Ranitidine Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:458460406
Width:250
Jan:ranitidine hydrochloride
Tradename:Zantac,[1] others
Dailymedid:Ranitidine
Pregnancy Au:B1
Pregnancy Au Comment:[2]
Routes Of Administration:By mouth, intravenous (IV)
Class:Histamine H2 receptor antagonist, aka H2 blocker
Atc Prefix:A02
Atc Suffix:BA02
Atc Supplemental:
(ranitidine bismuth citrate)
Legal Au:S4
Legal Au Comment:/ S2 (Pharmacy Medicine)
Legal Ca:Rx-only
Legal Ca Comment:/ OTC[3] [4] [5]
Legal Uk:POM
Legal Uk Comment:/ GSL/ P[6] [7] [8]
Legal Us:Rx-only
Legal Us Comment:/ OTC[9] [10]
Legal Eu:Rx-only
Bioavailability:50% (by mouth)
Protein Bound:15%
Metabolism:Liver

FMOs, including FMO3; other enzymes

Onset:55–65 minutes (150 mg dose)
55–115 minutes (75 mg dose)[11]
Elimination Half-Life:2–3 hours
Excretion:30–70% kidney
Index2 Label:HCl
Cas Number:66357-35-5
Cas Number2:66357-59-3
Pubchem:3001055
Pubchem2:3033332
Iuphar Ligand:1234
Drugbank:DB00863
Drugbank2:DBSALT000487
Chemspiderid:4863
Chemspiderid2:43590
Unii:884KT10YB7
Unii2:BK76465IHM
Kegg:D00422
Kegg2:D00673
Chebi:8776
Chebi2:8777
Chembl:1790041
Chembl2:2110372
Synonyms:Dimethyl [(5-<nowiki/>{[(2-<nowiki/>{[1-(methylamino)-2-nitroethenyl]amino}ethyl)sulfanyl]methyl}furan-2-yl)methyl]amine
Iupac Name:N-(2-[(5-[(Dimethylamino)methyl]furan-2-yl)methylthio]ethyl)-N-methyl-2-nitroethene-1,1-diamine
C:13
H:22
N:4
O:3
S:1
Smiles:CNC(=C[N+](=O)[O-])NCCSCC1=CC=C(O1)CN(C)C
Stdinchi:1S/C13H22N4O3S/c1-14-13(9-17(18)19)15-6-7-21-10-12-5-4-11(20-12)8-16(2)3/h4-5,9,14-15H,6-8,10H2,1-3H3
Stdinchikey:VMXUWOKSQNHOCA-UHFFFAOYSA-N

Ranitidine, previously sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It was commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome. It can be given by mouth, injection into a muscle, or injection into a vein.

In September 2019, the probable carcinogen N-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls.[12] [13] [14] [15] In April 2020, ranitidine was withdrawn from the United States market and suspended in the European Union and Australia due to these concerns.[16] [17] [18] [19] [20]

In 2022, these concerns were confirmed in a Taiwanese nationwide population study finding "significant trends of increased liver cancer risk with an increasing dose of ranitidine" (up to 22% higher than control) and increased gastric, pancreatic, lung and overall cancer risk.[21]

Common side effects include headaches, and pain or burning sensation if given by injection. Serious side effects may include cancer,[22] liver problems, a slow heart rate, pneumonia, and the potential of masking stomach cancer. It is also linked to an increased risk of Clostridium difficile colitis.[23] Ranitidine is an H2 histamine receptor antagonist that works by blocking histamine, thus decreasing the amount of acid released by cells of the stomach.[24]

Ranitidine was discovered in England in 1976, and came into commercial use in 1981.[25] It is on the World Health Organization's List of Essential Medicines.[26] [27] [28] It has been withdrawn at regulator request from most markets, including the United States;[24] according to the UK NHS, it has been discontinued globally.[29]

Former medical uses

Contraindication

Ranitidine has been discontinued globally, according to the NHS, and is contraindicated due to excess cancer risk and the ready availability of H2 antagonist and PPI alternatives.

Adverse effects

These adverse effects for ranitidine have been reported as events in clinical trials:

Central nervous system

Rare reports have been made of ranitidine causing malaise, dizziness, somnolence, insomnia, and vertigo. In severely ill, elderly patients, cases of reversible mental confusion, agitation, depression, and hallucinations have been reported.

