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Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis: A Case Series

Naga Chalasani, MD; Raj Vuppalanchi, MD; Victor Navarro, MD; Robert Fontana, MD; Herbert Bonkovsky, MD; Huiman Barnhart, PhD; David E. Kleiner, MD; Jay H. Hoofnagle, MD, on behalf of the Drug-Induced Liver Injury Network
[+] Article, Author, and Disclosure Information

From Indiana University School of Medicine, Indianapolis, Indiana; Temple University School of Medicine, Philadelphia, Pennsylvania; University of Michigan, Ann Arbor, Michigan; Carolinas Medical Center, Charlotte, North Carolina; Duke Clinical Research Institute, Durham, North Carolina; and the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Acknowledgment: The authors thank Primus Pharmaceuticals and Dr. Robert Levy, Chief Medical Officer, for providing the case histories reported to them of 8 patients with suspected flavocoxid-induced liver injury.

Financial Support: The DILIN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (https://dilin.dcri.duke.edu/). This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0176.

Reproducible Research Statement: The authors are willing to provide the narratives and laboratory data of the cases reported in this paper to the interested public.

Requests for Single Reprints: Naga Chalasani, MD, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 1050 Wishard Boulevard, RG 4100, Indianapolis, IN 46202; e-mail, mailto:nchalasa@iupui.edu.

Current Author Addresses: Drs. Chalasani and Vuppalanchi: Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 1050 Wishard Boulevard, RG 4100, Indianapolis, IN 46202.

Dr. Navarro: Thomas Jefferson University, Main Building, Suite 480, 132 South 10th Street, Philadelphia, PA 19107.

Dr. Fontana: University of Michigan, Alfred Taubman Health Care Center, 1500 East Medical Center Drive, Floor 3, Reception D, Room 3326, Ann Arbor, MI 48109-5362.

Dr. Bonkovsky: Carolinas HealthCare System, Suite 201, Cannon Research Center, 1542 Garden Terrace, Charlotte, NC 28203.

Dr. Barnhart: Duke University, Duke Box 3850, Durham, NC 27710.

Dr. Kleiner: National Cancer Institute, Building 10, Magnuson CC, Room 2B44, 10 Center Drive, Bethesda, MD 20892.

Dr. Hoofnagle: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 31, Room 9A27, Bethesda, MD 20892.

Author Contributions: Conception and design: N. Chalasani, R. Vuppalanchi, H. Bonkovsky, J.H. Hoofnagle.

Analysis and interpretation of the data: N. Chalasani, V. Navarro, R. Fontana, H. Bonkovsky, H. Barnhart, D.E. Kleiner, J.H. Hoofnagle.

Drafting of the article: N. Chalasani, R. Fontana, H. Bonkovsky, H. Barnhart.

Critical revision of the article for important intellectual content: N. Chalasani, V. Navarro, H. Bonkovsky, D.E. Kleiner, J.H. Hoofnagle.

Final approval of the article: N. Chalasani, V. Navarro, R. Fontana, H. Bonkovsky, H. Barnhart, D.E. Kleiner, J.H. Hoofnagle.

Provision of study materials or patients: N. Chalasani, R. Vuppalanchi, V. Navarro, R. Fontana, H. Bonkovsky.

Statistical expertise: H. Barnhart.

Obtaining of funding: N. Chalasani, H. Bonkovsky, H. Barnhart.

Administrative, technical, or logistic support: J.H. Hoofnagle.

Collection and assembly of data: N. Chalasani, R. Vuppalanchi, R. Fontana, D.E. Kleiner, J.H. Hoofnagle.

Ann Intern Med. 2012;156(12):857-860. doi:10.7326/0003-4819-156-12-201206190-00006
Text Size: A A A

Background: Flavocoxid is a prescription medical food that is used to treat osteoarthritis. It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively.

Objective: To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid.

Design: Case series.

Setting: Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004.

Patients: Four adults with liver injury.

Measurements: Clinical characteristics, liver biochemistry values, and outcomes.

Results: Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1268 U/L; range, 741 to 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 µmol/L [9.4 mg/dL]; range, 34.2 to 356 µmol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient.

Limitation: The frequency and mechanism of liver injury could not be assessed.

Conclusion: Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation.

Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.





