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JAMA Network Open Sep 2023Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern.
OBJECTIVE
To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs.
DESIGN, SETTING, AND PARTICIPANTS
This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021.
EXPOSURE
The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine).
MAIN OUTCOMES AND MEASURES
The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality.
RESULTS
Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration.
CONCLUSIONS AND RELEVANCE
In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.
Topics: Female; Humans; Middle Aged; Male; Ranitidine; Cohort Studies; Thyroid Neoplasms; Histamine H2 Antagonists; Skin Neoplasms
PubMed: 37725377
DOI: 10.1001/jamanetworkopen.2023.33495 -
Clinical and Translational Science Jul 2020Ranitidine has been the topic of recent media reports. Current findings, confirmed by the US Food and Drug Administration, indicate that some ranitidine products contain...
Ranitidine has been the topic of recent media reports. Current findings, confirmed by the US Food and Drug Administration, indicate that some ranitidine products contain a substance that may be carcinogenic. Providers and patients require additional information on the risks of continuing therapy vs. the benefits of the medication. This article comments on what is currently known about the evolving situation of elevated N-nitrosodimethylamine levels in ranitidine and the limits of the existing information to assess best practices.
Topics: Carcinogenesis; Dimethylnitrosamine; Drug Contamination; Drug Recalls; Drug Stability; Gastroesophageal Reflux; Humans; Information Dissemination; Mass Media; Neoplasms; Ranitidine; United States; United States Food and Drug Administration
PubMed: 32107850
DOI: 10.1111/cts.12753 -
European Review For Medical and... Oct 2020H2 receptors' antagonists (H2RA) are widely used drugs and they are generally well-tolerated. Ranitidine hypersensitivity reactions (HR) are rarely reported. The article... (Review)
Review
H2 receptors' antagonists (H2RA) are widely used drugs and they are generally well-tolerated. Ranitidine hypersensitivity reactions (HR) are rarely reported. The article emphasizes the importance of recognizing ranitidine as a cause of anaphylaxis and the advantages and limits of allergological evaluation to establish a positive diagnose. We reviewed a series of published cases of ranitidine-induced hypersensitivity reactions, starting from a clinical case presentation. Moreover, we analyzed the ranitidine related adverse events in the Eudravigilance European database of adverse reactions. Most of the allergic reactions induced by ranitidine are type I HR with immediate onset after exposure, with variable clinical presentation. But in a few cases, there were also described delayed reactions, some after occupational exposure. The article underlines the importance of allergy evaluation to avoid future contact with the drug to reduce the risk of more severe reactions. The suspected reactions should be reported, allowing pharmacovigilance systems to analyse them and to establish further recommendations for clinicians.
Topics: Drug Hypersensitivity; Histamine H2 Antagonists; Humans; Ranitidine; Rhinitis, Allergic; Skin Tests
PubMed: 33155242
DOI: 10.26355/eurrev_202010_23443 -
Journal of Food and Drug Analysis Mar 2021Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA)... (Review)
Review
Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA) contamination in ranitidine products, there have been many recalls and registration suspensions. Here, we revise the literature information confirming ranitidine association with NDMA. Then, we highlight the documented mechanisms for NDMA release from ranitidine. In addition, the stability issue for this medicine is discussed. After that, we review and discuss the results of the United States Food and Drug Administration and the Australian Therapeutic Goods Administration laboratory testing of ranitidine products and the detected NDMA levels. Finally, the case of NDMA generation in Angiotensin II Receptor Blockers (ARBs) and ranitidine were compared in an attempt to address the circumstances leading to the current contamination.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Australia; Dimethylnitrosamine; Pharmaceutical Preparations; Ranitidine; United States
PubMed: 35696227
DOI: 10.38212/2224-6614.1133 -
Scientific Reports Dec 2022N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people...
N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people treated with ranitidine, we conducted a cohort study using the National Health Insurance Service-National Sample Cohort data (2002-2015) of South Korea. Patients were aged 40 or above as of January 2004 and began receiving ranitidine or other histamine-2 receptor antagonist (H2RA), active comparator, without a history of H2RAs prescription during the prior 2-years. The lag time was designated up to 6 years. The outcomes were an overall incident cancer risk and the risk of major single cancers during the follow-up. The association between ranitidine use and cancer risk was examined by Cox regression model. After exclusion and propensity score matching, 25,360 patients were available for analysis. The use of ranitidine was not associated with the overall cancer risk and major individual cancers [overall cancer: incidence rate per 1000 person-years, 2.9 vs 3.0 among the ranitidine users and other H2RAs users, respectively; adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for all cancers, 0.98 (0.81-1.20)]. The higher cumulative exposure to ranitidine did not increase the cancer risk. Given the insufficient follow-up period, these findings should be interpreted carefully.
Topics: Humans; Ranitidine; Dimethylnitrosamine; Cohort Studies; Neoplasms; Republic of Korea
PubMed: 36575247
DOI: 10.1038/s41598-022-26691-0 -
Pharmacology Research & Perspectives Aug 2022Paclitaxel is a commonly used chemotherapeutic agent. To minimize the risk of hypersensitivity reactions (HSRs), which occur in approximately 16-42% of patients,...
