Hypertension Hot Potato — Angiotensin-Receptor Blocker Recalls
- Authors:
- Byrd JB, Chertow GM, Bhalla V.
- Citation:
- Hypertension Hot Potato — Anatomy of the Angiotensin-Receptor Blocker Recalls. N Engl J Med 2019;380:1589-1591.
The following are key points to remember from this perspective on the angiotensin-receptor blocker (ARB) recalls:
- On January 25, 2019, the Food and Drug Administration (FDA) released a statement to the public regarding the large-scale voluntary recall of products containing angiotensin-receptor blockers (ARBs). On the same day, the Wall Street Journal reported that as many as 2 million patients were exposed. Three nitrosamines that are probable carcinogens were identified in valsartan, irbesartan, and losartan from two factories located in China and India and distributed by specific manufacturers, which resulted in 20 recalls.
- The compounds are known as genotoxic impurities because they have the potential to damage DNA. The FDA found N-nitrosodimethylamine (NDMA) in affected valsartan products in concentrations ranging from 300 to 20,000 ng per tablet. In December 2018, the FDA announced that it had set interim acceptable limits of NDMA (96 ng/day) and N-nitroso-N-diethylamine (NDEA) (26.5 ng/day), which would estimate to confer a 1 in 100,000 risk of causing cancer after 70 years of exposure.
- FDA officials believe that US patients have been ingesting ARBs containing carcinogenic impurities for approximately 4 years; they estimate that for every 8,000 patients taking the highest dose of an affected product for the full 4 years, one new cancer above the background incidence would be expected. More than 61 million prescriptions were written for valsartan, irbesartan, or losartan in the United States in 2016. Because often a few manufacturers of the active pharmaceutical ingredients supply a large number of the companies who make the pills and these companies may sell them to another for repackaging, the process of identifying who has taken products of concern is very complex.
- Patients and clinicians hear about recalls through the news media, social media, pharmacies, health care providers, or friends. The public may hear about a recall of a “hypertension drug,” but not know the specific product and manufacturer. Thus, recalls may trigger unnecessary concern among many people receiving antihypertensive therapy — and may be ignored by people who take ARBs for heart failure or chronic kidney disease. The burden of response has fallen to clinicians, pharmacies, and health care systems, most of which lack the infrastructure or resources to respond promptly to patients’ concerns.
- Switching patients from one ARB to another presents the problems of selecting one that “might be safe,” lack of equipotent doses using a different formulation, and rarely are there comparisons of drugs within the class. To avoid hyperkalemia, hypotension, undertreated hypertension, and harmful drug–drug interactions, costly additional laboratory tests and patient communications or visits are required to assess safety and efficacy. As recalls emerged slowly, some clinicians switched patients from a drug that was recalled early (valsartan) to one that was recalled later (irbesartan or losartan), further increasing the frustration to all.
- The authors summarized the needs as follows: the ARB recalls provide an opportunity for the FDA, pharmacies, and health systems to evaluate all aspects of the response, from timely identification of potential impurities, to removal of recalled lots, to helping patients navigate the complexities of prescription changes, to monitoring them for adverse events after these changes are made. We can hope that efforts of the FDA and other regulatory agencies will prevent the need for future recalls, but health systems and care providers should prepare themselves for what will happen if they do not.
Note: The senior author Dr. Brian Byrd sent the following FDA website listing ARBs free of impurities: https://www.fda.gov/Drugs/DrugSafety/ucm634620.htm.
Keywords: Angiotensin Receptor Antagonists, Antihypertensive Agents, Biphenyl Compounds, Carcinogens, Diethylamines, Dimethylnitrosamine, Drug Interactions, Health Personnel, Heart Failure, Hyperkalemia, Hypertension, Hypotension, Losartan, Neoplasms, Nitrosamines, Primary Prevention, Receptors, Angiotensin, Renal Insufficiency, Chronic, Social Media
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