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ФАРМАЦИЯ И ФАРМАКОЛОГИЯ
(с0
application of drug-related problems approach to analysis of non-steroidal anti-inflammatory drugs' safety
A.V. Matveev1,2, А.Е. Krasheninnikov1, Е.А. Egorova2, Е.I. Konyaeva2
1 National Pharmacovigilance Research Center,
2/2, Malaya Sukharevskaya sq., Moscow, Russia, 127051
2 Medical Academy n. a. S.I. Georgievsky of Vernadskjy CFU,
5/7, Lenin Avenue, Simferopol, Republic of Crimea, Russia, 295051
E-mail: elena212007@rambler.ru
Received 15 June 2019 Review (1) 3 August 2019 Review (2) 14 August 2019 Accepted: 20 August 2019
Summary. A Drug-Related Problem is an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes.
The aim of the study was the analysis of the adverse drug reactions (ADR) associated with prescription of the non-steroidal anti-inflammatory drugs (NSAIDs) using the DRP PCNE V5.01 qualification system.
Materials and methods. The objects of the study were 415 notification forms about adverse drug reactions of NSAIDs recorded in the regional database of spontaneous reports and called ARCADe (Adverse Reactions in Crimea, Autonomic Database) for the period from 1 January 2009 to 31 December of 2018. The study and analysis of the problems associated with drugs were carried out using the qualification system DRP PCNE V5.01 (Pharmaceutical Care Network Europe) 2006 in the modification of Prof. Zimenkovsky.
Results. Among other representatives of the NSAID group, Ibuprofen and Diclofenac became the "leaders" in the incidence of ADR. The frequency of ADR cases for Ibuprofen was 142 reports (34.22% of the total number of ADR for NSAIDs), and for Diclofenac it was 90 cases (21.69%). The calculation of DRP values for each of the presented cases made it possible to determine that in 81 (19.51%) and 91 (21.9%) cases, the DRP value was 6 and 7, respectively. DRP values in the range of 8-10 were found in 92 reports. The highest DRPs value was observed after the administration of Parecoxib (13 problems but only one case was found in the database), the DRPs value of Dexketoprofen was 12.5 (95% CI: 7-17) and the DRPs value of Diclofenac combinations was 10 DRPs; 95% CI: 5-17 DRP). The minimum DRPs values were associated with Naproxen, Rofecoxib, and Etoricoxib prescriptions.
Conclusion. Using the DRP system in the analysis of NSAIDs, ADRs allow to identify the medicines which have a high risk of causing safety problems, such as Parecoxib, Dexketoprofen and Diclofenac combinations. The prescription of these drugs should be carried out with special cautions and control to the indications and contraindications, the dose and duration of treatment, as well as to a possible interaction of them with concomitant drugs.
Keywords: drug-related problems (DRPs), non-steroidal anti-inflammatory drugs (NSAIDs), adverse drug reactions (ADRs) List of abbreviations: DRP - drug-related problems; MP - medicinal products; ADRs - adverse drug reactions; NSAIDs -non-steroidal anti-inflammatory drugs; COX - cyclooxygenase; ATC-code - code of product according to Anatomical Therapeutic Chemical (ATC) classification system.
For citation: A.V. Matveev, А.Е. Krasheninnikov, Е.А. Egorova, E.I. Konyaeva. Application of drug-related problems approach to analysis of nonsteroidal anti-inflammatory drugs' safety. Pharmacy & Pharmacology. 2019;7(4): 215-223. DOI: 10.19163/2307-9266-2019-7-4-215-223 © А.В. Матвеев, А.Е. Крашенинников, Е.А. Егорова, Е.И. Коняева, 2019
Для цитирования: А.В. Матвеев, А.Е. Крашенинников, Е.А. Егорова, Е.И. Коняева. Применение системы проблем, связанных с лекарственными препаратами (drug-related problems), на примере группы нестероидных противовоспалительных средств. Фармация и фармакология. 2019;7(4): 215-223. DOI: 10.19163/2307-9266-2019-7-4-215-223
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применение системы проблем, связанных
С лекарственными ПРЕПАРАТАМИ (DRUG-RELATED
problems), на примере группы нестероидных противовоспалительных средств
А.В. Матвеев1,2, А.Е. Крашенинников1, Е.А. Егорова2, Е.И.Коняева2
Автономная некоммерческая организация «Национальный научный центр Фармаконадзора»,
127051, Российская Федерация, Москва, ул. Малая Сухаревская площадь, д. 2, корп. 2 2 Медицинская академия им. С.И. Георгиевского ФГАОУ ВО «КФУ им. В.И. Вернадского», 295051, Российская Федерация, г. Симферополь, бул. Ленина, 5/7
E-mail: elena212007@rambler.ru
Получено 15.06.2019 Рецензия (1) 03.08.2019 Рецензия (2) 14.08.2019 Принята к печати 20.08.2019
Проблемы, связанные с лекарственными препаратами (drug-related problems, DRP), - это события или изменения, связанные с фармакотерапией, которые реально или потенциально препятствуют достижению желаемых результатов в процессе лечения.
