INTRODUCTION. Geriatric patients are the fastest growing demographic group, accounting for over half of all medicinal product users. Pharmacovigilance in this population is influenced by age-related physiological changes and social factors. Risk management plans (RMPs), developed by marketing authorisation holders, play a preventive role in managing the risks associated with the use of medicinal products in elderly patients.
AIM. This study aimed to evaluate the completeness of information on the geriatric group within target populations in RMPs for medicinal products launched in the Russian pharmaceutical market in 2024.
MATERIALS AND METHODS. This study analysed 110 RMPs for medicinal products potentially applicable to geriatric populations, submitted to the Scientific Centre for Expert Evaluation of Medicinal Products between January and December 2024. All the documents included full modules and sections.
RESULTS. The analysis revealed critical gaps in RMPs data for geriatric populations, including the epidemiology of indication(s) and target population(s) (these data were missing in 52.0% of cases); clinical trial exposure (patients over 60 years were excluded from clinical trials in 47.3% of cases); populations not studied in clinical trials (these data were unreported in 63.6% of cases); post-authorisation experience in elderly or senile patients (these data were missing in 83.6% of cases); and potential harm from overdose (risk warnings were absent in 96.4% of cases). There were no additional risk minimisation measures for emphasising the considerations for medicinal product use in the geriatric population in the analysed documents.
CONCLUSIONS. When drafting RMPs, marketing authorisation holders and medicinal product developers do not pay sufficient attention to geriatric populations and often underestimate the risks associated with medicinal product use in elderly and senile patients. The issues associated with the use of medicinal products in geriatric patients can be mitigated through rigorous risk management practices applied during pharmacotherapy. The parties concerned should consider this when drafting the summary of medicinal product characteristics and the patient information leaflet, labelling the medicinal product, and selecting the package size.

INTRODUCTION. In the Russian Federation, risk-based approaches/methods to assess the safety of medicinal products have been used since 2016, but existing models based on them are few and applicable mainly to healthcare organizations. This underscores the need to systematise risk assessment procedures for medicinal products within pharmacovigilance frameworks by pharmacovigilance specialists using a risk-based approach in the risk management system.

AIM. This study aimed to analise of the key tools of the risk-based approach and optimise their application in medicinal product risk management systems.

RESULTS. A four-stage risk management framework for medicinal products was developed using a risk-based methodology: identification of risks associated with medicinal product use, determination of risk factors specific to individual medicinal products, correlation and evaluation of data for each risk factor with each of the identified risks and a conclusion on the benefit-risk ratio of medicinal products use. Key tools for implementing this approach include: 1) organization of work with information about adverse drug reactions; 2) active monitoring of drug safety; 3) development, implementation, and evaluation of risk mitigation measures; 4) targeted communication of safety issues to healthcare professionals, patients, and caregivers. Spontaneous reports, reports of adverse drug reactions received on request from the holder of the registration certificate, data from pharmacoepidemiological studies, information published in the scientific medical literature, as well as Internet resources are used as sources of information to identify the risks of adverse drug reactions at the post-registration stage of medicinal products circulation. Risk factors for the development of adverse drug reactions in the use of medicinal products are physiological changes in the patient's body, gender, age, presence of comorbidities, genetic predisposition, differences in pharmacokinetics and pharmacodynamics of medicinal products depending on the patient's age, use of off-label medicinal products. A five-step algorithm for medicinal product risk assessment was developed: parameters and objectives of risk evaluation, data sources, potential risks, severity and probability of risks, and benefit-risk ratio assessment. Additional risk minimisation measures are summarised.

CONCLUSIONS. The proposed variant of the risk-based approach using available tools can be used by pharmacovigilance specialists in drug risk management.

