While famotidine (the new ingredient in Zantac 360) acts similar to ranitidine (the old ingredient), there is no longer N-nitrosodimethylamine (NDMA) detectable which was a concern as a potential cancer risk. It comes in two different strengths (10 mg and 20 mg).
My take: In my view, it is a bad decision to allow Zantac to be relaunched with this new ingredient; this is like allowing some hot dogs to be sold as hamburgers.
Methods: The authors utilized the Explorys database (IBM, New York) which is a source of longitudinal real world deidentified data collected from electronic medical records from over 40 health systems nationwide (65 million) from 1999-2019.
1.62 million users of ranitidine were identified, 3.37 million users of famotidine, and 59.63 million individuals who did not use either H2 blocker.
Users of ranitidine and famotidine when compared to the general population, and users of famotidine when compared to ranitidine, were older (p<0.001), smokers (p<0.001), obese (p<0.001), had liver cirrhosis (p<0.001), a history of alcohol use (p<0.001), and a family history of cancer (p<0.001).
Ranitidine users had a numerically lower risk for GI cancers (liver, stomach, esophageal, colorectal, and pancreatic cancers) compared to famotidine. Among subjects without risk factors including smoking, obesity, alcohol use, family history, cirrhosis and GERD, the risk of all cancers (excluding non-melanoma skin cancers) was identical for ranitidine and famotidine (OR=1, CI=1.01-1.02, p=0.001).
My take: This large database did NOT identify an increased risk of malignancy with ranitidine over a 20 year span. Despite this, I don’t expect that the FDA will reverse its recall.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition
While the study suggested more rapid clearance of SARS-CoV-2 virus at day 6 in those treated with hydroxychloroquine/azathioprine (n=20), the authors excluded 6 from the treatment group including one patient who died and three who were transferrred to the ICU. In addition, the treatment group had a lower viral load at the start of treatment.
Other viral infections, including influenza, have also had in vitro data suggesting efficacy with hydroxychloroquine but this did not translate into clinical efficacy in clinical trials.
“The hydroxychloroquine shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival.”
A Di Giorgio et al (J Pediatr 2020; 218: 121-9) provide long-term data (median f/u of 14.5 years) from a retrospective review on 83 children with autoimmune hepatitis (AIH, n=54)/autoimmune sclerosing cholangitis (ASC, n=29). Median age at presentation, between 2000-2004 was 12.1 years
29% had histologic evidence of cirrhosis at diagnosis
At a median followup of 14.5 years, 99% were alive, 11 underwent transplantation. In those who underwent transplantation, 5-year and 10-year survival was 95% and 88% respectively.
ASC was associated with IBD in 73% of cases, compared to 33% of AIH patients.
Treatment: 95% of all patients had normalization with transaminases with immunosuppressive treatment (most commonly azathioprine with prednisone 2.5-5 mg/day). ASC patients also received ursodeoxycholic acid 15-20 mg/kg/day.
Immunologic remission: 47% achieved immunologic remission which required normal IgG levels and negative/low ANA/SMA <1:20 in addition to normal transaminases.
Liver transplantation was needed in 28% of ASC compared to 9% of AIH patients; overall, 83% experienced 15-year transplant-free survival. Median age of those needing a liver transplant was 19.3 years.
Immunosuppression withdrawal was attempted in 12 patients after a median of 4.5 years of treatment. 9 were able to stay off immunosuppression.
An increase in case frequency was noted during the last 4 decades at this center, from 3.6 cases/year to 5.4 case/year.
Four patients had isolated infrequent autoantibodies of anti-SLA (n=3) nad antiLC-1 (n=1). SLA =liver soluble antigen, LC-1 =liver cytosol antibody type 1. Thus, in those with suspected AIH/ASC, testing for these autoantibodies is important in ~5%.
Pathology: 18% did not have classical features of interface hepatitis. Instead, some had lymphocytic/lymphoplasmocytic infiltrate without spillover into the parenchyma.
Progression from AIH to ASC occurred in 3 patients on followup cholangiography.