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Physicians Should Aquaint Themselves With Product Information
Posted on June 22, 2012
Robert M. Levy, MD, Director of Clinical Development, Bruce P Burnett, PhD, Director of Scientific Affairs
Primus Pharmaceuticals, Inc.
Conflict of Interest: None Declared



We appreciate the report of Dr. Chalasani, et al (Ann Intern Med. 2012.156:857-860.) for calling attention to an issue often overlooked by physicians. Primus added specific warnings regarding liver toxicity to its package insert more than two years ago.


Flavocoxid (Limbrel®) is classified as a medical food indicated for the clinical dietary management of osteoarthritis. Medical foods are an FDA regulated class of therapeutic agents distinct from drugs and supplements (1).  A medical food is defined at Volume 21 USC [Code] Section 360ee(b)(3) as  "a food which is formulated to be consumed or administered enterally [orally] under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation." Unlike supplements intended to preserve function in healthy people, medical foods are, by statute, intended for the management of chronic diseases under physician supervision and must be composed of so-called GRAS (generally recognized as safe) ingredients, the same as conventional foods. Obtaining GRAS status requires extensive review by a panel of toxicology experts. This does not mean, however, that these products are devoid of potential adverse effects, just as certain foods which may elicit allergic responses.

 Of all marketed anti-inflammatory agents, flavocoxid (Limbrel®) is arguably the safest based on clinical and in-market experience (0.1% reported adverse event rate in n=324,929 people exposed as of March 2012 in 8+ years of marketing in the US/Puerto Rico). Primus Pharmaceuticals, Inc. monitors its adverse event rate and makes this on its website unlike most pharmaceutical companies (pharmacovigilance available to the public at http://www.limbrel.com/downloads/post_mkt_surv.pdf). Flavocoxid has essentially no upper gastrointestinal, renal, cardiovascular or coagulation toxicity and has been used in patients with prior ulcer disease, azotemia and/or renal failure on dialysis, hypertension, atherosclerotic disease and those taking warfarin and anti-platelet agents (2). However, as pointed out in the paper by Chalassani, et al, Limbrel has produced some liver toxicity. It is also important to understand that the patients reported by Chalassani, et al (2012) included 4 cases out of 877 who were already being investigated in the DILIN network because they had liver abnormalities and that this bears no relation to the incidence of abnormal LFTs in the total exposed population. In post-marketing surveillance and clinical trials, liver toxicity of flavocoxid  appears to be comparable to every other anti-inflammatory agent including both NSAIDs and selective COX-2 inhibitors as reported in these agents’ package inserts, a 5-15% incidence of elevated transaminases (3). In clinical trials, the incidence of symptomatic adverse events was similar to placebo (4) and hepatotoxicity was comparable to naproxen (5). The problem is further complicated in that many herbal supplements have been associated with hepatotoxicity and use of these products is far more common than most physicians appreciate and are often not reported by patients (6). The advantage of a medical food in terms of pharmacovigilance is that the physician must be involved in the dosing and monitoring of the therapeutic use of these products unlike over-the-counter supplements and drugs. Physicians have the responsibility to ensure that medical foods are used safely considering potential drug/herbal interactions and comorbidities that are unique to each patient. Finally, acetaminophen, one of the most ubiquitous OTC drugs, accounts for about 50% of all cases of liver failure in the U.S (7).


In conclusion, the issue is not that flavocoxid may occasionally be associated with abnormal liver function tests but that, because of the category name, “Medical Foods”, physicians may erroneously assume a total lack of potential adverse effects. In fact, as with any effective therapeutic agents, flavocoxid, despite having the best overall safety profile of all anti-inflammatory agents, it is not totally devoid of potential adverse effects. We are grateful to Chalasani, et al (2012) for calling attention to the fact that therapeutic category names may be misleading and although manufacturers make an attempt to provide detailed information about their products, physicians should acquaint themselves with the information in product inserts and elsewhere so they use and monitor these medications appropriately and safely.




Robert M. Levy, MD, Director of Clinical Development


Bruce P Burnett, PhD, Director of Scientific Affairs

Primus Pharmaceuticals, Inc.



1. Morgan SL, Baggott JE. Medical foods: products for the management of chronic diseases. Nutr Rev. 2006.64(11):495-501.

2. Pillai L, Levy RM, Yimam M, et al. Flavocoxid, an Anti-inflammatory Agent f Botanical Origin Does Not Affect Coagulation or Interact with Anticoagulation Therapies. Adv Ther. 2010. Adv Ther.27(6):400-11.

3. Rubenstein J & Laine L. A systematic review: the hepatotoxicity of nonsteroidal anti-            inflammatory drugs. Aliment Pharm Ther. 2004.20;373-80.

