Off-Label Semaglutide Linked to Deaths, Hospitalizations Calling for Compounding Regulation

Approximately 10 deaths and 100 hospitalizations in the United States have been linked to use of off-brand, compounded semaglutide (Ozempic; Novo Nordisk), according to the drug’s manufacturer Novo Nordisk. The report comes after the company called on the FDA to prohibit compounding of semaglutide in October 2024, citing significant safety concerns around use of off-brand products.¹

Compounding semaglutide poses significant risks to patients due to the complexities of their formulation, leading to an increased chance of AEs. Image Credit: © Fernanda - stock.adobe.com

“Semaglutide products belong on these lists due to the complexities associated with their formulations, delivery mechanisms, dosage forms, achievement of bioavailability, compounding processes, and physicochemical and analytical testing,” the company stated. “We request that FDA convene and consult an advisory committee on compounding to discuss the addition of semaglutide products to both DDC [Demonstrable Difficulties for Compounding] Lists and promulgate regulations adding semaglutide products to the DDC Lists.”²

Semaglutide has gained significant public interest with increasing demand over the years, leading to the drug's limited availability. This is largely due to its observed success as off-label a weight loss therapy. In 2023, the FDA issued a letter stating there were over 350 cases of adverse events (AEs) linked to use of compounded semaglutide, particularly in aesthetic medical centers, med spas, and some online pharmacies.^2-4

Reports received by the company indicate that dosing error, higher doses than approved by the FDA, and products containing salt forms of the product instead of the base forms are responsible for cases of AEs. Additionally, some facilities were selling semaglutide in combination with BPC-157, which has been prohibited by the FDA. Despite the dangers of compounded semaglutide, the FDA has stated that drugs on the drug shortage list can be compounded.^2-4

This happens alongside additional controversy surrounding tirzepatide (Zepbound, Mounjaro; Eli Lilly), which the FDA suddenly removed from the drug shortage list, resulting in a lawsuit filed by the Outsourcing Facilities Association (OFA). The OFA requested the decision be vacated in addition to a temporary order allowing their members to continue manufacturing compounded versions during the pending lawsuit. On October 17, 2024, the FDA stated that it would reevaluate the decision.^5,6

“The FDA’s removal of tirzepatide from the shortage list without the due process of proper federal notice, at a time when they acknowledge that shortages still exist, is the definition of arbitrary and capricious,” said Lee H Rosebush, chairman of OFA, in the news release. “The agency’s decision will have tremendous implications across the nation for patients and physicians, as well as the outsourcing facilities that made an enormous investment to meet patient demand in light of product shortages and delays.”⁵

Concerns surrounding compounding of tirzepatide have also been raised. In June 2024, the company released an open letter regarding the proliferation of counterfeit products. According to the related press release, the company discovered that come compounded drugs meant to imitate tirzepatide contained bacteria, high impurity levels, different colors, or a different chemical structure from the FDA-approved medicines. Additionally, certain online pharmacies advertised a compounded pill alternative to a subcutaneous injection, which no regulatory body has evaluated for adequate safety or effectiveness.⁷

In response, Eli Lilly filed to add tirzepatide to the DDC under sections 503A and 503B, which the FDA opposed as of November 7, 2024.⁸

“Even assuming that the process of creating the tirzepatide molecule may be complex for Eli Lilly, compounding finished drug products using that active pharmaceutical ingredient (API) after it has been manufactured is not complex. 503A pharmacies and 503B outsourcing facilities regularly compound drug preparations whose compounding processes are more complex than preparing tirzepatide injection,” the official response stated.⁸

Compounding semaglutide poses significant risks to patients due to the complexities of their formulation, leading to an increased chance of AEs. The proliferation of these products, particularly during drug shortages, raise serious safety concerns and underscore the challenges of ensuring quality and efficacy outside of FDA-approved manufacturing processes. The reported hospitalizations and deaths linked to off-label semaglutide emphasize the dangers of using compounded products.

Pharmacists play an essential role by educating patients about the risks of compounded medications and advocating for the use of FDA-approved treatments. Their expertise in drug formulation and regulation positions them as essential for addressing medication safety concerns and navigating drug shortages. By staying informed and working collaboratively with regulatory bodies, pharmacists can help ensure patients receive safe, effective, and high-quality care, even amidst challenges like rising demand and limited supply of critical therapies.

REFERENCES

1. Ten die and 100 sent to hospital after taking off-brand ozempic. The Times. November 6, 2024. Accessed November 8, 2024. https://www.thetimes.com/life-style/health-fitness/article/ozempic-fake-side-effects-weight-loss-gf8djkgws

2. Novo nordisk calls for fda to prohibit compounding pharmacies from providing semaglutide. Pharmacy Times. October 25, 2024. Accessed November 8, 2024. https://www.pharmacytimes.com/view/novo-nordisk-calls-for-fda-to-prohibit-compounding-pharmacies-from-providing-semaglutide

3. Purchasing discounted medications online can pose dangers for patients. Pharmacy Times. January 12, 2024. Accessed November 8, 2024. https://www.pharmacytimes.com/view/purchasing-discounted-medications-online-can-pose-dangers-for-patients

4. Compounded, counterfeit semaglutide poses severe risk to patients. Pharmacy Times. May 2, 2024. Accessed November 8, 2024. https://www.pharmacytimes.com/view/compounded-counterfeit-semaglutide-poses-severe-risk-to-patients

5. Outsourcing facilities association sues fda over sudden removal of tirzepatide from drug shortage list. Pharmacy Times. October 14, 2024. Accessed November 8, 2024. https://www.pharmacytimes.com/view/outsourcing-facilities-association-sues-fda-over-sudden-removal-of-tirzepatide-from-drug-shortage-list

6. FDA to reevaluate removal of tirzepatide from drug shortage list. Pharmacy Times. October 23, 2024. Accessed November 8, 2024. https://www.pharmacytimes.com/view/fda-will-reevaluate-removal-of-tirzepatide-from-drug-shortage-list

7. Lilly warns patients about counterfeit and compounded medicines releases open letter and takes further legal action against counterfeit, fake, unsafe, and untested products. Eli Lilly. June 20, 2024. Accessed November 8, 2024. https://investor.lilly.com/news-releases/news-release-details/lilly-warns-patients-about-counterfeit-and-compounded-medicines

8. Alliance for Pharmacy Compounding. Response in opposition to eli lilly’s nomination of tirzepatide to drug products that present demonstrable difficulties for compounding under sections 503a and 503b of the federal food, drug, and cosmetic act docket no. fda-2017-n-2562. Published November 7, 2024. Accessed November 8, 2024. https://a4pc.org/files/2024-11-07-APC-letter-to-FDA-opposing-nomination-of-Tirzepatide-to-DDC-List.pdf