Evaluating the Impact of Loperamide on Irinotecan-induced Adverse Events: a Disproportionality Analysis of Data from the World Health Organization Pharmacovigilance Database (VigiBase)

Overview

Journal Eur J Clin Pharmacol

Specialty Pharmacology

Date 2024 Oct 23

PMID 39443366

Authors

Tomoaki Akagi

Hirofumi Hamano

Hirotaka Miyamoto

Tatsuaki Takeda

Yoshito Zamami

Kaname Ohyama

Affiliations

Soon will be listed here.

Abstract

Purpose: SN-38, the active metabolite of irinotecan, may cause adverse events necessitating treatment discontinuation and management. Diarrhea, which is treated with loperamide, is one such event. However, loperamide may delay SN-38 elimination, causing more adverse events. Therefore, understanding the adverse events caused by symptomatic drugs is crucial for safe drug therapy. This study aimed to assess the association between loperamide and irinotecan-induced adverse events.

Methods: We analyzed data up to December 2022 from VigiBase, the World Health Organization's adverse event database. The study used reporting odds ratios (RORs) to evaluate the associations between concomitant medications and irinotecan-induced adverse events. Fisher's exact probability test was used to analyze the adverse events. Logistic regression analysis was performed to identify associated adverse event signals.

Results: Of the 32,520,983 cases analyzed, 57,454 involved the use of irinotecan. Among these, 1589 (2.8%) patients were co-treated with loperamide. Signals for neutropenia (ROR 1.37, 95% confidence interval (CI) 1.20-1.57, p < 0.001), anemia (ROR 1.81, 95% CI 1.43-2.30, p < 0.001), and alopecia (ROR 1.89, 95% CI 1.30-2.74, p < 0.01) were detected with concomitant loperamide. Multivariate logistic regression analysis confirmed that concomitant loperamide use was associated with signals for neutropenia, anemia, and alopecia.

Conclusion: Our results suggest that loperamide increases the risk of irinotecan-induced adverse events and enhances irinotecan toxicity. The study methodology may be useful for predicting adverse event risk when choosing symptomatic therapy drugs during irinotecan use.

References

Fujii H, Ueda Y, Hirose C, Ohata K, Sekiya K, Kitahora M . Pharmaceutical intervention for adverse events improves quality of life in patients with cancer undergoing outpatient chemotherapy. J Pharm Health Care Sci. 2022; 8(1):8. PMC: 8889741. DOI: 10.1186/s40780-022-00239-w. View

Yamamoto N, Takahashi T, Kunikane H, Masuda N, Eguchi K, Shibuya M . Phase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan. Clin Pharmacol Ther. 2008; 85(2):149-54. DOI: 10.1038/clpt.2008.152. View

Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E . Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 1996; 56(16):3752-7. View

Rothenberg M, Eckardt J, Kuhn J, Burris 3rd H, Nelson J, Hilsenbeck S . Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol. 1996; 14(4):1128-35. DOI: 10.1200/JCO.1996.14.4.1128. View

Kornblau S, Benson A, Catalano R, Champlin R, Engelking C, Field M . Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage. 2000; 19(2):118-29. DOI: 10.1016/s0885-3924(99)00149-9. View

Regnard C, Twycross R, Mihalyo M, Wilcock A . Loperamide. J Pain Symptom Manage. 2011; 42(2):319-23. DOI: 10.1016/j.jpainsymman.2011.06.001. View

Oka Y, Matsumoto J, Takeda T, Iwata N, Niimura T, Ozaki A . Adverse events of nivolumab plus ipilimumab versus nivolumab plus cabozantinib: a real-world pharmacovigilance study. Int J Clin Pharm. 2024; 46(3):745-750. DOI: 10.1007/s11096-024-01713-1. View

Matsumoto J, Iwata N, Watari S, Ushio S, Shiromizu S, Takeda T . Adverse Events of Axitinib plus Pembrolizumab Versus Lenvatinib plus Pembrolizumab: A Pharmacovigilance Study in Food and Drug Administration Adverse Event Reporting System. Eur Urol Focus. 2022; 9(1):141-144. DOI: 10.1016/j.euf.2022.07.003. View

Bergvall T, Noren G, Lindquist M . vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. Drug Saf. 2013; 37(1):65-77. PMC: 6447519. DOI: 10.1007/s40264-013-0131-x. View

10.

Brown E, Wood L, Wood S . The medical dictionary for regulatory activities (MedDRA). Drug Saf. 1999; 20(2):109-17. DOI: 10.2165/00002018-199920020-00002. View

11.

Noren G, Sundberg R, Bate A, Ralph Edwards I . A statistical methodology for drug-drug interaction surveillance. Stat Med. 2008; 27(16):3057-70. DOI: 10.1002/sim.3247. View

12.

Groopman J, Itri L . Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999; 91(19):1616-34. DOI: 10.1093/jnci/91.19.1616. View

13.

Wang-Gillam A, Li C, Bodoky G, Dean A, Shan Y, Jameson G . Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2015; 387(10018):545-557. DOI: 10.1016/S0140-6736(15)00986-1. View

14.

Nichetti F, Rota S, Ambrosini P, Pircher C, Gusmaroli E, Droz Dit Busset M . NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024; 7(1):e2350756. PMC: 10774994. DOI: 10.1001/jamanetworkopen.2023.50756. View

15.

Barbounis V, Koumakis G, Vassilomanolakis M, Demiri M, Efremidis A . Control of irinotecan-induced diarrhea by octreotide after loperamide failure. Support Care Cancer. 2001; 9(4):258-60. DOI: 10.1007/s005200000220. View

16.

Miller T, Agostoni C, Duggan C, Guarino A, Manary M, Velasco C . Gastrointestinal and nutritional complications of human immunodeficiency virus infection. J Pediatr Gastroenterol Nutr. 2008; 47(2):247-53. PMC: 4627636. DOI: 10.1097/MPG.0b013e318181b254. View

17.

Hirose K, Kozu C, Yamashita K, Maruo E, Kitamura M, Hasegawa J . Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene. Oncol Lett. 2012; 3(3):694-698. PMC: 3362497. DOI: 10.3892/ol.2011.533. View

18.

Hamano H, Mitsui M, Zamami Y, Takechi K, Nimura T, Okada N . Irinotecan-induced neutropenia is reduced by oral alkalization drugs: analysis using retrospective chart reviews and the spontaneous reporting database. Support Care Cancer. 2018; 27(3):849-856. DOI: 10.1007/s00520-018-4367-y. View

19.

Matsuno O . Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches. Respir Res. 2012; 13:39. PMC: 3426467. DOI: 10.1186/1465-9921-13-39. View

20.

Zhang D, Chando T, Everett D, Patten C, Dehal S, Humphreys W . In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005; 33(11):1729-39. DOI: 10.1124/dmd.105.005447. View