Paclitaxel is a commonly used chemotherapeutic agent. To minimize the risk of hypersensitivity reactions (HSRs), which occur in approximately 16-42% of patients, premedication with dexamethasone, clemastine, and ranitidine was standard of care. As of October 2019, ranitidine is no longer available. We compared the risk of HSRs to paclitaxel with and without premedication with ranitidine, hypothesizing that the incidence of HSRs to paclitaxel will be similar. In this retrospective cohort study, all first-time paclitaxel users in the Groene Hart Hospital were included from January 2019 to August 2020. The primary outcome was the incidence of HSRs, using a Student's t-test. One-hundred and eight patients who were first-time users of paclitaxel in the Groene Hart Hospital met the inclusion criteria. Most patients were treated for breast or ovarian cancer, followed by lung cancer. Analysis of all 836 paclitaxel administrations was performed. Following 349 administrations with ranitidine as premedication, eight HSRs occurred (2.3%), while following 487 administrations without ranitidine, 12 HSRs occurred (2.5%), p-value of 0.87. An additional analysis on the occurrence of HSRs per patient was performed: 45 patients received premedication in the form of ranitidine, of which eight patients (17.8%) had a HSR. Sixty-three patients did not receive premedication in the form of ranitidine, of whom 10 (15.8%) had a HSR, p-value of .80. In conclusion, we found no difference in the incidence of HSRs during paclitaxel infusions between patients who received ranitidine as premedication versus those who did not.
Topics: Antineoplastic Agents, Phytogenic; Dexamethasone; Drug Hypersensitivity; Humans; Incidence; Paclitaxel; Ranitidine; Retrospective Studies
PubMed: 35811355
DOI: 10.1002/prp2.985 -
International Journal of Biological... 2020Trimethylamine N-oxide (TMAO) leads to the development of cardiovascular and chronic kidney diseases, but there are currently no potent drugs that inhibit the production...
Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota.
Trimethylamine N-oxide (TMAO) leads to the development of cardiovascular and chronic kidney diseases, but there are currently no potent drugs that inhibit the production or toxicity of TMAO. In this study, high-fat diet-fed ApoE-/- mice were treated with finasteride, ranitidine, and andrioe. Subsequently, the distribution and quantity of gut microbiota in the faeces of the mice in each group were analysed using 16S rRNA sequencing of the V3+V4 regions. Pathological examination confirmed that both ranitidine and finasteride reduced atherosclerosis and renal damage in mice. HPLC analysis also indicated that ranitidine and finasteride significantly reduced the synthesis of TMAO and the TMAO precursor delta-Valerobetaine in their livers. The 16S rRNA sequencing showed that all 3 drugs significantly increased the richness and diversity of gut microbiota in the model mice. Bioinformatic analysis revealed that the faeces of mice treated with ranitidine and finasteride, had significant increases in the number of microbes in the families g_Helicobacter, f_Desulfovibrionaceae, ASF457, and g_Blautia, whereas the relative abundances of microbes in the families sp._IPC1-8 and g_Bacteroides were significantly reduced. The microbiota metabolic pathways, such as nucleotide and cofactor and vitamin metabolism were also significantly increased, whereas the activities of metabolic signalling pathways related to glycan biosynthesis and metabolism and cardiovascular diseases were significantly reduced. Therefore, our study indicates that in addition to their known pharmacological effects, ranitidine and finasteride also exhibit potential cardiovascular and renal protective effects. They inhibit the synthesis and metabolism of TMAO and delay the deposition of lipids and endotoxins through improving the composition of the gut microbiota.
Topics: Animals; Atherosclerosis; Chromatography, High Pressure Liquid; Finasteride; Gastrointestinal Microbiome; Kidney; Kidney Diseases; Male; Methylamines; Mice; RNA, Ribosomal, 16S; Ranitidine
PubMed: 32071549
DOI: 10.7150/ijbs.40934 -
International Journal of Environmental... Sep 2022N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and... (Observational Study)
Observational Study
N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and cancer emergence over time. Using the Taiwan National Health Insurance Research Database, a population-based cohort study was conducted. A total of 55,110 eligible patients who received ranitidine between January 2000 and December 2018 were enrolled in the treated cohort. We conducted a 1:1 propensity-score-matching procedure to match the ranitidine-treated group with the ranitidine-untreated group and famotidine controls for a longitudinal study. The association of ranitidine exposure with cancer outcomes was assessed. A multivariable Cox regression analysis that compared cancer risk with the untreated groups revealed that ranitidine increased the risk of liver (hazard ratio (HR): 1.22, 95% confidence interval (CI): 1.09-1.36, < 0.001), lung (HR: 1.17, CI: 1.05-1.31, = 0.005), gastric (HR: 1.26, CI: 1.05-1.52, = 0.012), and pancreatic cancers (HR 1.35, CI: 1.03-1.77, = 0.030). Our real-world observational study strongly supports the pathogenic role of NDMA contamination, given that long-term ranitidine use is associated with a higher likelihood of liver cancer development in ranitidine users compared with the control groups of non-ranitidine users treated with famotidine or proton-pump inhibitors.