INTRODUCTION. Both low-molecular-weight and unfractionated heparins are frequently used to prevent and treat COVID-19-associated thrombosis, placing patients at an increased risk of developing heparin-induced thrombocytopenia (HIT) as an adverse reaction. Vaccination has played a key role in combating the COVID-19 pandemic, yet careful consideration is needed for potential adverse events following immunisation, in particular, for vaccine-induced immune thrombotic thrombocytopenia (VITT) associated with adenoviral vector vaccines.
AIM. This study aimed to conduct a comparative analysis of HIT and VITT prevalence, pathogenetic mechanisms, clinical manifestation patterns, and treatment considerations in order to select the most effective therapeutic strategies for each condition and optimise them for clinical use.
DISCUSSION. This comparative analysis covers full-text systematic reviews, meta-analyses, clinical trial reports, review articles, and case reports in Russian and English published from 1992 to March 2024 and retrieved from bibliographic databases, including PubMed.gov, Lens.org, and eLIBRARY.RU. According to the analysis, HIT incidence is higher in women who had previous cardiovascular or orthopaedic surgery, women on extracorporeal membrane oxygenation, and critically ill patients with COVID-19, whereas VITT is more common in women under 55 taking oral contraceptives and immunised with an adenoviral vector vaccine. The first signs of HIT usually show 5–10 days after heparin initiation, and the time of VITT onset varies from 4 days to 1 month. In contrast to HIT, VITT is characterised by atypical localisation of thrombosis. In HIT, platelet-activating anti-heparin/platelet factor 4 IgG antibodies bind to FcγRIIA receptors, which leads to platelet activation and aggregation. In VITT, the polyanion that triggers the immune system is either hexon protein or adenoviral vector DNA from neutrophil extracellular traps. Potential treatments for HIT include heparin discontinuation or switching from unfractionated heparins to low-molecular-weight heparins, fondaparinux sodium, or non-heparin anticoagulants (direct thrombin inhibitors and oral anticoagulants). Treatment options for VITT include non-heparin anticoagulants, fondaparinux sodium, and intravenous immunoglobulins. Switching to non-heparin anticoagulants in VITT is optional. Venous thrombosis is the main cause of death in both adverse reactions.
CONCLUSIONS. Medical professionals should be alert to the potential development of VITT after vaccination with adenoviral COVID-19 vaccines and HIT during the use of heparins. Patients with suspected adverse reactions require prompt hospital admission, haematologist consultation, and laboratory and instrument testing.

INTRODUCTION. With the expanding product range and the introduction of novel biological medicinal products for haemophilia A, haemophilia B, and von Willebrand disease in the Russian pharmaceutical market, post-marketing safety surveillance becomes especially important.
AIM. This study aimed to comprehensively evaluate the data on adverse reactions (ARs) to biological medicinal products for haemophilia A, haemophilia B, and von Willebrand disease reported in the Russian Federation and submitted to the national pharmacovigilance database, with a view to updating the safety data of these medicinal products.
MATERIALS AND METHODS. The study analysed spontaneous reports of ARs to medicinal products used as substitution therapy in various types of haemophilia and von Willebrand disease. The analysis focused on spontaneous reports submitted to the Pharmacovigilance database of the Automated Information System of the Russian Federal Service for Surveillance in Healthcare (Roszdravnadzor) in 2019–2023.
RESULTS. The analysis identified 126 spontaneous reports documenting 129 ARs associated with biological medicinal products for various types of haemophilia and von Willebrand disease (9 groups of medicinal products according to the Anatomical Therapeutic Chemical (ATC) classification system). The most prolific reporters were pharmaceutical companies (76.2%), whereas healthcare institutions (12.7%) and regional offices of Roszdravnadzor, pharmacovigilance centres, and distributors (11.1%) reported ARs less often. The most frequently reported ARs occurred with emicizumab and medicinal products belonging to the coagulation factor VIII group according to the ATC classification. The most common ARs included haemarthroses, medicinal product ineffectiveness, haemorrhages, and administration site bleeding. Unexpected ARs accounted for 34.1% of cases. The majority of unexpected ARs were haemarthroses, including 5 (31.3%) cases reported with emicizumab and 5 (31.3%) cases associated with octocog alfa (recombinant human coagulation factor VIII). One death was reported with a medicinal product under the International Non-proprietary Name (INN) emicizumab. A comparison of the data obtained in this study with the data available from the international VigiBase database identified spontaneous reports of similar ARs to all the biological medicinal products analysed.
CONCLUSIONS. Marketing authorisation holders, manufacturers, and regulatory authorities should continuously monitor the safety of biological medicinal products for the treatment of haemophilia A, haemophilia B, and von Willebrand disease. Prescribing doctors should be vigilant about the haemorrhagic and thrombotic ARs specific to these medicinal products, as well as about potential ineffectiveness, and make timely adjustments to the dose and treatment regimen if necessary.

