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This literature review provides information on the deficit of clinically proven data on the drugs use in pediatric practice. Issues on why children are widely administrated with drugs that are normally intended for use in adults without any prior qualitative estimation of their safety and efficacy in appropriate clinical studies involving children have been analyzed. The authors considered the issues of carrying out clinical trials with the participation of children as study subjects: ethical, regulatory, and psychological aspects of this complex task. There are decisions for every of the listed aspect. The authors of analyzed sources and the authors of this article believe that these decisions may help to address all the challenges and evade the incorrect assessment and interpretation of initial data by children’s parents and adoptive parents (legal representatives). Issues of doctors’ alertness were considered separately. Information and excerpts from regulatory acts were given, as well as information from publications on awareness raising and in support of doctors-researches. This literature review has been carried out to solve problems of information gap in the field of drugs safety and efficacy in pediatric practice. The disclosure of discussion points for clinical trials with children will ultimately help to improve the quality of healthcare provided to children in the future and take advantage of recent technologies used in patients’ cohorts of other age groups.

Currently, due to the lack of specific etiotropic therapy, rituximab is widely used for the treatment of most autoimmune diseases of the central and peripheral nervous system. Rituximab is a chimeric monoclonal antibody with specificity for CD20, the antigen found on the surface of normal and malignant B-lymphocytes. It is used mainly in hematological practice. It is used off-label for the treatment of neurological diseases. The world literature describes the use of rituximab for the treatment of such pathologies as autoimmune encephalitis, neuromyelitis optica spectrum disorder, multiple sclerosis, primary angiitis of the central nervous system, immune-mediated inflammatory polyneuropathy, myasthenia gravis, refractory to basic immunosuppressive therapy. This article provides an overview of the world literature on the use of rituximab in neurological practice, describes our own experience of its use on the basis of the Department of Neurology № 1 of Pavlov University (Saint Petersburg, Russia).

Immunoglobulin E (IgE) and mast cells play a key role in various allergic diseases. Treatment with omalizumab, a monoclonal anti-IgE antibody, has significantly improved the control of these diseases and ushered in a new era in the treatment of severe allergic conditions. Long-term experience with omalizumab in severe allergic asthma has confirmed its effectiveness and safety, reducing the symptoms and incidence of severe exacerbations in patients. In addition to treating severe asthma, Omalizumab has been approved for the treatment of chronic spontaneous urticaria (CSU), and although the mechanisms underlying the action of omalizumab in CSU are not fully understood, almost 90% of CSU patients show complete or partial response to omalizumab treatment. Omalizumab has also recently been approved for the treatment of severe Japanese cedar pollinosis (JC) based on the successful results of a study of omalizumab in inadequately controlled severe hay fever treated with antihistamines and nasal corticosteroids. In recent years, there have been a number of scientific publications showing the successful off-label use of omalizumab in diseases in which IgE plays a key role such as allergic rhinitis, allergic bronchopulmonary aspergillosis, anaphylaxis, keratoconjunctivitis, food allergy, drug allergy, non-atopic asthma, mastocytosis, atopic dermatitis, nasal polyps, Churg-Strauss syndrome, eosinophilic otitis media, chronic rhinosinusitis, bullous pemphigoid, systemic lupus and contact dermatitis. Its safe use in pregnant women with asthma, as well as the concomitant use of omalizumab and allergen-specific immunotherapy, has already been confirmed. Therefore, the potential for omalizumab in other chronic conditions should be considered. [ABSTRACT FROM AUTHOR]

IgE plays an important role in the allergic diseases. More and more publications focus the attention ot IgE participation in non-allergic conditions. Therefore, there are already publications on the successful off-label use of anti-IgE therapy (omalizumab) in diseases such as mastocytosis, urticaria - vasculitis, systemic lupus erythematosus, bullous dermatoses and others. We present our clinical experience in the off-label application of omalizumab in 2 children: a 10-year-old boy with cystic fibrosis and aspergillosis and a 9-year-old girl with normocomplementary urticaria-vasculitis. [ABSTRACT FROM AUTHOR]

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.

LLC Novartis Pharma, Moscow, Russian Federation Abstract. The problem of off-label use is still unsolved during the pharmacotherapy in children. In connection with the above, the need to stimulate the conduct of specially organized clinical studies, the purpose of which will be to evaluate the efficacy and safety of using drugs in children in different age groups, becomes evident. However the complexity of the organization of clinical studies in pediatrics is associated not only with regulatory aspects but also with lack of understanding of the importance of these studies by pediatricians and parents. The authors conducted a study aimed at finding out the frequency of off-label prescriptions in the Russian Federation in pediatric practice and doctors’ and parents’ attitude to this kind of use of medications. The study has shown the evidence that the off-label prescription practice is widely-used in healthcare in Russia and is routine for most respondents. The highest frequency of off-label prescriptions is observed in the group of children from 0 to 5 years. The majority of physicians and parents don’t consider themselves responsible for popularization of clinical trials which indicates that this problem should be widely discussed in the society. Parents trust physicians in terms of therapy choices or their recommendations regarding participation in clinical trials. A portrait of a typical “staunch opponent” of clinical trials among parents.

