Side effects and interactions with the use of rivaroxaban: Global pharmacovigilance data

Abstract

This study aimed to review literature data on the side effects and interactions when using rivaroxaban according to global pharmacovigilance data as of March 23, 2022. The data obtained are based on the VigiLyze expert-level analytical system and the use of the international VigiBase database of the WHO International Drug Monitoring Program.

Data processing and storage were performed using Microsoft Excel. The authors provided a consolidated expert opinion based on professional experience in clinical and scientific work. The received data contained 112,654 individual case safety reports (ICSR) about cases of adverse reactions to drugs, particularly rivaroxaban. When processing the ICSR database, duplicates and reports containing incomplete information that were not comparable with the Medical Dictionary for Regulatory Activities were excluded.

After processing, 32,779 ICSRs were extracted according to the criteria, which accounted for 29.1% of the total number of all ICSRs. Basic data on ICSR were recorded from the USA, Germany, France, Great Britain, and Japan. Most often, adverse reactions were observed in patients aged >75 years (31.9%), followed by patients aged 65–74 (20.0%) and 45–64 (15.3%). By age, more adverse reactions were observed in male (46.0%) patients. Countries that have developed pharmacomonitoring system contributed significantly to the development of the ICSR of the adverse reactions of rivaroxaban, namely, USA (n=62,992; 55.3%), Germany (n=9912; 8.8%), France (n=6983; 6.2%), Great Britain (n=5632; 5.0%), and Japan (n=5294; 4.7%). Adverse reactions were reported by 57.8% of ICSRs from medical and pharmaceutical professionals, including doctors, pharmacists, pharmacists, and other healthcare professionals. Adverse reactions with rivaroxaban include hospitalizations or its prolongation (47.8%), deaths (12.4%), and gastrointestinal bleeding (14.1%). Serious adverse reactions were observed in 99.4% of the cases. Drugs that were used in parallel or were not discontinued during the prescription of rivaroxaban were acetylsalicylic acid, clopidogrel, warfarin, and enoxaparin sodium. The risks of side effects increase when rivaroxaban is combined with other drugs, which must be taken into account when writing prescriptions.

Keywords

drugs / rivaroxaban / drug interactions / side effects / bleeding / safety / VigiBase

References

[1] Sychev DA. What is polypragmasy? In: Otelyonov VA, Kirilochev OO, Andreev DA, et al. Polypragmasy in clinical practice: problems and solutions. 2nd edition. Saint Petersburg: COP “Professiya”; 2018. P. 10–12. EDN: PWZISQ

[2] Cычев Д.А. Что такое полипрагмазия? В кн.: Отделёнов В.А., Кирилочев О.О., Андреев Д.А., и др. Полипрагмазия в клинической практике: проблема и решения. 2-е изд. Санкт-Петербург: ЦОП «Профессия», 2018. С. 10–12. EDN: PWZISQ

[3] Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5):820–829. doi: 10.1111/j.1538-7836.2008.02939.x

[4] Wong P.C., Crain E.J., Xin B., et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies // J Thromb Haemost. 2008. Vol. 6, N 5. P. 820–829. doi: 10.1111/j.1538-7836.2008.02939.x

[5] Romanov BK, Dibirova GO, Dmitrieva NB, et al. Side effects of drugs recommended for the treatment of harmful alcohol use. Russian Medicine. 2023;29(1):59–65. EDN: ARPWOA doi: 10.17816/medjrf109084

[6] Романов Б.К., Дибирова Г.О., Дмитриева Н.Б., и др. Побочные действия лекарственных средств, рекомендуемых для лечения пагубного употребления алкоголя // Российский медицинский журнал. 2023. Т. 29, № 1. С. 59–65. EDN: ARPWOA doi: 10.17816/medjrf109084

[7] Kazakov AS, Darmostukova MA, Bukatina TM. Comparative analysis of international databases of adverse drug reactions. Safety and Risk of Pharmacotherapy. 2020;8(3):134–140. EDN: UIRDRQ doi: 10.30895/2312-7821-2020-8-3-134-140

[8] Казаков А.С., Дармостукова М.А., Букатина Т.М., и др. Сравнительный анализ международных баз данных о нежелательных реакциях лекарственных средств // Безопасность и риск фармакотерапии. 2020. Т. 8, № 3. С. 134–140. EDN: UIRDRQ doi: 10.30895/2312-7821-2020-8-3-134-140

[9] Wakao R, Taavola H, Sandberg L, et al. Data-driven identification of adverse event reporting patterns for Japan in VigiBase, the WHO Global Database of Individual Case Safety Reports. Drug Saf. 2019;42(12):1487–1498. doi: 10.1007/s40264-019-00861-y

[10] Wakao R., Taavola H., Sandberg L., et al. Data-driven identification of adverse event reporting patterns for Japan in VigiBase, the WHO Global Database of Individual Case Safety Reports // Drug Saf. 2019. Vol. 42, N 12. P. 1487–1498. doi: 10.1007/s40264-019-00861-y

[11] Watson S, Chandler RE, Taavola H, et al. Safety concerns reported by patients identified in a collaborative signal detection workshop using VigiBase: results and reflections from lareb and Uppsala Monitoring Centre. Drug Saf. 2018;41(2):203–212. doi: 10.1007/s40264-017-0594-2

