In September 2019, the probablecarcinogenN-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls.[11][12][13][14] In April 2020, ranitidine was withdrawn from the United States market and suspended in the European Union and Australia due to these concerns.[15][16][17][8][18][19]
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[b] and overall[c] cancer risk.[20]
Ranitidine was discovered in England in 1976 and came into commercial use in 1981.[23] It is on theWorld Health Organization's List of Essential Medicines.[24][25][26] It has been withdrawn at regulator request from most markets, including the United States;[9] according to the UKNHS, it was temporarily discontinued globally in 2021.[27] It has since been re-approved in Australia, with a new formula, and is again available in pharmacies.[28][29]
Part of a multidrug regimen forHelicobacter pylori eradication to minimise the risk of duodenal ulcer recurrence
Recurrent postoperative ulcer
Upper GI bleeding
For prevention of acid-aspiration pneumonitis during surgery, it can be administered preoperatively. The drug increases gastricpH, but generally has no effect on gastric volume. In a 2009 meta-analysis comparing the net benefit of PPIs and ranitidine to reduce the risk of aspiration before anaesthesia, ranitidine was found to be more effective than PPIs in reducing the volume of gastric secretions.[31] Ranitidine may have an anti-emetic effect when administered preoperatively.
Ranitidine has been discontinued globally, according to theNHS,[27] and is contraindicated due to excess cancer risk and the ready availability ofH2 antagonist andPPI alternatives.
Rare reports have been made of ranitidine causingmalaise,dizziness,somnolence,insomnia, andvertigo. In severely ill, elderly patients, cases of reversible mental confusion, agitation, depression, andhallucinations have been reported.[1]
All drugs in theH2 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 ofimmunoglobulin 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.[medical citation needed]
Ranitidine and otherhistamine H2 receptor antagonists may increase the risk ofpneumonia in hospitalised patients.[45] Ranitidine increases the risk of community-acquired pneumonia in adults and children.[46][47]
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 andanemia.[48]
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 withporphyria, as it may precipitate an attack.[49][50]
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 ofnecrotizing enterocolitis in very-low-birth-weight (VLBW) neonates.[51] In addition, about a six-fold increase in mortality, necrotizing enterocolitis, and infection such assepsis, pneumonia,urinary tract infection was reported in patients receiving ranitidine in a cohort analysis of 274 VLBW neonates.[52]
In June 2019,Valisure informed the USFood and Drug Administration (FDA) thatZantac-branded and generic ranitidine resulted in very high levels of NDMA in the human body "due to an inherent instability of the ranitidine molecule".[54][55]
In September 2019, the FDA acknowledged that ranitidine medicines, including some products sold under the brand name Zantac, contained anitrosamine impurity calledN-nitrosodimethylamine (NDMA), classified as a probable human carcinogen, at unacceptable levels.[12][15][56]Health Canada announced that it was assessing NDMA in ranitidine[11] and requested that manufacturers stop the distribution of ranitidine products in Canada until the NDMA levels in the products are found to be safe.[57] Health Canada announced that ranitidine drugs were being recalled by Sandoz Canada, Apotex Inc., Pro Doc Limitée, Sanis Health Inc., and Sivem Pharmaceuticals ULC.[57] TheEuropean Medicines Agency (EMA) started aEuropean Union-wide review of ranitidine medicines at the request of theEuropean Commission.[13][58]
In October 2019, the US 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 agas chromatography–mass spectrometry method to test for NDMA invalsartan andangiotensin II receptor blockers.[59] The FDA stated that it recommends using aLiquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) testing protocol to test samples of ranitidine.[60] 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.[14] The FDA provided additional guidance about using another LC-MS method based on a triple-quadrupole MS platform.[14][61]
In September 2019, Sandoz issued a "precautionary distribution stop" of all medicines containing ranitidine,[62][63] followed a few days later by a recall of ranitidine hydrochloride capsules in the United States.[64][65][66] The Italian Medicines Agency recalled all ranitidine that uses anactive pharmaceutical ingredient from Saraca Laboratories.[67][68][69] The Federal Union of German Associations of Pharmacists (Arzneimittelkommission der Deutschen Apotheker) published a list of recalled products,[70] as did theTherapeutic Goods Administration in Australia.[71]
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.[72][73] 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.[72][73] 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).[14] At the same time, it indicated that some levels of NDMA found in medicines still exceeded the agency's acceptable levels.[72][73]
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.[74]
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.[75] 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, 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.[16] The testing also showed that the level of NDMA increases as ranitidine medication ages.[16] These conditions may raise the NDMA level above the acceptable daily intake limit.[16] 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.[76]
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.[77] In September 2020, the FDA issued guidance about the control of nitrosamine impurities in human drugs.[78][79][80] An implementation plan was issued in February 2021.[81]
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".[20] Overall cancer risk also increased by 10% (p < 0.001).[20]
The FDA issued revised guidelines about nitrosamine impurities in September 2024.[82]
In October 2019, the UKMedicines and Healthcare products Regulatory Agency issued a drug alert for ranitidine "... to proactively communicate the recall to hospitals, pharmacies, dispensing practices, retailers and wholesalers in the UK."[90] This included all Zantac-branded preparations,[91][92] along with all generic preparations of ranitidine from Teva UK Limited,[93][94] Rosemont Pharmaceuticals Limited,[95] Omega Pharma Limited and Galpharm International Limited,[96] Perrigo Company plc,[97] Creo Pharma Limited and Tillomed Laboratories Limited,[98][99] OTC Concepts Ltd, Relonchem Ltd, Noumed Life Sciences Ltd, and Medreich Plc.,[100][101] Accord Healthcare,[102] Medley Pharma Limited,[103] and Medreich Plc.[104]