INTRODUCTION. Elevated liver enzyme levels are common in patients with COVID-19. Personalised prescribing to reduce the risk of hepatotoxicity requires studying the role of pharmacotherapy in the development of liver dysfunction in COVID-19 patients.

AIM. This study aimed to identify the presence and strength of the relationship between an increase in alanine transaminase (ALT) levels and the use of potentially hepatotoxic medicinal products in hospitalised patients with COVID-19 to provide practising clinicians with a case-specific approach for selecting medicinal products with a lower risk of hepatotoxicity.

MATERIALS AND METHODS. The authors analysed 1,296 medical records of COVID-19 patients who had been admitted to a Volgograd Region hospital for infectious diseases in 2020–2022. A case-control study was performed using the pair-matched case–control method, with pairs of patients matched by their sex, age, and COVID-19 severity and outcomes. The authors identified the medical records of COVID-19 patients with baseline alanine transaminase (ALT) levels <1 or 2 times the upper limit of the normal range (ULN) and selected the medical records of the patients who had been having elevated ALT levels ≥2, 3, and 5 ULN (cases) or ALT levels <2 ULN (controls) throughout their hospital stay.

RESULTS. There was a significantly higher likelihood of detecting the use of ≥3 medicinal products associated with a high risk of drug-induced liver injury (DILI) in the medical records of all case groups than in those of the controls (odds ratio (OR)=2.38 (1.54–3.67), p<0.001, for detecting the use of ≥3 high-risk medicinal products and an increase in ALT levels from <1 ULN at baseline to >2 ULN, 195 pairs; OR=2.59 (1.48–4.53), p<0.001, for detecting the use of ≥3 high-risk medicinal products and an increase in ALT levels from <1 ULN at baseline to >3 ULN, 115 pairs). Certain medicinal products were associated with a significant increase in the risk of ALT rising to levels >2 ULN in patients with baseline levels <1 ULN (remdesivir: OR=4.38 (2.98–6.42), p<0.001; olokizumab: OR=7.83 (3.35–18.32), p<0.001; and levilimab: OR=3.0 (1.19–7.56), p=0.014) and levels >3 ULN in patients with baseline levels <2 ULN (remdesivir: OR=2.0 (1.21–3.30), p=0.006; olokizumab: OR=3.94 (2.35–6.62), p<0.001; and levilimab: OR=2.67 (1.24–5.74), p=0.009).

CONCLUSIONS. According to this study, there is a statistically significant association between elevated ALT levels in hospitalised COVID-19 patients and the use of several hepatotoxic medicines. Further studies are required to assess the safety of medicines used to treat COVID-19. It is also necessary to develop methods for the early detection and prevention of DILI.

