Distributor ignores FDA warning over anti-inflammatory drug in supplement

The U.S. Food and Drug Administration in April 2023 issued a public notification, recommending consumers not use a specific product marketed as a dietary supplement and sold for arthritis or joint pain.

An FDA lab analysis verified the product called AK Forte contained three substances not declared on the label: diclofenac, dexamethasone and methocarbamol.

FDA advised the public that diclofenac is a nonsteroidal anti-inflammatory drug (or NSAID), which may cause increased risk of cardiovascular events such as heart attack and stroke, as well as serious gastrointestinal (GI) damage, including bleeding, fatal perforation of the stomach and intestines, and ulceration.

A distributor of AK Forte, Suprimo Imports, subsequently received a June 22, 2023, warning letter from FDA’s Center for Drug Evaluation and Research (CDER). FDA cautioned the firm that its products were unapproved new and misbranded drugs sold in violation of the Federal Food, Drug and Cosmetic Act (FDCA).

In an investigation that began in 2023 to determine how the distributor responded to FDA’s actions — and whether AK Forte was removed from the market or reformulated — SupplySide Supplement Journal (formerly known as Natural Products Insider obtained and reviewed several FDA documents and had AK Forte tested by two separate companies with deep expertise analyzing supplements

Related:FDA targets AK Forte distributor for selling drugs, not supplements

This is the first in a series of articles about AK Forte. Key findings from SupplySide Supplement Journal's investigation are below:

As of last week, Suprimo Imports was continuing to sell products on its website, including AK Forte, according to an online search. The product did not appear, however, in a search of AK Forte on the day of this article’s publication — several days after SupplySide Supplement Journal reached out via email to the distributor for comment.

Following publication of this story, SupplySide Supplement Journal observed Suprimo Imports' website was no longer selling products. The website now has a banner "Coming Soon."

When asked whether FDA has initiated a civil or criminal probe into the matter, an FDA spokesperson in the Office of Regulatory Affairs said the agency does not comment on possible investigations.

Bob Durkin, a Washington, D.C.-based lawyer with Arnall Golden Gregory LLP and former FDA official in the Office of Dietary Supplement Programs, said in a brief interview that he wondered what actions FDA took to follow up on its AK Forte advisory and warning letter to ensure the agency was “effective in removing the hazard from commerce.”

“As a former fed, I would like to think [FDA officials] have commenced civil or criminal actions in this matter,” he said. “It’s just unfortunate that it seems to take this long.”

Testing of AK Forte

Flora Research Laboratories in Grants Pass, Oregon, specializes in botanical identity and dietary supplement testing. Its founder and director James Kababick said his firm has been testing for pharmaceutical drugs for over a quarter century.

Within a year of Viagra being introduced to the U.S. market, Flora Research Laboratories started seeing it in products from China marketed as all-natural herbal products/dietary supplements, Kababick reflected in an interview. Sildenafil is the active ingredient in Viagra.

A January 2024 analytical report from Flora Research Laboratories detected sildenafil in a sample of a product distributed by Suprimo Imports, “Reinforced Premium Super Pack, 6 Golden Garlics.” The lab further identified the presence of diclofenac and dexamethasone in a sample of AK Forte containing 100 tablets.

The lab conducted its analysis by HPLC, or high-performance liquid chromatography, using DAD (diode array detection) and accurate mass Q (quadrupole)-TOF (time-of-flight) mass spectrometry, Kababick said. The samples arrived on Oct. 30, 2023, within a month of him ordering them from the website of Suprimo Imports.

In a subsequent quantitative analysis of AK Forte, Flora Research Laboratories found 8.75% diclofenac and 0.09% dexamethasone. Based on the average unit weight of the capsule/tablet multiplied by the percentage of the compound, the lab determined AK Forte contained 52 mg per tablet of diclofenac and half a mg of dexamethasone, Kababick told SupplySide Supplement Journal. In its quantitative analysis of AK Forte, Flora Research Laboratories specifically targeted diclofenac and the other compounds flagged by FDA in its public advisory.

The AK Forte sample has an expiration date of July 14, 2026, and lot number 19522. That lot number matches up with a manufacturing code number of AK Forte in an FDA document obtained by SupplySide Supplement Journal.

On July 31, 2023, at the request of SupplySide Supplement Journal, NOW Foods ordered products from Suprimo Imports and had them tested the following month. Mark Krzeszowiec, method development supervisor for NOW, said the products were dissolved in methanol and analyzed by HPLC high-resolution accurate mass spectrometry using untargeted data acquisition.

Through testing a sample of AK Forte, NOW — headquartered in Bloomingdale, Illinois, and among the country’s largest supplement brands — detected the same three compounds as FDA (diclofenac, dexamethasone and methocarbamol, a muscle relaxant) plus two other substances: gabapentin and guaifenesin.

Two other products tested by NOW (H-Force and 6 Ajos Dorados) and sold by Suprimo Imports identified the presence of sildenafil and many of the compounds referenced above. Another product tested by NOW, Bob Marley Cannabis King, was found to contain no CBD or THC, though other compounds identified suggested the presence of citrus seed, Krzeszowiec said. FDA’s warning letter to Suprimo Imports flagged a similar product marketed as a dietary supplement and called Bob Marley CannaKing, noting CBD is excluded from the definition of a dietary supplement.

NOW confirmed the presence of diclofenac, dexamethasone, methocarbamol and sildenafil with reference standards, Krzeszowiec said.

Subsequent quantitative testing of AK Forte by NOW identified 380 micrograms (mcg) per tab of dexamethasone, 65 mcg of methocarbamol, 0.11 mcg of gabapentin, 82 mcg of guaifenesin and 1,300 mcg (or 1.3 mg) of diclofenac.

