LETTERS TO THE EDITOR
nature publishing group
Response to Chalassani et al. Robert Levy, MD1 doi:10.1038/ajg.2014.426
To the Editor: I was interested to read the article by Chalassani, et al. (1) and wish to offer some comments. I greatly admire the work of the Drug Induced Liver Injury Network (DILIN) in increasing awareness of the breadth of chemical entities that can cause liver injury. However, the authors seem more conversant with those molecules classified as drugs compared with those of botanical origin, which has resulted in some errors of commission and omission in this article. Some of the statements in the section on regulatory issues related to supplements and medical foods (MFs) were inaccurate. Medical foods are not considered supplements and are not defined or regulated under supplement statutes. In the article, reference #52 sites the following website: http://fda. gov/food/foodsafety/product-specificinformation/medicalfoods/default.htm. However, neither I nor several other people have been able to find such a site and are told no such site exists when we enter it into our browsers. Supplements are regulated under DSHEA. Medical Foods are regulated under the Orphan Drug Act of 1988. There are vast differences between the supplement and MF categories. Most importantly, supplements are, by statute, intended to maintain health in healthy people and cannot make disease claims, whereas MFs are, by statute, intended for people with chronic diseases and must make disease claims. Medical foods must be administered under the direction of a physician, whereas supplements can be purchased over the counter. In addition, MFs must be composed of GRAS (generally recognized as safe) ingredients, which must be present in the food chain, even if in low concentrations. © 2015 by the American College of Gastroenterology
As such, the requirements for safety demonstration that are an integral part of the NDA process for new molecular entities are vastly different for products derived from dietary sources than for products synthesized in a laboratory for which we are not genetically programed to recognize or utilize and for which no historical evidence of safety exists. My second issue is with the use of flavocoxid (id, not ib) as the primary example of DILI associated with “herbal” products. Flavocoxid, marketed by Primus Pharmaceuticals, Inc. as Limbrel, is classified as a medical food and, while it is composed of botanically derived molecules, it is not an herbal supplement but, rather, a serious medication intended for people with chronic inflammatory diseases such as osteoarthritis. Flavocoxid has some potential for liver injury, but it is no greater, and probably less than that of NSAIDs, all of which give incidences of 10–15% in their package inserts. Only two cases of elevated liver tests have been reported to Primus in the past 20 months. However, as opposed to all NSAIDs, flavocoxid, although having efficacy comparable with naproxen in clinical trials, does not cause gastrointestinal (GI) ulcerations, raise blood pressure, increase risk of myocardial events, cause renal disease, alter platelet function, or interact with warfarin. In fact, it can and has been used successfully in patients with NSAIDinduced GI ulcerations and nephropathy. All medications, indeed, all chemical entities with physiological activity, have the potential for adverse events. Although we all wish that were not so, in the practice of medicine it is, ultimately, the overall risk to benefit ratio that should determine choices of therapy. Nowhere in this article is flavocoxid’s risk of liver toxicity put in perspective by comparing it with the known similar risk of NSAIDs. Primus is grateful to Dr Chalassani and the DILIN for raising awareness of the need to monitor for liver toxicity when prescribing flavocoxid, and we hope this information will complement that given in the Limbrel package insert, on the Lim-
brel website, and in an open letter sent to prescribers several years ago. However, I believe that the inaccuracies and selective omissions in this paper create a biased and inaccurate impression that is unwarranted. Sadly, the net effect of these omissions might be that patients are denied access to what is undoubtedly the safest prescription anti-inflammatory agent on the market. CONFLICT OF INTEREST The author is a full time salaried employee of Primus Pharmaceuticals, Inc. REFERENCES 1. Chalasani NP, Hayashi PH, Bonkovsky HL et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2015;110:471–2 (this issue). 1
Primus Pharmaceuticals, Inc., Clinical Development, Scottsdale, Arizona, USA. Correspondence: Robert Levy, MD, Primus Pharmaceuticals, Inc., Clinical Development, 7373N. Scottsdale Road, Scottsdale, Arizona 85253, USA. E-mail: [email protected]
Response to Levy Victor Navarro, MD1 and Naga P. Chalasani, MD2 doi:10.1038/ajg.2015.14
To the Editor: We thank Dr Levy, Director of Clinical Development for Primus Pharmaceuticals, manufacturer of Limbrel (flavocoxid), for his comments and clarification (1). The website referenced in the Guidelines was operational at the time of submission. As of this writing, the following website should lead the readers to detailed information (frequently asked questions) regarding the regulation of medical foods: http://www.fda.gov/Food/ GuidanceRegulation/GuidanceDocuments RegulatoryInformation/MedicalFoods/ ucm054048.htm. Although oversight of medical foods is the responsibility of the same regulaThe American Journal of GASTROENTEROLOGY
471
Copyright of American Journal of Gastroenterology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
