Results of pharmacovigilance of the safety of medicinal products in Ukraine for 2020

The State Expert Center of the Ministry of Health of Ukraine (hereinafter – the Center) organizes and coordinates the pharmacovigilance system in Ukraine, in accordance with the Charter, on the basis of national legislation harmonized with international legislation. The main goals on which pharmacovigilance activities are organized are monitoring the safety and efficacy of the use of medicinal products and vaccines/tuberculin in the post-registration period.

The Pharmacovigilance Division of the Center (hereinafter – PD) carefully collects and analyzes information on adverse reactions (hereinafter – AR) and/or lack of efficacy (hereinafter – LoE) in the medical use of medicinal products (MPs), and on adverse events following immunization (hereinafter – AEFI), including AR following the use of vaccines/tuberculin, providing appropriate recommendations.

The year 2020 was marked by the onset of the pandemic of coronavirus disease (COVID-19) caused by the coronavirus SARS-CoV-2. The outbreak of the disease began in December 2019 in the city of Wuhan, Hubei, PRC, and was declared a pandemic by the WHO on March 11, 2020. The resulting situation made its adjustments to the process of healthcare professionals submitting reports to the Center on adverse reactions/lack of efficacy of medicinal products.

In Ukraine, a strict quarantine was in effect from 13 March to 22 June 2020, and until the end of 2020 an adaptive quarantine, which provided for the closure of departments in healthcare facilities (hereinafter – HCFs) for elective patients and elective surgeries, and most hospitals were repurposed for patients with coronavirus infection. Most HCFs in the regions of Ukraine did not admit patients during this quarantine, which affected the operation of the entire healthcare system in the country.

During 2020, experts of the Center's Pharmacovigilance Directorate took part in a number of webinars of the World Health Organization (hereinafter – WHO) and the European Medicines Agency (EMA) on the treatment and prevention of coronavirus infection. Much information was received and discussed regarding licensing of the COVID-19 vaccine in the EU, and communication issues of public engagement were discussed with a view to further implementation in the relevant regulatory processes and monitoring the safety of COVID-19 vaccines.

Experts of the Pharmacovigilance Department translated, analyzed, and posted on the Center's official website 15 global reports of the Uppsala Monitoring Centre (UMC) on cases of ARs following the use of medicinal products used in the treatment of COVID-19 and included in the WHO “SOLIDARITI” trial, and of other medicinal products used to treat COVID-19, which were received in the WHO global database VigiBase.

According to WHO data, a pharmacovigilance system is considered effective if a country receives at least 200 report forms on ADRs to medicinal products per 1 million population. In Ukraine, the Center has pharmacovigilance representatives in all regions of the country. Currently, 73 Center representatives work successfully on these matters in all oblasts and in the city of Kyiv. Thanks to the coordinated activities of the Pharmacovigilance Division and the Center's pharmacovigilance representatives in the regions, in 2020, 423 report forms on ADRs and/or lack of efficacy and AEFI in the medical use of medicinal products and vaccines/tuberculin (hereinafter – report forms) per 1 million population were received.

The introduction of the Automated Pharmacovigilance Information System (hereinafter – AISP) has simplified online reporting of adverse reactions to medicinal products and speeded up the receipt of report cards by the Center. Thus, in 2020, 96,7 % of report cards were received by the Center through the AISP, whereas in 2019 this percentage was 89,5% relative to reports received on paper.

In 2020, the Center received a total of 17 587 reports of adverse reactions and/or lack of efficacy, and adverse events following immunization, during the medical use of medicinal products, vaccines/tuberculin, which is 9 837 reports fewer than in 2019. However, the qualitative indicator of the information content of the report forms, and accordingly the number of valid report forms, increased in 2020.

Thus, in 2019, 1054 report forms were counted as invalid, which amounted to 3,8% of the total number of reports, whereas in 2020 the number of invalid report forms was 597 (3,4%, respectively). Such indicators were achieved thanks to the coordinated work of the staff of the Pharmacovigilance Department and the Center's pharmacovigilance representatives in the regions using the AISF.

