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.

Резюме. Европейским агентством по лекарственным средствам (далее -EMA) в 2012 году было сформулировано современное законодательство, определяющее порядок осуществления фармаконадзора -Правила надлежащей практики фармаконадзора (Good Pharmacovigilance Practices, далее GVP), которое заменило существовавшие ранее положения Руководства по фармаконадзору для лекарственных препаратов для человека. Положение по управлению сигналом включено в один из модулей GVP EMA и стало частью Правил GVP ЕАЭС. В 2017 году EMA опубликовало руководство по обнаружению сигнала в базах спонтанных сообщений, которое стало Приложением к Модулю IX Правил GVP «Управление сигналом». Предлагаемый в Приложении подход дополняет классический анализ диспропорциональности другими сведениями, на основе как статистических, так и клинических данных. В статье разбирается проблема выявления сигналов о безопасности лекарственных средств. Рассмотрены основные параметры, которые определяют эффективность методов выявления сигналов о диспропорциональности и позволяющие сравнивать разные статистические методы относительно друг друга. Разбираются приоритетные направления при оценке сигнала, а также приведены ключевые элементы качественного метода выявления сигналов, составленные с учетом экспертного мнения. Ключевые слова: сигнал; методы диспропорциональности; алгоритм определения сигнала; эффективность системы обнаружения сигналов; безопасность лекарственных средств; фармаконадзор Для цитирования: Журавлева ЕО, Вельц НЮ, Кутехова ГВ, Дармостукова МА, Аляутдин РН. Сигнал как инструмент системы фармаконадзора. Безопасность и риск фармакотерапии 2018; 6(2): 61-67. https://doi. 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. Abstract. The European Medical Agency (EMA) in 2012 formulated modern legislation defining the procedure for pharmacovigilance -the Good

Резюме. В связи с повторяющимися сообщениями о побочных эффектах при применении антибиотиков фторхинолоновой группы эти препараты вновь и вновь становятся объектом пристального внимания специалистов фармаконадзора и врачей. Цель работы: изучение частоты и характера нежелательных реакций, связанных с применением препарата ципрофлоксацин, на основе анализа спонтанных сообщений, поступивших в российскую службу фармаконадзора. Материалы и методы: проведен ретроспективный анализ спонтанных сообщений о препарате ципрофлоксацин за период с 2008 по 2018 г. по базе данных «Фармаконадзор» автоматизированной информационной системы Росздравнадзора. Результаты: всего было зарегистрировано 3403 нежелательные реакции, возникшие у 2083 пациентов при применении ципрофлоксацина. Чаще всего развивались реакции со стороны кожи и подкожных тканей (37,3 %), общие расстройства и нарушения в месте введения (21,1 %), реакции со стороны желудочно-кишечного тракта (14,9 %). Более трети сообщений содержали информацию о серьезных нежелательных реакциях. Были выявлены непредвиденные реакции, не зафиксированные в инструкции по медицинскому применению ципрофлоксацина: брадикардия, предсердная аритмия, цианоз, повышение артериального давления. Выводы: антибиотики фторхинолонового ряда с доказанной эффективностью и многолетним опытом клинического применения продолжают оставаться препаратами, безопасность которых требует постоянного контроля. Результаты исследования подтвердили возможность выявления широкого спектра нежелательных реакций методом спонтанных сообщений. Регуляторным органам Российской Федерации целесообразно рекомендовать держателям регистрационных удостоверений внести в инструкцию по медицинскому применению ципрофлоксацина информацию о нежелательных реакциях, которые были зарегистрированы в постмаркетинговый период. Ключевые слова: ципрофлоксацин; фторхинолоновые антибиотики; нежелательные реакции; фармаконадзор; безопасность лекарств

An important part of treating patients infected with SARS-CoV-2 is to ensure effective pathogenetic and symptomatic therapy before life-threatening complications, such as pneumonia, acute respiratory distress syndrome, or sepsis begin to develop. Current COVID-19 treatment protocols often use remdesivir and tocilizumab, though safety data on these drugs are insufficient. Therefore, experts of the Centre for Evaluation of Medicinal Products’ Safety of the Federal State Budgetary Institution “Scientific Centre for Expert Evaluation of Medicinal Products” of the Ministry of Health of the Russian Federation studied adverse reactions to remdesivir and tocilizumab, which are registered in the VigiBase (as of August 27, 2020), the global database of individual case safety reports.

Myopathy is a life-threatening disease that can be caused, among other things, by the intake of various medications. Despite the fact  that many drug-induced myopathies are well known, however, many  health professionals are not alert to myopathies caused by drug  interactions. Myopathy is a wellknown adverse reaction of statins,  and muscle damage can range from minor muscle pain and  weakness to life-threatening rhabdomyolysis. Colchicine can also  cause myopathy, including rhabdomyolysis. The combination of  colchicine and statins can significantly increase the risk of myopathy  compared with their intake separately. In cases of development of  myopathy in patients receiving colchicine and statins simultaneously, the most common manifestation of drug interaction was muscle  weakness, occurring in almost every case, and in some cases,  muscle weakness was so severe that the patient lost the ability to  move. In a third of cases, the development of muscle weakness was  accompanied by muscular pain, and darkening of urine to tea shade.  One study showed that 40 % of patients received concurrent combinations of drugs that increased the risk of muscle  damage. It is concluded that the simultaneous administration of  colchicine and statins requires an assessment of the “benefit-risk”  ratio, as well as the administration of drugs in minimally effective doses.

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.

Human papillomavirus refers to DNA-containing viruses and infects the skin and mucosal epithelium. One common way is to change the  expression of cellular genes by integrating the viral genome into  cellular DNA. The reason for the resistance of HPV infection is the  presence of complex mechanisms of inhibiting the immune response  of the macroorganism. An important infectious agent involved in  carcinogenesis are human papillomavirus (HPV) viruses, which cause  a significant part of oncological diseases. Viruses create the  prerequisites for malignant cells by introducing an oncogene or  blockade of suppressor proteins in cells to disrupt the regulation of  cell division. Two proteins, E6 and E7, encoded by the DNA of the  virus, play a leading role in this process. More than 100 different types of HPV have been identified, and approximately one- third of them infect epithelial cells in  the genital tract. HPV is also  the cause of carcinoma of the penis, vulva, anus and contribute to  the occurrence of more than 40 % of oropharyngeal cancer. To date,  the most effective way to combat HPV infection is  immunoprophylaxis. To date, there are three commercially available  HPV vaccines: Cervarix®, Gardasil®, Gardasil®9. These three  vaccines effectively prevent HPV infections, causing the production of neutralizing antibodies that bind to viral particles and block their  entry into host cells. However, these vaccines are not effective in  eliminating pre-existing infections. Currently, there are no  therapeutic vaccines against HPV, approved for use in humans. The  review discusses the types of vaccines against HPV infection and the effectiveness of vaccination.

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.