Cardiovascular

Arrhythmias such as tachycardia, bradycardia, atrioventricular block, and premature ventricular beats have also been reported.[1]

Gastrointestinal

All drugs in the H2 receptor blocker class of medicines have the potential to cause vitamin B12 deficiency, secondary to a reduction in food-bound vitamin B12 absorption.[35] Elderly patients taking H2 receptor antagonists are more likely to require B12 supplementation than those not taking such drugs.[36] H2 blockers may also reduce the absorption of drugs (azole antifungals, calcium carbonate) that require an acidic stomach.[37] In addition, multiple studies suggest the use of H2 receptor antagonists such as ranitidine may increase the risk of infectious diarrhoea, including traveller's diarrhoea and salmonellosis.[38] [39] [40] [41] [42] A 2005 study found that by suppressing acid-mediated breakdown of proteins, ranitidine may lead to an elevated risk of developing food or drug allergies, due to undigested proteins then passing into the GI tract, where sensitisation occurs. Patients who take these agents develop higher levels of immunoglobulin E against food, whether they had prior antibodies or not.[43] Even months after discontinuation, an elevated level of IgE in 6% of patients was still found in the study.

Liver

Cholestatic hepatitis, liver failure, hepatitis, and jaundice have been noted, and require immediate discontinuation of the drug.[1] Blood tests can reveal an increase in liver enzymes or eosinophilia, although in rare instances, severe cases of hepatotoxicity may require a liver biopsy.[44]

Lungs

Ranitidine and other histamine H2 receptor antagonists may increase the risk of pneumonia in hospitalised patients.[45] Ranitidine increases the risk of community-acquired pneumonia in adults and children.[46]

Blood

Thrombocytopenia is a rare but known side effect. Drug-induced thrombocytopenia usually takes weeks or months to appear, but may appear within 12 hours of drug intake in a sensitised individual. Typically, the platelet count falls to 80% of normal, and thrombocytopenia may be associated with neutropenia and anemia.[47]

Skin

Rash, including rare cases of erythema multiforme, and rare cases of hair loss and vasculitis have been seen.[1]

Precautions

Disease-related concerns

Relief of symptoms due to the use of ranitidine does not exclude the presence of a gastric malignancy. In addition, with kidney or liver impairment, ranitidine must be used with caution. It should be avoided in patients with porphyria, as it may precipitate an attack.[48] [49]

Children

In children, the use of gastric acid inhibitors has been associated with an increased risk for development of acute gastroenteritis and community-acquired pneumonia.[46] A cohort analysis including over 11,000 neonates reported an association of H2 blocker use, and an increased incidence of necrotizing enterocolitis in very-low-birth-weight (VLBW) neonates.[50] In addition, about a six-fold increase in mortality, necrotizing enterocolitis, and infection such as sepsis, pneumonia, urinary tract infection was reported in patients receiving ranitidine in a cohort analysis of 274 VLBW neonates.[51]

Drug tests

Ranitidine may return a false positive result with some commercial urine drug screening kits for testing for drugs of abuse.[52]

Cancer-causing due to inherent instability

In June 2019, Valisure informed the U.S. Food and Drug Administration (FDA) that Zantac-branded and generic ranitidine resulted in very high levels of NDMA in the human body "due to an inherent instability of the ranitidine molecule".[53] [54] In September 2019, the U.S. Food and Drug Administration (FDA) acknowledged that ranitidine medicines, including some products sold under the brand name Zantac, contained a nitrosamine impurity called N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen, at unacceptable levels.[55] Health Canada announced that it was assessing NDMA in ranitidine and requested that manufacturers stop the distribution of ranitidine products in Canada until the NDMA levels in the products are found to be safe.[56] Health Canada announced that ranitidine drugs were being recalled by Sandoz Canada, Apotex Inc., Pro Doc Limitée, Sanis Health Inc., and Sivem Pharmaceuticals ULC. The European Medicines Agency (EMA) started a European Union-wide review of ranitidine medicines at the request of the European Commission.[57]

In October 2019, the U.S. FDA observed that the third-party laboratory that found very high levels of NDMA was using higher temperatures in its tests to detect nitrosamine impurities. The NDMA was mostly generated by the added heat, but the higher temperatures are recommended for using a gas chromatography–mass spectrometry method to test for NDMA in valsartan and angiotensin II receptor blockers.[58] The FDA stated that it recommends using a Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) testing protocol to test samples of ranitidine.[59] Its LC-HRMS testing method does not use elevated temperatures, and has shown the presence of much lower levels of NDMA in ranitidine medicines than were reported by the third-party laboratory. International regulators using similar LC-MS testing methods have also shown the presence of lower but still unacceptable levels of NDMA in ranitidine samples. The FDA provided additional guidance about using another LC-MS method based on a triple-quadrupole MS platform.[60]

