Ranitidine Induced Hepatotoxicity: A Review
Abstract
Background: Ranitidine (RAN) is one of the common drugs associated with idiosyncratic adverse drug reactions (IADRs) in humans. It was found to be associated with severe adverse drug reactions due to the presence of contaminants such as N-Nitrosodimethylamine (NDMA) which is claimed to be carcinogenic. As a consequence, on April 1, 2020, United States Food and Drug Administration (USFDA) had decided to call off all the RAN products from the market. The exact cause of RAN associated idiosyncratic hepatotoxicity is not clear yet.
Purpose: To summarize and analyze the reason behind the withdrawal of RAN products from the market and whether ranitidine will be available again in future or will FDA withdraw approvals of ranitidine National Drug Authority (NDA) and an abbreviated new drug application (ANDA)?
Methods: We performed a systematic PubMed/MEDLINE search of studies investigating the reason behind the withdrawal of RAN products and explored the possible mechanism associated with RAN induced hepatotoxicity.
Conclusion: RAN induced liver injury is difficult to diagnose and study because of its relative rarity and unpredictive occurrence. Recent studies suggest that most of the RAN associated idiosyncratic reactions may lead to hepatocyte damage, followed by a series of events, such as activation of specific T- and B-cells, release of proinflammatory mediators like TNFα, interleukins, various cytokines and chemokines. The exact cause of RAN associated idiosyncratic hepatotoxicity is not clear yet. More studies must be carried out on this to know about the exact reason behind RAN associated hepatotoxicity.
- Page Number : 39-46
- Keywords
DILI, Ranitidine withdrawal, RAN induced hepatotoxicity - DOI Number
https://doi.org/10.15415/jptrm.2020.81006 -
Authors
- Onkar BediChitkara College of Pharmacy, Chitkara University, Punjab-140401, India
- Amit Bandyopadhyay BanerjeeChitkara College of Pharmacy, Chitkara University, Punjab-140401, India
- Thakur Gurjeet SinghChitkara College of Pharmacy, Chitkara University, Punjab-140401, India
- Sandeep AroraChitkara College of Pharmacy, Chitkara University, Punjab-140401, India
- Manisha GuptaChitkara College of Pharmacy, Chitkara University, Punjab-140401, India
References
- Alfirevic, A., & Pirmohamed, M. (2012). Predictive genetic testing for drug-induced liver injury: considerations of clinical utility. Clin Pharmacol Ther., 92(3), 376-380. https://doi.org/10.1038/clpt.2012.107
- Barr, G.D., & Piper, D.W. (1981). Possible ranitidine hepatitis. Medical Journal of Australia, 2(8), 421. https://doi.org/10.5694/j.1326-5377.1981.tb101036.x
- Berson, A., Descatoire, V., Sutton, A., Fau, D., Maulny, B., Vadrot, N., Feldmann, G., Berthon, B., Tordjmann, T., & Pessayre, D. (2001). Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. The Journal of Pharmacology and Experimental Therapeutics, 299(2), 793-800.
- Black, M., Scott, W.E., & Kanter, R. (1984). Possible ranitidine hepatotoxicity. Annals of Internal Medicine, 101(2), 208-210. https://doi.org/10.7326/0003-4819-101-2-208
- Blazka, M.E., Elwell, M.R., Holladay, S.D., Wilson, R.E., & Luster, M.I. (1996). Histopathology of acetaminophen-induced liver changes: role of interleukin 1α and tumor necrosis factor α. Toxicologic Pathology, 24(2), 181-189. https://doi.org/10.1177/019262339602400206
- Blazka, M.E., Wilmer, J.L., Holladay, S.D., Wilson, R.E., & Luster, M.I. (1995). Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology, 133(1), 43-52. https://doi.org/10.1006/taap.1995.1125
- Bleibel, W., Kim, S., D’Silva, K., & Lemmer, E.R. (2007). Drug-induced liver injury. Digestive Diseases and Sciences, 52(10), 2463-2471. https://doi.org/10.1007/s10620-006-9472-y
- Chalasani, N., & Björnsson, E. (2010). Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology, 138(7), 2246-2259. https://doi.org/10.1053/j.gastro.2010.04.001
- Cleator, I.G. (1983). Adverse effects of ranitidine therapy. Canadian Medical Association Journal, 129(5), 405b-405.
- Devuyst, O., Lefebvre, C., Geubel, A., & Coche, E. (1993). Acute cholestatic hepatitis with rash and hypereosinophilia associated with ranitidine treatment. Acta Clinica Belgica, 48(2), 109-114. https://doi.org/10.1080/17843286.1993.11718294
- Drug regulator cautions against over-the-counter use of ranitidine. (2019, September 25). The Hindu. https://www.thehindu.com/news/national/drug-regulator-cautions-against-over-the-counter-use-of-ranitidine/article29511521.ece
- Fagius, J., Osterman, P.O., Siden, A., & Wiholm, B.E. (1985). Guillain-Barré syndrome following zimeldine treatment. Journal of Neurology, Neurosurgery and Psychiatry, 48(1), 65-69. https://doi.org/10.1136/jnnp.48.1.65
- Francis, S.-A., Barnett, N., & Denham, M. (2005). Switching of prescription drugs to over-the-counter status. Drug Aging, 22(5), 361-370. https://doi.org/10.2165/00002512-200522050-00001
- Fung, M., Thornton, A., Mybeck, K., Wu, J.H.-H., Hornbuckle, K., & Muniz, E. (2001). Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets-1960 to 1999. Drug information journal : DIJ / Drug Information Association, 35(1), 293-317. https://doi.org/10.1177/009286150103500134
- Holt, M.P., & Ju, C. (2006). Mechanisms of drug-induced liver injury. The AAPS Journal, 8(1), E48-E54. https://doi.org/10.1208/aapsj080106
- Ishida, Y., Kondo, T., Ohshima, T., Fujiwara, H., Iwakura, Y., & Mukaida, N. (2002). A pivotal involvement of IFN-' in the pathogenesis of acetaminophen-induced acute liver injury. The FASEB Journal, 16(10), 1227-1236. https://doi.org/10.1096/fj.02-0046com
- Kaplowitz, N. (2004). Drug-induced liver injury. Clinical Infectious Diseases, 38(Supplement_2), S44-S48. https://doi.org/10.1086/381446
- Kaplowitz, N. (2005). Idiosyncratic drug hepatotoxicity. Nature Reviews Drug Discovery, 4(6), 489-499. https://doi.org/10.1038/nrd1750
- Lednicer, D. (Eds.) (1993). Chronicles of drug discovery. (Vol. 3). American Chemical Society: Washington D.C.