The Center also receives reports of adverse reactions (AR) and/or lack of efficacy (LOE) during the medical use of medicinal products from applicants. In 2019, 58 684 such reports were received, whereas in 2020 – 46 486. The receipt of reports of AR and/or LOE during the medical use of medicinal products indicates the activity and responsibility of applicants in carrying out pharmacovigilance of the medicinal products they represent on the Ukrainian market.

Among the methods of information collection used in pharmacovigilance, passive pharmacovigilance predominates, that is, the method of collecting spontaneous reports of ARs and/or lack of efficacy of medicinal products from the medical community, patients and/or their representatives. This is a quite effective and widespread method of collecting information, which makes it possible to cover all strata of the population, analyze identified ARs by seriousness and expectedness, and draw appropriate conclusions and recommendations.

In 2020, the UF, on the instructions of the MoH of Ukraine, conducted enhanced pharmacovigilance of the medicinal products PROGRAF and TAKPAN in patients in the pre- and postoperative period of transplantation, and of the medicinal product DIAVITEK PD 1,5%, 2,5%, 4,25% in patients requiring peritoneal dialysis. Representatives of the Center for pharmacovigilance in the administrative-territorial units were involved in carrying out this method of information collection. The Center reported monthly to the MoH of Ukraine on the results of the enhanced pharmacovigilance of these medicinal products.

In 2020, 4425 reports of adverse reactions and/or lack of efficacy of medicinal products were sent to the WHO database, which is 23,3% (3396 reports) more than in 2019.

In the course of pharmacovigilance in Ukraine, the analysis of the data obtained made it possible to distribute adverse reactions by the pharmacotherapeutic group of the medicinal product, by systemic manifestations according to the MedDRA classification, and by the disease class name, in accordance with ICD-10.

In Table 1, based on AISF data, the share of pharmacotherapeutic groups of medicinal products of the first level of the Anatomical Therapeutic Chemical classification (hereinafter – ATC) for which reports of AR/AEFI of medicinal products were received for 2020 is presented.

Table 1

All other medicinal products account for a share of less than one.

The largest share of ADR reports concerns the use of antimicrobials for systemic use (65,6%). This figure rose slightly compared with 2019 (63,1%). Thus, antimicrobials for systemic use remain in first place on this list. The level of consumption of precisely this group of medicinal products by the population of Ukraine remains unchanged. Increased consumption of medicinal products of this pharmacotherapeutic group leads to the development of resistance in the human body and a lack of sensitivity of the pathogen to the action of many antibacterial medicinal products and other antimicrobials. At present, this is one of the important global problems in the field of health care.

In second place on this list are agents affecting the cardiovascular system (9,8%). Somewhat fewer cases of AR were observed with agents acting on the nervous system (6,6%), as well as on the digestive system and metabolism (4,0%). For all other pharmacotherapeutic groups of medicinal products, the Center received a much smaller share of reports of AR/NPPI of medicinal products.

Table 2 presents, according to AISF data, 10 pharmacotherapeutic groups of medicinal products of the second level of the ATC classification, the use of which generated the largest number of adverse reaction reports during 2020, expressed as a percentage of the total number of reports.

Table 2

Two pharmacotherapeutic groups account for half of all reports received by the Center, namely reports of adverse reactions (AR) to agents acting on mycobacteria (29,5%) and to antibacterials for systemic use (27,5%). Reports of AEFI with the use of vaccines accounted for 5,5%, relating to the corresponding reaction of the vaccinated person's immune system to the administration of an immunobiological preparation, accompanied by general and/or local manifestations characteristic of each type of vaccine. The share of AR manifestations with the use of antivirals for systemic use was 4,6%. All other medicinal products account for a share of less than four.

Table 3 presents 10 systemic manifestations of ADRs/AEFIs that occurred more often than others with the use of medicinal products in 2020 according to AISP data.

Table 3

The most common manifestations were gastrointestinal disorders (26,55%) and skin and subcutaneous tissue disorders (20,89%), since these body systems are the first to react to the use of any medicinal products. These manifestations can be either non-serious or serious, and require medication to resolve them.