4. Morgan SL, Bagott JE, Moreland L, et al. The safety of Flavocoxid, a Medical Food, in the Dietary      Management of Knee Osteoarthritis. J Med Food 2009.12:1143-8.

5. Levy, RM, Khokhov A, Kopenkin S, et al Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee. Adv Ther. 2010.27:731-42.

6. Pak E, Esrason KT, Wu VH. Hepatotoxicity of Herbal remedies: an Emerging dilemma. Prog Transplant. 2004.14:91-6.

7. Kaplowitz N. Drug induced liver disorders: implications for drug development and regulation. Drug Saf. 2001.24;483-90



Acute liver injury and flavocoxid (Limbrel), a Medical Food for Osteoarthritis
Posted on July 3, 2012
Miguel A Gonzalez, MD
Arthritis, Rheumatic Diseases & Osteoporosis
Conflict of Interest: None Declared

Dear Editor

In reference to the report of Dr. Chalasani et at (Ann Intern Med. 2012.156:857-860.) warning on potential liver toxicity of flavocoxid(Limbrel), medical food for the clinical dietary management of osteoarthritis: as a long time prescriber, in my clinical experience I have not encountered any cases of liver injury that require to stop treatment, in my practice patients with baseline persistent elevations of liver functions will not be treated with this product.

After reviewing the reported cases, I conclude how relevant it is to be familiar with our patients comorbidities, medication list ( statins, tizanidine and other drugs that are a higher risk for liver injury). Updating and reviewing toxic habits like alcohol intake that in most instances goes underreported.

In my day to day management of the most challenging cases of osteoarthritis, flavocoxid (Limbrel) offers a valuable therapy for those who wish to take a more natural product or those who could not use conventional treatments ( NSAID, prednisone, acetaminophen and even topical analgesics) due to systemic diseases, allergies or intolerances. Idiosyncratic abnormal responses to foods, supplements and medications do occur most of the time impredictably. Patient education is essential. Baseline and periodic liver function monitoring is much needed for early detection and prevention of liver injury as we add new treatments to our patients.

A Clinician’s Perspective
Posted on July 25, 2012
Howard M. Busch DO FACR
Conflict of Interest: Disclosures: speaker/consultant; Abbott, Amgen,Genentech,Forrest,Primus,UCB,Takeda

I would like to comment in response to the Chalassani article as well as the editorial by Reichenbach and Juni. Although I was aware of reported flavocoxid induced liver injury, It was helpful to learn that the patients depicted in the Chalassani trial (3) where 4 of 877 patients had reversible hepatotoxicity . This is in contrast to liver toxicity which may be NSAID induced. In particular the COX2 inhibitors have been found to lead to cholestatic liver failure, in some cases requiring liver transplantation (1,2). This of course is in addition to the well described toxicities of renal insufficiency, peptic ulcer disease, stroke, ischemic heart disease, hypertension and drug interactions particularly with anticoagulants. For the practitioner who is forced to treat osteoarthritis in a myriad of individuals, many of whom are on polypharmacy , some with renal insufficiency, or with a-fib on warfarin therapy, have few options. There are patients that require surgical intervention but for comorbidities, will never be granted medical clearance and unfortunately continue to live with the pain of osteoarthritis. As an observation I found that the Chalassani article (3) was unbiased. However, I was surprised that the Reisenbach and Juni editorial stated that in essence there is no place for flvocoxid in our armamentarium. They cited that the American College of Rheumatology has not sanctioned these compounds and thus, should not be a consideration for use in practice.

Still I am left with a large contingent of patients who have found that flavocoxid is quite helpful in reducing pain in osteoarthritis. I monitor the medical food as I would any anti-inflammatory and as yet have not seen any signals that would raise a red flag. What I found most intriguing is the concept of comparing an FDA approved drug to the medical food, flavocoxid (5,6). The research comparison with Naprosyn was not required of Primus and certainly not at the level of what we would see coming from big Pharma, but again that is the issue. Primus and others more than likely are not in a financial position to fund the research and development to the level of a pharmaceutical company, nor is it a requirement of the FDA. As medical foods are GRAS (generally regarded as safe) substances and in public domain they are not patenable. Unfortunately , this leads to a less than robust interest in funding these medical food companies.

