AUTHORITATIVE OPINION
The COVID-19 pandemic has profoundly affected all aspects of people’s lives, with the global community facing threats unprecedented in this century. To tackle the challenge posed by the pandemic, nations have turned to the results of previous fundamental research. The Russian healthcare system and manufacturers have worked in close cooperation to develop new vaccines in the shortest time possible.
The pandemic is still continuing, and so are the extensive efforts to fight it. However, the medical and pharmaceutical community has had enough time to draw certain conclusions and learn important lessons that may come useful in dealing with the current and future epidemics.
We have discussed these and other COVID-19-related questions with Vladimir Chulanov, Chief Freelance Specialist of the Ministry of Health of Russia, Doctor of Medical Sciences, Professor of the Chair of Infectious Diseases of the Sechenov University, Deputy Director for Science and Innovations of the National Medical Research Center of Tuberculosis and Infectious Diseases.
Interview by Nataliya Velts
MAIN TOPIC: MEDICINAL PRODUCTS FOR COVID-19 TREATMENT AND PREVENTION: EFFICACY AND SAFETY
The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disor ders; gastrointestinal disorders, neurological disorders, and allergic reactions; and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia; neutropenia is also characteristic of a number of interleukin inhibitors. Haemo static adverse reactions to anticoagulants depend on the patient’s dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions.
By June 1, 2022, there were 38 prophylactic COVID-19 vaccines approved in 197 countries around the world. The ongoing approval of new vaccines and the accumulation of more than a year's worth of data on their use give particular importance to the consolidation and analysis of information on the safety of such vaccines.
The aim of study was to analyse the information on adverse events after immunisation (AEFIs) with coronavirus vaccines in the individual case safety reports entered into the VigiBase database by June 1, 2022.
Materials and methods: the author analysed safety reports retrieved from VigiBase through the VigiLyze interface in the expert access mode. The search was carried out using the generic keyword “Covid-19 vaccine” in combination with the trade names of all 38 coronavirus vaccines.
Results: the article presents consolidated information on the number and content of the safety reports on COVID-19 vaccines. The author noted that the reports were characterised by a high level of information completeness and quality, which could be due to the fact that the main reporters were the countries with developed pharmacovigilance systems. The analysis of patient complaints showed that the reported symptoms of AEFIs coincided with the manifestations of side effects of the vaccines included in the package leaflets. The author carried out a review of the cases of serious AEFIs and the cases of adverse events of special interest requiring additional monitoring after immunisation. It revealed a positive correlation of individual vaccines with the cases of somnolence in post-COVID-19 patients.
Conclusions: the data obtained on the global safety of coronavirus vaccines may be of practical interest to doctors, researchers, developers, and healthcare regulators.
There is considerable interest worldwide in developing safe and effective vaccines against COVID-19. Pharma-covigilance of adverse events following immunisation (AEFIs) is a key to making informed decisions regarding the global COVID-19 vaccination campaign. In the Kyrgyz Republic, there have been developed a national immunisation information system (IIS) for automated recording of vaccines, vaccinated persons, and AEFIs and a mobile application for AEFI reporting, called Den Sooluk.
The aim of the study was to analyse the pattern of AEFIs against COVID-19 in the Kyrgyz Republic.
Materials and methods: the study analysed the spontaneous safety reports submitted to the national IIS database through the Den Sooluk mobile application from 29.03.2021 to 25.09.2022.
Results: according to the data available by 25.09.2022, the total number of vaccinated people in the country amounted to 2,940,082. At the time, the IIS database included 2111 AEFIs: 1 fatal (and coincidental), 3 severe and 2108 minor ones. AEFIs were more frequent in the young and middle-aged population (81.5%), than in the elderly (18.5%). The following AEFIs were reported: injection site pain (21.25%), fatigue (20.7%), headache (19.8%), body temperature above 38 °C (10.10%), miscellaneous symptoms (5.12%), chills (4.41%), dizziness (4.32%), sore throat (3.36%), myalgia (2.9%), and nausea (2.2%).
Conclusions: all COVID-19 vaccines used in the Kyrgyz Republic can be considered adequately safe. Pharmacovigilance of AEFIs is an integral part of the requirements to ensure the safe use of vaccines, and collecting of spontaneous reports on AEFIs supports adequate functioning of the post-marketing surveillance system. It is essential to provide access to electronic information platforms to health professionals and patients in order to ensure vaccination transparency and coordination and enable quick and safe reporting of AEFIs associated with the use of COVID-19 vaccines.
Timely, effective, and safe antiviral therapy in COVID-19 patients reduces complications, disability and mortality rates. The greatest concern with remdesivir is the risk of drug-induced liver injury, including in patients whose liver function is compromised by COVID-19.