The AK Forte sample tested by NOW had the same lot number as the one tested by FDA and Flora Research Laboratories. There was a significant discrepancy between the quantity of diclofenac detected by NOW (1.3 mg per tab) and the amount identified by FDA (51 mg) and Flora Research Laboratories (52 mg).

Krzeszowiec said it’s hard to determine why NOW’s results concerning the amount of diclofenac in AK Forte differed from those produced by FDA and Flora Research Laboratories.

One possibility is NOW’s “method was not optimized specifically for diclofenac,” while Flora Research Laboratories may have been, he said in an email. “Our method is an untargeted method and run without a priori knowledge of what is in the sample. Therefore, it is impossible to really optimize extraction for any one compound. We did not choose to optimize the method for a targeted analysis of diclofenac; doing so may have given us more accurate results, but ultimately it doesn’t change the fact that the presence of any amount of these active pharmaceutical compounds is forbidden.”

Jonathan DeCenzi, laboratory manager at NOW, noted his company is unaware of the lot sizes, and the potential exists for variability from bottle to bottle within the same lot. He also reiterated NOW’s “method as it exists is intended to be qualitative in order to detect compounds that are not supposed to be present at any level.”

Therefore, NOW “never optimized the sample prep portion of the method for the specific extraction of diclofenac and estimated the amount using standard addition,” DeCenzi added.

Suprimo Imports did not respond to an emailed request for comment on the labs’ findings or respond to previous requests regarding FDA’s actions in 2023.

Diclofenac, dexamethasone medical uses

As an FDA-approved drug, diclofenac is used in the treatment and management of acute and chronic pain associated with inflammatory conditions, particularly those involving the musculoskeletal system, according to a 2023 article published in StatPearls, a continuing education resource for medical professionals.

“Generally, diclofenac potassium is administered in either 25 mg or 50 mg doses 1 to 4 times per day for total doses between 50 to 200 mg per day,” the authors wrote. “This treatment is the indicated regimen for migraines, osteoarthritis, generalized pain, primary dysmenorrhea and rheumatoid arthritis.”

According to FDA’s warning letter to Humberto Cecena of Suprimo Imports, diclofenac was approved in 1998 by FDA as a new drug under the trade name Voltaren, while dexamethasone was approved in 1960 as a new drug under the trade name Hexadrol.

“Given that diclofenac and dexamethasone were not marketed as dietary supplements or as food before Voltaren and Hexadrol were approved, ‘AK Forte,’ which contains diclofenac and dexamethasone, is excluded from the definition of a dietary supplement under section 201(ff)(3)(B)(i) of the [FDCA] Act,” FDA advised Cecena.

Dexamethasone is a corticosteroid generally used to treat inflammatory conditions, according to FDA’s 2023 public notification regarding AK Forte. Use of a corticosteroid can impair someone’s ability to battle infections and cause high blood sugar levels, muscle injuries and psychiatric problems — and at high doses, or when taken for a prolonged period, corticosteroids can suppress the adrenal gland, FDA said.

“In addition, the undeclared dexamethasone in AK Forte may cause serious side effects when combined with other medications,” the public notification warned.

When nonsteroidal anti-inflammatory drugs like diclofenac are “used at reasonable doses for the correct indication,” they are generally beneficial and safe, according to Preston Williams, M.D., a senior internal medicine resident at Cambridge Health Alliance and clinical fellow at Harvard Medical School.

“However, these medications also inhibit the enzymes that synthesize the protective layer of our stomach and help regulate normal kidney function. Because of these side effects, taking these medications for long periods of time — particularly if a patient were unaware they were taking them — could cause many health problems, including stomach ulcers, severe damage to the liver or kidney failure,” Williams told SupplySide Supplement Journal. “These effects are well known and there are many contraindications to NSAIDs for patients with specific medical conditions, and we tell these patients to stay away from medications like diclofenac, naproxen and ibuprofen. For example, patients with severe liver disease, otherwise known as cirrhosis, cannot take any NSAIDs, because of that known toxicity to the liver.”

Williams warned that prescription-level doses of diclofenac unknowingly consumed by a person with cirrhosis or chronic kidney disease could greatly endanger their health and worsen their liver failure.

“I have seen patients in the hospital have to receive dialysis due to overuse of NSAIDs, and have similarly admitted many patients for bleeding stomach ulcers due to their overuse of NSAIDs,” he shared.

Reaction from CSPI

Peter Lurie, M.D., is president and executive director of consumer watchdog group the Center for Science in the Public Interest (CSPI) — based in the nation’s capital — and previously served as associate commissioner for public health strategy and analysis at FDA.

Commenting in a recent interview on the amount of diclofenac in AK Forte detected by FDA and Flora Research Laboratories, Lurie said, “Those are significant quantities, and a person who buys a dietary supplement is not expecting to get a drug, and that is in fact what they were getting. They were getting a drug at a therapeutic dose — and with all of the benefits and side effects that come with that, but without them knowing.”

“Broadly, this speaks to a gross lack of quality control for this product,” Lurie continued.

Either the product was unintentionally contaminated with diclofenac — in which case, the brand has an authentic quality assurance (QA) problem — or the more likely scenario was AK Forte was intentionally tainted, the former FDA official said.

The larger issue, Lurie suggested in a 2023 interview after SupplySide Supplement Journal first reached out to him about AK Forte, is trust in the reliability of the products marketed as dietary supplement products.

Lurie summarized, “At a certain point, if testing of a variety of products from this distributor and others keeps identifying bad apples, one has to ask about the overall … status of the entire bag.”