In September 2019, Sandoz issued a "precautionary distribution stop" of all medicines containing ranitidine,[61] [62] followed a few days later by a recall of ranitidine hydrochloride capsules in the United States.[63] [64] [65] The Italian Medicines Agency recalled all ranitidine that uses an active pharmaceutical ingredient from Saraca Laboratories.[66] [67] [68] The Federal Union of German Associations of Pharmacists (Arzneimittelkommission der Deutschen Apotheker) published a list of recalled products,[69] as did the Therapeutic Goods Administration in Australia.[70]

In November 2019, the FDA stated that its tests found levels of NDMA in ranitidine and nizatidine that are similar to those that one may typically ingest with common foods such as grilled or smoked meats.[71] [72] The FDA also stated that its simulated gastric fluid model tests and simulated intestinal fluid model tests indicated that NDMA is not formed when exposed to acid in the stomach with a normal diet. The FDA advised companies to recall their ranitidine if testing shows levels of NDMA above the acceptable daily intake (96 nanograms per day or 0.32 parts per million for ranitidine). At the same time, it indicated that some levels of NDMA found in medicines still exceeded the agency's acceptable levels.

In December 2019, the FDA asked manufacturers of ranitidine and nizatidine products to expand their NDMA testing to include all lots of the medication before making them available to consumers.[73]

By the end of 2019, ranitidine had already fallen from the 40th most commonly prescribed medication in the United States in 2018, to 53rd place for 2019, with about 13.6million prescriptions for the year, versus nearly 19 million the previous year.[74] This reflects total prescriptions for all of 2019, while safety concerns affected sales in only the final 4 months of the year.

In April 2020, new FDA testing and evaluation prompted by information from third-party laboratories confirmed that NDMA levels increase in ranitidine even under normal storage conditions, and NDMA has been found to increase significantly in samples stored at higher temperatures, including those at which the product may be exposed during distribution and handling by consumers. The testing also showed that the level of NDMA increases as ranitidine medication ages. These conditions may raise the NDMA level above the acceptable daily intake limit. The EMA completed and issued their EU-wide review at the end of the month and the European Commission suspended all ranitidine products in the EU.[75]

In August 2020, the EMA provided guidance to marketing authorization holders for avoiding the presence of nitrosamine impurities and asked them to review all chemical and biological human medicines for the presence of nitrosamines and to test the products at risk.[76] In September 2020, the FDA issued guidance about the control of nitrosamine impurities in human drugs.[77] [78] [79] An implementation plan was issued in February 2021.[80]

In 2022, these concerns were confirmed in a Taiwanese nationwide population study finding "significant trends of increased liver cancer risk with an increasing dose of ranitidine" (22% higher than control) and increased gastric, pancreatic, lung (26%, 35%, and 17% respectively), but "only liver cancer displayed a significant association with long-term ranitidine use" and "there was no continuous dose–response relationship among the other individual cancers". Overall cancer risk also increased by 10% (p < 0.001).

List of recalls

In September 2019, Apotex recalled all over-the-counter ranitidine tablets sold in the United States at Walmart, Rite Aid, and Walgreens.[81] [82] These retailers, along with CVS, removed Zantac and some generics from their shelves.[83] [84] [85] [86] [87]

On 8 October 2019, the Medicines and Healthcare products Regulatory Agency of the United Kingdom (UK) issued a drug alert for ranitidine "... to proactively communicate the recall to hospitals, pharmacies, dispensing practices, retailers and wholesalers in the UK." This included all Zantac-branded preparations,[88] [89] along with all generic preparations of ranitidine from Teva UK Limited,[90] [91] Rosemont Pharmaceuticals Limited,[92] Omega Pharma Limited and Galpharm International Limited,[93] Perrigo Company plc,[94] Creo Pharma Limited and Tillomed Laboratories Limited,[95] [96] OTC Concepts Ltd, Relonchem Ltd, Noumed Life Sciences Ltd, and Medreich Plc.,[97] [98] Accord Healthcare,[99] Medley Pharma Limited,[100] and Medreich Plc.[101]

On 15 October 2019, the Department of Health and Social Care of the United Kingdom issued a supply distribution alert (SDA/2019/005) for all oral formulations of ranitidine.[102]

In October 2019, Sanofi recalled all over-the-counter Zantac in the United States and Canada,[103] [104] [15] Perrigo issued a worldwide recall of ranitidine,[105] [15] Dr. Reddy's issued a recall of all ranitidine products in the United States,[106] [15] andNovitium Pharma recalled all ranitidine hydrochloride capsules in the U.S.[107] [15]