Nervous system disorders rank third, accounting for 13,22%. General disorders and administration site conditions account for approximately the same share – 12,07%. Manifestations on examination account for 7,41%. Psychiatric disorders, musculoskeletal and connective tissue disorders, and respiratory, thoracic and mediastinal disorders account for approximately the same percentage, respectively – 3,86%, 3,0%, 2,93%. For all other body systems, manifestations are reported less frequently and account for a much smaller percentage.

In 2020, by degree of seriousness, among the total number of reports received, non-serious adverse reactions accounted for 93,72%, and serious ones for 6,28%. The frequency of serious adverse reactions by reason of seriousness was: 0,02% – deaths, 23,73% – life-threatening conditions, 15,64% – hospitalization of outpatients, 37,0% – prolongation of hospitalization, 1,09% – prolonged incapacity for work, 0,55% – disability, and 18,45% – other medically important health conditions.

Table 4 presents the ten classes of diseases (according to ICD – 10) in the treatment or prevention of which adverse reactions/AEFI were identified with the use of medicinal products in 2020 according to the data of the Automated Information System of Pharmacovigilance.

Table 4

Among all classes of diseases, according to ICD-10, in the treatment of which AR/AEFI were identified, almost half were certain infectious and parasitic diseases (code – A00-B90) – 40,78%. The share of occurrence of AR in this disease class is the highest, since the treatment of these common diseases requires the use of various groups of medicinal products. A larger percentage is also taken by conditions not falling under the ICD-10 classification – 15, 88%. Diseases of the respiratory system and diseases of the circulatory system also take a larger percentage – 11,10% and 9,91% respectively. Factors influencing the state of health of the population and contacts with healthcare facilities account for 6,04%. An approximately equal percentage is taken by diseases of the digestive system, diseases of the musculoskeletal system and connective tissue, mental and behavioral disorders, and diseases of the genitourinary system – 2,79%, 2,52%, 2,31, 2,06% respectively. A somewhat smaller percentage is taken by diseases of the nervous system – 1,32%. All other classes of diseases, in the treatment or prevention of which AR/AEFI were identified with the use of medicinal products, account for a percentage of less than one.

It should be noted that, by gender indicators, there is no significant difference in the occurrence of adverse reactions when using medicinal products between men and women, namely 42,75% and 39,32% respectively. Among the pediatric population, boys and girls, there is likewise no difference by gender indicators – 7,02% and 6,55% respectively.

In 2020, the Center received information on 15 cases of unexpected adverse reactions associated with the use of medicinal products.

Three cases of unexpected ADRs occurred with the use of Sodium Chloride 0,9% solution from different manufacturers. The other cases of unexpected ADRs were classified as 3 cluster cases of ADRs, i.e., the cases occurred in 3 healthcare facilities. One cluster case of unexpected ADRs was noted with the use of Glucose 5% solution for infusion, and two cluster cases with Sodium Chloride 0,9% solution. The cluster cases were characterized by the fact that in each healthcare facility, the use of one medicinal product led to an ADR manifesting with identical clinical manifestations, linked in time of onset, in two or more patients.

A cluster case of ADRs with the use of Glucose 5% for infusions manifested as hyperthermia and chills in 2 patients. The ADR manifestations disappeared after discontinuation of the suspected medicinal products and administration of drug therapy to eliminate them.

The next cluster of cases was observed in one hospital ward in 2 patients after the use of Sodium chloride 0,9% solution from one manufacturer. The clinical manifestations were hyperthermia, convulsions and chills in both patients. The manifestations of the AR were relieved with hormone therapy, analgesics, psycholeptic and sedative drugs. Concomitant therapy was not discontinued.

The third case of a cluster adverse reaction (AR) occurred in one hospital in 8 patients almost simultaneously after the use of Sodium Chloride 0,9% solution from one manufacturer. Clinical manifestations of the AR in the form of hyperthermia and fever disappeared after discontinuation of the suspected medicinal product.

In all cases, the use of a medicinal product with the same active substance from a different manufacturer and a different batch in further treatment did not cause undesirable effects.

