The Angiotensin Receptor Blocker (ARB) recalls have been an issue of concern for healthcare practitioners and patients since the first batches of valsartan were recalled back in July 2018. The first recalled lot of valsartan was from Zhejiang Huahai Pharmaceutical Co. Ltd., in Linhai, Taizhou Zhejiang China.¹ ARBs previously received negative press almost a decade ago, when news stations reported ARB-associated cancer following a Lancet publication in 2010.^2,3 It has since been shown that ARBs and Angiotensin Converting Enzyme inhibitors (ACEI) are unlikely to cause any type of cancer.⁴ The current recall is related to impurities found in ARB formulations.

Many manufacturers have recalled their products involuntarily or voluntarily, based on reports from the Food and Drug Administration (FDA), although the total volume of recalled lots is small.⁵ Certain manufacturers have recalled irbesartan due to the possibility that their product may be contaminated.¹ The two initially identified impurities involved were N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA). NDMA and NDEA are categorized as group 2A carcinogens (Table 1). Since July 2018, there has been a new impurity identified that crossed safety thresholds. N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) has been identified in certain losartan lots in March 2019. Most recently, Valisure LLC conducted its own testing of valsartan batches and found a fourth group 2A carcinogen, dimethylformamide (DMF). The company created a citizen petition that was sent to the FDA in June 2019.⁶ To be considered a Group 2A carcinogen, at least two of the following criteria are required: ^7,8

Table 1. The International Agency for Research on Cancer (IARC) Carcinogenic Classifications
Classification	Definition
Group 1	Carcinogenic to humans
Group 2A	Probably carcinogenic to humans
Group 2B	Possibly carcinogenic to humans
Group 3	Not classifiable as to its carcinogenicity to humans
Group 4	Probably not carcinogenic to humans

NDEA, NMBA, and NDMA have relatively simple chemical structures, NDEA: C₄H₁₀N₂O; NDMA: C₂H₆N₂O; NMBA: C₅H₁₀N₂O₃.^9,10,11 They are ubiquitous in nature and are formed by various reactions of chemicals with amines or nitrites.¹² These reactions are easy to replicate and large amounts of NDMA and NDEA are used in cancer research to induce tumor growth in animals. NDMA is often studied at a dose of 0.1 mg/kg/day to induce tumor growth, which is many times greater than the acceptable daily limit set by the FDA.¹³ 

The FDA states that the acceptable daily intake of NDMA and NMBA is 96 nanograms and 26.5 nanograms for NDEA. Acceptable risk is defined as daily exposure to a compound that results in a 1:100,000 cancer risk after 70 years of exposure. To put that into perspective, if 100,000 patients were taking 96 nanograms of NDMA for 70 years, it would result in one patient developing cancer. It has been estimated that the recently recalled ARB batches have been available since 2014. If 8,000 people took valsartan 320 mg from the recalled batches daily for the full four years, there may be one additional case of cancer over the lifetimes of these 8,000 people.⁵ 

The FDA issued a statement in March 2018 to utilize more scrutiny when testing for impurities, which led to the discovery of NDEA and NDMA contamination in July 2018, and NMBA in March 2019.¹³ The FDA announced on January 25, 2019 that they identified one of the sources of contamination; the reuse of solvents required for the production of drugs. Other root causes are still under investigation, but it became apparent that certain manufacturers reused solvents in order to decrease production costs.¹⁴

Since ARBs offer additional benefit beyond that of simply reducing blood pressure, it would be unfortunate if this treatment option were not available. There are not many therapeutic options available for patients who cannot tolerate and ACEI but require therapy for mortality benefit (e.g., those with heart failure or those who with diabetic renal disease).15,16 A link between NDMA-containing ARBs and cancer has not been identified.¹⁷ More long-term research on NDMA and the other impurities is still needed.

