Meta-Analysis

Authors: Seng Chan You, Seung In Seo, Thomas Falconer...

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Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020.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 Trial

Authors: Albert E Jergens, C Alan Schreiner, Dagmar E Frank...

The clinical course of inflammatory bowel disease (IBD) in dogs is characterized by spontaneous exacerbations and remissions, which makes assessment of disease burden difficult. The objectives of this study were to develop a scoring system for evaluation of canine IBD activity and to validate this scoring method by correlating it to objective laboratory and histologic indices of intestinal inflammation. Fifty-eight dogs with IBD were evaluated prospectively and compared to 9 disease-free control dogs. Clinical disease activity was quantified by a simple scoring system, the canine IBD activity index (CIBDAI), and compared to serum concentrations of C-reactive protein (CRP), haptoglobin (HAP), alpha-acid glycoprotein (AGP), and serum amyloid A (SAA), as well as histology scores derived from endoscopic biopsy specimens. Forty-six dogs were available for a reevaluation of the CIBDAI, CRP HAP, and AGP, and 34 dogs had repeat analysis of SAA performed after medical therapy. Serum concentrations of CRP were significantly (P < .02) increased in dogs with CIBDAI scores > or = 5 (mild disease activity or greater) compared to controls. Among IBD dogs, the CIBDAI showed good correlation (r = 0.82, P < .0001) to both histology and HAP scores, but CRP also was a strong co-correlate of disease activity. The IBD dogs showed significantly (P < .0001) decreased CIBDAI and CRP values but significantly (P < .0001) increased HAP concentrations after medical therapy compared to pretreatment values. We conclude that the CIBDAI is a reliable measure of inflammatory activity in canine IBD and that CRP is suitable for laboratory evaluation of the effect of therapy in these patients.

Topics: Aging; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Diet; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Histamine H2 Antagonists; Inflammatory Bowel Diseases; Male; Metronidazole; Prednisone; Ranitidine; Sulfasalazine

PubMed: 12774968
DOI: 10.1111/j.1939-1676.2003.tb02450.x

Authors: Jennifer A Wagner, Jennifer M Colombo

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

Review

Authors: I C Bocșan, O Sabin, D Matei...

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

Review

Authors: Fahad S Aldawsari, Yahya M Alshehry, Thamer S Alghamdi...

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

Meta-Analysis

Authors: Xiao-Jing Gu, Rui Chen, Chen-Hui Sun...

This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. Trial registration PROSPERO: CRD42016039735.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Body Weight; Female; Humans; Male; Placebos; Protective Agents; Randomized Controlled Trials as Topic; Ranitidine; Schizophrenia; Weight Gain

PubMed: 28718688
DOI: 10.1177/0300060517716783

Authors: Kyung-In Joung, Jung Eun Hwang, In-Sun Oh...

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

Authors: Anouk I Haine, Cornelia Marije A W Notenboom, Liong Vincent P Tan...

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

Randomized Controlled Trial

Authors: Shailender Madani, Ralph Kauffman, Pippa Simpson...

To characterize and compare acid suppression (pharmacodynamics) and pharmacokinetics of IV famotidine and ranitidine in critically ill children at risk for stress gastritis. Single-blind, randomized study in PICU patients 6 months to 18 years requiring mechanical ventilation with continuous gastric pH monitoring, randomized to IV famotidine 12 mg/m(2) or ranitidine 60 mg/m(2) when gastric pH < 4.0 >1 hour with serial blood sampling following first dose. Twenty-four children randomized to either famotidine (n = 12) or ranitidine (n = 12). Sixteen out of twenty-four completed both PK and PD study arms (7/12 famotidine; 4.7 ± 3.4 years; 9/12 ranitidine; 6.6 ± 4.7 years; p = 0.38). Time to gastric pH 4.0 and total time pH above 4.0 similar with no difference in pH at 6 and 12 hours (p > 0.2). No difference between drugs in clearance, volume of distribution and half-life (p > 0.05). Ratio of AUC pH to AUC drug concentration 0-12 hours after first dose was significantly greater for famotidine (0.06849 ± 0.01460 SD) than ranitidine (0.02453 ± 0.01448; p < 0.001) demonstrating greater potency of famotidine. pH lowering efficacy of both drugs is similar. Greater potency of famotidine may offer clinical advantage due to lower drug exposure and less frequent dosing to achieve same pH lowering effect.

Topics: Child; Child, Preschool; Critical Illness; Famotidine; Female; Gastric Acid; Gastric Acidity Determination; Gastritis; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Infant; Infusions, Intravenous; Ranitidine; Single-Blind Method

PubMed: 24258773
DOI: 10.1002/jcph.219

Observational Study

Authors: Chun-Hsiang Wang, I-I Chen, Chung-Hung Chen...

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