ARB Concerns Continue as Macleods Pulls Contaminated Losartan

Patrice Wendling

June 27, 2019

Macleods Pharmaceuticals is recalling 32 lots of losartan potassium USP tablets and losartan potassium/hydrochlorothiazide (HCTZ) combination tablets after discovering trace amounts of the potential carcinogen N-methylnitrosobutyric acid (NMBA).

The impurity was found in 32 lots of active pharmaceutical ingredient (API) manufactured by Hetero Labs that is above the US Food and Drug Administration's (FDA's) interim acceptable exposure limit of 9.82 ppm, according to a June 26 FDA news release.

The nationwide recall, to the patient level, includes two lots of losartan potassium 50 mg tablets, 12 lots of losartan/HCTZ 50 mg/12.5 mg, three lots of losartan/HCTZ 100 mg/12.5 mg, and 15 lots of losartan/HCTZ 100 mg/25 mg distributed to Macleods' wholesale distributor and retail customers.

Macleods is notifying its distributors and customers via phone and/or letter about the presence of the impurity and is advising they immediately stop distribution and return the recalled product per its instructions.

Details on the specific lot numbers and expiration dates of the recalled products are available here.

The company recommends that patients continue taking their losartan medication and contact their pharmacist, physician, or medical provider for advice regarding an alternative treatment.

To date, Macleods has not received any reports of adverse events related to this recall, according to the release.

The recall marks renewed activity this month after a brief lull in the long-running wave of angiotensin II receptor blocker (ARB) recalls that began in 2018 and has involved three nitrosamine potential carcinogens. On June 10, Teva Pharmaceuticals expanded its nationwide recall of losartan tablets after detecting NMBA in one lot of API produced by Hetero Labs.

Days later, a fourth potential carcinogen, dimethylformamide (DMF), was identified by the online pharmacy Valisure in lots of valsartan made by five of the six pharmaceutical companies it tested, including Macleods and Novartis. DMF is classified as a class 2 solvent by the FDA and is commonly used in the production of APIs. It was reclassified in 2018 as a probable carcinogen by the World Health Organization.

In its June 13 citizen petition to the FDA, the New Haven, Connecticut–based company called on the agency to recall the contaminated lots of valsartan and to conduct examinations and investigations regarding the products, their manufacturing process, and manufacturer submissions made for FDA approval.

In addition, Valisure urged the agency to significantly lower the daily acceptable intake limit of DMF from its current level of 8.8 million nanograms to less than 1000 ng, and potentially as low as 96 ng.

"It is important to note that the amounts of DMF being reported are more than 100 times less than those determined by international standards as the level of concern to patients," FDA spokesperson Jeremy Kahn told | Medscape Cardiology via email.

Valisure contends the switch by the drug manufacturing industry to the use of DMF "may be largely responsible" for the formation of the nitrosamine impurities NDMA and N-nitrosodiethylamine (NDEA) and points out that, at least in the case of valsartan, DMF and NDMA often cocontaminate tablets.

"Considering that valsartan has on many occasions been found to contain other probable human carcinogens like NDMA and NDEA, the presence of DMF could serve to further exacerbate even low levels of such carcinogens, which have also been found in Valisure's analysis of the same lots containing DMF," the petition says.

Kahn noted that the pharmaceutical quality system of a manufacturer extends to the control and review of any outsourced activities and quality of purchased materials. "The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and the quality of purchased materials," he said.

The FDA continues to advise patients to continue taking their medication and maintains that the risk associated with abruptly discontinuing the use of ARBs far outweighs the low risk that its scientists estimate to be associated with continuing the medicine until a replacement can be provided.

"We'll continue to prioritize our investigation into this ongoing issue surrounding ARBs, and we'll provide additional updates to consumers, healthcare professionals, and industry on our investigation and assessments to ensure patient safety," Kahn said.

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