ASC would have been overlooked in 41% if one relied on pathology alone -reaffirming need for biliary imaging.
My take: This article has a number of useful points and with an overarching message that long-term outcomes are good for children with AIH/ASC.
B Freiberg et al.2020; 218: 221-31. This grand rounds describes the extensive workup of a 12 year old with splenomegaly ultimately due to splenic vein stenosis. The report provides a nice review of hepatologic, hematologic, infectious, and other causes of splenomegaly as well as a work-up algorithm. (look for everything).
Initial evaluation per algorithm should start with CBC/d, retic, blood smear, liver biochemistries, GGT, coags, EBV VCA IgM, CMV IgM, Parvovirus IgM, and complete abdominal ultrasound with doppler.
Hepatologic causes of splenomegaly include the following:
storage disease and inborn errors of metabolism which includes lipidosis (Gaucher, Niemann-Pick), mucopolysaccharidoses, defects in carbohydrate metabolism (galactosemis, hereditary fructose intolerance), sea-blue histiocyte syndrome
The U.S. Food and Drug Administration today announced it is requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately. This is the latest step in an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac). The agency has determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. As a result of this immediate market withdrawal request, ranitidine products will not be available for new or existing prescriptions or OTC use in the U.S.
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. 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. These conditions may raise the level of NDMA in the ranitidine product above the acceptable daily intake limit.
The recent FDA safety alert might be causing concern among your patients about their heartburn treatment.
The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, that were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.
The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential impact on patients who have been taking ranitidine.
With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available.
TALKING TO YOUR PATIENTS
The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that:
Ranitidine is an H2 blocker (antihistamine) — available OTC and in prescription strength — used to prevent and relieve heartburn associated with acid ingestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.
Not all ranitidine medicines marketed in the U.S. are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.
It might be prudent to hold off taking Zantac until a final FDA conclusion.
Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.
Recently, there have been concerns about zantac (ranitidine). NASPGHAN has made the following preliminary recommendations:
NASPGHAN has been in conversation with the FDA and would like to offer the following language for you/your office/your division and your patients/parents.
The U.S. Food and Drug Administration has learned that some ranitidine medicines, including some products commonly known as the brand-name drug Zantac, contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. The FDA has been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year, and when it discovered unacceptable levels of nitrosamines the ARBs have been recalled.
The FDA is evaluating whether the low levels of NDMA in ranitidine pose a risk to patients and will post that information when it is available.
It is important to note that although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.
The agency is working with international regulators and industry partners to determine the source of this impurity in ranitidine. The agency is examining levels of NDMA in ranitidine and evaluating any possible risk to patients. The agency will provide more information as it becomes available.
The FDA is not calling for individuals to stop taking ranitidine at this time; however, patients taking prescription ranitidine who wish to discontinue use should talk to their health care professional about other treatment options. People taking OTC ranitidine could consider using other OTC medicines approved for their condition. There are multiple drugs on the market that are approved for the same or similar uses as ranitidine.
Previously, this blog has noted an association between ranitidine usage and necrotizing enterocolitis (NEC) (see below). Now, another study provides insight into a potential mechanism (JPGN 2013; 56: 397-400).
This study examined the fecal microbiota in 76 premature infants who were enrolled in a case-controlled, cross-sectional study. 25 infants receiving H2-blockers were compared with 51 matched controls.
Results: microbial diversity was lower, relative abundance of Proteobacteria was increased, and Firmicutes was decreased in the stools of infants receiving H2-blockers.
While this study did not specifically examine the effect of H-2 blockers on NEC (no infants in this study had NEC), there are multiple reasons why the findings should be a cause for concern.
Gastric acidity acts as a natural defense against bacterial growth and H-2 blockers (as well as proton pump inhibitors) inhibit this defense
Previous studies have shown an association between NEC and with diminished microbial diversity/increased Proteobacteria. Proteobacteria include well-known pathogens like Klebsiella, Shigella, Escherichia coli, and Citrobacter.