million cases of adverse reactions occur in childhood. Objective: search and analysis for signal information in the post-marketing period of the use of drugs in children to increase the safety of pharmacotherapy in pediatric practice. Results: а causal relationship between desloratadine and weight gain was detected. Desloratadine is an active metabolite of loratadine so the researchers have considered reports on desloratadine and also on loratadine. In VigiBase there are reports of weight gain when taking desloratadine (44 messages) and loratadine (115 messages) in 2016. Among them, 22 reports on weight gain in children from 2 to 11 years. The Pharmacovigilance Risk Assessment Committee of the European Medical Agency (PRAC EMA) recommended marketing authorization holders to add an information about weight gain in children in prescribing information of drugs which contains desloratadine and loratadine. In September 2017, the Committee on Drugs for Human Use, following a review and analysis of VigiBase, approved the recommendations of PRAC EMA. Appropriate changes were made to the instructions for medical use for loratadine tablets. Conclusions. These results confirm the importance of long post-marketing studies, the results of which will provide significant assistance in improving the safety of pharmacotherapy in children.

The monitoring of information on the safety of various drugs is becoming more relevant day by day, as the number of drugs on the pharmaceutical market increases, generic drugs, bio-analogous drugs appear. Long-term post-marketing use of a medicinal product allows to accumulate a sufficient evidence base and experience of application in various population groups, to study the features of the use of this drug. Information on the safe use of new drugs can be obtained in selected scientific publications. In addition to publications in the specialized scientific literature, regulators of different countries on the basis of new information give opinions on the need to make changes in instructions for medical use. When analyzing the recommendations of Russian and foreign regulatory authorities on restricting the circulation of medicines and / or the need to amend the instructions for their medical use in connection with the change in the assessment of the safety profile, we identified 16 administrative decisions of foreign regulatory bodies containing information about the following drugs registered in Russia. We consider all recommendations to be important information on the safety of medicines, which is addressed to specialists in the field of medicine, in particular to persons authorized by pharmacovigilance in pharmaceutical companies. In addition, this information may be of interest to physicians of various specialties who in their practice use buprenorphine, venlafaxine, gadolinium contrast drugs hydroxyethyl starch, daclizumab, duloxetine, denosumab, cladribine, clomifene citrate, milnacipran, methotrexate, pemetrexet, radium dichloride, rifampicin, phoebusostat, flupirtine.

Non-steroidal anti-inflammatory drugs (NSAIDs) are liders in selling both in the Russian Federation and worldwide. The combination of analgesic, anti-inflammatory and antipyretic effects make the drugs of this group very popular in patients with various diseases. The realization of NSAIDs in pharmacies occurs both by prescription and over-the-counter, so the safety assessment of the use of this group of drugs remains relevant. In the current practice, self-administration (responsible selfmedication) of drugs of the NSAID group is an additional factor affecting the safety of their intake. According to the studies, about 40 % of patients taking NSAIDs consider that NSAIDS are absolutely safe, and more than 30 % of those taking OTC NSAIDs use them in excess of the recommended dosages. We analyzed 3963 individual case safety reports (ICSR) in the federal database «Pharmacovigilance» from 07.12.2008 to 31.08.2017. The inclusion criterions was the presence of information on the off-label application of NSAIDs in the ICSR, reports of adverse effects that may be associated with the use of this drug or erroneous reports on the active substance, which was not present in this drug. The most frequent mistakes in the application were an increase of the daily dose, a change in the method of administration to patient who are contraindicated with this drug. There were 9 ICSR of burning sensation in the anus with the introduction of ibuprofen suppositories (not in the label), and 7 ICSR of ineffectiveness of the active substance, which was not present in this drug.

The European Medical Agency (EMA) in 2012 formulated modern legislation defining the procedure for pharmacovigilance — the Good Pharmacovigilance Practices (GVP), which replaced the earlier provisions of the Pharmacovigilance Guidelines for Human Medicines. The signal management position is included in one of the GVP EMA modules and became part of the EAEC GVP Rules. EMA in 2017 published a regulatory guide for detecting a signal in spontaneous reporting databases, which became an Annex to Module IX of the GVP Rules «Signal Management». The approach proposed in the Appendix supplements the classical analysis of disproportionality with other data, based on both statistical and clinical judgments. The article deals with the problem of detecting signals about the safety of medicines. The main parameters that determine the effectiveness of methods for detecting signals on disproportionality and allowing to compare the productivity of different statistical methods with respect to each other are considered. Priority directions are considered when evaluating the signal, and key elements of a qualitative method for detecting signals are drawn up, taking into account the expert opinion.

Diabetes mellitus is the most acute medical and social problem related to the priorities of national health systems. The dramatic and urgent problems of diabetes mellitus are determined by the high prevalence of diabetes, high mortality and early disability of patients. The prevalence of diabetes mellitus in Western countries is 2–5 % of the population, and in developing countries reaches 10–15 %. Inhibitors of dipeptidylpeptidase-4 are one of the classes of drugs for the treatment of patients with diabetes mellitus type II. Now days the analysis of regulatory reports from developed countries show that the number of reports FDA, Health Canada on the risk of serious adverse reactions has increased. Not all detected adverse reactions are listed in the instructions for use among the possible side effects of the group of inhibitors of DPP-4. The article deals with reports of adverse reactions detected during the monitoring of databases of the Russian Federation and regulatory authorities of foreign countries. The safety research of the use of DPP-4 inhibitors is ongoing.

The article is devoted to the problems of safety of non-steroidal anti-inflammatory drugs. The analysis of 3,963 spontaneous reports to the Russian database for the period from December 7, 2008 to August 31, 2017, with the aim of identifying information on adverse reactions that have occurred during the application of NSAIDs is presented. Most often unwanted reactions were registered for preparations of acetylsalicylic acid, diclofenac, ibuprofen, ketorolac. A total of 6,257 adverse reactions were recorded. The greatest specific weight among all cases of undesirable reactions were disorders of the immune system, skin, subcutaneous tissues and gastrointestinal tract. The lack of therapeutic effectiveness of drugs was recorded in 280 cases. Most often, such ADR on NSAIDs were angioedema, urticaria, erosive gastritis, skin rash, increased blood pressure. In case of using of the over-the-counter drugs and self-medication it is necessary to work with the population to form a responsible attitude to the use of medicines, warn of possible complications of self-medication and conditions requiring compulsory medical attention.