In November 2019, Aurobindo Pharma, Amneal Pharmaceuticals, American Health Packaging, Golden State Medical Supply, and Precision Dose recalled some lots of ranitidine tablets, capsules, and syrup.[108] [109] [110] [111] [112]

In December 2019, Glenmark Pharmaceutical Inc., USA, recalled some lots of ranitidine tablets.[113]

In January 2020, Appco Pharma LLC and Northwind Pharmaceuticals recalled some lots of ranitidine tablets and capsules.[114] [115]

In February 2020, American Health Packaging recalled some lots of ranitidine tablets manufactured by Amneal Pharmaceuticals.[116]

In April 2020, the FDA requested a manufacturer's market withdrawal of ranitidine,[117] meaning that ranitidine products would not be available for prescription or over-the-counter sale in the U.S.

In April 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended the suspension of all ranitidine medicines in the European Union because of the presence of unacceptable levels of NDMA.[118] [119]

A ranitidine manufacturer requested a re-examination of the decision, but in December 2020, the EMA confirmed its recommendation to suspend all ranitidine medicines in the European Union. The UK National Health Service (NHS) Web site said "Ranitidine is not currently available in the UK or globally... It's not yet known whether it will be available again in future." A March 2024 review left the message up.[120]

In 2021, Solara Active Pharma Sciences, which supplies ranitidine active pharmaceutical ingredient (API), said that it had mitigated the risks of the formation of NDMA during the manufacturing of ranitidine API. The company was granted a revised certificate by the European Directorate for the Quality of Medicines and Healthcare, which proves that the API complies with certain European rules. GlaxoSmithKline, Sanofi, and Teva said they had no plans to reintroduce the drug in the EU, but Accord Healthcare considered the possible reintroduction of ranitidine.[121] However a control strategy regarding NDMA formation through the end of the product’s shelf life, despite heat, time and digestion due to endogenous formation from the API, would be required.

Pharmacology

Mechanism of action

Ranitidine is a competitive, reversible inhibitor of the action of histamine at the histamine H2 receptors found in gastric parietal cells. This results in decreased gastric acid secretion and gastric volume, and reduced hydrogen ion concentration.[122] Ranitidine's acid-lowering effect is more pronounced for basal and nocturnal acid secretion than it is for food-stimulated acid secretion. Additional indirect effects of ranitidine are decreased pepsin secretion and increased nitrate-reducing bacterial flora.

Pharmacokinetics

Oral absorption: 50%

Protein binding: 15%[123]

Metabolism: The major metabolite in the urine is ranitidine N-oxide, which represents less than 4% of the dose. Other metabolites of ranitidine include ranitidine S-oxide (1%) and desmethyl ranitidine (1%).[124]

Half-life elimination: With normal renal function, ranitidine taken orally has a half-life of 2.5–3.0 hours. If taken intravenously, the half-life is generally 2.0–2.5 hours in a patient with normal kidney function and normal creatinine clearance. In patients with kidney dysfunction, the half-life may increase to 4 to 5 hours.

Excretion: The primary route of excretion is the urine. In addition, about 30% of the orally administered dose is collected in the urine as unabsorbed drug in 24 hours.[125]

Elderly

In the elderly population, the plasma half-life of ranitidine is prolonged to 3–4 hours secondary to decreased kidney function causing decreased clearance.[1]

Children

In general, studies of pediatric patients (aged one month to 16 years) have shown no significant differences in pharmacokinetic parameter values in comparison to healthy adults, when correction is made for body weight.[1]

History

Ranitidine was first prepared in England as AH19065 by John Bradshaw in the summer of 1977 in the Ware research laboratories of Allen and Hanburys, part of the former Glaxo organisation.[126] [127] Its development was a response to the first in class histamine H2 receptor antagonist, cimetidine, developed by Sir James Black at Smith, Kline and French, and launched in the United Kingdom as Tagamet in November 1976. Both companies eventually merged as GlaxoSmithKline (GSK), following a sequence of mergers and acquisitions, starting with the integration of Allen and Hanbury's Ltd and Glaxo to form Glaxo Group Research in 1979, and ultimately with the merger of Glaxo Wellcome and SmithKline Beecham in 2000. Ranitidine was the result of a rational drug-design process using what was by then a fairly refined model of the histamine H2 receptor and quantitative structure-activity relationships.

