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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.

INTRODUCTION. Osteoporosis is a leading cause of morbidity, disability, reduced quality of life, and premature mortality in the elderly population. Denosumab is a treatment for osteoporosis; however, denosumab discontinuation may cause a rebound effect, which is a severe adverse drug reaction (ADR) leading to an increase in the rate of bone tissue loss. Studying the mechanism of the rebound effect and potential ways to manage it can improve the safety of denosumab therapy.AIM. This study aimed to summarise up-to-date information regarding the mechanism of the rebound effect and ways to manage it after denosumab discontinuation.DISCUSSION. Osteoporosis results from an imbalance in bone remodelling. Recent studies have shown that mature osteoclasts are able to fission into osteomorphs, which separate from the polykaryon and fuse with neighbouring osteoclasts or other osteomorphs (osteoclast recycling). The mechanism of action of denosumab is based on the inhibition of osteoclast recycling, which results in the accumulation of pre-osteoclasts and osteomorphs. Research into processes occurring in bone tissue shows that denosumab creates a pool of induced cells, and when denosumab therapy is discontinued, these induced cells quite quickly and abundantly differentiate into osteoclasts causing bone resorption (rebound effect) and increasing the risk of fractures. In order to improve mineral bone density and to prevent fractures after denosumab discontinuation, it is reasonable to use antiresorptive medicines from the bisphosphonate class. Bisphosphonates accumulate in bone tissue and concentrate in areas of active bone metabolism.CONCLUSIONS. Further studies of the rebound effect mechanism, including a deeper understanding of the role of osteomorphs in osteogenesis, will improve the measures taken to reduce the risk of fractures after denosumab discontinuation. Further research is needed to evaluate the effect of antiresorptives on bone tissue loss after denosumab discontinuation.

Introduction. Advanced therapy medicinal products (ATMPs) rely on recent advances in medical science, but alongside with potential benefits they may also bring safety concerns for patients. The inherent complexity of the ATMP production and use calls for special approaches to risk management throughout their lifecycle, from obtaining the raw materials to administration to the patient.Aim. The aim of the present study was to develop approaches to risk management for ATMPs, using the example of CAR T-cell therapy.Materials and methods. The study analysed the relevant regulatory frameworks currently in force in the European Union and the United States of America, namely the regulations and guidelines adopted by the Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency.Results and discussion. The paper provides a classification of patient risks, which was developed based on the European risk-based approach. It formulates the principles of risk management for each of the risks, depending on the stage of the product life cycle. Each type of risk was considered separately. The following risk minimization strategies were determined: compliance with the good practices, ensuring the necessary qualifications or expertise of all parties involved in the product life cycle. The main element of risk control is the detailed description of the medicinal product use in the summary of product characteristics and patient information leaflet.Conclusion. The study identified the main stages at which ATMP risks may occur, and each type of risk was considered separately. The following requirements should be put in place in order to manage the ATMP risks: requirements for distributors on how to perform the product transportation and storage and to keep records for the marketing authorisation holder; requirements for healthcare facilities on how to perform the product storage, its preparation for use, advising and informing the patients on the treatment risks, symptoms of adverse events, preparatory and follow-up medical procedures, and on how to keep records for the marketing authorisation holder; requirements for the qualifications of healthcare professionals who are in charge of the product storage, its preparation for use, treatment procedures, advising and informing the patients on the treatment risks, symptoms of adverse events, and follow-up medical procedures. The data obtained will be used in the preparation of recommendations for ATMP developers.

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.

Aminoglycosides are broad-spectrum antibacterial agents used in the treatment of urinary tract infections, tuberculosis, visceral leishmaniasis, sepsis in newborns, as well as cystic fibrosis. However, the use of aminoglycosides is limited due to their ototoxicity — the risk of developing serious adverse reactions, in particular, persistent irreversible hearing loss and vestibular disorders associated with the death of hair cells in the inner ear. The review analyzes scientific data on the possible mechanisms of aminoglycosides’ damaging effect on the hair cells of the inner ear. Genetically determined causes contributing to the manifestation of ototoxic properties of drugs of this group are described. The necessity of genetic screening for the carriage of mutations m.1555A>G and m.1494C>T in the MT-RNR1 gene of mitochondrial DNA is substantiated in order to minimize the risk of hearing disorders in patients with hereditary predisposition. Understanding the mechanisms of ototoxicity of aminoglycosides will make it possible to find ways to prevent and correct hearing loss after their use.

