Active pharmaceutical ingredients showing up in products purporting to be supplements is an ongoing issue plaguing the industry. Weight loss products, erectile dysfunction products and sports performance formulations have been the categories of highest risk.
In weight loss, the renegade APIs most often cited by FDA is sibutramine, which at one time was a prescription appetite suppressant before being pulled from the market over cardiovascular safety concerns. In the ED arena the APIs of choice that FDA annually sends dozens of citations about are the knockoff versions of ED drugs such as Viagra and Cialis (sildenafil and tadalafil).
But fluoxetine is a newbie on this list. It was cited by FDA for inclusion in a weight loss products called Xcel and sold on a site called zixiutangforyourfigure.com. The fact that FDA caught this instance and the one cited below may be due to its development of a rapid screening technology for finding undeclared APIs in weight loss products. Fluoxetine was one of the ingredients included in the list of APIs the process was designed to detect.
Two other weight loss products were cited by FDA at the same time for the inclusion of phenolphthalein, one called Xcel Advanced and the other branded as Ultimate Boost. Phenolphthalein has shown up from time to time as an adulterant in weight loss products. It was used for many years as a laxative but was withdrawn from the market when a study in the 1990s indicated an unacceptably high cancer risk associated with the drug.
So including an undeclared laxative API in a weight loss formulation, while illegal and indefensible, is at least understandable from a pharmacological perspective. But fluoxetine? The drug belongs to a broad category of antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) and was one of the first to market under the brand name Prozac. FDA takes the extreme view of the risks of SSRI use, saying: “Uses of SSRIs have been associated with serious side effects including suicidal thinking, abnormal bleeding, and seizures. In patients on other medications for common conditions (aspirin, ibuprofen, or other drugs for depression, anxiety, bipolar illness, blood clots, chemotherapy, heart conditions, and psychosis), ventricular arrhythmia or sudden death can occur.”
While these are the outlier side effects, the risk is hard to quantify without knowing the dosage, which is of course the crux of the matter when it comes to undeclared APIs. But one of the more common side effects of SSRI use is weight gain. So again, why turn to this drug to supercharge your “dietary supplement?”
Off label uses
In addition to treating the more common variants of depression, fluoxetine has also been used in the treatment of the eating disorder bulimia and has also been applied in cases of obsessive compulsive disorder, which can sometimes have an eating component. Those mentions on a list might be just enough for one of the renegade formulators who might be casting about for a new hidden ingredient, said Dr Rick Kingston, clinical professor of pharmacy at the University of Minnesota.
“I suspect the reason why they put that in there is there are some conditions that are amenable to treatment with an SSRI that could lead to weight gain such as bulimia or obsessive compulsive disorder. SSRIs have been studied in other weight loss indications and conditions with varying degrees of success,” Kingston, who also holds the title of president, regulatory and scientific affairs with SafteyCall International, told NutraIngredients-USA.
But even with that slender pharmacological reed to rest on, Kingston said the choice of using this ingredient might just come down to a lack of sophistication and a matter of price.
“The drug has been generic for a long time so it’s probably cheap enough,” he said. “And you have to remember, a lot of the time these aren’t the smartest guys in the world if they are resorting to this kind of adulteration. They look at each individual ingredient, try to come up with a justification for its use, and they throw it in there. Sometimes you can come up with some pretty strange blends.”
Case of counterfeiting
Fluoxetine was also mentioned in a case that drew the attention of members of Congress. Recently three Senators, Dick Durbin, D-IL, Dianne Feinstein, D-CA, and Richard Blumenthal, D-CT sent a letter to FDA requesting the agency investigate Oxy ELITE Pro Super Thermogenic products for their inclusion of fluoxetine. FDA issued a warning on the products in late February.
This line of products was once manufactured by USP Labs, which said in response to the lawmakers’ letter that it recalled all product and ceased manufacture of the line in 2013 after an outbreak of acute hepatitis in Hawaii linked with the product. USP Labs claims that the products cited by the Senators are in fact counterfeits.
“An investigation has determined that the product in question was not manufactured or distributed by or for USPLabs. It is a counterfeit.As soon as this was discovered, USPLabs immediately alerted the FDA,” the company stated.
While this manufacturer has had a history of difficult dealings with regulators, this latest claim of counterfeiting has at least the ring of truth, observers said. Counterfeiting happens more often than many in the supplement world realize, said attorney Justin Prochnow, a shareholder in the firm Greenberg Traurig. He said a client of his had brought in a counterfeited product and the only difference between that and the legitimate label was a slight variation in color, imperceptible without having the two examples side by side.
How regulations can help
Marc Ullman, an attorney in the firm Ullman, Shapiro & Ullman, said that careful attention to the letter of labeling regulations can help lessen the risk of counterfeiting.
“People complain about the labeling regulations, having to keep records of and controlling your labels. But this is an example of regulations having a significant business benefit. People comb through dumpsters at regulated facilities to see if they can get their hands on legitimate labels. I’m not saying that this is one of those cases, but in cases where people have gotten hold of actual labels it makes controlling the counterfeiting problem incredibly difficult,” said attorney Marc Ullman of Ullman, Shapiro & Ullman.