Цель - анализ случаев нежелательных реакций (НР) на препараты группы нестероидных противовоспалительных средств (НПВС) с помощью квалификационной системы DRP PCNE V5.01.
Материалы и методы. Объектами исследования стали 415 карт-извещений о нежелательных реакциях НПВС, зарегистрированные в региональной базе спонтанных сообщений ARCADe (Adverse Reactions in Crimea, Autonomic Database) за период 2009-2018 гг. Изучение и анализ проблем, связанных с лекарственными препаратами, проводился с использованием квалификационной системы DRP PCNE V5.01 (Pharmaceutical Care Network Europe) 2006 г. в модификации А.Б. Зименковского.
Результаты. «Лидерами» по частоте развития НР среди отдельных представителей группы НПВС стали препараты ибупрофен и диклофенак. Частота встречаемости случаев НР для ибупрофена составила 142 случая (34,22% от всего количества случаев НР на НПВС), а для диклофенака - 90 случаев (21,69%). Расчет значений DRP для каждого из представленных случаев НР позволил определить, что в 81 (19,51%) и 91 (21,9%) случае значение DRP было равно 6 и 7 соответственно. Значения DRP в пределах значений 8-10 встречались в 92 случаях. Наиболее высокие значения DRP наблюдались при назначении парекоксиба- 13 проблем (зарегистрирован 1 случай), декскетопрофена - 12,5 DRP (95% ДИ: 7-17) и комбинированных препаратов, содержащих диклофенак - 10 DRP (95% ДИ: 5-17 DRP). Минимальные значения DRP были выявлены при назначении напроксена, рофекоксиба и эторикоксиба.
Заключение. Использование системы проблем, связанных с лекарственными препаратами (DRP), для проведения анализа нежелательных реакций препаратов группы НПВС позволило выделить отдельных представителей группы, обладающих высоким риском развития неблагоприятных последствий при их применении в практической медицине. Среди таких препаратов стоит отметить парекоксиб, декскетопрофен и комбинированные препараты, содержащие диклофенак. Назначение представленных выше препаратов должно проводиться со строгим учетом показаний и противопоказаний к применению, дозы и курса лечения, а также вероятности возможного взаимодействия этих препаратов с сопутствующими лекарственными средствами.
Ключевые слова: проблемы, связанные с лекарственными препаратами, DRP, нестероидные противовоспалительные средства
Список сокращений: РГЗТ - реакция гиперчувствительности замедленного типа, РПГА - реакция прямой гемагглюти-нации, ФИ - фагоцитарный индекс, ФЧ - фагоцитарное число
INTRODUCTION
Drug-related problems are defined as "any circumstance related to the patient's use of a drug that actually or potentially prevents the patient from gaining the intended benefit of the drug" [1, 2]. Such undesirable consequences due to the use of medicinal products (MPs) are common in medical institutions both at the stage of primary medical care (in hospitals) and at the stage of outpatient (ambulatory) treatment of patients. Most of these problems are revealed at the stage of prescribing,
dosing or intake of drugs by patients. Potential causes of DRPs are: the simultaneous prescription of five or more drugs (polypharmacy), complex regimens for the use of medicinal products, as well as the use of new MPs in clinical practice, which is associated with a high risk of adverse drug reactions (ADRs) during their use [3, 4]. Another important reason for the development of DRPs in patients is the lack of clear recommendations from doctors about the use of concomitant medications or alternative methods of treatment [5].