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.

Herbal medicinal products (HMPs) are widely used in medical practice due to their availability, ease of use, and relatively safe pharmacological profile. However, medicinal plants are capable of accumulating heavy metals and arsenic which can have toxic effect on the human body when found in HMPs. The aim of the study was to summarise and analyse requirements of the Russian and foreign pharmacopoeias for the limits of heavy metals and arsenic in HMPs. National and regional pharmacopoeias have limits for the content of the major toxic elements (lead, cadmium, mercury, chromium, and arsenic) in HMPs. The study showed that the Indian and Japanese pharmacopoeias include only semi-quantitative methods for determination of heavy metals and arsenic, while the Russian and Chinese pharmacopoeias allow for the use of both quantitative and semi-quantitative methods. It was demonstrated that the limits for heavy metals and arsenic are the same for herbal substances and HMPs. The development of consistent approaches to determination of heavy metals and arsenic content, a systematic transition to quantitative methods of analysis, and establishment of individual limits for toxic elements in different HMP dosage forms, will make it possible to achieve the so-called consistent harmonisation, ensure reliable assessment of the content of heavy metals and arsenic, and minimize the risk of their entering human body with HMPs.

The Russian Federation and the member states of the Eurasian Economic Union (EAEU) are working on the creation of a common pharmaceutical market. EAEU marketing authorisation may be granted to those pharmaceutical companies whose activities comply with the Good Pharmacovigilance Practice (GVP). The aim of the study was to analyse pharmacovigilance system documents submitted as part of registration dossiers of medicines and to identify problems that may arise during preparation of the pharmacovigilance system master file (PSMF). The authors analysed the PSMF, which makes part of the registration dossier, for compliance with the EAEU GVP requirements for submission, content, and completeness of all sections of the document. They identified the most common types of errors in PSMF preparation and analysed conditions when a PSMF is required or, alternatively, when a brief summary of the pharmacovigilance system of the marketing authorisation holder will suffice. The paper summarises specific aspects of incorporating pharmacovigilance system documents in regulatory submissions, as well as aspects of presenting pharmacovigilance system data when bringing the registration dossier in line with the EAEU requirements. This information may be useful for marketing authorisation holders who are the main stakeholders in the medicine authorisation process and who are directly involved in the pharmacovigilance system management during the authorisation and post-authorisation stages of the drug life-cycle.

Analysis of administrative decisions of foreign regulatory authorities on the recall of medicines and/or the need for changes in the instructions for their medical use due to changes in the safety profile, conducted by experts of the Scientific Centre for Expert Evaluation of Medicinal Products revealed 19 administrative decisions. These decisions contained information on the following medicines registered in Russia: amikacin, tobramycin, gentamicin, neomycin, ciprofloxacin, delafloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, сeftriaxone, ceftaroline, rifapentine, tigecycline, bacitracin, ertapenem, daptomycin, erythromycin, fosfomycin, ampicillin+sulbactam, chloroquine, hydroxychloroquine.

In 1968 the World Health Organisation initiated the development of an international programme for collection of data from the maximum number of sources about potential adverse effects of medicines. In order to implement this programme, a number of databases were created, such as the global database VigiBase, the European database EudraVigilance, and the database of the Eurasian Economic Union (EAEU). The aim of the present study was to compare approaches of the international spontaneous reports databases to collection, processing, and analysis of information on adverse drug reactions. It was demonstrated that the international databases VigiBase, EudraVigilance, and the EAEU database of adverse drug reactions contain different numbers of spontaneous reports, but serve the same objectives, namely to collect, process, and analyse information submitted as spontaneous reports. Unlike VigiBase that contains reports on authorised medicines coming from the national pharmacovigilance centres only, EudraVigilance also receives data from marketing authorisation holders and has reports on adverse drug reactions observed during clinical trials. The exchange of information between countries ensures rapid identification of safety signals concerning potential risks of medicines, and increases the likelihood of detecting rare and late-onset adverse reactions that may go unnoticed when analysing national data in a particular country. Spontaneous reports databases are an essential tool of the international drug safety monitoring community. Effective measures in this area will ultimately help to improve patients’ health and quality of life.

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.

