Should You Be Worried About the Latest Drug Recall?
Cancer-causing chemicals in the popular heartburn drug Zantac have led to its removal from store shelves. Here’s what you need to know.
If you are one of the 75 million Americans suffering from high blood pressure, you may have been affected by the recent recalls of heart medicines found to be contaminated with cancer-causing agents, or carcinogens. Over the past 18 months, hundreds of lots of generic valsartan, losartan, and irbesartan, drugs known as angiotensin II receptor blockers (ARBs), were recalled. And in September, the FDA stated that the same type of impurity was found in medicines used to treat heartburn, including the popular over-the-counter drug Zantac. The alert has since led to yet more recalls.
To learn that a medicine you have been taking for years contains unacceptable levels of carcinogens is disturbing. So is the feeling that this has seemingly become a recurrent issue. If you are facing this circumstance, understanding some of the nuances and complexities of this issue might help you stay calm and navigate the decisions you will need to make next, such as consulting your doctor, talking to your pharmacist, checking the lists of contaminant-free drugs, and, ultimately, switching medications.
The contaminants found in the blood pressure and heartburn drugs are chemicals called nitrosamines, especially one named N-Nitrosodimethylamine (NDMA). Studies have found that NDMA can cause cancer in animals, and the compound is classified as “probably carcinogenic” to humans by the International Agency for Research on Cancer. This means that although there is enough evidence from animal studies that NDMA can lead to cancer, the evidence in humans is still limited. (Red meat and certain types of insecticides and herbicides are listed in the same category.)
These nitrosamines are also far more common than we might assume. “NDMA is in virtually all municipal water supplies to some extent,” says C. Michael White, a professor at the University of Connecticut School of Pharmacy. As it turns out, NDMA is a product of water treatment, and levels of up to 0.1 microgram per liter in drinking water are considered acceptable, according to the World Health Organization. It is even present in some of the food we eat, especially smoked products and processed grilled meat, such as bacon and burgers.
But it definitely shouldn’t be in the drugs we take, according to a public statement by Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA. How these impurities ended up there has been a question that the FDA and some manufacturers have been trying to answer for the past several months.
When it comes to the recently recalled heart meds, the FDA has determined that the problem occurred in the drugs’ manufacturing process. Either the plants used ingredients that formed NDMA under certain conditions or the impurities resulted from the reuse of materials such as solvents (substances that dissolve other chemicals) and catalysts (which precipitate chemical reactions). What may have happened, according to White, is that some manufacturing plants send the used catalysts and solvents to other facilities to be reactivated. In this process, they may be mixed with materials used by other plants that may contain traces of NDMA. When the materials come back to the drug manufacturer, these traces may end up in the drug ingredients.
He believes this type of problem could be avoided if the FDA had been inspecting foreign drug manufacturers with the same rigor directed at U.S. drugmakers. Most ARBs affected by the recent recalls are generic drugs coming from overseas or using active ingredients produced abroad.
Former FDA medical officer David Gortler, now a consultant for the group Former FDA, agrees. “Eighty percent to 90% of generic drugs come from India and China, where FDA inspections are much too lenient,” he says. “One of the reasons these countries can keep their production cost so low is because they are using low-quality, impure chemical reagents, taking shortcuts, and sidestepping globally recommended quality-control procedures in drug manufacturing.”
In response to this critique, an FDA spokesperson said in an email that the agency identifies the facilities of greatest risk, regardless of their location, and prioritizes those inspections. “The majority of facilities — both in the U.S. and overseas — are operating within the standards U.S. patients deserve,” the spokesperson added.
As for the more recent problem with the heartburn drug ranitidine, including Zantac and other generic versions, the FDA states that it is still investigating the true source of the NDMA impurities. But the main hypothesis is that the issue is not related to manufacturing, as was observed with the blood pressure drugs, but rather chemically related, says the FDA spokesperson, without specifying which chemically related problem is being investigated.
An analysis by Valisure, the pharmacy that first alerted the FDA about the presence of NDMA in ranitidine, suggests that the NDMA is the result of the “inherent instability” of ranitidine molecule.
“At this time, we do not have enough information on the root-cause analysis of any potential ranitidine impurity to be able to provide any further information,” says a spokesperson for Sanofi, the maker of Zantac. “Our evaluations are ongoing on both drug substance (active ingredient) and finished drug product.”
The danger of stopping the blood pressure treatment is perhaps the most concrete risk for people who take these meds.
