Introduction

Flavocoxid is a medical food consisting of plant derived flavonoids which have antiinflammatory activity and are used to treat chronic osteoarthritis. Flavocoxid has been linked to minor elevations in serum enzyme levels during therapy and to rare instances of clinically apparent liver injury.

Background

Flavocoxid (flay" voe kox' id) is a proprietary blend of purified plant derived bioflavonoids including baicalin and catechins. Flavocoxid inhibits cyclooxygenases (both Cox-1 and Cox-2) as well as lipoxygenases (5-Lox) in vitro and in animal models, which may account for its antiinflammatory and antioxidant activity. Flavocoxid inhibits the conversion of arachidonic acid to reactive prostaglandins and reduces the levels of these inflammatory mediators in synovial fluid. Flavocoxid was approved for use as a medical food in the United States in 2004. However, this approval was withdrawn in December 2017 and it is not longer available as an FDA approved medical food. It was previously available by prescription for use in chronic osteoarthritis in tablets of 500 mg under the commercial name Limbrel. The typical dose was 500 mg twice daily. Side effects were not common and were similar in frequency to those experienced by patients on placebo.

Hepatotoxicity

In premarketing clinical trials, serum aminotransferase elevations occurred in up to 10% of patients on flavocoxid therapy, but elevations above 3 times the upper limit of normal occurred in only 1% to 2% of recipients. Since its release, however, there have been several reports of clinically apparent acute liver injury attributed to flavocoxid. Most cases have occurred in women, who perhaps are more likely to use flavocoxid. The time to onset was 1 to 5 months, and the pattern of enzyme elevations was usually hepatocellular or mixed. Most cases were moderate in severity and no instance of acute liver failure or death has been reported. Resolution upon stopping flavocoxid occurred in 1 to 3 months. Immunoallergic features were present in some patients, but were mild and autoantibodies were not common. At least one instance of recurrence upon rechallenge has been reported.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

Flavocoxid is a proprietary mixture of plants and herbs and it is unclear which component(s) might be responsible for liver injury. The mixture includes extracts from Scutellaria baicalensis (skullcap, containing the phytochemical baicalin) and Acacia catechu (catechin), both of which have been implicated in causing rare instances of idiosyncratic acute liver injury, but the mechanism is unknown.

Outcome and Management

No instances of acute liver failure or chronic liver injury have been linked to flavocoxid use and all cases have been self-limited, without subsequent chronic hepatitis or vanishing bile duct syndrome. Recurrence upon reexposure has been reported and rechallenge should be avoided. There is no information on possible cross sensitivity of hepatic injury with other medications or herbal agents such as skull cap or green tea.

Drug Class: Herbal and Dietary Supplements; Antirheumatic Agents

Case 1. Acute hepatitis with jaundice after flavocoxid therapy.

[Modified from Case 1: Chalasani N, Vuppalanchi R, Navarro V, Fontana R, Bonkovsky H, Barnhart H, Kleiner DE, Hoofnagle JH. Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series. Ann Intern Med 2012; 156: 857-60, W297-300. PubMed Citation]

A 58 year old woman developed jaundice 10 weeks after starting flavocoxid (500 mg twice daily) for osteoarthritis. She had no history of liver disease, risk factors for viral hepatitis and did not drink alcohol. Other medications included aspirin, tramadol, omeprazole, ezetimibe, zolpidem, glucosamine, calcium, flaxseed oil and vitamins, all of which she had taken chronically. Physical examination was largely unremarkable, but her laboratory tests showed elevations in serum bilirubin (2.5 mg/dL), ALT (1105 U/L), AST (1198 U/L) and alkaline phosphatase (487 U/L) (Table). There was no eosinophilia and the prothrombin time was normal. Liver tests had been normal on several occasions in the past. Flavocoxid was discontinued, but over the next week she became jaundiced (peak bilirubin 7.3 mg/dL) and serum enzyme levels remained elevated. Tests for hepatitis A, B, C and E were negative as were autoantibodies. Ultrasound of the abdomen showed no evidence of biliary obstruction or hepatic masses. A liver biopsy showed a moderately severe, acute lobular hepatitis with portal inflammation (including eosinophils) without evidence of chronic liver disease or fibrosis. Two weeks after stopping flavocoxid she began to improve. Symptoms resolved within a month and all liver tests were normal when she was seen 3 months after onset. Flavocoxid was not restarted.