ФАРМАЦИЯ И ФАРМАКОЛОГИЯ
The medical conditions resulting from DRPs, are serious issues for patients and society, as the suffering of patients and the costs of corrections caused by these problems are significant [6-8]. The economic consequences of DRPs in the United States of America (USA) are estimated at more than $ 150 billion annually [9]. Moreover, the estimate of the costs associated with medical errors when using drugs ambulatory varies from 30.1 to 136.8 billion US dollars [10, 11].
Among the main causes of DRPs, the following ones are distinguished: off-label prescription and use of drugs, discrepancies between the doctor-prescribed and real regimes of the use of MPs, irrational choice of drugs, poor patients' compliance to treatment, drug interactions, as well as interactions with the food components, adverse reactions, overdose, the use of subtherapeutic doses and the need for additional drug therapy [12-15]. According to the systematic review published by Krähenbühl Melcher et al., about 8% of hospitalized patients have adverse drug reactions and 5-10% of prescriptions in these patients are erroneous [16]. Forster A.J. and colleagues studied the frequency of ADRs and revealed that those reactions occurred in 15% of patients at the hospitalization stage, and in 12-17% of patients after their discharge from a medical institution [17-19].
The identification and study of drug-related problems, as well as the identification of the main groups and individual representatives of the drugs with a high risk of developing DRPs, are important stages in the treatment of patients. They can reduce morbidity, mortality and increase compliance of patients to treatment [20].
According to our search in Russian medical literature, the DRPs methodology is practically not used in domestic practice, and the number of such studies is occasional [21, 22].
The aim of the current study is to analyze the cases of ADRs caused by non-steroidal anti-inflammatory drugs (NSAIDs) using the DRP PCNE V5.01 qualification system.
MATERIALS AND METHODS
The objects of this study were the cases of ADRs development after the use of NSAIDs described in official notification forms and recorded in the regional database of spontaneous reports called "ARCADs (Adverse Reactions in Crimea, Autonomic Database)" for the period of January 2009 - December 2018. For the covered period, 415 forms containing information about the ADRs of varying severity in the patients treated in medical institutions, in outpatient settings and the cases of self-treatment were found.
The detection of ADRs was carried out by the codes
of the Anatomical Therapeutic Chemical (ATC) classification of medicines of the World Health Organization [23], the data from the instructions for medical use (analogue of Short Medical Product Characteristics) found in the State Drug Registers of the Russian Federation and Ukraine (for the cases registered before the incorporation of the Republic of Crimea into the Russian Federation).
The study of the frequency and severity of DRPs and their further analysis were carried out using the DRP PCNE V5.01 (Pharmaceutical Care Network Europe) 2006 qualification system in the modification of Andriy B. Zimenkovsky [24]. This system is based on the coding in 4 main categories: P - problems, C - causes, I - interventions and O - consequences. According to the "P" code, DRPs are divided into the following groups: manifestations of ADRs (allergic/non-allergic), the rationality of the choice of a suspect and concomitant drugs, their dosage regimen and dosage form, the errors that occur during the drug intake, the possibility of drug interactions and some others problems. The causes of DRPs standardized by code "C" are classified as follows:
3 DRP associated with the choice of the suspected drug, and its dose;
3 DRP caused by the use of concomitant drugs and the possibility of drug interactions;
3 patient-oriented psychological factors (i.e. a patient's inability to take a suspected and/or concomitant drug);
3 DRPs resulting from the low awareness of doctors and patients about a rational use of drugs (lack of knowledge of the instructions for medical use and/or patients' treatment protocols);
3 DRP related to pharmaceutical logistics (drug availability).
The interventions of a doctor or a clinical pharmacist, indicated by the code "I", are divided into 3 subgroups: the first one is the level of the specialist who prescribed the medicine, the second subgroup is the level of the patient and the third subgroup is the level of the medicine itself. Among such interventions, the cancellation of a suspected drug, the withdrawal of concomitant MPs, as well as the administration of a new drug to correct the consequences caused by ADRs have been distinguished. Among the outcomes of DRPs (code "O"), there are 2 main options: the drug-related problem is completely solved and the drug-related problem is not solved [24-27].
