Ranitidine

Ranitidine, sold under the trade name Zantac among others, is a medication that decreases stomach acid production.[3] It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome.[3] There is also tentative evidence of benefit for hives.[5] It can be taken by mouth, by injection into a muscle, or into a vein.[3]

Ranitidine
Clinical data
Pronunciation/rəˈnɪtɪdiːn/
Trade namesZantac[1] (original), and others
Other namesDimethyl [(5-{[(2-{[1-(methylamino)-2-nitroethenyl]amino}ethyl)sulfanyl]methyl}furan-2-yl)methyl]amine, ranitidine hydrochloride (JAN JP)
AHFS/Drugs.comMonograph
MedlinePlusa601106
License data
Pregnancy
category
  • AU: B1 [2]
  • US: B (No risk in non-human studies) [2]
    Routes of
    administration    		By mouth, intravenous (IV)
    Drug classHistamine H2 receptor antagonist, aka H2 blocker[1]
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only) / S2 (Pharmacy Medicine)
    • UK: POM (Prescription only) / GSL (General sales list)
    • US: ℞-only / OTC
    Pharmacokinetic data
    Bioavailability50% (by mouth)[3]
    Protein binding15%
    MetabolismLiver: FMOs, including FMO3; other enzymes
    Onset of action55–65 minutes (150 mg dose)[4]
    55–115 minutes (75 mg dose)[4]
    Elimination half-life2–3 hours
    Excretion30–70% kidney
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.060.283
    Chemical and physical data
    FormulaC13H22N4O3S
    Molar mass314.40 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Common side effects include headaches, and pain or burning if given by injection.[3] Serious side effects may include liver problems, a slow heart rate, pneumonia, and the potential of masking stomach cancer.[3] It is also linked to an increased risk of Clostridium difficile colitis.[6] It is generally safe in pregnancy.[3] Ranitidine is an H2 histamine receptor antagonist that works by blocking histamine, and thus decreasing the amount of acid released by cells of the stomach.[3]

    Ranitidine was discovered in England, UK in 1976, and came into commercial use in 1981.[7] It is on the World Health Organization's List of Essential Medicines.[8] It is available as a generic medication.[3] In 2017, it was the 48th most commonly prescribed medication in the United States, with more than 16 million prescriptions.[9][10]

    In September 2019, the carcinogen N-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls.[11][12][13][14] In April 2020, it was withdrawn from the United States market and suspended in the European Union and in Australia due to these concerns.[15][16][17][18]

    Medical uses
    • Relief of heartburn[1]
    • Short-term, and maintenance therapy of gastric and duodenal ulcers[1]
    • Ranitidine can also be given with nonsteroidal anti-inflammatory drugs (NSAIDs) to reduce the risk of ulceration.[1] Proton-pump inhibitors (PPIs) are more effective for the prevention of NSAID-induced ulcers.[19]
    • Pathologic gastro-intestinal (GI) hypersecretory conditions such as Zollinger–Ellison syndrome
    • Gastroesophageal reflux disease (GORD / GERD)
    • Erosive esophagitis
    • Part of a multi-drug regimen for H. pylori eradication to minimise the risk of duodenal ulcer recurrence
    • Recurrent post-operative ulcer
    • Upper GI bleeding
    • Prevention of acid-aspiration pneumonitis during surgery: ranitidine can be administered preoperatively to reduce the risk of aspiration pneumonia. The drug increases gastric pH, but generally has no effect on gastric volume. In a 2009, meta-analysis comparing the net benefit of proton pump inhibitors and ranitidine to reduce the risk of aspiration before anaesthesia, ranitidine was found to be more effective than proton pump inhibitors in reducing the volume of gastric secretions.[20] Ranitidine may have an anti-emetic effect when administered preoperatively.
    • Prevention of stress-induced ulcers in critically ill patients[21]
    • Used together with diphenhydramine as secondary treatment for anaphylaxis; after first-line epinephrine.[22][23]

    Dosing

    For ulcer treatment, a night-time dose is especially important; as the increase in gastric / duodenal pH promotes healing overnight, when the stomach and duodenum are empty. Conversely, for treating acid reflux, smaller and more frequent doses are more effective.

    Ranitidine was originally administered long-term for acid reflux treatment, sometimes indefinitely. However, for some, proton-pump inhibitors (PPIs) have taken over this role. In addition, in children, a fairly rapid tachyphylaxis can develop within six weeks of initiation of treatment, further limiting its potential for long-term use.[24]

    People with Zollinger–Ellison syndrome have been given very high doses without any harm.[25]

    Contraindication

    Ranitidine is contraindicated for people known to have excessive sensitivity to the drug.