In October 2019,Sanofi recalled all over-the-counter Zantac in the United States and Canada,[106][107][14]Perrigo issued a worldwide recall of ranitidine,[108][14]Dr. Reddy's issued a recall of all ranitidine products in the United States,[109][14] and Novitium Pharma recalled all ranitidine hydrochloride capsules in the US.[110][14]
In December 2019, Glenmark Pharmaceutical recalled some lots of ranitidine tablets.[116]
In January 2020, Appco Pharma and Northwind Pharmaceuticals recalled some lots of ranitidine tablets and capsules.[117][118]
In February 2020, American Health Packaging recalled some lots of ranitidine tablets manufactured by Amneal Pharmaceuticals.[119]
In April 2020, the FDA requested a manufacturer's market withdrawal of ranitidine,[16][120] meaning that ranitidine products would not be available for prescription or over-the-counter sale in the US.[15][16]
A ranitidine manufacturer requested a re-examination of the decision,[8] but in December 2020, the EMA confirmed its recommendation to suspend all ranitidine medicines in the European Union.[8] The UKNational Health Service (NHS) Web site as of December 2021[update] 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.[122]
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.[123]GlaxoSmithKline,Sanofi, andTeva said they had no plans to reintroduce the drug in the EU, butAccord Healthcare considered the possible reintroduction of ranitidine.[123] 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.[123]
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.[124] 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.[124]
Metabolism: The major metabolite in the urine is ranitidineN-oxide, which represents less than 4% of the dose. Other metabolites of ranitidine include ranitidineS-oxide (1%) and desmethyl ranitidine (1%).[1]
Half-life elimination: With normal renal function, ranitidine taken orally has a half-life of 2.5–3.0 hours.[124] If taken intravenously, the half-life is generally 2.0–2.5 hours in a patient with normal kidney function and normalcreatinine clearance.[medical citation needed] In people with kidney dysfunction, the half-life may increase to 4 to 5 hours.[124]
Excretion: The primary route of excretion is the urine.[124] In addition, about 30% of the orally administered dose is collected in the urine as unabsorbed drug in 24 hours.[1]
In the elderly population, the plasma half-life of ranitidine is prolonged to 3–4 hours secondary to decreased kidney function causing decreasedclearance.[1]
In general, studies of children aged 1 month to 16 years of age have shown no significant differences in pharmacokinetic parameter values in comparison to healthy adults, when correction is made for body weight.[1]
Zantac 300 mg tablets fromGlaxoSmithKline (GSK) as sold in Australia
Ranitidine was first prepared in England as AH19065 by John Bradshaw in the summer of 1977 in theWare research laboratories ofAllen and Hanburys, part of the formerGlaxo organisation.[126][127] Its development was a response to the first in class histamine H2 receptor antagonist,cimetidine, developed bySir James Black atSmith, Kline and French, and launched in the United Kingdom asTagamet in November 1976. Both companies eventually merged asGlaxoSmithKline (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 arational drug-design process using what was by then a fairly refined model of the histamine H2 receptor andquantitative structure-activity relationships.
Glaxo refined the model further, by replacing theimidazole ring of cimetidine with afuran ring with anitrogen-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. feweradverse drug reactions), longer-lasting action, and 10 times the activity of cimetidine. Ranitidine has 10% of the affinity that cimetidine has toCYP450, so it causes fewer side effects, but other H2 blockersfamotidine andnizatidine have no CYP450 significant interactions.[128]
Ranitidine was introduced in 1981, and was the world's biggest-selling prescription drug by 1987.[129] Subsequently, it was largely superseded by the more effectiveproton-pump inhibitor (PPI) class of drugs, withomeprazole becoming the biggest-selling drug for many years.[citation needed] 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.[130][131]
In September 2019, the probablecarcinogenN-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. NDMA is a possible carcinogen and has been detected as an environmental contaminant.[132]
In 2024, ranitidine was re-approved for sale in Australia after the local sponsor of Zantac changed suppliers and tablet formulation.[29] The new formulation was demonstrated to be stable throughout its shelf life and that nitrosamines are controlled within internationally established acceptable intake limits applied to the maximum daily dose.[28]
Preparations of ranitidine products include oral tablets (75, 150, and 300 mg), effervescent tablets, and syrups,[1] and injectable solutions;[90] 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 wereschedule 2 pharmacy medicines.[medical citation needed] Larger doses and pack sizes required a prescription.[medical citation needed] In the United States, 75- and 150-mg tablets were available OTC.[133][134] In India, it is sold under multiple brand names.[47]
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^"Earliest NDMA alert".www.valisure.com.Valisure discovered the link of Zantac and its generics to the carcinogen NDMA during its routine testing of every batch of every medication, and first notified the FDA of its initial findings in June of 2019
^Palmer E (19 September 2019)."Novartis doesn't wait for FDA investigation and halts distribution of its generic Zantac".FiercePharma.Archived from the original on 20 September 2019. Retrieved20 September 2019.Novartis on Wednesday said it was stopping worldwide distribution of its generic versions of the antacid while regulators investigate the fact that the impurity NDMA has been detected in these ranitidine-based drugs.
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^"Nitrosamine impurities".European Medicines Agency (EMA). 6 August 2020.Archived from the original on 4 August 2020. Retrieved6 August 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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^Zantac in the United States is now a brand offamotidine.
^Gastric, pancreatic, and lung cancer risk increased by up to 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".[20]
^Overall cancer risk increased by 10%,p < 0.001[20]
This article incorporates text from this source, which is in thepublic domain.
