Uncertain about valsartan

October 15, 2018 0 By CH Unnikrishnan

In July, India’s drug regulator said the agency was starting an investigation on all companies importing the active pharmaceutical ingredient (API) to make heart drug valsartan from Zhejiang Huahai Pharmaceuticals of China. This unprecedented action by the Drug Controller General of India (DCGI) came in the wake of a recall of the medicines containing valsartan by countries including the US and Germany.

The ongoing probe in the US and Europe to check for the presence of a potential carcinogen in valsartan has put regulators all over the world on high alert. Valsartan, a commonly prescribed angiotensin-II-receptor antagonist (ARB) to manage hypertension, is used for heart failure indication as well.

The DCGI’s announcement prompted drug control offices in the country to be vigilant on the import of the raw materials for the drug. The drug regulator said all port offices were asked to check the consignments imported into the country and conduct tests on each batch to address the issue.

Even as Indian manufacturers Torrent Pharmaceuticals and Hetero Drugs voluntarily withdrew their valsartan drugs from the US market, latest reports indicate that India’s Central Drug Standard Control Organisation (CDSCO), the top regulator’s office, has assured that the ingredient that is suspected to have the impurity is not present in the drugs available in India.

NDMA: The suspect

The entire issue came to the fore when Prinston Pharmaceuticals, Inc. contacted the USFDA’s Center for Drug Evaluation and Research (CDER) about some of its products containing valsartan API manufactured by Zhejiang Huahai Pharmaceutical Co. (ZHP), on 19th June, 2018.

Prinston informed CDER that they had stopped making valsartan products because ZHP had detected an impurity – a chemical known as N-nitrosodimethylamine (NDMA) — in the API. NDMA is a probable cancer-causing chemical found in trace amounts in water and some foods. The levels of NDMA in ZHP’s valsartan API, though only in trace amounts, were unacceptable.

“Although the risk to patients taking the affected products is extremely low, we take matters of pharmaceutical quality very seriously. We took immediate steps to address these findings,” said a statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., director of the Center for Drug Evaluation and Research, on FDA’s ongoing investigation into valsartan impurities and recalls.

The US drug regulator is closely coordinating with the European Medicines Agency (EMA), European Directorate for the Quality of Medicines (EDQM), Regulatory Operations and Regions Branch and Therapeutic Products Directorate of Health Canada, and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, sharing the developments on the investigation.

International regulators have since identified another API manufacturer, Zhejiang Tianyu Pharmaceutical Co., with NDMA in its valsartan API. The USFDA said that no valsartan products in the US market use this API.

The FDA estimates that if 8,000 people took the highest valsartan dose (320 mg) from NDMA-affected medicines daily for four years (the amount of time it believes the affected products have been on the U.S. market), there may be one additional case of cancer over the lifetimes of these 8,000 people beyond the average cancer rate among Americans.

“This estimate represented the highest possible level of NDMA exposure. It was a measure of the risk under the most extreme circumstances. Most patients who were exposed to the impurity through the use of valsartan received less exposure than this worst-case scenario,” it said.

Difficult to determine

NDMA’s properties make it difficult to find. To determine if valsartan products do contain this impurity, CDER’s scientists have developed the gas chromatography-mass spectrometry (GC/MS) headspace testing method. It has posted this method to the web to help manufacturers and regulators detect NDMA in valsartan API and tablets.

“Specifically, a combination of conditions, which include certain chemicals, processing conditions and production steps, could lead to the formation of the NDMA impurity. We believe that these risks are introduced through a specific sequence of steps in the manufacturing process, where certain chemical reactions are needed to form the active ingredient. Before we undertook this analysis, neither regulators nor industry fully understood how NDMA could form during this process,” said the FDA officials.

The US drug watchdog has been conducting a review of ARBs from 2010, according to the documents. In light of the valsartan issue, the FDA is conducting a study on all ARBs to check for the presence of NDMA.

Low risk potential?

The EMA officials in August said that the NDMA levels detected in batches of valsartan from Zhejiang Tianyu are much lower than the levels seen in the active substance from Zhejiang Huahai, which triggered a recall of several valsartan medicines in July 2018.

While the DCGI assures that the contaminated batches of the ingredient has not touched Indian shores, experts say that there are alternatives available for the drug and that doctors can switch to other products in order to avoid any possible risk.

In India, valsartan is available as a single drug as well as in fixed-dose combinations. Patients taking this drug should not stop the drug without consulting their doctors for two reasons: First, not all valsartan containing products are recalled and second, many equally efficacious alternatives to valsartan are available, alert experts. “Physicians should take caution prescribing drugs containing valsartan unless they can confirm that the particular API is not sourced from the companies mentioned above,” says Dr Anoop Agrawal, Consultant, Interventional Cardiology, CARE Hospitals, Hyderabad. FDA has listed the recalled manufacturers on their website. He suggests that in India, authorities should aggressively test the available drugs for the said impurity and put out our own list of recalled and not-recalled brands.