INTRODUCTION. The natural morpho-functional involution of the ageing body is accompanied by an age-related decline in homeostasis, which leads to changes in the pharmacodynamics, pharmacokinetics, and toxicity of medicines. Mathematical prediction models (MPMs) are a promising tool for predicting age-associated pharmacotherapy risks in elderly and senile patients.
AIM. This study aimed to develop a simple linear mathematical model for predicting age-related changes in the relative risk of pharmacotherapy.
MATERIALS AND METHODS. A basic statistical hypothesis for the MPM was formulated using generally accepted approaches and methods adapted to the original physiological concept of age-related decline in homeostasis. The prediction hypothesis has theoretical and clinical prerequisites. Statistically, the proposed MPM is a single-factor linear regression model. The main parameters and key criteria of the model include age (predictor), life expectancy, and the rates of population and physiological age-related decline in homeostasis.
RESULTS. The algorithm developed for predicting the relative risk of pharmacotherapy based on the concept of age-related decline in homeostasis includes the following steps: 1) establishing the rate of population-based decline relative to the linear trend of hypothetical physiological decline; 2) determining the probability limits for critical age-related decline in homeostasis; 3) extrapolating the relative risk (RR) and the odds ratio (OR) of age-related decline in homeostasis to the corresponding pharmacotherapy parameters; and 4) using the available data on the risk of pharmacotherapy in young and middle-aged patients to convert predictions into quantitative characteristics of adverse drug reactions. The predictions based on the data obtained are in good agreement with clinical observations that indicate a 2–7-fold increase in the risk of developing adverse drug reactions during pharmacotherapy in elderly and senile patients. The physiological homeostatic decline rate in centenarians within the linear model corresponds to the age-related decline in human pharmacokinetic clearance parameters. The physiological homeostatic decline parameters allow researchers to assess the impact of population risk factors on age-related decline in homeostasis.
CONCLUSIONS. The MPM developed in this study provides a means to predict the relative risk of pharmacotherapy in elderly and senile patients based on the concept of age-related decline in homeostasis. The results support further evaluation of the predictive effectiveness of the model.

INTRODUCTION. Frostbite is a common cold injury that is associated with high rates of disability and requires long and difficult treatment. A vascular endothelial growth factor (VEGF)-encoding pCMV-VEGF165 plasmid-based gene therapy product designed for therapeutic angiogenesis may be a promising tool to promote microcirculation recovery and accelerate lesion healing in local cold injury. This hypothesis needs to be tested in an experimental animal study.
AIM. This study aimed to evaluate the efficacy of the pCMV-VEGF165 plasmid gene therapy product for the management of cold injury of a limb in rats.
MATERIALS AND METHODS. The study included 42 mature female outbred white laboratory rats. A third to fourth-degree local cold injury was experimentally induced on the dorsal surface of the left hind paw by applying a neodymium magnet frozen in liquid nitrogen. The animals received periwound injections of the test product (super-coiled circular double-stranded plasmid deoxyribonucleic acid at a dose of 60 μg) and placebo (water for injections) on days 2 and 7 after frostbite modelling. The authors evaluated the general condition of the animals, the condition of the damaged paw, the wound area, the healing rate, the body mass, and, after planned euthanasia, the mass of the hind paws.
RESULTS. Starting from day 7, the rats treated with the test product showed significantly faster tissue regeneration at the site of cold injury than the control animals. The mean wound surface area reduction in the test animals amounted to 47.36% [25.55; 55.45], whereas that in the control animals was 28.95±18.55% (p<0.05). On day 10, the test group still had a significantly higher tissue regeneration rate than the control group (58.70±15.35% vs 42.01±17.41%, respectively, p<0.05). Later, there was no statistically significant difference in the wound surface healing rates between the groups, which could probably be attributed to the nature of wound healing in the experimental model since rodent wounds heal predominantly by contraction.
CONCLUSIONS. The pCMV-VEGF165 plasmid gene therapy product injected in the periwound area at a dose of 60 μg on days 2 and 7 after cold injury simulation in rats reduces damage, accelerates tissue regeneration under the scab, and expedites scarring. 

INTRODUCTION. This work is a continuation of the studies of an original biological product based on the secretome of human mesenchymal stromal cells (MSCs) and intended for the restoration of spermatogenesis and fertility. To ensure the safety of the product, it is necessary to conduct preclinical studies in two types of animals, including rodents (the results of rodent studies were presented earlier) and non-rodents.

AIM. This study aimed to investigate the systemic toxicity, safety pharmacology, pyrogenicity, immunotoxicity, reproductive toxicity, and local tolerance of the original MSC secretome product in mature rabbits after two injections under the tunica albuginea of the testes.

