Acute Liver Injury Linked to Flavocoxid for OA

Janis C. Kelly

June 18, 2012

June 18, 2012 — Flavocoxid (Limbrel, Primus Pharmaceuticals), a prescription medical food that is used to treat osteoarthritis (OA) has been linked to liver toxicity in a case series.

The case series, reported in the June 19 issue of the Annals of Internal Medicine by Naga Chalasani, MD, from the Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, and colleagues on behalf of the Drug-Induced Liver Injury Network, includes 4 cases of liver toxicity. Flavocoxid was judged highly likely to be the cause in 3 cases and possibly the cause in 1 case.

Flavocoxid is a botanical product derived from the root of Scutellaria baicalensis (Chinese skullcap) and the bark of Acacia catechu (Mimosa catechu). Unlike dietary supplements, medical foods are designed to treat specific medical conditions and are not to be taken by healthy individuals. Unlike drugs, medical foods are not required to pass premarketing safety and efficacy trials

The importance of this finding is highlighted in an accompanying editorial by Stephan Reichenbach, MD, and Peter Jüni, MD, both from the University of Bern, Switzerland, who warn, "Consumers are likely to assume that other supplements and medical foods are safe, but the case series by Chalasani and colleagues in this issue suggests that this may not always be true."

The researchers analyzed 877 patients enrolled in the Drug-Induced Liver Injury Network Prospective Study, which has been ongoing at 8 academic medical centers in the United States since 2004. They identified and closely analyzed 4 patients who presented with liver injury within 3 months after beginning flavocoxid. Signs and symptoms included marked elevations in alanine aminotransferase (mean peak, 1268 U/L; range, 741 - 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 288 - 770 U/L) and serum bilirubin (mean peak, 160.7 μmol/L [9.4 mg/dL]; range, 34.2 - 356 μmol/L [2.0 - 20.8 mg/dL]) levels; jaundice; pruritus; abdominal pain; fever; and rash. All 4 patients were women, ranging in age from 57 to 68 years.

In all 4 cases, liver manifestations began to resolve within a few days after discontinuation of flavocoxid, and serum enzyme levels decreased to normal within 1 to 3 months. Again, causality was judged likely a result of flavocoxid in 3 cases and possibly a result of flavocoxid in 1 case (which was complicated by exposure to other potential hepatotoxins including pregabalin, duloxetine, and tizanidine).

The authors write, "The clinical signature of flavocoxid-induced liver injury seems to be a mild to moderate, mixed hepatocellular-cholestatic hepatitis that arises 2 to 12 weeks after starting the medication and resolves rapidly once it is stopped."

Study limitations include that risk factors for and mechanism of liver injury caused by flavocoxoid could not be assessed. The researchers speculate that hypersensitivity could be involved.

Dr. Reichenbach and Dr. Jüni write, "As Chalasani and colleagues report, flavocoxid is one of the products that can result in acute liver injury and should always be considered as a potential cause of such injury." They suggest that the policy of marketing such products in the absence of clinical evidence might need to be reconsidered.

The Drug-Induced Liver Injury Network is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Chief Medical Officer of Primus Pharmaceuticals provided the case histories reported to them of 8 patients with suspected flavocoxid-induced liver injury. Dr. Chalasani has received consultancy fees from Gilead, Genentech, Amylin, Karobio, Johnson & Johnson, Teva Pharmaceuticals, Eli Lily, Merck, Mochida, Vertex, Salix, Biolex, GSK, Aegiron, and Abbott, and grant funding from Lilly, Intercept, and Amylin. One coauthor has received consultancy fees from BMS and speaker's fees from Genentech and Vertex. One coauthor has received consultancy fees from Medtronic, GSK, and Merck, and grant funding from BMS and Vertex. One coauthor has received consultancy fees from Clinuvel and Lundbeck A/S; grant funding from Vertex; and speaker's fees from Clinuvel, Lundbeck A/S, Merck, and Meeting in Medicine. The other authors as well as the editorialists, Dr. Reichenbach and Dr. Jüni, have disclosed no relevant financial relationships.

Ann Intern Med. 2012;156:857-860, 894-895.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: