Ranitidine Induced Hepatotoxicity: A Review

Onkar  Bedi; Amit Bandyopadhyay  Banerjee; Thakur Gurjeet  Singh; Sandeep  Arora; Manisha  Gupta

doi:10.15415/jptrm.2020.81006

Authors

Onkar Bedi Chitkara College of Pharmacy, Chitkara University, Punjab-140401, India
Amit Bandyopadhyay Banerjee Chitkara College of Pharmacy, Chitkara University, Punjab-140401, India
Thakur Gurjeet Singh Chitkara College of Pharmacy, Chitkara University, Punjab-140401, India
Sandeep Arora Chitkara College of Pharmacy, Chitkara University, Punjab-140401, India
Manisha Gupta Chitkara College of Pharmacy, Chitkara University, Punjab-140401, India

DOI:

https://doi.org/10.15415/jptrm.2020.81006

Keywords:

DILI, Ranitidine withdrawal, RAN induced hepatotoxicity

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.

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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