It is noteworthy that after laboratory quality control of samples of suspected medicinal products, the results were positive.

In 2020, the Center received information on 4 cases of death associated with the use of medicinal products. Three of them occurred after the use of one suspected medicinal product (monotherapy) and one after the use of several medicinal products (combination therapy).

Fatal cases after monotherapy with the suspected medicinal product

Table 5

Fatal cases after combination therapy with the suspected medicinal products

Table 6

All cases of patient death occurred after use of the medicinal product in a healthcare facility due to anaphylactic shock.

Death due to anaphylactic shock after the use of a combined infusion solution belonging to the pharmacotherapeutic group of blood substitutes and plasma protein fractions occurred in the gynecology department of a central district hospital in a postpartum woman after a successfully performed cesarean section. The suspected medicinal product was used to replenish blood circulation against a background of reduced blood pressure. Signs of anaphylactic shock appeared immediately after administration of 10 mL of the solution. The resuscitation measures carried out had no positive effect. The woman died within an hour after the onset of ADR manifestations.

The second death after the use of the medicinal product Carbetocin also occurred in the maternity ward of a central district hospital during a surgical intervention – a cesarean section. To treat the manifestations of uterine atony, 1 mL of the suspected medicinal product was administered intravenously, after which the woman showed signs of anaphylactic shock. The resuscitation measures carried out proved ineffective, and within 2,5 hours the biological death of the patient was recorded.

The third fatal case due to anaphylactic shock after the use of the medicinal product Ceftriaxone occurred in the cardiology department of a central district hospital, to which the woman was admitted with severe cardiovascular pathology, pneumonia, and diabetes mellitus following a previous coronavirus infection. On day 5 of the treatment process, the patient was given the medicinal product Ceftriaxone for the first time, after which manifestations of anaphylactic shock developed. Despite resuscitation measures, the woman died within a day.

The fourth death of a female patient, a girl born in 2012, occurred in the surgical department of a children's hospital, where she was admitted with a diagnosis of acute appendicitis, unspecified. After general anesthesia drugs were administered in the operating room (Ditilin, Ketamine, Propofol and Fentanyl), the patient developed signs of anaphylactic shock. Resuscitation measures in the operating room had no positive effect, and after 3 hours the biological death of the girl was recorded.

Thus, using the example of these fatal cases, it can be noted how severe and irreversible the consequences of anaphylactic shock can be after the use of medicinal products from various pharmacotherapeutic groups, despite timely and qualified medical care, even in inpatient medical facilities.

In all cases of death, a possible causal relationship (hereinafter – CR) was established. The WHO qualitative method was used for the CR. When applying this method, the CR in the cited cases should be considered possible, since the time between the use of the medicinal products and the onset of clinical manifestations is plausible, and the clinical manifestations may be related to concomitant diseases, or to the use of other medicinal products, or to a chemical substance.

The priority area of pharmacovigilance in Ukraine remains patient safety, which is ensured by preventing the negative consequences of the use of medicinal products, identifying their hazardous properties, timely informing medicinal product applicants, the medical community, and patients, and making appropriate regulatory decisions.

During 2020, 46 decisions and recommendations of the European Medicines Agency, 1 recommendation of the U.S. Food and Drug Administration, and 21 signals published by the Uppsala Monitoring Centre on VigiBase were published on the official website of the Center in the section “Pharmacovigilance. Decisions and recommendations of regulatory agencies”. The recommendations concerned changes to the instructions or other recommendations regarding 56 different active substances or groups of medicinal products.

In 2020, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (PRAC) recommended revoking the marketing authorization for Ulipristal acetate for uterine fibroids, thereby making it impossible to sell them in the territory of the European Union and in other countries where it was registered. The PRAC review confirmed that 5 mg of Ulipristal acetate, used for the treatment of symptoms of uterine fibroids, may cause liver damage, including the need for a liver transplant. Since it was impossible to identify which patients were at greatest risk, and no measures that could reduce the risk were identified, PRAC concluded that the risks of using these medicines outweigh their benefits. Based on the PRAC recommendation, the Pharmacovigilance Directorate submitted a request to 3 advisory expert groups of the Center (AEGs), which decided that alternative treatment of uterine fibroids, other than Ulipristal acetate products, is possible. Based on the recommendations of the AEGs and the decision of the Scientific Expert Council (SEC), the Pharmacovigilance Directorate submitted a recommendation to the MoH on banning the use of medicinal products containing ulipristal acetate in the territory of Ukraine.