Glaxo refined the model further, by replacing the imidazole ring of cimetidine with a furan ring with a nitrogen-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and 10 times the activity of cimetidine. Ranitidine has 10% of the affinity that cimetidine has to CYP450, so it causes fewer side effects, but other H2 blockers famotidine and nizatidine have no CYP450 significant interactions.[128]

Ranitidine was introduced in 1981, and was the world's biggest-selling prescription drug by 1987. Subsequently, it was largely superseded by the more effective proton-pump inhibitor (PPI) class of drugs, with omeprazole becoming the biggest-selling drug for many years. When omeprazole and ranitidine were compared in a study of 144 people with severe inflammation and erosions or ulcers of the oesophagus, 85% of those treated with omeprazole healed within eight weeks, compared with 50% of those given ranitidine. In addition, the omeprazole group reported earlier relief of heartburn symptoms.[129] [130]

In September 2019, the probable carcinogen N-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls; in April 2020, it was withdrawn from the United States market and suspended in Europe and Australia.

Preparations

Preparations of ranitidine products include oral tablets (75, 150, and 300 mg), effervescent tablets, and syrups,[1] and injectable solutions;[131] with doses of specific ranitidine product preparations are available over-the-counter (OTC) in various countries. In the United Kingdom, only the lowest-strength, 75-mg tablet was available to purchase without a prescription.[1] In Australia, packs containing seven or 14 doses of the 150-mg tablet were available in supermarkets, small packs of 150-mg and 300-mg tablets were schedule 2 pharmacy medicines. Larger doses and pack sizes required a prescription. In the United States, 75- and 150-mg tablets were available OTC.[132] [133] In India, it is sold under multiple brand names.[134]