RESULTS AND DISCUSSION
To study the drug-related problems, in the regional database of spontaneous reports about adverse reac-
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tions, an automatic search was performed and 415 notification forms corresponding to the M01 ATC classification code were selected. They amounted to 5.96% of the total number of ADRs for the period from 1 January 2009 till 31 December 2018 (the total number of records was 6960).
The first stage of the work was devoted to identifying the frequency of ADRs for each representative of the NSAIDs group. Ibuprofen and Diclofenac became
the "leaders" by the incidence of reactions. The occurrence of cases for Ibuprofen was 142 cases (34.22% of the total number of records for NSAIDs), and for Diclofenac it was 90 cases (21.69%). Much less frequently, ADRs occurred when patients took Nimesulide (45 cases, 10.84%), Ketorolac (44 records, 10.6%) and Meloxicam (23 cases, 5.54%). The frequency of ADRs for other active substances from M01 group is presented in Table 1.
Table 1 - Frequency of adverse reactions associated with prescription of NSAIDs and registered in the Republic of Crimea for the period of 2009-2018
NSAIDs ATC code Quantity of reports (absolute) Quantity of reports (% of total NSAIDs ADRs)
Ibuprofen M01AE01 142 34.22
Diclofenac M01AB05 90 21.69
Nimesulide M01AX17 45 10.84
Ketorolac M01AB15 44 10.60
Meloxicam M01AC06 23 5.54
Dexketoprofen M01AE17 14 3.37
Diclofenac combinations M01AB55 14 3.37
Lornoxicam M01AC05 9 2.17
Nimesulide combinations M01AX67 5 1.20
Etoricoxib M01AH05 5 1.20
Aceclofenac M01AB16 5 1.20
Celecoxib M01AH01 3 0.72
Rofecoxib M01AH02 3 0.72
Naproxen M01AE02 2 0.48
Parecoxib M01AH04 2 0.48
Other NSAIDs combinations M01BX 2 0.48
Ibuprofen combinations M01AE51 1 0.24
Mefenamic acid M01AG01 1 0.24
Glucosamine M01AX05 1 0.24
Chondroitin sulfate M01AX25 1 0.24
The combination of Glucosamine and Chondroitin sulfate M09AX 1 0.24
Ketoprofen M01AE03 1 0.24
Indomethacin M01AB01 1 0.24
The calculation of DRPs values for each of the recorded cases made it possible to determine the following: in 81 (19.51%) and 91 (21.9%) cases, the DRPs value was 6 and 7, respectively. The DRPs values in the range of 8-10 were found in 92 cases (8 DRPs - 38 records (9.16%), 9 DRP - 20 records (4.8°%) and 10 DRP - 34 reports (8.2°%)). Special attention was paid to forms, in which the DRPs values amounted to more than 10 problems per case (124 reports, 29.9%).
Such high rates most likely indicate an irrational choice of the NSAIDs, incorrect dosing or possible drug interactions. The frequency of DRPs values for NSAIDs
is shown in Fig. 1. The total number of DRPs for all the cases was 3785 (therefore, the average value was 9 DRPs / a patient).
At the next stage of the work, the DRPs values for each NSAID were calculated. Our analysis of the ADRs records revealed that the highest DRPs values were observed for Parecoxib (13 problems) though the only case for this substance was found in the database. The results also included Dexketoprofen with an average amount of 12.5 DRPs / a case (95% CI: 7-17) and Diclofenac combinations with 10 DRPs / a case (95% CI: 5-17 DRP).
