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Prescribing valsartan, losartan becomes more difficult as recalls continue
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In light of many voluntary recalls of angiotensin II receptor antagonists due to impurities, more work must be done to inform doctors and patients of the available treatment options before prescriptions are filled, according to a perspective published in The New England Journal of Medicine.
“Often, neither the prescriber nor the patient knows which manufacturer’s product will be available at the pharmacy, so physicians must rely on pharmacies to ensure that they are not distributing a recalled product,” J. Brian Byrd, MD, MSCI, assistant professor at University of Michigan in Ann Arbor, and colleagues wrote. “Health systems and physicians may therefore have limited insight into the number of patients who are affected.”
Impurities in angiotensin receptor antagonists
As Cardiology Today previously reported, the impurities, which include N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), are probable human carcinogens and have been found in generic versions of angiotensin II receptor antagonists such as valsartan, losartan and irbesartan. Another impurity — N-nitroso-N-methyl-4-aminobutyric acid (NMBA) — was also identified during the FDA’s ongoing investigation and resulted in more recalls.
The recalls led to concerns about the ability for health systems to respond to drug recalls such as these, in addition to drug manufacturing regulation, uncertain drug-dose equivalences and trust between patients and providers, Byrd and colleagues wrote.
Another finding of the FDA’s investigation is that carcinogenic impurities in angiotensin II receptor antagonists have been ingested by patients for approximately 4 years, and for every 8,000 patients who took the highest dose, there was one new cancer to be expected, according to the paper.
The affected compounds resulting in at least 20 recalls are genotoxic impurities due to their potential ability to damage DNA. The impurities may have been a result of a change in the process of how Zhejiang Huahai, a Chinese pharmaceutical company, manufacture the active ingredients.
“Zhejiang Huahai has patented a method of manufacturing tetrazoles, a chemical group present in valsartan, irbesartan and losartan and common to certain other [angiotensin receptors blockers] and additional drug products,” Byrd and colleagues wrote. “The European Medicines Agency and other experts have identified the reaction of dimethylamine and sodium nitrite under acidic conditions in synthesizing tetrazole groups as a potential source of NDMA.”
Not only have these recalls affected the availability of these therapies in pharmacies, but also their prices, according to the paper. Some manufacturers that were unaffected by the recalls have increased the price of valsartan by at least twofold.
Response to FDA reports
The response and dissemination of information related to FDA reports have been uneven, Byrd and colleagues wrote.
They added, “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 [angiotensin receptors blockers] for heart failure or chronic kidney disease.”
Response to reports from the FDA has been left to pharmacies, physicians and health care systems, which often lack the resources or infrastructure to respond to patients’ concerns in a timely manner, according to the paper.
“The [angiotensin receptors blocker] 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,” Byrd and colleagues wrote. “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 don’t.” – by Darlene Dobkowski
Disclosures: Byrd reports he received a grant from the NIH and is a co-investigator on a project funded by Apple. Please see the study for all other authors’ relevant financial disclosures.
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