External links

Notes and References

  1. Web site: Zantac 150 (ranitidine hydrochloride) Tablets, USP Zantac 300 (ranitidine hydrochloride) Tablets, USP . DailyMed . 28 June 2018 . 18 February 2021 . 4 July 2022 . https://web.archive.org/web/20220704051405/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=379425 . live .
  2. Web site: Ranitidine use during pregnancy . Drugs.com . 2 December 2019 . 18 December 2019 . 29 October 2019 . https://web.archive.org/web/20191029013537/https://www.drugs.com/pregnancy/ranitidine.html . live.
  3. Web site: Nitrosamine impurities in medications: Medications affected . . 19 March 2021 . 7 January 2024.
  4. Web site: Acid Reducer (Ranitidine) Tablet: N-nitrosodimethylamine (NDMA) impurity . . 6 December 2021 . 7 January 2024.
  5. https://pdf.hres.ca/dpd_pm/00003505.PDF
  6. Web site: Ranitidine 50mg/2ml Solution for Injection and Infusion . medicines.org.uk . 13 October 2021 . 7 January 2024.
  7. Web site: Boots Heartburn & Indigestion Relief 75mg Tablets (P) . medicines.org.uk . 3 October 2016 . 7 January 2024.
  8. Web site: Boots Heartburn & Indigestion Relief 75mg Tablets . medicines.org.uk . 3 October 2016 . 7 January 2024.
  9. Web site: Zantac 150 . DailyMed . 3 April 2018 . 18 February 2021 . 4 July 2022 . https://web.archive.org/web/20220704051407/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=530989 . live .
  10. Web site: Ranitidine hydrochloride capsule . DailyMed . 21 November 2018 . 7 January 2024.
  11. Gardner JD, Ciociola AA, Robinson M, McIsaac RL . Determination of the time of onset of action of ranitidine and famotidine on intra-gastric acidity . Alimentary Pharmacology & Therapeutics . 16 . 7 . 1317–1326 . July 2002 . 12144582 . 10.1046/j.1365-2036.2002.01291.x . 34396030 . free . doi .
  12. Web site: 13 September 2019 . Health Canada assessing NDMA in ranitidine . live . https://web.archive.org/web/20190926211206/https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70989a-eng.php . 26 September 2019 . 26 September 2019 . Health Canada.
  13. Web site: 13 September 2019 . Statement alerting patients and health care professionals of NDMA found in samples of ranitidine . live . https://web.archive.org/web/20190926210751/https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine . 26 September 2019 . 26 September 2019 . U.S. Food and Drug Administration (FDA).
  14. EMA to provide guidance on avoiding nitrosamines in human medicines . European Medicines Agency . 13 September 2019 . 19 September 2019 . 31 December 2019 . https://web.archive.org/web/20191231050132/https://www.ema.europa.eu/en/news/ema-provide-guidance-avoiding-nitrosamines-human-medicines . live.
  15. Web site: 28 October 2019 . FDA updates and press announcements on NDMA in Zantac (ranitidine) . live . https://web.archive.org/web/20191029011848/https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine . 29 October 2019 . 28 October 2019 . U.S. Food and Drug Administration (FDA) . FDA observed the testing method used by a third-party laboratory uses higher temperatures. The higher temperatures generated very high levels of NDMA from ranitidine products because of the test procedure. The FDA published the method for testing angiotensin II receptor blockers (ARBs) for nitrosamine impurities. That method is not suitable for testing ranitidine because heating the sample generates NDMA.
    FDA recommends using an LC-HRMS testing protocol to test samples of ranitidine. FDA's LC-HRMS testing method does not use elevated temperatures and has shown the presence of much lower levels of NDMA in ranitidine medicines than reported by the third-party laboratory. International regulators using similar LC-MS testing methods have also shown the presence of low levels of NDMA in ranitidine samples..
  16. Web site: 11 October 2019 . Questions and Answers: NDMA impurities in ranitidine (commonly known as Zantac) . live . https://web.archive.org/web/20191024040431/https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-ranitidine-commonly-known-zantac . 24 October 2019 . 23 October 2019 . U.S. Food and Drug Administration (FDA).
  17. FDA Requests Removal of All Ranitidine Products (Zantac) from the Market . U.S. Food and Drug Administration (FDA) . 1 April 2020 . 1 April 2020 . 28 March 2021 . https://web.archive.org/web/20210328103217/https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market . live .
  18. Suspension of ranitidine medicines in the EU . European Medicines Agency . 30 April 2020 . 2 June 2020 . 5 January 2021 . https://web.archive.org/web/20210105083734/https://www.ema.europa.eu/en/news/suspension-ranitidine-medicines-eu . live .
  19. Web site: Ranitidine . Therapeutic Goods Administration (TGA) . 2 April 2020 . 19 July 2020 . 29 August 2021 . https://web.archive.org/web/20210829025912/https://www.tga.gov.au/alert/ranitidine-0 . live .
  20. Wagner JA, Dinh JC, Lightdale JR, Gold BD, Colombo JM . Is this the end for ranitidine? NDMA presence continues to confound . Clinical and Translational Science . 14 . 4 . 1197–1200 . July 2021 . 33934515 . 8301580 . 10.1111/cts.12995 .
  21. Wang CH, Chen II, Chen CH, Tseng YT . Pharmacoepidemiological Research on N-Nitrosodimethylamine-Contaminated Ranitidine Use and Long-Term Cancer Risk: A Population-Based Longitudinal Cohort Study . International Journal of Environmental Research and Public Health . 19 . 19 . 12469 . September 2022 . 36231768 . 9566239 . 10.3390/ijerph191912469 . free . doi .