ФАРМАЦИЯ И ФАРМАКОЛОГИЯ
LO
CÛ <
1/1 ос
О <
3 О
100 90 80 70 60 50 40 30 20 10 0
91
81
23
38
34
20
18
21
25 24
14
4 ■
4 ■
4 ■
2 4 5 6
8 9 10 11 12 13 14 15 16 17 18 19 20 DRP's VALUE
Figure 1 - Frequency of DRP's Values in NSAIDs ADRs records
The average values of DRPs / a case in the range of 9-9.5 were observed in the records for Ketorolac, Meloxicam and Aceclofenac. High maximum DRPs values for Ketorolac and Meloxicam (20 and 19 DRP, respectively) are noteworthy, as
they indicate the irrational prescription of MPs and a high risk of serious ADRs developing during their use. The distribution of the NSAIDs according to the median, maximum and minimum DRPs values is presented in Table 2.
Table 2 - Median, maximum and minimum of NSAIDs-related problems
NSAID Maximum Minimum Median Range
Dexketoprofen 17 7 12.5 10
Diclofenac combinations 17 5 10 12
Ketorolac 20 5 9.5 15
Meloxicam 19 5 9 10
Aceclofenac 12 5 9 7
Diclofenac 19 6 8 13
Ibuprofen 16 4 7 12
Lornoxicam 10 6 7 4
Nimesulide 17 2 7 15
Celecoxib 13 6 7 7
Nimesulide combinations 14 4 7 10
Naproxen 7 5 6 2
Rofecoxib 8 6 6 2
Etoricoxib 11 6 6 5
The results presented above, indicate that Naproxen (a non-selective inhibitor of cyclooxygenase-2 (COX-2)), Rofecoxib and Etoricoxib (highly selective COX-2 inhibitors) have a better safety profile compared to other NSAIDs [28]. When administrated, the amount of this drug-related problems was lower than that of the other representatives of the group.
The fourth stage of the analysis was devoted to the
study of NSAIDs' administration routes (local, rectal, intravenous, intramuscular and per os) and their association with DRPs values. The results of the analysis showed that most often ADRs occurred when NSAIDs were taken per os. The frequency of such cases was 270 (65%). Less often, adverse reactions were observed after intramuscular (125 cases, 30.1%), intravenous (9 cases, 2.2%), rectal (9 cases, 2.2%) and local (2 cases, 0.5%) administration routes (Fig. 2).
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0,7
0,6
0,5
a. o
< 0,4
3 O
0,3
0,2
0,1
30,1
2,2
2,2
0,5
Peros Intramuscular Intravenous Rectal
Administration Routes
Figure 2 - Distribution of ADR according to administration routes
Local
The analysis of DRPs values for each of the presented routes revealed that high DRPs values were observed in case of rectal (4 records with DRPs values of more than 11, which amounted to 44.4% of all the cases for this administration route) and intramuscular routes (50 cases with DRPs values of more than 11 cases, which
amounted to 40% of all the cases with intramuscular administration). For oral route, high DRPs values (DRP > 11) were observed in 64 records, which amounted to 23.7% of the total number of peroral intake of NSAIDs. The distribution of DRPs values for all the routes of administration is presented in Table 3.
Table 3 - Distribution of DRPs values according to administration routes
Route (total amount of records) Range of DRPs values Cases of ADRs (abs.) Cases of ADR (% from total amount of cases per route)
Per os 0-5 23 8.5
270 records 6-10 183 67.8
11-15 55 20.4
16-20 9 3.3
Intramuscular 0-5 3 2.4
125 records 6-10 72 57.6
11-15 37 29.6
16-20 13 10.4
Intravenously 6-10 6 66.7
9 records 11-15 3 33.3
Per rectum 0-5 1 11.1
9 records 6-10 5 55.5
11-15 4 44.4
Local 2 records 6-10 2 100
The obtained results indicate a higher risk of DRPs pharmacokinetics of NSAIDs after intramuscular and in-when parenteral routes of administration are used. In travenous injections.
our opinion, it is primarily due to the peculiarities of the Special attention was paid to the analysis of ADRs
ФАРМАЦИЯ И ФАРМАКОЛОГИЯ
records with DRPs values equal to 18-20. The total number of such reports was 10: 5 were associated with Ketorolac use, 3 and 2 cases - with Meloxicam and Diclofenac, respectively.
Such high values of DRPs in 8 cases were were caused by an irrational combination of two or more NSAIDs in one patient. In 3 cases there was an excess of single and/or daily doses of the suspected drug and in 3 clinical situations, there was an excess of the course of treatment. In some cases, two or more reasons for such high rates of DRPs were found.