[12] Watson S., Chandler R.E., Taavola H., et al. Safety concerns reported by patients identified in a collaborative signal detection workshop using VigiBase: results and reflections from lareb and Uppsala Monitoring Centre // Drug Saf. 2018. Vol. 41, N 2. P. 203–212. doi: 10.1007/s40264-017-0594-2

[13] Fernandez S, Lenoir C, Samer CF, Rollason V. Drug-drug interactions leading to adverse drug reactions with Rivaroxaban: a systematic review of the literature and analysis of VigiBase. J Pers Med. 2021;11(4):250. doi: 10.3390/jpm11040250

[14] Fernandez S., Lenoir C., Samer C.F., Rollason V. Drug-drug interactions leading to adverse drug reactions with Rivaroxaban: a systematic review of the literature and analysis of VigiBase // J Pers Med. 2021. Vol. 11, N 4. P. 250. doi: 10.3390/jpm11040250

[15] Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76(3):455–466. doi: 10.1111/bcp.12075

[16] Mueck W., Kubitza D., Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects // Br J Clin Pharmacol. 2013. Vol. 76, N 3. P. 455–466. doi: 10.1111/bcp.12075

[17] Kubitza D, Becka M, Roth A, Mueck W. Absence of clinically relevant interactions between rivaroxaban — an oral, direct Factor Xa inhibitor — and digoxin or atorvastatin in healthy subjects. J Int Med Res. 2012;40(5):1688–1707. doi: 10.1177/030006051204000508

[18] Kubitza D., Becka M., Roth A., Mueck W. Absence of clinically relevant interactions between rivaroxaban — an oral, direct Factor Xa inhibitor — and digoxin or atorvastatin in healthy subjects // J Int Med Res. 2012. Vol. 40, N 5. P. 1688–1707. doi: 10.1177/030006051204000508

[19] Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF trial). Am Heart J. 2015;170(4):675–682.e8. doi: 10.1016/j.ahj.2015.07.006

[20] Bansilal S., Bloomgarden Z., Halperin J.L., et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF trial) // Am Heart J. 2015. Vol. 170, N 4. P. 675–682. doi: 10.1016/j.ahj.2015.07.006

[21] Van Thiel D, Kalodiki E, Wahi R, et al. Interpretation of benefit-risk of enoxaparin as comparator in the RECORD program: rivaroxaban oral tablets (10 milligrams) for use in prophylaxis in deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Clin Appl Thromb Hemost. 2009;15(4):389–394. doi: 10.1177/1076029609340163

[22] Van Thiel D., Kalodiki E., Wahi R., et al. Interpretation of benefit-risk of enoxaparin as comparator in the RECORD program: rivaroxaban oral tablets (10 milligrams) for use in prophylaxis in deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery // Clin Appl Thromb Hemost. 2009. Vol. 15, N 4. P. 389–394. doi: 10.1177/1076029609340163

[23] Cohen AT, Bauersachs R. Rivaroxaban and the EINSTEIN clinical trial programme. Blood Coagul Fibrinolysis. 2019;30(3):85–95. doi: 10.1097/MBC.0000000000000800

[24] Cohen A.T., Bauersachs R. Rivaroxaban and the EINSTEIN clinical trial programme // Blood Coagul Fibrinolysis. 2019. Vol. 30, N 3. P. 85–95. doi: 10.1097/MBC.0000000000000800

[25] Spyropoulos AC, Raskob GE, Cohen AT, et al. Association of bleeding severity with mortality in extended thromboprophylaxis of medically ill patients in the MAGELLAN and MARINER trials. Circulation. 2022;145(19):1471–1479. doi: 10.1161/CIRCULATIONAHA.121.057847

[26] Spyropoulos A.C., Raskob G.E., Cohen A.T., et al. Association of bleeding severity with mortality in extended thromboprophylaxis of medically ill patients in the MAGELLAN and MARINER trials // Circulation. 2022. Vol. 145, N 19. P. 1471–1479. doi: 10.1161/CIRCULATIONAHA.121.057847

[27] Savel’ev VS, Kirienko AI, Zolotukhin IA, Andriiashkin AV. Prevention of postoperative venous thromboembolism in the Russian federation’s hospitals (preliminary results of the Safety Zone project). Journal of Venous Disorders. 2010;4(3):3–8. EDN: NDYPTP

[28] Савельев В.С., Кириенко А.И., Золотухин И.А., Андрияшкин А.В. Профилактика послеоперационных венозных тромбоэмболических осложнений в российских стационарах (предварительные результаты проекта «Территория Безопасности») // Флебология. 2010. Т. 4, № 3. С. 3–8. EDN: NDYPTP

[29] Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(4):1129. Corrected and republished from: Chest. 2012;142(6):1698. doi: 10.1378/chest.1412S3

[30] Guyatt G.H., Akl E.A., Crowther M., et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines // Chest. 2012. Vol. 141, N 4. P. 1129. Corrected and republished from: Chest. 2012. Vol. 142, N 6. P. 1698. doi: 10.1378/chest.1412S3

[31] Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319–1330. doi: 10.1056/NEJMoa1709118

[32] Eikelboom J.W., Connolly S.J., Bosch J., et al. Rivaroxaban with or without Aspirin in stable cardiovascular disease // N Engl J Med. 2017. Vol. 377, N 14. P. 1319–1330. doi: 10.1056/NEJMoa1709118

RIGHTS & PERMISSIONS

Eco-Vector