Impurities Alert

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Angiotensin-receptor blockers (ARBs) are one of four classes of drugs recommended for the initial treatment of hypertension—a condition found in over 45 percent of adult Americans—plus heart failure and chronic kidney disease. Early this year, the Food and Drug Administration (FDA) issued a large-scale voluntary recall of certain lots of ARBs, namely valsartan, losartan, and irbesartan, due to the presence of small amounts of three carcinogens found in them. Then, a few months ago, the FDA issued a second recall for additional lots of the same medications. The FDA now estimates that U.S. patients have been ingesting these impurities for at least four years. The recalls have caused widespread confusion and alarm among patients, doctors, and pharmacists. Many patients, once they were notified of the recall, just simply stopped taking them. Suddenly stopping these medications can be very dangerous, but people were understandably scared. To understand how this happened, one must understand the manufacturing and distribution process.

It is estimated that as many as two million patients ingested the impurities, specifically N-nitrosodimethylamine (NDMA), N-nitroso-N-diethylamine (NDEA), or N-nitroso-N-methyl-4-aminobutyric acid (NMBA). They were found in medications manufactured in two factories, one in China and one in India. The impurities are genotoxic, meaning that they may be harmful to DNA and cause genetic mutations and cancers. It turns out that manufacturers, mostly located in China, Europe, Latin America, and India, produce mass quantities of medications. Smaller pharmaceutical firms then purchase the product in bulk and press it into capsules and tablets. In addition, the pills are often sold to other pharmaceutic firms who repackage them. The production of medications has become global which makes the task of quality testing them for impurities, proper dosing amounts, etc., extremely complicated. Because of this, the FDA has established offices and testing facilities all over the globe. In the manufacture of ARBs, tetrazole groups must be synthesized. Tetrazoles are created from dimethylamine and sodium nitrite. Any small error in the manufacturing process has the potential to create the impurities that were found.

When you consider the fact that over 61 million ARB prescriptions were written last year in this country alone, you begin to realize the huge, daunting task the FDA has in ensuring that the medications taken by Americans do not contain impurities, but do contain what the label says they do and in the proper amounts. In 2015, for the first time the FDA conducted more foreign than domestic medication inspections. As the manufacturing of pharmaceuticals and ingredients used in their synthesis spreads out around the globe, so must the FDA. As many countries, especially developing countries, have less regulation and control over drug manufacturing, it is less expensive to operate there than it is here in the USA, which is why the FDA must follow the manufacturers. In this case, although it took time, the FDA found the threat. Many experts predict more pharmaceutical recalls in the future.

If you would like to know more about the sartan contamination story go to:

https://blogs.sciencemag.org/pipeline/archives/2019/01/04/the-sartan-contamination-story

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