1. During this period of drug recall and limited availability, pharmacists can do the following:
2. Focus on proper patient education - With the new FDA statement requiring better impurity testing techniques, the next drug recall is likely unavoidable. Be prepared to answer questions from patients and providers and understand the background and reasons for the recall. Focus on proper prescriber education - Pharmacists should inform physicians not to discontinue medications without checking to see if other manufacturers are available. Switching medications that have not been affected can be counterproductive. It can increase workload for pharmacists who are already working on replacing affected drugs. This can in turn lead to increased wait times and even more patient dissatisfaction. 
3. Take an active role in replacing affected medications – Aim for minimal interruption to a patient’s medication regimen. Some hospital pharmacies have released specific instructions for lot substitutions. They have also notified healthcare workers about the lot and manufacturer changes. In many cases, hospital pharmacies have switched from an affected ARB to an unaffected one without interrupting patients’ therapies. Community pharmacists reached out to patients to notify them if their medications have been affected. Ambulatory care pharmacists should educate patients and prescribers about the nature of the recall to prevent unnecessary adjustments at the prescriber level. 
4. Check the FDA recall list to see when/if new recalls are announced: https://www.fda.gov/Safety/Recalls/default.htm  Check the FDA ARB recall list for specific information on ARBs: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan
5. Consider the whole picture. When answering questions about possible dangers and risks, remember to focus on life-time exposure and weigh the benefits-risks for each patient.

In conclusion, pharmacists should be prepared for the next drug recall and should check the FDA website whenever another recall does occur to be prepared to educate patients and physicians. 

References:

1.       Food and Drug Administration. Major Pharmaceuticals Issues Voluntary Nationwide Recall of Valsartan Due to The Potential Presence of a Probable Carcinogen (NDMA) (July 2018). www.fda.gov/Safety/Recalls/ucm613625.htm (accessed 2019 Jan 31).

2.       Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010;11(7):627-636.

3.       Angiotensin receptor blockers linked to “modest” increase in cancer risk, Lancet study reveals. The Pharmaceutical Journal. 2010;284:602.

4.       Chiang YY, Chen KB, Tsai TH, Tsai WC. Lowered cancer risk with ACE inhibitors/ARBs: a population-based cohort study. J Clin Hypertens (Greenwich). 2014;16(1):27-33.

5.       Food and Drug Administration. FDA updates on angiotensin II receptor blocker (ARB) recalls including valsartan, losartan and irbesartan (June 2019).
fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan (accessed 2019 June 19).

6.       Citizen Petition from Valisure, LLC (June 2019).
regulations.gov/document?D=FDA-2019-P-2869-0001 (accessed 2019 June 19).

7.       World Health Organization. International Agency for Research on Cancer. IARC Monographs on the Identification of Carcinogenic Hazards to Humans Preamble (2019).
monographs.iarc.fr/wp-content/uploads/2019/01/Preamble-2019.pdf (accessed 2019 Jan 31).

8.       World Health Organization. International Agency for Research on Cancer. Agents Classified by the IARC Monographs, Volumes 1-123 (2018).
monographs.iarc.fr/wp-content/uploads/2018/09/List_of_Classifications.pdf (accessed 2019 Jan 31).

9.       N-Nitrosodiethylamine. Pubchem Open Chemistry Database. US National Library of Medicine. pubchem.ncbi.nlm.nih.gov/compound/5921 (accessed 2019 Jan 31).

10.   N-Nitrosodimethylamine. Pubchem Open Chemistry Database. US National Library of Medicine.
pubchem.ncbi.nlm.nih.gov/compound/6124 (accessed 2019 Jan 31).

11.   N-Methyl-N-(3-carboxypropyl)nitrosamine. Pubchem Open Chemistry Database. US National Library of Medicine.
pubchem.ncbi.nlm.nih.gov/compound/N-Methyl-N-_3-carboxypropyl_nitrosamine (accessed 2019 June 19).

12.   Liteplo RG, Meek ME, Windle WE. Concise International Chemical Assessment Document 38: N-Nitrosodimethylamine. World Health Organization. 2002.

13.   US Food and Drug Administration (FDA). M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk Guidance for Industry (March 2018). www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf (accessed 2019 Jan 31).

14.   Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., director of the Center for Drug Evaluation and Research on the FDA’s ongoing investigation into valsartan and ARB class impurities and the agency’s steps to address the root causes of the safety issues (January 2019). www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629796.htm (accessed 2019 Jan 31).

15.   Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869

16.   Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial - the Losartan Heart Failure Survival Study, ELITE II. Lancet. 2000;355:1582–1587

17.   Potegard A, Kristensen KB, Ernst MT, Johanses NB, Quartarolo P, Hallas J. Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study. BMJ. 2018;362:k3851.