MATERIALS AND METHODS. The study was conducted in 50 male Soviet chinchilla rabbits (5 groups of 10 animals). The lyophilised MSC secretome product (MediReg) was reconstituted, mixed with collagen gel (Applicoll), and administered to rabbits subalbugineally on days 1 and 28 at a dose equal to the therapeutic dose (≥0.76 ng of vascular endothelial growth factor (VEGF)), 1.5 therapeutic doses (≥1.14 ng of VEGF), or 2.5 therapeutic doses (≥1.9 ng of VEGF). The control groups included intact rabbits and rabbits that received Applicoll mixed with water for injection. The animals were assessed in terms of their clinical condition, body temperature, electrocardiogram changes, heart and respiratory rates, blood pressure, modified Irwin test results, urinalysis findings, blood counts and biochemistry, haemostasis parameters, arterial blood gas measurements, and spermogram changes. Further, the animals were necropsied, and selected organs were weighed and subjected to histopathology. The follow-up period was 60 days.

RESULTS. On day 3, the groups receiving 1.5 and 2.5 therapeutic doses of the medicinal product demonstrated a significant decrease in prothrombin time; however, only the placebo group still had decreased prothrombin time levels during the follow-up period. The histological examination revealed occasional splitting areas in the intertubular connective tissue with the formation of cavities filled with a loose substance with pronounced eosinophilic staining and deformation of the tubules along the walls of the cavities as a result of compression in 1–2 of 5 (20–40%) rabbits in all groups that received either the medicinal product or placebo. This was probably caused by mechanical compression of the tubules by the administration of large volumes of substances. In the placebo group, 2 of 5 (40%) animals had a transient increase in the size of the vesicular glands; the lobules were markedly expanded and contained a transparent secretion. The histological appearance of the vesicular glands was normal.

CONCLUSIONS. When administered twice under the tunica albuginea of the testes of rabbits, the medicinal product comprising the MSC secretome and the Applicoll collagen gel carrier has an acceptable safety profile.

INTRODUCTION. Many countries are implementing an increasing number of alternatives to animal testing in the research, development, and quality control of medicines under the concept of 3Rs (replacement, reduction, and refinement). However, the implementation of in vitro alternatives to in vivo methods into batch release testing of biologicals, primarily vaccines, is a challenging process. The introduction of the 3Rs principles into regulatory and industry standards requires a comprehensive analysis, including, among other things, a study of specific considerations for national frameworks.
AIM. This study aimed to analyse the degree of global integration of the 3Rs principles in the quality control of biological medicinal products and to assess existing challenges and opportunities for a successful transition to non-animal quality control methods in the Russian Federation.
DISCUSSION. The key advantages of in vitro biological methods over in vivo approaches for quality control of medicinal products include reduced variability, higher specificity, and shorter testing timelines. Analysis of assessments by regulatory authorities and pharmaceutical manufacturers regarding the opportunities and challenges in implementing the 3Rs principles has identified the following main arguments for replacing in vivo methods: ethical considerations, relevance of reducing testing time, decreased variability. The integration of in vitro methods is hindered by insufficient information on alternative approaches and the lack of harmonised regulatory frameworks for adopting 3Rs principles. For instance, the European Pharmacopoeia has eliminated all general safety testing of biological medicinal products in animals as part of its 3Rs implementation. Furthermore, the World Health Organization has developed guidelines for the phased discontinuation of animal testing in the quality control of biological products.
CONCLUSIONS. The main challenges associated with 3Rs implementation include the difficulty of confirming the in vitro – in vivo correlation (particularly, by comparing in vivo and in vitro methods), the lack of regulatory harmonisation, and the insufficient regulatory support for manufacturers in adopting alternative methods. The international harmonisation of regulatory requirements is necessary to effectively address these issues and successfully implement the 3Rs principles in the quality control procedures for biologicals released in different countries, including the Russian Federation.