Topics: Cohort Studies; Dimethylnitrosamine; Famotidine; Humans; Longitudinal Studies; Neoplasms; Proton Pump Inhibitors; Ranitidine
PubMed: 36231768
DOI: 10.3390/ijerph191912469 -
The Cochrane Database of Systematic... Mar 2012Urticaria is a common skin disease characterised by itching weals or hives, which can occur almost anywhere on the body. There are a number of different subtypes and a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Urticaria is a common skin disease characterised by itching weals or hives, which can occur almost anywhere on the body. There are a number of different subtypes and a range of available treatment options. There is lack of agreement on the efficacy of H2-receptor antagonists used in the treatment of urticaria.
OBJECTIVES
To assess the safety and effectiveness of H2-receptor antagonists in the treatment of urticaria.
SEARCH METHODS
We searched the following databases up to 7 October 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2011, Issue 4), MEDLINE (from 2005), EMBASE (from 2007), and LILACS (from 1982). We also searched online trials registries for ongoing trials.
SELECTION CRITERIA
Randomised controlled trials of H2-receptor antagonists in people with a clinical diagnosis of urticaria of any duration or of any subtype. Studies including H1-antihistamines for chronic urticaria are the topic of a separate Cochrane review; thus, they were not included in this review.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trial quality and extracted and analysed data.
MAIN RESULTS
Four studies of a relatively small size, involving 144 participants, were included in this review. A combination of ranitidine with diphenhydramine was more effective at improving the resolution of urticaria than diphenhydramine administered alone (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.07 to 2.36). Although there was a similar improvement in itching, weal size, and intensity, cimetidine provided no statistically significant greater overall improvement in symptoms of urticaria when compared to diphenhydramine. However, a combination of these medications was more effective than diphenhydramine alone (RR 2.02, 95% CI 1.03 to 3.94). Adverse events were reported with several of the interventions, i.e. ranitidine and diphenhydramine, causing drowsiness and sedation, but there was no significant difference in the level of sedation from baseline with either famotidine or diphenhydramine.
AUTHORS' CONCLUSIONS
The very limited evidence provided by this review was based on a few old studies of a relatively small size, which we categorised as having high to unclear risk of bias. Thus, at present, the review does not allow confident decision-making about the use of H2-receptor antagonists for urticaria. Although some of these studies have reported a measure of relief of symptoms of urticaria and rather minimal clinical improvement in some of the participants, the evidence was weak and unreliable. We have emphasised the lack of precision and limitations in the reported data where appropriate in this review.
Topics: Cimetidine; Diphenhydramine; Drug Therapy, Combination; Famotidine; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Randomized Controlled Trials as Topic; Ranitidine; Urticaria
PubMed: 22419335
DOI: 10.1002/14651858.CD008596.pub2 -
PloS One 2021Ranitidine HCl, a selective, competitive histamine H2-receptor antagonist with a short biological half-life, low bioavailability and narrow absorption window, is an...
Ranitidine HCl, a selective, competitive histamine H2-receptor antagonist with a short biological half-life, low bioavailability and narrow absorption window, is an ideal candidate for gastro-retentive drug delivery system (GRDDS). Controlled release with an optimum retentive formulation in the upper stomach would be an ideal formulation for this drug. The aim of the present study was therefore to develop, formulate and optimize floating, bioadhesive, and swellable matrix tablets of ranitidine HCl. The matrix tablets were prepared using a combination of hydroxypropyl methylcellulose (HPMC) and sodium carboxymethyl cellulose (NaCMC) as release retarding polymers, sodium bicarbonate (NaHCO3) as gas generating agent and microcrystalline cellulose (MCC) as direct compression diluent. Central composite design (CCD) was used to optimize the formulation and a total of thirteen formulations were prepared. Concentration of HPMC/NaCMC (3:1) (X1) and NaHCO3 (X2) were selected as independent variables; and floating lag time (Y1), bioadhesive strength (Y2), swelling index at 12 h (Y3), cumulative drug release at 1 h (Y4), time to 50% drug release (t50%) (Y5) and cumulative drug release at 12 h (Y6) were taken as the response variables. The optimized batch showed floating lag time of 5.09 sec, bioadhesive strength of 29.69 g, swelling index of 315.04% at 12 h, t50% of 3.86 h and drug release of 24.21% and 93.65% at 1h and 12 h, respectively, with anomalous release mechanism. The results indicate that sustained release matrix tablet of ranitidine HCl with combined floating, bioadhesive and swelling gastro-retentive properties can be considered as a strategy to overcome the low bioavailability and in vivo variation associated with the conventional ranitidine HCl tablet.
Topics: Cellulose; Delayed-Action Preparations; Drug Liberation; Ranitidine; Sodium Bicarbonate; Tablets
PubMed: 34170952
DOI: 10.1371/journal.pone.0253391