  22. News: 15 February 2023 . Zantac's Maker Kept Quiet About Cancer Risks for 40 Years . en . Bloomberg.com . 20 February 2023 . 19 February 2023 . https://web.archive.org/web/20230219212613/https://www.bloomberg.com/news/features/2023-02-15/zantac-cancer-risk-data-was-kept-quiet-by-manufacturer-glaxo-for-40-years . live .
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  93. Web site: Class 2 Medicines recall: Zantac 75 Relief Tablets, Zantac 75 Tablets, Galpharm Indigestion Relief 75mg Tablets, Boots Heartburn & Indigestion Relief 75mg Tablets, Kirkland Indigestion Relief 75mg Tablets, Morrisons Indigestion & Heartburn Relief 75mg Tablets, Boots Heartburn & Indigestion Relief 75mg Tablets (EL (19)A/30). GOV.uk. United Kingdom. Medicines and Healthcare products Regulatory Agency (MHRA). 25 October 2019. 30 March 2020. Omega Pharma Limited and Galpharm International Limited are recalling unexpired stock from pharmacies and retail stores as a precautionary measure due to possible contamination with an impurity.. 31 December 2019. https://web.archive.org/web/20191231101940/https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-zantac-75-relief-tablets-zantac-75-tablets-galpharm-indigestion-relief-75mg-tablets-boots-heartburn-indigestion-relief-75mg-tablets-kirkland-indigestion-relief-75mg-tablets-morrisons-indigestion-heartburn-. live.
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  97. Web site: Class 2 Medicines recall: Ranitidine 75mg Tablets, (various liveries) (EL(19)A/37). GOV.uk. United Kingdom. Medicines and Healthcare products Regulatory Agency (MHRA). 21 November 2019. 30 March 2020. OTC Concepts Ltd, Relonchem Ltd, Noumed Life Sciences Ltd and Medreich Plc. are recalling stock from pharmacies and retail stores as a precautionary measure due to possible contamination with an impurity.. 21 February 2020. https://web.archive.org/web/20200221130923/https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-ranitidine-75mg-tablets-various-liveries-el-19-a-37. live.
  98. Web site: Press release – MHRA drug alert: recalls for 13 over-the-counter Ranitidine medicines. GOV.uk. United Kingdom. Medicines and Healthcare products Regulatory Agency (MHRA). 21 November 2019. 30 March 2020. A drug alert has been issued to retailers and healthcare professionals as 4 companies are recalling batches of certain over-the-counter Ranitidine medicines used to treat conditions such as stomach ulcers and heartburn.. 22 November 2019. https://web.archive.org/web/20191122161922/https://www.gov.uk/government/news/mhra-drug-alert-recalls-for-13-over-the-counter-ranitidine-medicines. live.
  99. Web site: Class 2 Medicines recall: Ranitidine 150mg Film-Coated Tablets, PL 20075/0063, Ranitidine 300mg Film-Coated Tablets, PL 20075/0064 (EL(19)A/40). GOV.uk. United Kingdom. Medicines and Healthcare products Regulatory Agency (MHRA). 5 December 2019. 30 March 2020. Accord Healthcare are recalling all unexpired stock of the below products from pharmacies and retail stores as a precautionary measure.. 4 March 2020. https://web.archive.org/web/20200304222737/https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-ranitidine-150mg-film-coated-tablets-pl-20075-0063-ranitidine-300mg-film-coated-tablets-pl-20075-0064-el-19-a-40. live.
  100. Web site: Class 2 Medicines Recall: Medley Pharma Limited, Ranitidine 150mg Tablets BP, PL 43870/0026, Ranitidine 300mg Tablets BP, PL 43870/0027 (EL(19)A/41). GOV.uk. United Kingdom. Medicines and Healthcare products Regulatory Agency (MHRA). 16 December 2019. 30 March 2020. Medley Pharma Limited is recalling all unexpired stock of the below products from pharmacies and retail stores as a precautionary measure.. 5 March 2020. https://web.archive.org/web/20200305080928/https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-medley-pharma-limited-ranitidine-150mg-tablets-bp-pl-43870-0026-ranitidine-300mg-tablets-bp-pl-43870-0027-el-19-a-41. live.
  101. Web site: Class 2 Medicines recall: Medreich PLC, Ranitidine 150mg Tablets, PL 21880/0091, Ranitidine 300mg Tablets, PL 21880/0092 (EL (20)A/05). GOV.uk. United Kingdom. Medicines and Healthcare products Regulatory Agency (MHRA). 3 February 2020. 30 March 2020. Medreich Plc is recalling all unexpired stock of the above products from pharmacies and wholesalers as a precautionary measure due to possible contamination with an impurity N-nitrosodimethylamine (NDMA) which has genotoxic and carcinogenic potential.. 16 June 2020. https://web.archive.org/web/20200616081649/https://www.gov.uk/drug-device-alerts/class-2-medicines-recall-medreich-plc-ranitidine-150mg-tablets-pl-21880-0091-ranitidine-300mg-tablets-pl-21880-0092-el-20-a-05. live.
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  103. News: Zantac recall widens as Sanofi pulls its drug over carcinogen fears. The New York Times. Thomas K . 18 October 2019. 18 October 2019 . 18 October 2019. https://web.archive.org/web/20191018170303/https://www.nytimes.com/2019/10/18/health/zantac-recall-carcinogen-sanofi.html. live.
  104. Web site: Sanofi provides update on precautionary voluntary recall of Zantac OTC in U.S.. U.S. Food and Drug Administration (FDA). 23 October 2019. https://web.archive.org/web/20191024035253/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/sanofi-provides-update-precautionary-voluntary-recall-zantac-otc-us. 24 October 2019. live. 23 October 2019.