In our opinion, the range, i.e. the differences between the maximal and minimal DRPs values, is of special interest, as it can reflect the potential risk of a drug problem for each drug included in the analysis. As follows from the data in Table 2, the highest risk of prob-
lems determined by the range of the values is associated with Nimesulide, Ketorolac and Diclofenac prescriptions. Undoubtedly, the final and clear index should include not only the range of values but also the minimum value.
The analysis of violations of the dosing regimen (a low dose or an extended duration / an extended dose or a short duration) is also of a scientific interest. It is a priori a determining factor in the occurrence of DRPs. Information on a dosing regimen is presented in category "P" of the DRPs PCNE V5.01 qualification system. It made possible to obtain the data on the frequency of such mistakes for NSAIDs. The excess of the dose was found in 23 cases (5.53% of the total amount of NSAIDs ADRs), the doses below the minimum therapeutic ones were found in 16 cases (3.85%). The distribution of dosing violations is presented in Fig. 3.
Dose is correct according to Instructions for medical use
376
еэ
Ш
ОС Q
^ Dose is very high or drug is prescribed too often 23
I
i/i О Q i/i Q
Dose is very low or duration is prolonged 16
I
0 50 100 150 200 250 300 350 400 AMOUNT OF NSAID ADR s (ABS.)
Figure 3 - Distribution of ADRs cases with violations of the dosage regimen
It is worth noting that the use of the DRPs system in the practice of doctors, clinical pharmacologists and pharmacists is an important and promising tool which makes it possible to improve the quality of pharmacotherapy and adherence to treatment. For drug safety professionals, the DRPs system makes it possible to identify priority areas in pharmacovigilance.
The results of the carried out analysis made it possible to identify NSAIDs, the prescription of which needs special attention due to the high risks of drug-related problems (Parecoxib, Dexketoprofen, Nimesulide, Diclofenac and Ketorolac).
In addition, the analysis of DRPs values using the DRP PCNE V5.01 qualification system made it possible to identify NSAIDs with a good safety profile. Among
these drugs, it is worth to note Naproxen, Rofecoxib and Etoricoxib associated with a low amount of DRPs.
CONCLUSION
Using the drug-related problems (DRPs) system in the analysis of the safety of NSAIDs made it possible to identify the representatives of this group which may have an extra risk of ADRs in real medical practice. Among NSAIDs, it is worth to note Parecoxib, Dexketo-profen and Diclofenac combinations. The prescription of the mentioned products should be carried out with strict regard to the approved indications and contraindications for use, dose and duration of treatment, as well as taking into consideration all kinds of possible drug-drug interaction.
FINANCIAL SUPPORT
This study did not have any financial support from third parties.
RESEARCH ARTICLE Sdentific and Practical J°umal
PHARMArY Ri
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AUTHOR CONTRIBUTIONS
All authors had equally contributed to the research work.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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AUTHORS
Matveyev Alexander Vasilyevich - PhD (Medicine), docent of the Department of Internal Medicine No.1 with the course of Clinical Pharmacology of Medical Academy n.a. S.I. Georgievsky of Vernadskjy CFU; executive director of ANO "National Pharmacovigilance Research Center". ORCID 0000-0002-6636-3950. E-mail: avmcsmu@gmail.com
Krasheninnikov Anatoly Evgenievich - PhD (Pharmacy), CEO of ANO "National Pharmacovigilance Research Center". ORCID 0000-0002-7791-6071. E-mail: anatoly.krasheninnikov@drugsafety.ru.
Egorova Elena Aleksandrovna - PhD (Pharmacy), assistant of the Department of Internal Medicine No.1 with the course of Clinical Pharmacology of Medical Academy n.a. S.I. Georgievsky of Vernadskjy CFU. ORCID 0000-0003-4012-2523. E-mail: elena212007@ rambler.ru
Konyaeva Elena Ivanovna - PhD (Medicine), docent of the Department of Internal Medicine No.1 with the course of Clinical Pharmacology of Medical Academy n.a. S.I. Georgievsky of Vernadskjy CFU. E-mail: konyae-va.simferopol@gmail.com
