Ranitidine – What Happened and What Do We Learn?

Oct 31, 2019

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

What happened?

Ranitidine is a drug used for treating various gastric disorders including peptic ulcer disease, gastroesophageal reflux disease, Zollinger–Ellison syndrome and heartburn.

Ranitidine was developed in the 1970s and commercialized in 1981. It was the second H2 blocker to hit the market in many countries. By 1988 it was the world’s top selling drug with sales over $1 billion. Generics arrived in 1987 after the patent ran out in the US and it went over the counter (OTC) starting in 2014. The ranitidine market was valued at over $400 million in 2018. It is available in several doses and routes of administration.

Ranitidine is nearly 40 years old and the safety profile has been mild and has been felt to be well established. Until it wasn’t.

On September 13, 2019 FDA announced it was reviewing the safety of ranitidine. On September 23, Dr. Janet Woodcock head of FDA’s CDER announced that an impurity called N-nitrosodimethylamine (NDMA) was found at low levels in some ranitidine samples tested. NDMA is classified as a probable human carcinogen and is a known environmental contaminant found in water and food.

This followed a major recall of the anti-hypertensive valsartan due to NDMA found in some samples. Hence NDMA is a focus of interest in other products.

Starting on September 24, several pharma companies and retailers stopped selling ranitidine or voluntarily withdrew the products from the market.

The amounts found in the drugs were low and FDA stated: “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.” FDA continued the evaluation of NDMA.

On October 2, FDA noted that the testing method for NDMA in valsartan involved heating the material which, itself, could produce NDMA. The agency requested that companies test ranitidine using a different methodology (which FDA described) that did not involve heating. FDA added that, using its limited testing of ranitidine using the preferred methodology, they found unacceptable levels of NDMA.

Three weeks later FDA issued another more readily available method that could be used for testing for NDMA in ranitidine. Several other companies recalled all prescription and OTC ranitidine.

FDA suggested that patients speak to their health care providers about whether to stop ranitidine or switch to alternative therapies. For OTC patients, FDA advise considering the use of other H2 blockers or PPI’s which do not contain NDMA if they wished to change. The FDA has a website which it frequently is updating with the latest information.

The EMA has also reacted. In mid-September they sent out a notice to marketing authorization holders (MAHs) to take steps to investigate their products that might contain NDMA and other nitrosamines. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf

They requested: the companies to:

  • Evaluate possibility of nitrosamines being present in every concerned medicine within 6 months
  • Prioritise evaluations, starting with medicines more likely to be at risk of containing nitrosamines
  • Take into account findings from CHMP’s review of sartans
  • Notify authorities of outcome of risk evaluations
  • Test products at risk of containing any nitrosamines
  • Immediately report detection of nitrosamines to authorities
  • Apply for necessary changes to marketing authorisations to address nitrosamine risk
  • Complete all steps within 3 years, prioritising high risk products

Not surprisingly, many countries and companies around the world began withdrawing ranitidine from their markets.

Questions remain however. There is some controversy over whether the NDMA is a contaminant or a breakdown product of an unstable molecule. In other words, does Ranitidine break down into NDMA? See: https://www.medpagetoday.com/gastroenterology/gerd/82550

In addition, it is not clear yet whether the levels found are clinically significant.

So this issue is ongoing but it is likely that ranitidine will be off the market or, if still on the market, rarely used. Drugs in this situation rarely come back even if exoneration occurs. Since there are many alternatives to ranitidine (other H2 blockers and PPIs) without NDMA, there seems little reason to continue use of ranitidine.

What do we learn?

There are several important points to take from this still ongoing signal and safety issue.

  • Safety issues and SAEs can occur very late after a drug is introduced

Safety issues can occur at anytime during the lifecycle of a drug. There are many reasons for this including other drugs (legal or illicit) that interfere or interact, new routes of administration, new populations taking the drug, increases in patients using the drug (e.g. after going OTC), new diseases “popping up”, new diagnostic modalities allowing the discovery of previously unthought-of contaminants, toxins, changes in manufacture, new excipients and additives, quality changes etc. and other difficult to discern causes.

The chart below illustrates this point very dramatically. This chart was prepared by FDA and shows safety-related drug label changes as a function of time after first introduction of the drug to the US market. It covers label changes made from October 2002 to August 2005 (about 33 months) for 1601 drugs. On the x-axis is the time in years post-approval of the drug and on the y-axis the number of label changes. Several points are noteworthy:

  • Few changes occurred in the first year of use
  • A large plurality of the changes occurred in the first 9 years after introduction with the peak being around 5 years
  • Changes then tapered down over the next 20 years
  • Changes occurred as late as 50 to 60 years after first introduction!
  • Changes included black box warnings, adverse reactions, warnings, precautions and contraindications
  • Most of the changes for the first decade were adverse reactions and precautions but all the changes were seen over the decades. Black box warnings could occur many decades after introduction.

Several conclusions can be drawn here.

  • We need continuous and continuing safety surveillance of drugs – even very old drugs and those presumed to be quite safe (e.g. drugs that went OTC).
  • The safety profile of a drug is never fully known. We cannot become complacent. A high level of suspicion must be maintained particularly with odd and unexpected safety signals and SAEs.
  • Late appearing safety issues can be totally out of the blue, totally unexpected. Who would have suspected that diethylstilbesterol (DES) would cause vaginal cancer in the offspring of pregnant women who took the drug during pregnancy.
  • There should widely shared, complete databases of SAEs, AEs and safety issues.
  • Everytime a patient takes a drug, it is an n=1 experiment. Something can happen.

So what happened with ranitidine? The investigations are ongoing, but several things seem to be evident now.

  • Nitrosamines and NDMA were not suspected or even an issue in the 1970s when the drug was first developed and in the decades of marketing.
  • The technology to discover low levels of NDMA probably did not exist then and, even now, the FDA has had to clarify the preferred methodology for detection. The controversy remains.
  • It is unclear if the NDMA is an artifact of testing or is produced by metabolism of ranitidine in the body.
  • It is by no means clear that NDMA, if present at these levels, is harmful. There do not appear to be any AEs or SAEs reported. As the nitrosamines are carcinogens, we would need some long term studies (epidemiology) to determine if there are any apparent associations of malignancy and ranitidine.

There are also some longer-term implications. It seems that the discovery of this issue in valsartan triggered the look at ranitidine. The EMA and presumably the FDA is looking at other drugs that might contain NDMA. Will we now see several other drugs in this situation? This is not a public health problem for ranitidine as several other alternatives without any NDMA. Will we now see several other drugs in this situation? This is not a public health problem for ranitidine as several other alternatives without any NDMA issues exist for patients. But what about drugs that have no adequate replacements? Are we opening a can of worms?

Finally, from a commercial point of view, it is highly unlikely that ranitidine, even if kept on the market will ever be widely used again. Even if the drug is somehow “totally exonerated” few will use it if good alternatives are available. One also expects lawsuits to start.

So, once again we see that drug safety and pharmacovigilance are fascinating, frightening and fraught fields.

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