The aim of the study was to investigate the efficacy and safety of remdesivir in patients with confirmed SARS-CoV-2 infection who had been admitted to an infectious diseases hospital in the Volgograd region in March 2022. Materials and methods: the authors carried out an open, non-randomised, single-arm study using medical records of 234 patients who had been diagnosed with “U07.1 COVID-19, virus identified” and prescribed remdesivir upon admission. The effectiveness of therapy was evaluated using two criteria: the need for oxygen supplementation or ventilatory support, or mortality. The authors conducted the evaluation on days 7, 14, and 28 using the six-point ordinal severity scale by Y. Wang et al. The safety of therapy was assessed on the basis of complaints and changes in laboratory findings.
Results: for the patients prescribed remdesivir at admission, the 7-day mortality rate was 3.0%, the 14-day mortality rate was 5.6%, and the 28-day mortality rate was 7.3%. With the exception of a patient with myocardial infarction, all the patients who had been hospitalised with mild COVID-19 and prescribed remdesivir did not require oxygen therapy and/or transfer to intensive care and were discharged following recovery. The patients with moderate to severe COVID-19 had the 14-day mortality rate of 6.4% and the 28-day mortality rate of 8.6%. 17 patients (7.2%) discontinued remdesivir prematurely for various reasons, including adverse drug reactions. Remdesivir therapy of 5-10 days was associated with an increase in ALT activity by 2.7 ± 0.8 times in 15.9% of patients with mild COVID-19, by 3.8 ± 1.8 times in 20.4% of patients with moderately severe COVID-19, and by 4.8 ± 2.7 times in 24% (12/50) of patients with severe COVID-19. In two patients (0.9%), the increase exceeded 10-fold the upper limit of normal.
Conclusions: the obtained results support recommending remdesivir to patients with mild, moderate and severe COVID-19, including those with moderately elevated baseline activity of hepatic transaminases.
PHARMACOVIGILANCE
Serious adverse drug reactions (ADRs) to medicinal products can cause death. It is an immediate challenge for modern medicine to prevent the possibility of this outcome and to improve the safety of pharmacotherapy. The aim of this study was to identify and analyse the main methodological approaches to studying the prevalence, patterns, and risk factors of fatal ADRs. The authors identified three main methods for studying such reactions: analysis of death certificates, monitoring of spontaneous reports, and review of clinical trials with a particular focus on safety. Each of these methods has its advantages and limitations. Clinical trials provide the most accurate information on the prevalence of fatal ADRs. For inpatients, this value ranged from 0.05 to 0.95% of the total number of hospital admissions. Data from death certificates may be particularly useful for identifying the groups of medicinal products posing a high risk of death and for making longitudinal comparisons. Monitoring of spontaneous reports is very effective in rapidly identifying fatal adverse reactions to new medicinal products. According to the authors, not only the choice of a data collection method, but also its application can affect the results of an ADR study. It was noted that the data varied across clinical trials conducted in different countries. Such variations indicate the importance of studying the problem of fatal ADRs at the national level, as well as the need for initiating such studies in the Russian Federation.
Sodium metamizole (SM), analgin, was recalled from the pharmaceutical market by the regulatory authorities of some countries in the mid-60s because of side effects (agranulocytosis). However, there has been a trend towards a steady increase in its prescription rates in the recent decades. The aim of the study was to characterise the regulatory status of SM in different countries of the world, to assess the effectiveness and safety, and to analyse available data on medication errors in real clinical practice. According to the reviewed publications, SM is the most frequently used analgesic in surgical practice in German-speaking countries, the third most frequently prescribed analgesic in Switzerland, and a widely used one even in the countries where it has previously been recalled, such as the USA. The increase in the use of SM, according to experts, is due to the opioid crisis and the high risk of cardiotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs). In chronic pain, the efficacy of SM is superior to that not only of paracetamol, but also of NSAIDs; in postoperative pain and acute primary headache, it is not lower than that of other commonly used analgesics. SM has a pronounced analgesic effect in cancer patients; high doses are comparable to narcotic analgesics in effectiveness but have a significantly more favourable safety profile. Randomised and observational studies confirm that the short-term use of SM is quite safe, including in terms of the risk of developing myelosuppressive side effects. When administered as a course of less than 2 weeks, SM is characterised by a lower frequency of adverse events compared to opioids and an approximately equal one compared to placebo and paracetamol, while longer courses are associated with an increased risk of agranulocytosis. Adverse drug reactions may result from medication errors. The risk of lethal outcome associated with agranulocytosis increases when SM is co-administered with methotrexate or used in elderly patients. In the Russian Federation, SM is an over-the-counter medicinal product approved for a wide range of pain types; it can be used as a highly effective analgesic provided that the dose, route, and frequency of administration are appropriate, the baseline characteristics of patients are taken into account, and unreasonably long courses (more than 2 weeks) are avoided.