I would respectfully disagree with Reisenbach and Juni that physicians may see these compounds as safe because they are “natural products”. I believe that having to write a prescription for these compounds tends to give pause to the physician, and may in fact focus us on the ramifications of these products. In my opinion, I suspect the same care is not taken with nutraceuticals and this represents a clear distinction between these two classes of compounds. However, I do agree that the patient typically needs to be reminded that all ingested compounds can potentially lead to adverse events.In summary, as a clinician I would encourage more research in the area of OA particularly in the medical food category. I agree with both sets of authors that being aware of potential downside to these compounds is critical. But, in order to treat this potentially difficult cohort of patients, we may have to think “out of the box”. There are times when we must rely on our clinical experience when research does not provide us with the answers, which in Rheumatology appears to be a relatively common occurrence. I believe the Chalassani paper and the editorial of Reisenbach and Juni provided us with insight into potential hazards but have not provided a perspective as to whether this flavocoxid may in fact be less safe than what is presently available ( drug interaction,renal & gastrointestinal toxicity(8)). Does in fact the 4 of 877 patients (3) with liver toxicity presumably attributable to Flavocoxid translate into it being more toxic than the present NSAIDs available? That question has been addressed by Levy R et al, (4,5) and based on their preliminary data , flavocoxid appeared to be a safer compound than naproxen.

My perception was that Reisenbach and Juni had more of a problem with the requirements for the class of medical foods than specifically the flavocoxid. Do the authors feel the same way about folic acid which is also within the medical food category? We are all certainly aware of the issues that have transpired with the standard COX2 inhibitors over the past decade and even despite our “best efforts”, negative signals at times do arise (i.e, Rofecoxib (9)). I am sure Juni and Reisenbach recall their Lancet paper on the cardiovascular risk with Rofecoxib (10). Again, I am not intimating that we do less research, but maybe better define what is deemed to be a novel class of compounds. And although Reisenbach and Juni discussed the monoclonal antibody, tanezumab (6) for osteoarthritis, learning the cost of this biologic for our 35 million OA patients in the US will certainly inspire much needed discussion.

Sincerely,Howard M. Busch DO FACR


1) Galan MV,Gordon SC,Silwenna,AL Celebrex induced cholestatic hepatitis, Annals Int Med 2000;134;254

2) Hajj,E,Malik SM,Alwakeel NR,Obad S et al,Celebrex induced cholestatic liver failure requiring orthotopic liver transplantation, World of Gastoent,2009,aug 21;15(34) 7937- 39

3) Chalasani M, Vuppolanchi R,Navarro V,Fontana R,Banovsky H,Bonnart H etal,Drug induced liver injury network acute liver injury due to Flavocoxid (Limbrel) a medical food for OA- a case series, ann inten med 2012;156:857-60

4) Levy RMSarkvorsky R, Schmidt E, Khakhlov A,Burnett BP Favocoxid is as effective as naproxen for managing the signs and symptoms of OA at the knee in humans, ashort term randomized double blind pilot study Nutr Res 2009;29:298-304

5) Levy RM, Khokhlov A, Kopenkin S,Bart B, Ermolova T,Kantemirova R, et.al. Efficacy and safety of Flovocoxid a novel therapeutic compound with naproxen a randomized multicenter controlled trial in subjects with osteoarthritis of the knee. Adv Ther 2010;27:731-42

6) Lane NE, Schnitzer TJ, Birbara CA, Mokhatarani M,Shelton,DL, Smith MD,et al,Tanezumab for the treatment of pain from osteoarthritis of the knee, N Engl J Med 2010;363:1521-31.

7) FDA, Medical food category defined (1988)section 5(b) of orphan drug act (21 usc360ee (b)(3))

8) Britto,et al Flavocoxid an anti-inflammatory agent of botanical origin does not affect coagulation or interact with anticoagulation therapies. Adv ther.2010,27(6)400-11

9) Topol EJ,Failing the Public Health-Rofecoxib,Merck and the FDA NEJM, 10/21/04,35::1707-1709.

10) Juni P et.al.,Risk of cardiovascular events and Rofecoxib:cumulative meta analysis,Lancet 2004, Dec4-10;364(9450):2021-9.

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Summary for Patients

Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis

The full report is titled “Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis. A Case Series.” It is in the 19 June 2012 issue of Annals of Internal Medicine (volume 156, pages 857-860). The authors are N. Chalasani, R. Vuppalanchi, V. Navarro, R. Fontana, H. Bonkovsky, H. Barnhart, D.E. Kleiner, and J.H. Hoofnagle, on behalf of the Drug-Induced Liver Injury Network.


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