Drug Shortage

Shortage of leflunomide tablets

Two-dimensional representation of leflunomide contributed to Wikimedia by Fvasconcellos

The American Society of Health-System Pharmacists reports a shortage of leflunomide tablets, a member of the class of disease-modifying anti-rheumatic drugs. Once in the body, leflunomide is converted to its active form, originally known simply as M1, then designated A77 1726, and finally given its own international non-proprietary name, teriflunomide. This active metabolite exists as two isomers, the more stable of which is shown below. Sanofi patented teriflunomide and sells it under the brand name Aubagio.

Three-dimensional ball-and-stick model of teriflunomide (Z-enol) contributed to Wikimedia by Anypodetos

The unfortunate person with rheumatoid arthritis may be given a series of DMARDs over their lifetime when their disease becomes active and starts destroying their joints and also in hopes of keeping the disease in remission. The first one attempted is almost always methotrexate. People who can tolerate this drug may never need to take other DMARDs, but if it fails to prevent joint damage or becomes ineffective at some later date, choosing another will be necessary.

Both methotrexate and leflunomide have serious side effects, and sometimes people can’t tolerate them. The latter especially must be used with caution because it may have too great a toxic effect on the liver. Routine liver function tests are done, with particular attention to any increases in a liver enzyme known as alanine aminotransferase.

The Heritage Pharmaceuticals product is manufactured under contract with Emcure, which has manufacturing facilities in Kurkumbh and Pimpri, India. The company has recently had to recall other drugs for poor compliance with good manufacturing practices, an adequate explanation in itself for the leflunomide shortage arising there. There is also an FDA enforcement action dating from May 2014 concerning their tabletting facility which might be even more directly affecting the company’s ability to produce quality leflunomide tablets.

Apotex cites a delay in obtaining the active ingredient to make the tablets. This delay might be related to this FDA warning letter for their Bangalore plant. Note that section three, failure to prevent contamination of non-sterile products by objectionable microorganisms, might mean that any powdered leflunomide they had on hand to use for making tablets could be contaminated with “objectionable microorganisms.” Even if the tablets are still made in Toronto, the active ingredient might be supplied from Bangalore. To be clear, this is speculation.

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