  105. Web site: Perrigo Company plc issues voluntary worldwide recall of Ranitidine due to possible presence of impurity, N-nitrosodimethylamine (NDMA) impurity in the product. U.S. Food and Drug Administration (FDA). 23 October 2019. https://web.archive.org/web/20191024035720/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/perrigo-company-plc-issues-voluntary-worldwide-recall-ranitidine-due-possible-presence-impurity-n. 24 October 2019. live. 23 October 2019.
  106. Web site: Dr. Reddy's confirms its voluntary nationwide recall of all Ranitidine products in the U.S. market. U.S. Food and Drug Administration (FDA). 23 October 2019. https://web.archive.org/web/20191024035800/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/dr-reddys-confirms-its-voluntary-nationwide-recall-all-ranitidine-products-us-market. 24 October 2019. live. 23 October 2019.
  107. Web site: Novitium Pharma issues voluntary national recall of Ranitidine Hydrochloride capsules 150mg and 300mg due to an elevated amount of unexpected impurity, N-nitrosodimethylamine (NDMA). U.S. Food and Drug Administration (FDA). 25 October 2019. https://web.archive.org/web/20191029011927/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/novitium-pharma-issues-voluntary-national-recall-ranitidine-hydrochloride-capsules-150mg-and-300mg. 29 October 2019. live. 28 October 2019.
  108. Aurobindo Pharma USA, Inc. initiates voluntary nationwide consumer level recall of 38 lots of Ranitidine tablets 150mg, Ranitidine capsules 150mg, Ranitidine capsules 300mg and ranitidine Syrup 15mg/mL due to the detection of NDMA (Nitrosodimethylamine) impurity. U.S. Food and Drug Administration (FDA). 6 November 2019. https://web.archive.org/web/20191111033706/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/aurobindo-pharma-usa-inc-initiates-voluntary-nationwide-consumer-level-recall-38-lots-ranitidine. 11 November 2019. live. 10 November 2019.
  109. Amneal Pharmaceuticals, LLC. issues voluntary nationwide recall of Ranitidine tablets, USP, 150mg and 300mg, and Ranitidine syrup (Ranitidine Oral Solution, USP), 15 mg/mL, due to possible presence of N-nitrosodimethylamine (NDMA) impurity. U.S. Food and Drug Administration (FDA). 12 November 2019. https://web.archive.org/web/20191112234415/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/amneal-pharmaceuticals-llc-issues-voluntary-nationwide-recall-ranitidine-tablets-usp-150mg-and-300mg. 12 November 2019. live. 12 November 2019.
  110. American Health Packaging issues voluntary nationwide recall of Ranitidine syrup (Ranitidine Oral Solution USP) 150 mg/10 mL liquid unit dose cups due to the detection of N-nitrosodimethylamine (NDMA) impurity. U.S. Food and Drug Administration (FDA). 8 November 2019. https://web.archive.org/web/20191112234545/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/american-health-packaging-issues-voluntary-nationwide-recall-ranitidine-syrup-ranitidine-oral. 12 November 2019. live. 12 November 2019.
  111. Golden State Medical Supply, Inc. issues a voluntary nationwide recall of Ranitidine hydrochloride 150mg and 300mg capsules (manufactured by Novitium Pharma LLC) due to an elevated amount of unexpected impurity, N-nitrosodimethylamine (NDMA). U.S. Food and Drug Administration (FDA). 15 November 2019. https://web.archive.org/web/20191123070140/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/golden-state-medical-supply-inc-issues-voluntary-nationwide-recall-ranitidine-hydrochloride-150mg. 23 November 2019. live. 22 November 2019.
  112. Precision Dose Inc. issues voluntary nationwide recall of ranitidine oral solution, USP 150 mg/10 mL due to possible presence of N-nitrosodimethylamine impurity. U.S. Food and Drug Administration (FDA). 19 November 2019. https://web.archive.org/web/20191123070344/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/precision-dose-inc-issues-voluntary-nationwide-recall-ranitidine-oral-solution-usp-150-mg10-ml-due. 23 November 2019. live. 22 November 2019.
  113. Web site: Glenmark Pharmaceuticals Inc., USA voluntarily recalls all unexpired lots of its Ranitidine tablets and ceases distribution, due to possible presence of N-nitrosodimethylamine (NDMA) impurity. U.S. Food and Drug Administration (FDA). 17 December 2019. https://web.archive.org/web/20191218221805/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/glenmark-pharmaceuticals-inc-usa-voluntarily-recalls-all-unexpired-lots-its-ranitidine-tablets-and. 18 December 2019. live. 18 December 2019.
  114. Web site: Appco Pharma LLC issues voluntary nationwide recall of Ranitidine hydrochloride capsules 150 mg and 300 mg due to an elevated amount of unexpected impurity, N-nitrosodimethylamine (NDMA). U.S. Food and Drug Administration (FDA). 7 January 2020. 8 January 2020. 9 January 2020. https://web.archive.org/web/20200109033942/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/appco-pharma-llc-issues-voluntary-nationwide-recall-ranitidine-hydrochloride-capsules-150-mg-and-300. live.
  115. Web site: Denton Pharma, Inc. dba Northwind Pharmaceuticals voluntarily recalls all unexpired lots of its Ranitidine tablets and ceases distribution, due to possible presence of N-nitrosodimethylamine (NDMA) impurity. U.S. Food and Drug Administration (FDA). 6 January 2020. 8 January 2020. 9 January 2020. https://web.archive.org/web/20200109045121/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/denton-pharma-inc-dba-northwind-pharmaceuticals-voluntarily-recalls-all-unexpired-lots-its. live.
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