nature publishing group
Response to Chalassani et al. Robert Levy, MD1 doi:10.1038/ajg.2014.426
To the Editor: I was interested to read the article by Chalassani, et al. (1) and wish to offer some comments. I greatly admire the work of the Drug Induced Liver Injury Network (DILIN) in increasing awareness of the breadth of chemical entities that can cause liver injury. However, the authors seem more conversant with those molecules classified as drugs compared with those of botanical origin, which has resulted in some errors of commission and omission in this article. Some of the statements in the section on regulatory issues related to supplements and medical foods (MFs) were inaccurate. Medical foods are not considered supplements and are not defined or regulated under supplement statutes. In the article, reference #52 sites the following website: http://fda. gov/food/foodsafety/product-specificinformation/medicalfoods/default.htm. However, neither I nor several other people have been able to find such a site and are told no such site exists when we enter it into our browsers. Supplements are regulated under DSHEA. Medical Foods are regulated under the Orphan Drug Act of 1988. There are vast differences between the supplement and MF categories. Most importantly, supplements are, by statute, intended to maintain health in healthy people and cannot make disease claims, whereas MFs are, by statute, intended for people with chronic diseases and must make disease claims. Medical foods must be administered under the direction of a physician, whereas supplements can be purchased over the counter. In addition, MFs must be composed of GRAS (generally recognized as safe) ingredients, which must be present in the food chain, even if in low concentrations. © 2015 by the American College of Gastroenterology
As such, the requirements for safety demonstration that are an integral part of the NDA process for new molecular entities are vastly different for products derived from dietary sources than for products synthesized in a laboratory for which we are not genetically programed to recognize or utilize and for which no historical evidence of safety exists. My second issue is with the use of flavocoxid (id, not ib) as the primary example of DILI associated with “herbal” products. Flavocoxid, marketed by Primus Pharmaceuticals, Inc. as Limbrel, is classified as a medical food and, while it is composed of botanically derived molecules, it is not an herbal supplement but, rather, a serious medication intended for people with chronic inflammatory diseases such as osteoarthritis. Flavocoxid has some potential for liver injury, but it is no greater, and probably less than that of NSAIDs, all of which give incidences of 10–15% in their package inserts. Only two cases of elevated liver tests have been reported to Primus in the past 20 months. However, as opposed to all NSAIDs, flavocoxid, although having efficacy comparable with naproxen in clinical trials, does not cause gastrointestinal (GI) ulcerations, raise blood pressure, increase risk of myocardial events, cause renal disease, alter platelet function, or interact with warfarin. In fact, it can and has been used successfully in patients with NSAIDinduced GI ulcerations and nephropathy. All medications, indeed, all chemical entities with physiological activity, have the potential for adverse events. Although we all wish that were not so, in the practice of medicine it is, ultimately, the overall risk to benefit ratio that should determine choices of therapy. Nowhere in this article is flavocoxid’s risk of liver toxicity put in perspective by comparing it with the known similar risk of NSAIDs. Primus is grateful to Dr Chalassani and the DILIN for raising awareness of the need to monitor for liver toxicity when prescribing flavocoxid, and we hope this information will complement that given in the Limbrel package insert, on the Lim-
brel website, and in an open letter sent to prescribers several years ago. However, I believe that the inaccuracies and selective omissions in this paper create a biased and inaccurate impression that is unwarranted. Sadly, the net effect of these omissions might be that patients are denied access to what is undoubtedly the safest prescription anti-inflammatory agent on the market. CONFLICT OF INTEREST The author is a full time salaried employee of Primus Pharmaceuticals, Inc. REFERENCES 1. Chalasani NP, Hayashi PH, Bonkovsky HL et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2015;110:471–2 (this issue). 1
Primus Pharmaceuticals, Inc., Clinical Development, Scottsdale, Arizona, USA. Correspondence: Robert Levy, MD, Primus Pharmaceuticals, Inc., Clinical Development, 7373N. Scottsdale Road, Scottsdale, Arizona 85253, USA. E-mail: [email protected]
Response to Levy Victor Navarro, MD1 and Naga P. Chalasani, MD2 doi:10.1038/ajg.2015.14
To the Editor: We thank Dr Levy, Director of Clinical Development for Primus Pharmaceuticals, manufacturer of Limbrel (flavocoxid), for his comments and clarification (1). The website referenced in the Guidelines was operational at the time of submission. As of this writing, the following website should lead the readers to detailed information (frequently asked questions) regarding the regulation of medical foods: http://www.fda.gov/Food/ GuidanceRegulation/GuidanceDocuments RegulatoryInformation/MedicalFoods/ ucm054048.htm. Although oversight of medical foods is the responsibility of the same regulaThe American Journal of GASTROENTEROLOGY
471
Copyright of American Journal of Gastroenterology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