Nanoscale drugs differ in special physicochemical, biological, pharmacokinetic parameters. These properties can be used to provide targeted delivery, prolong the action of drugs, as well as reduce their side effects. An important problem that needs attention is the study of the potential risks arising from the treatment of such drugs. The aim of the study: analysis of the requirements of domestic and foreign regulators for the safety of nanoscale drugs. The paper presents the classification of the most promising nanosystems containing drugs, and an analysis of the existing principles for assessing their safety in Russia and abroad has been carried out. It was shown that when assessing the safety of nano-sized drugs, along with the properties of the active substance, it is necessary to take into account the properties of the nanosystem (polymer coating, carrier, etc.), related to its size, distribution pattern, charge of nanoparticles, and ability to induce oxidative stress. Domestic and foreign regulatory documents governing the procedure for assessing the safety of pharmacological substances derived from nanotechnology was analyzed. Conclusions: Despite the availability of recommendations from regulatory authorities, further improvement of the requirements for registration and safety assessment of nanoscale drugs is necessary. Further development of the regulatory framework governing the development, quality, efficiency and safety of nanomaterials in medicine is necessary, taking into account the structural issues of the active substance and nano-carriers.

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.

Due to repeated reports of adverse effects with the use of fluoroquinolone antibiotics, these drugs become over and over again the object of the close attention of pharmacovigilance specialists and health care specialists. The aim: to study the frequency and the nature of adverse reactions associated with the use of ciprofloxacin, based on the analysis of the spontaneous reports received by the Russian pharmacovigilance service. Materials and Methods: A retrospective analysis of the spontaneous reports of ciprofloxacin was conducted on the data-base «Pharmacovigilance» of the automated information system of Roszdravnadzor from 2008 to 2018. Results: 3403 adverse reactions that occurred in 2083 patients using ciprofloxacin were recorded. The most frequently developed reactions were from skin and subcutaneous tissues (37.3 %), general disorders and disorders at the injection site (21.1 %), gastrointestinal tract reactions (14.9 %). More than a one third of the reports contained information about serious adverse reactions. Unexpected reactions were identified as not recorded in the instructions for the medical use of ciprofloxacin: bradycardia, atrial arrhythmia, cyanosis, increased blood pressure. Conclusions: fluoroquinolone antibiotics with proven efficacy and years of experience in clinical use, continue to be drugs whose safety requires constant monitoring. The results of the study confirmed the possibility of detecting a wide range of the adverse reactions using the method of spontaneous reports. Regulatory authorities of the Russian Federation should recommend to registration certificate holders to include the information of adverse reactions of ciprofloxacin that were registered in the post-marketing period in the instructions for medical use.

Vaccine safety is an important aspect of mass immunization of the population. Adverse reactions that occur following vaccination result in a decrease in public confidence. The aim of this research was to identify information on the development of adverse events after immunization with vaccines included into the national vaccination calendars of the USA, European Union (EU), Japan, China, South Korea and India. Particular attention was paid to vaccines that are not included in the vaccination calendar, but are presented in the Russian Federation. During monitoring of vaccination against human papillomavirus information in the European Union, Japan and the United States, according the possible connection with development of autoimmune diseases was refuted. Monitoring of adverse events after vaccination with rotavirus vaccine I generation in the USA, EU and India, allowed to establish a link with the development of intestine invagination and limit the use of this medicinal product in favor of vaccine II generation. After starting vaccination against influenza was detected narcolepsy as a complication of this procedure; and when analyzing the complications of meningococcal vaccination Guillain — Barre syndrome was detected. We also analyzed information on various complications associated with vaccination against Japanese viral encephalitis, which was included into the national vaccination calendar of countries in Asia and the Pacifi c region — China, India, Japan, and South Korea. The main complications registered in the PRC after the introduction of Japanese encephalitis vaccine into the national vaccination calendar included: febrile seizures, thrombocytopenic purpura, encephalitis and meningitis. The main safety concerns about vaccines included into the national vaccination calendars of EU countries, the USA and the Asia-Pacific region concern vaccines that have recently appeared on the pharmaceutical market.

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.

SGLT2 inhibitors form a new class of hypoglycemic drugs. Despite of the pharmacodynamic profile, at the moment the opinion about their safety is controversial. This is due to increased number of reports given by FDA and EMA on the risk of serious adverse reactions - ketoacidosis, which is not specified in the instruction as a possible adverse effects. Ketatsidosis in patients with type 2 diabetes on therapy with SGLT2 inhibitors was appeared at moderately elevated glucose levels (200 mg/dL/11.1 mmol/L). The article deals with reports of ketoacidosis, caused by inhibition of SGLT2 and describes the alleged internal pathophysiological mechanisms associated with its development.