    Adverse effects

    The following 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.[26] Ranitidine causes fewer central nervous system (CNS) adverse reactions and drug interactions compared with cimetidine.

    Cardiovascular

    Arrhythmias such as tachycardia, bradycardia, atrioventricular block, and premature ventricular beats have also been reported.[26]

    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.[27] Elderly patients taking H2 receptor antagonists are more likely to require B12 supplementation than those not taking such drugs.[28] H2 blockers may also reduce the absorption of drugs (azole antifungals, calcium carbonate) that require an acidic stomach.[29] 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.[30][31][32][33][34] 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 gastrointestinal tract, where sensitisation occurs. Patients who take these agents develop higher levels of immunoglobulin E against food, whether they had prior antibodies or not.[35] Even months after discontinuation, an elevated level of IgE in six percent 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.[26] Blood tests can reveal an increase in liver enzymes or eosinophilia, although in rare instances, severe cases of hepatotoxicity may require a liver biopsy.[36]

    Lungs

    Ranitidine and other histamine H2 receptor antagonists may increase the risk of pneumonia in hospitalised patients.[37] They may also increase the risk of community-acquired pneumonia in adults and children.[38]

    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.[39]

    Skin

    Rash, including rare cases of erythema multiforme, and rare cases of hair loss and vasculitis have been seen.[26]

    Precautions

    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. Ranitidine should be avoided in patients with porphyria, as it may precipitate an attack.[40][41]

    Pregnancy

    Ranitidine is rated as pregnancy category B in the United States.[2]

    Lactation

    Ranitidine enters breast milk, with peak concentrations seen at 5.5 hours after the dose in breast milk. Caution should be exercised when prescribed to nursing women.[42]

    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.[43] 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.[44] In addition, about a sixfold increase in mortality, necrotizing enterocolitis, and infection such as sepsis, pneumonia, urinary tract infection (UTI) was reported in patients receiving ranitidine in a cohort analysis of 274 VLBW neonates.[45]

    Drug tests

    Ranitidine may return a false positive result with some commercial urine drug screening kits for testing for drugs of abuse.[46]

    Cancer-causing impurities

    See also: Valsartan § recalls, and Angiotensin II receptor blocker § recalls

    In September 2019, the U.S. Food and Drug Administration (FDA) learned that some 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 low levels.[12][15][47] Health Canada (HC) 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.[48] Health Canada announced that ranitidine drugs were being recalled by Sandoz Canada, Apotex Inc., Pro Doc Limitée, Sanis Health Inc., and Sivem Pharmaceuticals ULC.[48] The European Medicines Agency (EMA) started a European Union (EU) wide review of ranitidine medicines at the request of the European Commission.[13][49]

    In September 2019, Sandoz issued a "precautionary distribution stop" of all medicines containing ranitidine.[50][51] followed a few days later by a recall of ranitidine hydrochloride capsules in the United States.[52][53][54] The Italian Medicines Agency, AIFA, recalled all ranitidine that uses an active pharmaceutical ingredient (API) from Saraca Laboratories.[55][56][57] The Federal Union of German Associations of Pharmacists (Arzneimittelkommission der Deutschen Apotheker (AMK)) published a list of recalled products.[58] The Therapeutic Goods Administration (TGA) in Australia published a list of recalled products.[59]

    In September 2019, Apotex recalled all over-the-counter (OTC) ranitidine tablets sold in the United States at Walmart, Rite Aid, and Walgreens.[60][61] Subsequently, Walmart, Rite Aid, Walgreens, and CVS removed Zantac and some generics from their shelves.[62][63][64][65][66]

    In October 2019, the U.S. Food and Drug Administration (FDA) observed that a third-party laboratory was using higher temperatures in its tests to look for nitrosamine impurities. The NDMA was generated by the added heat, but the higher temperatures were recommended for using a gas chromatography–mass spectrometry (GC/MS) method to test for NDMA in valsartan and angiotensin II receptor blockers (ARBs).[67] The FDA stated that it recommends using a liquid chromatography-high resolution mass spectrometry (LC-HRMS) testing protocol to test samples of ranitidine.[68] 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 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.[14] The FDA provided additional guidance about using another liquid chromatography-mass spectrometry (LC-MS) method based on a triple-quadrupole MS platform.[14][69]

    On 8 October 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom issued a Drug Alert for ranitidine; "to proactively communicate the recall to hospitals, pharmacies, dispensing practices, retailers and wholesalers in the UK".[70] This included all Zantac branded preparations,[71][72] along with all generic preparations of ranitidine from Teva UK Limited,[73][74] Rosemont Pharmaceuticals Limited,[75] Omega Pharma Limited and Galpharm International Limited,[76] Perrigo Company plc,[77] Creo Pharma Limited and Tillomed Laboratories Limited,[78][79] OTC Concepts Ltd, Relonchem Ltd, Noumed Life Sciences Ltd, and Medreich Plc.,[80][81] Accord Healthcare,[82] Medley Pharma Limited,[83] and Medreich Plc.[84]