The state policy for the safety of medicinal products involves analysis of specialists' competence in identifying adverse drug reactions (ADRs) during the use of medicinal products. It is of particular importance for the group of essential medicines, including those used in cardiology.
The aim of the study was to assess ADR-reporting skills of doctors managing cardiology patients, with anti-arrhythmics as a case study.
Materials and methods: from October 2019 to June 2021, the authors surveyed a sample of 223 practitioners that treated cardiology patients in Moscow and the Moscow region (36 of the respondents took the survey in person, and 187 participated on-line). The questionnaire inquired about selection criteria for the medicinal products, their assessment in terms of efficacy and safety in real-life clinical practice, and the competence and active involvement of the doctors in reporting identified ADRs.
Results: most of the survey participants were high-level professionals (60.99% had 10 and more years of experience). Most of the doctors (90.13%) admitted having encountered ADRs in their practice, placing substandard quality of cardiovascular medicinal products among the causes. Moreover, 1.79% of the respondents faced such quality problems on a regular basis. Only 52.91% were familiar with the current documents regulating pharmacovigilance. A total of 61.88% applied information from Russian and foreign ADR databases in their practice. In 2021, 80.72% of the surveyed did not report data on the identified ADRs. According to the respondents, the main reasons for low reporting activity were high workload and lack of evidence for causality between a product and an ADR.
Conclusion: the study demonstrated the need to intensify the work with practitioners on the safety of medicinal products and ADR identification, particularly, to train them in pharmacovigilance. According to the study results, it is feasible to develop and implement simple and user-friendly risk-oriented information systems for analysis and systematisation of ADR case reports.
PRECLINICAL STUDIES
Phenosanic acid prevents convulsions, reduces the frequency of epileptic seizures, and improves cognitive, intellectual and mnestic functions in patients with epilepsy. Therefore, phenosanic acid-based medicinal products are promising candidates for inclusion in combination antiepileptic therapy. In order to combine medicinal products rationally and ensure that the therapy is safe, it is useful to study the pharmacokinetic interaction of medicinal products planned for clinical co-administration.
The aim of the study was to examine single-dose pharmacokinetic interactions between Dibufelon® 200 mg capsules (PIQ-PHARMA LLC, Russia) and two medicinal products planned for clinical co-application with it, namely, valproic acid and carbamazepine, in sexually mature dogs.
Materials and methods: the study included medicinal products of phenosanic acid (Dibufelon® 200 mg capsules by PIQ-PHARMA LLC, Russia), valproic acid (300 mg prolonged-release film-coated tablets), and carbamazepine (200 mg tablets). The medicinal products were administered to beagle dogs (2 groups of 9 males each) as a single oral dose separately and in the following combinations: phenosanic acid with valproic acid and phenosanic acid with carbamazepine. Dose selection involved adjusting maximum human therapeutic doses using interspecies conversion factors. Phenosanic acid was administered at a dose of 24 mg/kg; valproic acid and carbamazepine were administered at a dose of 60 mg/kg. Blood sampling took place at baseline and in 0.5, 0.75, 1, 2, 4, 6, 8, 10, and 24 h after dosing. Plasma concentrations of active substances were determined by HPLC-UV. Pharmacokinetic interactions were evaluated by changes in the main pharmacokinetic parameters (Сmax, Тmax, AUC0-24, MRT, Т1/2).
Results: the study demonstrated rapid gastrointestinal absorption and prolonged systemic circulation of phenosanic acid administered separately (Tmax 2–4 h, T1/2 13–28 h) and combined with valproic acid (Tmax 2 h, T1/2 22 h). When administered with carbamazepine, phenosanic acid was eliminated from the systemic blood flow faster (T1/2 7.4 h).
Conclusions: co-administration of phenosanic acid and valproic acid medicinal products had no significant effect on their respective pharmacokinetics. Whereas, the combination of phenosanic acid and carbamazepine demonstrated a significant decrease in the Tmax values of phenosanic acid and the MRT values of carbamazepine. The pharmacokinetic changes suggestive of a possible interaction between phenosanic acid and carbamazepine need further clinical investigation.
COCHRANE PUBLICATIONS
This article is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Review previously published in the Cochrane Database of Systematic Reviews. Original publication: Reis S, Metzendorf M-I, Kuehn R, Popp M, Gagyor I, Kranke P, et al. Nirmatrelvir combined with ritonavir for preventing and treating COVID-19.
Cochrane Database of Systematic Reviews 2022, Issue 9. Art. No.: CD015395. https://doi.org/10.1002/14651858. CD015395.pub2
THANK YOU FOR ALL OUR REVIEWERS
We are deeply grateful to our reviewers for their invaluable assistance in preparing the issues of Safety and Risk of Pharmacotherapy for publication.
ISSN 2619-1164 (Online)