The article presents data obtained in a retrospective analysis of spontaneous messages (SM) on drug adverse reactions during pregnancy, recieved in the Russian base «Pharmacovigilance» AIS Roszdravnadzor, for the period 1 January 2015 to 31 December 2015 included.

With the aim to harmonize the legislation between the Eurasian Economic Union countries and the European Union in the field of medicines circulation and taking into account the requirements of the European Union and the Organization for Economic Cooperation and Development (OECD) in 2015 were developed the Rules of Good Laboratory Practice EAEC. The article presents the results of a comparative analysis of good laboratory practice. Order of the Ministry of Health of the Russian Federation on the Rules of good laboratory practice will allow to provide the most objective study of the safety of new drugs at the preclinical stage and to identify and prevent using of unsafe drugs. Ultimately, it will protect the interests of patients and the healthcare system as a whole.

Inhibitors of the sodium-glucose cotransporter-2 SGLT2 is a new class of hypoglycemic drugs. This article presents the information on FDA reports (2013-2015) and AIS (May 2015 - February 2016) on the risk of new adverse reaction - ketoacidosis. Conjectural pathophysiological mechanisms of ADR associated with this class of drugs, which could lead to its development are presented.

Apremilast is a new selective inhibitor of phosphodiesterase 4 (PDE4) of the class of small molecules, approved for treatment of psoriatic arthritis and psoriasis. The efficacy and safety of apremilast in the treatment of moderate to severe plaque psoriasis have been demonstrated in multicenter, randomized, double-blind, placebo-controlled clinical trials of ESTEEM 1 and ESTEEM 2 (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis). These studies describe adverse reactions such as mental disorders: depression, suicidal thoughts, suicidal behavior. However, data on the increase in the incidence of these adverse reactions during longer treatment with apremilast were not obtained. The article presents the reports from the UK regulator (MHRA) and international database VigiBase on the increased risk of developing suicidal thoughts, suicide attempts, completed suicides and suicidal behavior during treatment with apremilast.

New rules of good laboratory practice in the Russian Federation and the Eurasian Economic Union were adopted in 2016. The rules of good laboratory practice of the Eurasian Economic Union in the field of drugs is a document that will allow for a coordinated policy in the field of pre-clinical studies and to establish common principles and rules for the evaluation of medicinal products in the Member States of the Union with a view to forming a common medical devices market circulation. Creating uniform rules and approaches to the drugs market regulation based on international experience will increase the safety of drugs available on the market and their accessibility to the population of states - members of the EAEU.

Malaria is one of the most challenging infectious diseases that poses a serious threat to the health and lives of patients around the world, including the Russian Federation. One of the main problems associated with the treatment of falciparum malaria is development of resistance to many drugs. A serious problem in Russia is a constant shortage of antimalarial drugs.

One of the main causes of death and disability in the world are the thrombotic complications. Using of anticoagulants is the effective method of preventing of these life-threatening conditions. However, the use of anticoagulants involves a significant risk of the bleeding. Safety of anticoagulants predominately are determined by the availability of specific antidotes. Until now new oral directly acting anticoagulants do not have any specific antagonists. Idarutsizumab is the dagibatran-specific antagonist which increases its safety.

The risk management system includes the process of determining the probability of occurrence of undesirable effects of pharmacotherapy, identifying the extent and magnitude of the risk analysis and the choice of risk management strategy, the selection of necessary for this risk management techniques and strategies of ways to reduce it. Thus, the risk management system is a modern and efficient pharmacovigilance tools aimed to improve the effectiveness and safety of pharmacotherapy.

Pregnancy is characterized by overexertion of metabolism in the liver and some changes in metabolism, which can lead to various, including severe organ, damage. During pregnancy, according to international epidemiological studies, more than 80 % of women take medicines. Under polypragmasy it is extremely difficult to isolate a particular medicine responsible for the drug pathology in the liver in pregnant women. The article presents a retrospective analysis of spontaneous reports accepted from the Russian database of AIS Roszdravnadzor for the period from 01.01.2009 to 31.12.2016.

Despite the differences in the chemical structure and pharmacological properties, the risk group for the occurrence of an acute attack of angle-closure glaucoma includes the majority of modern antidepressants. The possible mechanisms of influence of these psychotropic drugs on the intraocular pressure are discussed.