In December 2020, the decision of the European Commission to suspend the marketing authorizations for medicinal products containing ranitidine in the territory of the European Union because of the presence of a low level of the impurity nitrosodimethylamine (NDMA) was published on the official website of the European Medicines Agency. NDMA is classified as a probable human carcinogen based on animal studies. It is present in some foods and in water and is not expected to cause harm when ingested in very low amounts. The available safety data do not indicate that ranitidine increases the risk of cancer, and any possible risk is likely to be very low. However, in the EU, NDMA impurities exceeding acceptable levels were detected in several ranitidine products, and the question of the source of this impurity remains unresolved. There is some evidence that NDMA may form as a result of the degradation of ranitidine itself, with the level increasing over its shelf life. It is unclear whether NDMA may also form from ranitidine inside the body. By the Pharmacovigilance Department 24.12.2020, a request was made to 2 KEGs regarding the possibilities of alternative treatment of conditions accompanied by increased gastric juice production in patients with heartburn and gastric ulcer, in connection with the decision of the European Commission (EC) of 24.11.2020 to suspend the marketing authorizations for medicinal products containing ranitidine in the territory of the European Union. At present, the recommendations of the KEG confirm the availability of a wide range of medicinal products for the treatment of acid-related digestive disorders from the groups of H2-histamine blockers and proton pump inhibitors. At present, this issue is awaiting the recommendations of the NER.

During 2020, the following was published for applicants on the Center's official website at https://www.dec.gov.ua/applicant/2020-ema/?role=applicant – 24 notices with PRAC decisions based on the assessment of the analysis of periodic safety update reports (PSURs), with recommendations to amend the instructions for medical use with new safety information on the use of medicinal products with the relevant INN.

Based on the receipt of safety information on medicinal products, applicants developed 42 letters – appeals to healthcare professionals, of which 11 letters-appeals concerned the risk of heart valve regurgitation/insufficiency associated with the use of fluoroquinolones for systemic and inhalation use. All information, as agreed with the Center, is published on the website at https://www.dec.gov.ua/doctors/2020-listi-zvernennya-do-medichnih-ta-farmaczevtichnih-praczivnikiv/?role=doctors.

Applicants also developed, in cooperation with experts of the Pharmacovigilance Department 23, educational materials for healthcare professionals and patients on minimizing important risks and/or optimizing the benefit/risk balance when using medicinal products. This information was published on the official website of the Center at the link https://www.dec.gov.ua/doctors/2020-listi-zvernennya-do-medichnih-ta-farmaczevtichnih-praczivnikiv/?role=doctors and https://dec.gov.ua/patient/2020/?role=patient

Summarizing the results of the work of the Pharmacovigilance Directorate in 2020, we note that:

