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Adverse Effects / Safety Data

Adverse Effects / Safety Data

Pre-Clinical Toxicology

Acute and subchronic toxicity studies (unpublished) have been completed with CVT-E002.30 Acute oral toxicity of CVT-E002 was tested in healthy adult Sprague Dawley rats at a dose of 2 g per kilogram of body weight. Twenty rats were used (10 female and 10 male; body weight ranged from 130 to 220 g). Rats were either given a single oral dose of CVT-E002 or an equivalent amount of distilled water by oral gavage tube. On day 14, control and test animals were euthanized and necropsied. There were no abnormal clinical observations or mortality associated with CVT-E002. On necropsy, no signs of abnormality were found in any body tissues.

A sub-acute oral toxicity study was conducted in healthy adult Sprague Dawley rats (10 males and 10 pregnant females) at a dose of 50 mg/kg body weight daily for 18 days. Body weight ranged from 183 to 223 g for pregnant female rats and from 214 to 322 g for male rats. Ten of the 20 rats (5 females and 5 males) served as controls and were fed only a normal diet without CVT-E002 added. On day 18, control and test animals were euthanized and necropsied. There were no abnormal clinical observations or mortality associated with CVT-E002. On necropsy, there were no changes that could be attributed to the test medication. The number of feti, stage of development, and viability of feti were within the normally expected values for this strain of rat.

Human Safety Data

There is limited published safety data specific to CVT-E002/COLD-fX. The randomized, controlled clinical trials summarized in the Clinical Review section below provide clinically useful data sets, which, on the whole, suggest reasonable safety for the duration and doses tested.14,15,16 Reasonable adverse event monitoring was incorporated into trial methods, and no statistically significant differences in the rate of adverse effect occurrence were noted between COLD-fX and control groups. Adverse event monitoring included self-reported symptoms, and, in the case of the two-year McElhaney trial (2004), standard blood laboratory tests (complete blood count, sodium, potassium, phosphorus, calcium, uric acid, liver and kidney function tests, glucose, lipids, and pre-albumin, albumin and total protein).15 As reassuring as these results are that serious and prevalent adverse effects would likely be uncovered in trials of this size, statistical power considerations do not allow a positive safety assessment for rare but important events. For example, a major adverse event at a frequency of 1 in 100 could easily be missed by a trial of 323 participants, which is the largest and most important of the trials conducted to date.16 Substantially larger trials, or perhaps large cross-sectional or prospective cohort studies, would be needed to confidently exclude unusual but important adverse effects.

Post-marketing surveillance of COLD-fX in Canada follows standard operating procedure for all government-approved Natural Health Products, including receipt and analysis of spontaneous reports of adverse reactions. The manufacturer provides a toll-free telephone number to consumers and keeps track of all reported information. The data in this paragraph is based on such confidential information shared by the manufacturer and on adverse event reports received since market entry in Canada in 1996.30 Despite over 200 million doses of COLD-fX sold to consumers in Canada, less than 100 such reports have been filed. Of these, rare allergic reactions, including hives and other skin reactions, may be reasonably considered attributable to ingestion of the product. A potentially confounding factor is that rash is occasionally observed as a symptom of influenza or other infectious diseases that present similarly to cold and flu. One serious adverse event has been reported. A person experienced an anaphylactic-like event characterized by mouth and tongue swelling during both an initial event, and an event 2 weeks later following a second exposure. [Note: Allergy history of this person is not available.] It is important to note that allergic reactions can occur with virtually all foods, dietary supplements, natural health products, and drugs. Given the data available, the apparent rate of allergic reaction does not appear to be higher with COLD-fX than with many other substances in common use such as foods, dietary supplements, or drugs. Other reported reactions or adverse side effects have not formed patterns suggesting causal linkage to COLD-fX. These include headache, insomnia, dizziness, drowsiness, confusion, nausea, vomiting, abdominal pain, diuresis, lowered blood pressure, and joint pain. As these could all easily be due to underlying health conditions, causal linkage is considered possible, but unlikely.

There are no systematic safety reviews of products derived from P. quinquefolius, possibly because of the relatively low level use of this type of ginseng in North America, as well as the relatively good safety record of such use. However, in 2002 a systematic safety review of Asian ginseng (P. ginseng) was published that may be relevant, as all Panax species share some similar phytochemical constituents,31 even though, as noted throughout this monograph, CVT-E002/COLD-fX does not contain ginsenosides. This comprehensive review included assessment of safety data from 146 clinical trials involving 8,500 individuals, and evaluation of numerous case reports and regulatory data sources across several countries. The review concludes that, while there was some evidence for minor and transient adverse side effects such as abdominal discomfort, lightheadedness, or insomnia, no major risks or dose-dependent adverse effects have been proven for Asian ginseng. Other safety assessments of species of Panax exist. For example, a recent but limited safety review highlights potential endocrine effects (estrogenic and adrenergic) as well as both CNS excitation or depression.32 CVT-E002/COLD-fX has no known estrogenic effects; studies performed on polysaccharide-based aqueous American ginseng extracts similar to CVT-E002 demonstrated no estrogen-like activity.33

As noted, safety data on American ginseng products are substantially less extensive. Nevertheless, an assortment of small studies, including those detailed in this report, have failed to find any substantial dose-dependent or serious adverse effects attributable to CVT-E002 or conventional full-spectrum P. quinquefolius extracts.1,2,3,31,32,34,35 It appears reasonable to conclude that serious adverse effects from COLD-fX are unlikely because of the following: (1) CVT-E002/COLD-fX is comprised primarily of oligosaccharides and polysaccharides, complex sugars which are generally recognized as safe; (2) randomized trial and post-marketing surveillance data are reassuring regarding safety; and (3) the overall safety record of ginseng products is good to excellent.