The aim of this study was to evaluate the structure of etiotropic therapy used in the treatment of urinary tract infection in newborns, the frequency of using off-label etiotropic medicines, and assess the incidence of adverse drugs reactions (ADR). The work was carried out by a retrospective pharmacoepidemiology analysis of children hospitalized patient history (form 003/y) with infectious diseases in the period of the newborn. The object of the study is a case history of a stationary patient, the main method of research is the collection and analysis of information, the statistical processing of the data obtained. During the analysis, all the selected medical records were divided into two groups: the first - children, with the course of urinary tract infection, the second - with the course of infectious diseases of other localization. During the study it was demonstrated that the use of etiotropic therapy in children with urinary infection is higher than in children with the course of the infectious process of other localization. The frequency of off-label prescriptions for the treatment of urinary tract infection is 51%, and the incidence of ADR in the case of unadapted appointments is 1,4 times higher.

Purpose. To study the structure of serious adverse drug reactions and «off label» drug use in children by means of analysis of the national pharmacovigilance database. Materials and methods. We analyzed 341 spontaneous reports about serious adverse reactions in children, submitted to the Russian pharmacovigilance database in 2012, and 467 suchlike spontaneous reports registered in 2015. Results. Children of preschool age have higher risk of medical therapy complications. Most frequently, skin (33,4% in 2012 and 38,7% in 2015) and organism as a whole (21,4 and 21,1%, respectively) were involved in the pathological process. Antimicrobial drugs for systemic use (43,5% in 2012 and 43,8% in 2015) and drugs for nervous system (25,1 and 26,1% respectively) often caused them. Unexpected serious adverse reactions accounted for 16,9% of all complications in children in 2012, 10,8% in 2015. It was established that 58,7% of suspected medicines in 2012 and 47,5% in 2015, the use of which was associated with the development of serious complications in pharmacotherapy in children, were prescribed with deviations from the recommendations of approved prescribing drug information. The main types of «off-label» drug use were inappropriate indications, deviations from the recommended dosage regimen, the use of a drug in the age group of patients, wherein the drug has not been approved, and the use of a drug in the presence of contraindications to its use. Conclusion. Our research confirms that the practice of «off-label» drug use in children is an independent risk factor for developing adverse drug reactions. It is shown that the method of spontaneous reporting can help to identify the problems of drug safety and to develop recommendations for minimizing the risk of complications of pharmacotherapy in pediatric practice.

The predictability of results of pediatric clinical trials is often limited for a number of reasons. Among the main ones is the imperfect functioning of organ due to immature ontogeny of enzyme and organ systems in children, and the presence of special subpopulations of full-term newborns and preterm neonates sometimes being in a critical condition. The main task of a present-day pediatric investigational plan is to develop drugs and to elaborate doses that are «specifically designed», not simply «suitable» for neonates. Other reasons for limited predictability are as follows: adult data extrapolation constraint due to children’s anatomic and physiological features, the lack of clinical trial subjects resulting in inability to select an optimal dose by its escalation, the absence of consensus on the ethical aspect of pediatric clinical trials, the etiopathogenetic difference of some diseases and conditions depending on subject’s age, and prevalence of placebo-effect in children. Nowadays it is supposed to be very important to publish all, even failed, pediatric trials to improve the accuracy of pharmacological effects modeling in different subpopulations.

Научная и практическая значимость клинических исследований лекарственных средств сегодня не вызывает сомнений в медицинском сообществе, методологические и этические аспекты планирования и проведения клинических испытаний разработаны, доступны и соблюдаются добросовестными исследователями. Приверженность к применению лекарственных средств с доказанной эффективностью и безопасностью становится обычной в повседневной врачебной практике – но не для педиатров. По данным Европейской Комиссии, более 50% препаратов, используемых в педиатрии, не разрешены к применению у детей («unlicensed») или назначаются не по «разрешенным показаниям» («off-label»), потому, что клинические исследования этих препаратов у детей не проводились. Отсутствие контролируемых клинических исследований в подавляющем большинстве областей педиатрии приводит к тому, что многие неэффективные или даже опасные вмешательства применяются у детей раньше, чем их эффективность и безопасность была оценена в рандомизированных исследованиях, тогда как появление в педиатрической практике некоторых эффективных вмешательств необоснованно откладывается. Учитывая важность проблемы, в последние годы в Европейском Союзе (ЕС) предприняты многочисленные шаги по исправлению сложившейся ситуации, что в результате привело к значительным изменениям законодательства ЕС в области педиатрических исследований.

The article is a review of modern literature and an analysis of the legal framework regarding the use of local anesthetics in children under 4 years of age. There is a discussion of the validity of the off-label principle. In the domestic and foreign literature, there are publications highlighting the use of drugs based on 4% articaine in children under 4 years old, despite age-related contraindications according to the instructions. It is necessary to pay special attention to the regulatory status of the instructions for the medical use of the medicinal product. Summarizing the presented arguments, we can talk about the available spectrum of clinical studies, meta-analyzes and RCT data on the use of articaine in dental practice in children under 4 years of age, which indicates its effectiveness and is considered a safe alternative to lidocaine for use. in children of all ages.