Presence of Banned Drugs in Dietary Supplements Following FDA Recalls

Presence of Banned Drugs in Dietary Supplements Following FDA Recalls The US Food and Drug Administration (FDA) initiates class I drug recalls when products have the reasonable possibility of causing serious adverse health consequences or death.1 Recently, the FDA has used class I drug recalls in an effort to remove dietary supplements adulterated with pharmaceutical ingredients from US markets. Approximately half of all FDA class I drug recalls since 2004 have involved dietary supplements adulterated with banned pharmaceutical ingredients.2,3 Prior research has found that even after FDA recalls, dietary supplements remain available on store shelves.4 However, it is not known if the supplements on sale after FDA recalls are free of the adulterants. In the present study, dietary supplements purchased at least 6 months after FDA recalls were analyzed to determine if banned drugs were still present.

The US Food and Drug Administration (FDA) initiates class I drug recalls when products have the reasonable possibility of causing serious adverse health consequences or death. 1 Recently, the FDA has used class I drug recalls in an effort to remove dietary supplements adulterated with pharmaceutical ingredients from US markets. Approximately half of all FDA class I drug recalls since 2004 have involved dietary supplements adulterated with banned pharmaceutical ingredients. 2,3 Prior research has found that even after FDA recalls, dietary supplements remain available on store shelves. 4 However, it is not known if the supplements on sale after FDA recalls are free of the adulterants. In the present study, dietary supplements purchased at least 6 months after FDA recalls were analyzed to determine if banned drugs were still present.
Methods | Dietary supplements were analyzed if they met the following inclusion criteria: (1) recalled due to adulteration with pharmaceutical ingredients between January 1, 2009, and December 31, 2012 3,5 ; (2) available for purchase in July or August 2013 directly from websites of supplement manufacturers or retailers (as opposed to general e-commerce sites such as Amazon.com, eBay Inc, or Alibaba Group); and (3) the supplement name, manufacturer, and distributor listed on the purchased supplement was identical to the information provided in the FDA recall.
Dietary supplements were analyzed by Flora Research Laboratories (J.N-K.). Samples were labeled with the marketing claim on the supplement label (eg, weight loss, sexual enhancement, or sports enhancement), but did not include the supplement name, manufacturer, and prior FDA findings.
Analyses were performed using the same methods that the FDA's field laboratories use to screen for clandestine adulteration. In short, dietary supplements were analyzed using either gas chromatography mass spectrometry or liquid chromatography tandem mass spectrometry in data-triggered mode. Adulterants, except for anabolic steroids, were confirmed against a standard using retention time, mass spectrum, and UV spectrum.
Results | The FDA recalled 274 dietary supplements between January 1, 2009, and December 31, 2012. Twenty-seven of the 274 recalled supplements (9.9%) met our inclusion criteria and were analyzed. Supplements were purchased a mean (SD) of 34.3 (11.5) months after the FDA recall (range, 8-52 months). Seventy-four percent of supplements (20/27) were produced by US manufacturers.
Sixty-three percent of analyzed supplements (17/27) contained the same adulterant identified by the FDA. Six of the 27 (22.2%) supplements contained 1 or more additional banned ingredients not identified by the FDA (Table). Some supplements contained both the previously identified adulterant as well as additional pharmaceutical ingredients. Banned substances identified in recalled supplements included sibutramine, sibutramine analogs, sildenafil, fluoxetine, phenolphthalein, aromatase inhibitor, and various anabolic steroids. One novel adulterant, benzyl sibutramine, was first described as recently as 2013. 6 Discussion | To our knowledge, this is the first study to determine if adulterants remain in supplements sold after FDA recalls. We found that 66.7% of recalled supplements still available for purchase at least 6 months after FDA recalls remained adulterated with banned ingredients.
Our study has several limitations. First, we limited testing to common adulterants expected based on marketing claims (eg, weight loss supplements were tested for adulterants commonly found in weight loss products). Second, our analyses may have failed to detect recently introduced drug analogs. Third, although every effort was made to purchase recently manufactured supplements, it is not known if all supplements were manufactured after the FDA recall.
Action by the FDA has not been completely effective in eliminating all potentially dangerous adulterated supplements from the US marketplace. More aggressive enforcement of the law, changes to the law to increase the FDA's enforcement powers, or both will be required if sales of these products are to be prevented in the future.

Insulin vs Sulfonylureas for Second-Line Diabetes Treatment
To the Editor Dr Roumie and colleagues 1 reported that compared with sulfonylureas the addition of insulin to metformin to improve glycemic control was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality in patients with diabetes mellitus. Although the results presented require verification in carefully designed clinical trials, we have some concerns about the current analyses. Roumie et al 1 stated that subgroup analyses stratifying by age were consistent with the primary analysis. However, eFigure 3 showed that the hazard ratio (HR) for cardiovascular events or death was 1.14 (95% CI, 0.82-1.59) for patients younger than 65 years, whereas for those aged 65 years or older, the HR was 1.51 (95% CI, 1.19-1.92). For the composite death outcome, the HR was 1.28 (95% CI, 0.85-1.97) for patients younger than 65 years, whereas for those aged 65 years or older, the HR was 1.66 (95% CI, 1.29-2.14). Contrary to the conclusion made by the authors, the results suggest that insulin added to metformin is safe among patients younger than 65 years but appears to be hazardous in older patients with diabetes.
Part of the explanation may be differences in types of insulin used and hypoglycemia by age group. Of the patients in the metformin plus insulin group, 47% used long-acting agents only; 22%, both long-and short-acting agents; 17%, premixed insulin; and 11%, short-acting agents only. Although premixed insulin use in older adults can increase the risk of hypoglycemia compared with long-acting analogs, 2 even the choice of regular or analog insulin can influence the frequency of hypoglycemic episodes when multiple injections are used. 3 Thus, the type of insulin chosen for older patients with diabetes should be taken into consideration in such database analyses.
In addition, below a hemoglobin A 1c level of 8%, the risk of treatment-induced hypoglycemia increases. 4 Because mean achieved hemoglobin A 1c levels were 7% among sulfonylurea users and 6.9% among insulin users in this study, missing hypoglycemia data are of concern. Even though Roumie et al 1 used an extensive database, they were unable to obtain data on hypoglycemia frequency, especially the number of severe events requiring hospital admission.
Such information is essential for appropriate interpretation of the study. Although sulfonylurea drugs can also increase the risk hypoglycemia of among older patients, comparative data are still required.