- Liberopoulos, E.N., Nonni, A.B., Tsianos, E.V., & Elisaf, M.S. (2002). Possible ranitidine-induced cholestatic jaundice. Annals of Pharmacotherapy, 36(1), 172. https://doi.org/10.1345/aph.10420
- Lim, H.-H., Oh, Y.-S., & Shin, H.S. (2020). Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 189, 113460. https://doi.org/10.1016/j.jpba.2020.113460
- Luyendyk, J.P., Lehman-McKeeman, L.D., Nelson, D.M., Bhaskaran, V.M., Reilly, T.P., Car, B.D., Cantor, G.H., Maddox, J.F., Ganey, P.E., & Roth, R.A. (2006). Unique gene expression and hepatocellular injury in the lipopolysaccharide-ranitidine drug idiosyncrasy rat model: Comparison with famotidine. Toxicological Sciences, 90(2), 569–585. https://doi.org/10.1093/toxsci/kfj103
- Maddrey, W.C. (2005). Drug-induced hepatotoxicity: 2005. Journal of Clinical Gastroenterology, 39(4), S83-S89. https://doi.org/10.1097/01.mcg.0000155548.91524.6e
- Schubert-Zsilavecz, M. (2011). Drug withdrawals Recall in review. Pharmazeutische Zeitung. Retrieved from https://www.pharmazeutische-zeitung.de/index.php?id=38778
- Newhouse, K.E. (1986). Goodman and Gilman's The Pharmacological Basis of Therapeutics. Yale Journal of Biology and Medicine, 59(1), 71-72.
- Offit, K., & Sojka, D.A. (1984). Ranitidine. New England Journal of Medicine, 310, 1601-1606. https://doi.org/10.1056/NEJM198406143102413
- Pemoline. Drug Bank. Retrieved on July 20, 2020, from https://web.archive.org/web/20130927055300/http://www.drugbank.ca/drugs/DB01230
- Qureshi, Z.P., Seoane-Vazquez, E., Rodriguez-Monguio, R., Stevenson, K.B., & Szeinbach, S.L. (2011). Market withdrawal of new molecular entities approved in the United States from 1980 to 2009. Pharmacoepidemiology and Drug Safety, 20(7), 772-777. https://doi.org/10.1002/pds.2155
- Ramrakhiani, S., Brunt, E.M., & Bacon, B.R. (1998). Possible cholestatic injury from ranitidine with a review of the literature. The American Journal of Gastroenterology, 93(5), 822-826. https://doi.org/10.1111/j.1572-0241.1998.233_a.x
- Ranitidine (ZANTAC). (1982). The Medical Letter on Drugs and Therapeutics, 24(625), 111-113.
- Rashid, M., Goldin, R., & Wright, M. (2004). Drugs and the liver. Hospital Medicine, 65(8), 456–461. https://doi.org/10.12968/hosp.2004.65.8.15489
- Shaik, K.M., Sarmah, B., Wadekar, G.S., & Kumar, P. (2020). Regulatory Updates and Analytical Methodologies for Nitrosamine Impurities Detection in Sartans, Ranitidine, Nizatidine, and Metformin along with Sample Preparation Techniques. Critical Reviews in Analytical Chemistry, 1-9. https://doi.org/10.1080/10408347.2020.1788375
- Souza lima, M.A. (1984). Hepatitis associated with ranitidine. Annals of Internal Medicine, 101(2), 207-208. https://doi.org/10.7326/0003-4819-101-2-207
- Stepan, A.F., Walker, D.P., Bauman, J., Price, D.A., Baillie, T.A., Kalgutkar, A.S., & Aleo, M.D. (2011). Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chemical Research in Toxicology, 24(9), 1345-1410. https://doi.org/10.1021/tx200168d
- Thacker, T. (2019, October 14). Drug regulator steps up monitoring of ranitidine. The Economic Times. Retrieved from https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/drug-regulator-steps-up-monitoring-of-ranitidine/articleshow/71573124.cms?from=mdr
- Teschke, R., & Danan, G. (2018). Drug induced liver injury with analysis of alternative causes as confounding variables. British Journal of Clinical Pharmacology, 84(7), 1467-1477. https://doi.org/10.1111/bcp.13593
- Watkins, P.B. (2005). Idiosyncratic liver injury: challenges and approaches. Toxicologic Pathology, 33(1), 1-5. https://doi.org/10.1080/01926230590888306
- European Medicines Agency (2018). Withdrawal of pain medicine flupirtine endorsed. Retrieved from https://www.ema.europa.eu/en/news/withdrawal-pain-medicine-flupirtine-endorsed
- Woodcock, J. (2019). Statement on new testing results, including low levels of impurities in ranitidine drugs. Retrieved from https://www.fda.gov/news-events/press-announcements/statement-new-testing-results-including-low-levels-impurities-ranitidine-drugs
Published Date : 2020-05-20