• the pharmacovigilance system in Ukraine is being successfully implemented, as evidenced by the relevant indicators and achievements, ensured through the application of international standards specified in the normative document “Guideline. Medicinal Products. Good Pharmacovigilance Practices”, approved by the Ministry of Health of Ukraine on 05.04.2018 No. 620, and through compliance with the rules and requirements of national legislation, namely the Procedure for Pharmacovigilance, approved by order of the Ministry of Health of Ukraine of 27 December 2006 No. 898 (as amended by order of the Ministry of Health of Ukraine of 26 September 2016 No. 996) (hereinafter – the Pharmacovigilance Procedure);
• in accordance with the order of the Center of 14.07.2020 No. 120, a Working Group was established to amend the Procedure for Pharmacovigilance Implementation regarding the single expert evaluation of PSURs and other changes concerning the implementation of pharmacovigilance. By 16.10.2020, the Working Group had prepared a draft of amendments to the regulatory act;
• in order to finalize the draft, in December 2020 the Center initiated the establishment of a Working Group on improving legislation on the implementation of pharmacovigilance, involving the Center's experts and representatives of six business associations, in order to take into account the interests of manufacturers/applicants of medicinal products in this process. At the beginning of the Working Group's activity, some critical issues and contradictions arose that require changing the format of further processing of regulatory legal acts. In order to take into account the interests of stakeholders and to thoroughly work out the necessary changes to the regulatory legal acts of the Ministry of Health of Ukraine, it is planned to initiate the establishment of an Interagency Working Group on the basis of the Center with the participation of pharmacovigilance specialists of business associations, the Center's experts, representatives of the Ministry of Health of Ukraine and the State Service of Ukraine on Medicines and Drugs Control;
• despite the difficult situation in the country related to the SARS-CoV-2 coronavirus pandemic and the quarantines introduced in Ukraine, the effectiveness of the pharmacovigilance system in Ukraine is confirmed by the submission to the Center of 423 report forms on AR and/or lack of efficacy, AEFI per 1 million population in 2020
• the advantage of the automated pharmacovigilance information system has been confirmed in practice, namely, the submission of report cards by healthcare professionals to the Center online has increased to 96,7%;
• the number of report forms on adverse reactions (AR) and/or lack of efficacy (LOE), and adverse events following immunization (AEFI), received by the Center in 2020 decreased compared to 2019 by 35,8%, which is associated with a reduced functional involvement of healthcare facilities in the treatment process due to quarantine measures amid COVID-19;
• in 2020 there was an increase in the percentage of high-quality completion of report forms compared to 2019 by 3,8%;
• the effectiveness of the pharmacovigilance system in Ukraine in the pharmaceutical sector is also evidenced by the receipt from applicants of reports of adverse reactions and/or lack of efficacy during the medical use of medicinal products; their number in 2020 amounted to 46 486 reports;
• based on the results of 2020, the passive method of pharmacovigilance prevails in Ukraine, or the method of collecting spontaneous reports of adverse reactions and/or lack of efficacy of medicinal products from the medical community, patients, and/or their representatives, but methods such as enhanced pharmacovigilance were also used during the year;
• by 23,3% compared with 2019, the provision of information from the Center to the WHO VigiLyze database on adverse reactions and/or lack of efficacy of medicinal products increased;
• the largest percentage of adverse reaction reports in 2020, as in 2019, relates to the use of antimicrobials for systemic use at the first ATC level;
• in 2020, the largest percentage of adverse reaction reports by the second ATC level was received regarding the use of agents acting on mycobacteria and antibacterial agents for systemic use;
• by systemic manifestations of AR/AEFI, which occurred more often than others with the use of medicinal products in 2020, in first place were manifestations of the gastrointestinal system and skin and subcutaneous tissue disorders;
• the vast majority of adverse reaction (AR) reports received by the Center in 2020 are non-serious ARs. Among serious ARs, the predominant reason for seriousness is prolongation of hospitalization – 37,0 %;
• infectious and parasitic diseases account for almost half of all disease classes in the treatment of which ARs/AEFIs were identified;
• there is no significant difference in the occurrence of adverse reactions when medicinal products are used in men and women;
• the most vulnerable age period for the occurrence of ARs in women – 46-60 years, in men – 31- 43 years;
• the group of people least vulnerable to the occurrence of ARs are people older than 80 years and children from 0 to 27 days;
• among the unexpected adverse reactions reported to the Center in 2020, the most common were reports of group adverse reactions that occurred after the use of the medicinal product Sodium Chloride 0,9%;
• the cause of death associated with the use of medicinal products, reported in 2020, was the consequences of anaphylactic shock;
• a causal relationship in all cases of death was established as possible according to the WHO qualitative method;
• during 2020, 46 safety communications on the use of medicinal products were published on the official website of the Center on the basis of decisions and recommendations of international European agencies; following PRAC conclusions based on the assessment of the analysis of regularly updated safety reports and the analysis of periodic safety reports received by the Center, 24 communications were published; on the basis of known safety information on medicinal products, applicants developed and published 42 letters – communications to healthcare professionals and patients.