---

---

---

WARNING LETTER

UNITED PARCEL SERVICE SIGNATURE REQUIRED

May 4, 2022

RE: 622403

Dear Mr. Cohen:

This letter concerns your product Synedrex, which is labeled as a dietary supplement. As explained further below, introducing or delivering this product for introduction into interstate commerce violates the Federal Food, Drug, and Cosmetic Act (FD&C Act) because the product is an adulterated dietary supplement. You can find the FD&C Act through links on FDA’s website at https://www.fda.gov/regulatory-information/laws-enforced-fda/federal-food-drug-and-cosmetic-act-fdc- act and the FDA regulations at https://www.ecfr.gov/current/title-21.

Adulterated Dietary Supplement: New Dietary Ingredients

The label of your Synedrex product declares octopamine, hordenine, and higenamine as dietary ingredients. Octopamine is a “dietary ingredient” under section 201(ff)(1)(F) of the FD&C Act [21 U.S.C.
§ 321(ff)(1)(F)] because it is a constituent of bitter orange and other botanicals. Hordenine is a “dietary ingredient” under section 201(ff)(1)(F) of the FD&C Act [21 U.S.C. § 321(ff)(1)(F)] because it is a constituent of barley and other botanicals. Higenamine is a “dietary ingredient” under section 201(ff)(1)(F) of the FD&C Act [21 U.S.C. § 321(ff)(1)(F)] because it is a constituent of aconite, asarum, lotus, and other botanicals. As explained below, octopamine, hordenine, and higenamine are also “new dietary ingredients” (i.e., dietary ingredients not marketed in the United States before October 15, 1994) under section 413(d) of the FD&C Act [21 U.S.C. § 350b(d)].

Under section 413(a) of the FD&C Act [21 U.S.C. § 350b(a)], a dietary supplement that contains a new dietary ingredient shall be deemed adulterated under section 402(f) of the FD&C Act [21 U.S.C. § 342(f)] unless it meets one of two requirements:

1.    The dietary supplement contains only dietary ingredients that have been present in the food supply as an article used for food in a form in which the food has not been chemically altered; or

2.    There is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides FDA with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.

To the best of FDA’s knowledge, there is no information demonstrating that octopamine, hordenine, or higenamine were lawfully marketed as dietary ingredients in the United States before October 15, 1994, nor is there information demonstrating that octopamine, hordenine, or higenamine have been present in the food supply as articles used for human food in a form in which the food has not been chemically altered. Therefore, octopamine, hordenine, and higenamine are subject to the premarket new dietary ingredient notification requirement in section 413(a)(2) of the FD&C Act [21 U.S.C. § 350b(a)(2)] and 21 CFR 190.6. FDA has not received any NDI notifications pertaining to the use of octopamine, hordenine, or higenamine in dietary supplements. Products for which the manufacturer or distributor is required to submit a new dietary ingredient notification under section 413(a)(2) and 21 CFR 190.6, but for which the required notification has not been submitted, are adulterated under sections 402(f) and 413(a) of the FD&C Act [21 U.S.C. §§ 342(f) and 350b(a)].

Moreover, based on our evaluation of the relevant safety evidence, there is no history of use or other evidence of safety establishing that hordenine or higenamine will reasonably be expected to be safe when used as dietary ingredients. Therefore, even if new dietary ingredient notifications had been submitted for hordenine and higenamine, dietary supplements containing hordenine or higenamine would still be adulterated under sections 402(f) and 413(a) of the FD&C Act [21 U.S.C. §§ 342(f) and 350b(a)]. In the absence of adequate information to provide reasonable assurance that hordenine and higenamine do not present a significant or unreasonable risk of illness or injury, dietary supplements containing hordenine or higenamine are adulterated under section 402(f)(1)(B) of the FD&C Act [21 U.S.C. § 342(f)(1)(B)]. The introduction into interstate commerce of dietary supplements that are adulterated under sections 402(f) and 413(a) of the FD&C Act is prohibited under sections 301(a) and (v) of the FD&C Act [21 U.S.C. § 331(a) and (v)].

This letter is not intended to be an all-inclusive statement of violations that may exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure and injunction.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps you have taken to address any violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the time within which you will do so. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.

Your written reply should be directed to Aaron Dotson, Compliance Officer, via email at CFSANResponse@fda.hhs.gov. If you have any questions, you may also email at CFSANResponse@fda.hhs.gov.

 
Sincerely,
/S/
Ann M. Oxenham Director
Office of Compliance
Center for Food Safety and Applied Nutrition
Food and Drug Administration