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Medical Food and Food Supplements: Not Always as Safe as Generally Assumed

Stephan Reichenbach, MD, MSc; and Peter Jüni, MD
[+] Article and Author Information

From University of Bern, 3012 Bern, Switzerland.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0992.

Requests for Single Reprints: Peter Jüni, MD, Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; e-mail, juni@ispm.unibe.ch.

Current Author Addresses: Drs. Reichenbach and Jüni: Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.


Ann Intern Med. 2012;156(12):894-895. doi:10.7326/0003-4819-156-12-201206190-00012
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Food supplements and medical foods have gained popularity among consumers who often assume that they are safer than drugs. In this issue, Chalasani and colleagues report 4 cases of acute liver injury associated with the medical food flavocoxid. The editorialists discuss the case series and emphasize that clinical evidence from well-designed studies should be required of any health care intervention, including food supplements and medical foods.

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A Clinician’s Perspective:
Posted on July 25, 2012
Howard M. Busch DO FACR
None
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

References

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.

Physicians Need to Aware of Information in Product Inserts and Elsewhere
Posted on September 12, 2012
Robert M. Levy, MD, Director of Clinical Development, Bruce Burnett, PhD, Director of Scientific Affairs
Primus Pharmaceuticals, Inc.
Conflict of Interest: None Declared

Dear Editor:

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 (Morgan and Baggott, 2006).  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." Because of the regulatory category name, physicians not familiar with the category sometimes mistakenly equate medical foods with supplements and assume a total absence of adverse effects. In fact, medical foods were considered drugs until they were separated into their own category as part of the Orphan Drug Act of 1988 (21 U.S.C. Sec. 360ee (b)(3)). Unlike supplements which are intended to preserve health in healthy people, medical foods are, by statute, intended to be used for the management of chronic diseases under the direction of a physician. They must also be composed of what are called GRAS (generally recognized as safe) ingredients, a designation comparable to that of conventional foods. Obtaining GRAS status requires extensive review by a panel of toxicology experts. This does not mean, however, that these products are totally devoid of potential adverse effects just as certain foods may produce side effects such as allergies or intolerances in some people (e.g., peanut and milk products)

 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 over 8 years of marketing in the US and Puerto Rico). Primus Pharmaceuticals, Inc. monitors its adverse event rate and makes this pharmacovigilance available to the public on its website unlike most pharmaceutical companies (found 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 (Pillai et al., 2010a). However, as pointed out in the paper by Chalassani, et al, Limbrel has produced some liver adverse events. 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 DLI 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 appears to be comparable to that of every other anti-inflammatory agent including both NSAIDs and selective COX-2 inhibitors as reported in the package inserts of all of these agents of between 5-15% incidence of elevated transaminases Rubenstein 2005). In clinical trials, the incidence of symptomatic adverse events was similar to placebo (Morgan et al., 2009) and hepatotoxicity was comparable to naproxen (Levy et al., 2010a). Although unproven, we agree with Chalassani, et al (2012) that the most likely mechanism is idiosyncratic (hypersensitivity, allergic) rather chemical toxicity based on the presence of elevated eosinophil counts and inflammatory cell infiltrates in biopsy specimens in many of these patients. The assumption that catechin or epicatechin is responsible for the hepatotoxicity is reasonable, though unproven. The literature contains several reports about presumed hepatotoxicity from tea catechins (Mazzanti et al., 2009) although a review by the US Pharmacopeia was inconclusive (Sarma et al., 2008). The problem is further complicated by the fact that many herbal remedies 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 (Pak et al., 2004). Surveys of patients attending liver disease clinics have revealed that between 21% and 30% had used herbal remedies within the prior 12 months (Berk et al., 1999, Stickel et al., 2005). Other surveys of liver disease patients have reported between 33-75% (ave. 41%) CAM (complementary and alternative medicine) usage and 12-50% (ave. 20%) usage of herbal remedies (Seeff et al., 2001). The advantage of a medical food in terms of side effect pharmacovigilance is that, by Federal Statute, the physician must be involved in the dosing and monitoring of the therapeutic use of these products unlike over-the-counter supplements and drugs. Along with pharmacists, physicians can also make sure that these products are used safely considering potential drug/herbal interactions and comorbidities that are unique to each patient. Finally, it should be recalled that acetaminophen, one of the most ubiquitous OTC drugs, accounts for about 50% of all cases of liver failure in the U.S (Kaplowitz 2001, Ostapowitiz 2002).

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 agent, flavocoxid, despite having the best overall safety profile of all anti-inflammatory agents, it is not totally devoid of potential adverse effects just like shrimp and peanuts which can elicit unmonitored, serious adverse events. 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.

 Regards,

 Robert M. Levy, MD 

Director of Clinical Development

 Bruce P Burnett, PhD

Director of Scientific Affairs

 Primus Pharmaceuticals, Inc.

 References:

1. Berk BS, Chaya C, Benner KC, Flora KD. Comparison of herbal therapy for liver disease:1996 versus 1999. Hepatology. 1999.30:478A.

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

3. 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

4. Mazzanti G, Menniti-Ippolito F, Moro PA, et al. Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur. J Clin Pharmacol. 2009.65:331-41.

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

6. 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.

7. Ostapowicz G, Fontana RJ, Schiodt FV et al.  Results of a prospective study of acute liver failure at 1         tertiary care centers in the United States. Ann Intern med. 2002.137;947-54.

 

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

9. 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.

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

11., Sarma DL, Barrett ML, Chavez ML, et al. Safety of Green Tea Extracts. A systematic review by the US      Pharmacopeia. Drug Safety. 2008.31:469-84.

12. Seeff, LB, Lindsay KL, Bacon BR, et al.  Complementary and alternative medicine in chronic liver disease. Hepatology  2001.34:595-603.

13. Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol. 2005.43:901-10.

 

 

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