    On the 15 October 2019, the Department of Health and Social Care (DHSC) of the United Kingdom issued a Supply Distribution Alert (SDA/2019/005) for all oral formulations of ranitidine.[85]

    In October 2019, Sanofi recalled all over-the-counter Zantac in the United States and Canada,[86][87][14] Perrigo issued a worldwide recall of ranitidine,[88][14] Dr. Reddy's issued a recall of all ranitidine products in the United States,[89][14] and Novitium Pharma recalled all ranitidine hydrochloride capsules in the United States.[90][14]

    In November 2019, the FDA stated that their tests have found levels of NDMA in ranitidine and nizatidine that are similar to the levels you would expect to be exposed to if you ate common foods like grilled or smoked meats.[91][92] They also stated that their simulated gastric fluid (SGF) model tests and their simulated intestinal fluid (SIF) model tests indicate that NDMA is not formed when exposed to acid in the stomach with a normal diet.[91][92] 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, they indicated that some levels of NDMA found in medicines still exceed what the FDA considers acceptable for these medicines.[91][92]

    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.[93][94][95][96][97]

    In December 2019, the FDA asked manufacturers of ranitidine and nizatidine products to expand their testing for NDMA to include all lots of the medication before making them available to consumers.[98] In December 2019, Glenmark Pharmaceutical Inc., USA recalled some lots of ranitidine tablets.[99]

    In January 2020, Appco Pharma LLC and Northwind Pharmaceuticals recalled some lots of ranitidine tablets and capsules.[100][101]

    In February 2020, American Health Packaging recalled some lots of ranitidine tablets manufactured by Amneal Pharmaceuticals.[102]

    In April 2020, the FDA requested a manufacturer's market withdrawal of ranitidine.[16][103] This means ranitidine products will not be available for new or existing prescriptions or over-the-counter (OTC) use in the U.S.[15][16] 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 temperatures the product may be exposed to during distribution and handling by consumers.[16] The testing also showed that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA.[16] These conditions may raise the level of NDMA in the ranitidine product above the acceptable daily intake limit.[16]

    In April 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the suspension of all ranitidine medicines in the EU due to the presence of low levels NDMA.[104][105][17] There is some evidence that NDMA may form from the degradation of ranitidine itself with increasing levels seen over its shelf life.[105] It is not clear whether NDMA can also be formed from ranitidine inside the body.[105] Some studies suggest that it can while others do not.[105] Given the uncertainties, the CHMP has recommended a precautionary suspension of these medicines in the EU.[105]

    In June 2020, one of the companies that markets ranitidine in the European Union requested a re-examination of the CHMP's April 2020 opinion.[105]

    In August 2020, the European Medicines Agency (EMA) provided guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines and asked them to review all chemical and biological human medicines for the possible presence of nitrosamines and to test the products at risk.[106]

    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.

    Pharmacokinetics

    Absorption: Oral: 50%

    Protein binding: 15%

    Metabolism: N-oxide is the principal metabolite.

    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 creatinine clearance.

    Excretion: The primary route of excretion is the urine. In addition, about 30% of the orally administered dose is collected in the urine as non-absorbed drug in 24 hours.

    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.[26]

    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.[26]

    History
    Zantac 300 mg tablets from GlaxoSmithKline (GSK)

    Ranitidine was first prepared in England as AH19065 by John Bradshaw in the summer of 1977 in the Ware research laboratories of Allen & Hanburys, part of the larger Glaxo organisation.[107][108] 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 would eventually become merged as GlaxoSmithKline (GSK), following a sequence of mergers and acquisitions, starting with the integration of Allen & 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 (QSAR).

    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.[109]

    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.[110][111]

    Preparations

    Preparations of ranitidine products include oral tablets (75 mg, 150 mg, and 300 mg), effervescent tablets, and syrups,[1] and injectable solutions;[70] with doses of specific ranitidine product preparations are available 'over the counter' (OTC) in various countries. In the United Kingdom (UK), only the lowest strength 75 mg tablet is available to purchase without a prescription.[1] In Australia, packs containing seven or fourteen doses of the 150 mg tablet are available in supermarkets, small packs of 150 mg and 300 mg tablets are schedule 2 pharmacy medicines. Larger doses and pack sizes require a prescription. In the United States, 75  and 150 mg tablets are available OTC. Since 2017, Zantac is marketed in the U.S. by Sanofi.[112][113]

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