Regardless of how the cancer-causing impurities got into the drugs, what people really have been wondering about is how much risk they were submitted to. “Our patients are quite tuned in to medical news, so when these stories began to come out, they obviously generated a lot of interest and concern,” says James Januzzi, MD, a member of the board of trustees for the American College of Cardiology.
At this point, it is nearly impossible to measure the burden of risk imposed on each individual patient because of the many uncertainties surrounding the contaminations. For instance, it is unknown since when the drugs have been contaminated. It is also unclear how much NDMA was in each bottle of medicine—not every single lot was tested.
While the FDA considers consuming up to 0.096 micrograms of NDMA per day to be reasonably safe, the levels of contaminants found in the recalled blood pressure medications varied greatly, reaching up to 20 micrograms in a single tablet. But it is hard to pin down what this means in terms of cancer risk. “Although there is no question that, in previous experience, the compound NDMA has been linked to cancer—and the concentrations of NDMA in the generic drugs are clearly higher than the current cutoffs that the FDA would approve—it’s been very difficult to actually find clear evidence for short-term risk for cancer,” Januzzi says.
In an effort to find numbers to translate the increased risk in the long term, the FDA estimated that if 8,000 people took the highest dose of the most contaminated batch of the valsartan drug every day for four years, there would be one additional case of cancer over the lifetime of this group of people. Given that one in every three people in the United States will have cancer in their lifetime, the additional risk has been considered relatively small.
With the ranitidine heartburn drugs, the levels of NDMA were considerably lower, of up to 0.86 micrograms per tablet, according to FDA tests. Although the amount is higher than the daily acceptable dose, it is not much different from what you would expect to be exposed to if you treated yourself with a generous portion of bacon, for example, according to the FDA.
The fact that the amount of NDMA in ranitidine pills is comparable to what could be found in food goes to show that there is no reason for panic, according to Gary LeRoy, MD, president of the American Academy of Family Physicians. “Are we going to stop grilling burgers because there are very small amounts of NDMA in them? I doubt that very much. People should just take necessary precautions, have discussions with their physicians about alternatives.”
Although it is too early to assess how these events might affect cancer rates in the long term, the recalls are already affecting the lives of those in treatment for heart conditions in other ways. “The most common reaction from patients was of frustration because we needed to switch their medication,” says Januzzi, adding that to get used to a new medicine can be quite a challenge. To make matters worse, because there were dozens of recalls over the course of several months, some had to be switched more than once.
“On individual levels, there were examples of patients that, through the frustration of having to switch from one medicine to the next, often came up with the question: Do I really need to take this medication?” Januzzi says. At the moment, the danger of stopping the blood pressure treatment is perhaps the most concrete risk for people who take these meds. Doctors emphasize that the benefits of heart medications far outweigh what is hypothesized to be a very small increase in the risk for cancer.
The good news is that there are several alternatives to the recalled medications available on the market, both for high blood pressure and for heartburn. “Fortunately, these are not decisions that patients need to take in isolation,” says Caleb Alexander, MD, co-director of the Center for Drug Safety and Effectiveness at the Johns Hopkins Bloomberg School of Public Health. “We are talking about conditions for which there are dozens of options,” he adds.
The FDA recommends that people continue taking what is left of their ARB medicine, even if that lot has been recalled, until a doctor or pharmacist gives you a replacement. To help the general public and health professionals, the FDA has been updating a list of ARB drugs that are currently available on the market. The list states which ones have been found to be nitrosamine-free and which ones the agency has yet to completely assess.
As for the heartburn medications, some alternatives that the FDA has tested and did not contain any NDMA were Pepcid (famotidine), Tagamet (cimetidine), Nexium (esomeprazole), Prevacid (lansoprazole) and Prilosec (omeprazole).
Apart from consulting a health practitioner and switching to a different medication in case yours was recalled, there is no other action you should take. There is no recommendation to screen people for NDMA exposure or for cancers potentially attributed to NDMA, Januzzi says.
One last piece of advice by drug expert Gortler is that people should find one pharmacist they trust and stick to that person for guidance. “One of the big problems is that patients lost their relationship with their pharmacist. People go to a chain drugstore — or worse, mail-order pharmacies — and are unable to choose the option of having a traditional, reliable relationship with a pharmacist.”
Drug safety expert Alexander notes that events like these massive recalls, although they may garner public attention and concern, remain rare. “I don’t think that these events suggest any far-reaching and vast fundamental deficiencies on the part of the FDA, but I do think we can learn from them in order to further improve the drug safety system in the U.S.”