Compounded Injectable Semaglutide and Tirzepatide: Bad Choices for Any Use

In July 2024 the Food and Drug Administration (FDA) warned about dosing errors associated with compounded injectable semaglutide (OZEMPIC, WEGOVY) products that are marketed for type 2 diabetes and weight loss.[1] The compounding risk alert highlighted a risk of adverse events, some requiring medical attention or hospitalization, including overdoses due to dosing errors. The FDA warned that people who receive vials of compounded semaglutide may lack experience with self-injections, including unfamiliarity in transferring medicine from a vial into a syringe, and may be confused by the different units of measurement, such as milliliters, milligrams and “units.”

The FDA’s warning reinforces broader concerns that compounded drugs, including the related drug tirzepatide (MOUNJARO, ZEPBOUND), pose a higher risk to patients than FDA-approved drugs. As is the case with other compounded drugs, the FDA does not review compounded versions of semaglutide or tirzepatide for safety, effectiveness or quality. Because compounded drug products are subject to a lower regulatory standard than FDA-approved drug products and are not approved by the agency, Public Citizen’s Health Research Group recommends that these products should only be used by people whose medical needs cannot be met by an available FDA-approved drug product.[2]

Semaglutide is in a class of medications known as glucagon-like peptide (GLP-1) receptor agonists. As of October 2024 the FDA had approved two injectable semaglutide products (first approval in 2017) and two injectable tirzepatide products (first approval in 2022); there are no approved generic versions. The FDA also has listed semaglutide injection as “currently in shortage,” a designation that allows compounders to prepare versions of the drugs consistent with agency regulations.[3]

Wegovy is available as single-dose pre-filled pens that deliver a preset dose for once-weekly dosing by subcutaneous (under-the-skin) injection. The FDA approved Wegovy, in combination with a reduced-calorie diet and increased physical activity, to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight. The drug also is approved for reduction of body weight and maintenance of weight reduction in patients aged 12 years and older with obesity and for adults with overweight and at least one weight-related comorbid condition, such as dyslipidemia or hypertension.[4]

Ozempic is available as multiple-dose pre-filled pens for single-patient use and designed for once-weekly dosing by injection. The FDA approved Ozempic as an adjunct to diet and exercise for adults with type 2 diabetes and to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease.[5]

In addition to being a GLP-1 receptor agonist, tirzepatide is a gastric inhibitory polypeptide (GIP) receptor agonist. Both Zepbound and Mounjaro are available as single-dose pens or vials for once-weekly dosing by injection. The FDA approved Zepbound as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with obesity or overweight and at least one weight-related comorbid condition,[6] and Mounjaro as an adjunct to diet and exercise for adults with type 2 diabetes.[7] Although not approved for weight management, Ozempic and Mounjaro are used off-label for this purpose.

The FDA alert

The FDA alert highlighted “reports of dosing errors involving compounded semaglutide injectable products dispensed in multiple-dose vials.” Adverse events included “gastrointestinal effects (e.g., nausea, vomiting, abdominal pain), fainting, headache, migraine, dehydration, acute pancreatitis and gallstones.” Because semaglutide has a long half-life in the body (about a week), overdose symptoms may require a long period of observation and treatment. In severe overdose cases, dehydration or hypoglycemia can occur, particularly if the person is also using insulin or other diabetes drugs.[8],[9]

Some dosing errors are related to incorrect measurement of the intended dose; others are related to miscalculation of the intended dose. Unlike FDA-approved products, compounded injectable semaglutide products are offered in various packaging, containers and concentrations, leading to confusion for both patients and clinicians.[10]

Earlier in 2024, the FDA separately expressed concerns about reports that “compounders may be using salt forms of semaglutide, including semaglutide sodium and semaglutide acetate,” which have not been shown to be safe and effective. The salt forms contain different active ingredients than are used in the approved drugs, “which contain the base form of semaglutide.”[11]

Counterfeit and no-prescription products

Counterfeit versions of injectable semaglutide and tirzepatide and online purchases without a prescription also have safety risks. After detecting counterfeit batches of Ozempic in Brazil, the United Kingdom and the United States, the World Health Organization issued a warning noting potential harmful effects of products that lack the necessary ingredients, such as “health complications resulting from unmanaged blood glucose levels or weight. In other cases, another undeclared active ingredient may be contained in the injectable device, e.g. insulin, leading to an unpredictable range of health risks or complications.”[12]

An August 2024 study of no-prescription online semaglutide purchases in JAMA Network Open found that such products “are actively being sold without prescription by illegal online pharmacies, with vendors shipping unregistered and falsified products.” Of six products purchased in test buys, only three were received, because the vendors “engaged in nondelivery scams requesting extra payments.” The products that were received had “substantial deficiencies” in product packaging and labeling.[13]

The future of compounded obesity drugs

When the FDA’s “currently in shortage” designation of injectable semaglutide drug products ends, the continued availability of compounded versions will remain uncertain. Some large telehealth companies have built profitable business models based on selling compounded versions of the approved drugs and may seek to find ways to continue to sell them, such as by offering patient-specific doses, adding vitamins such as vitamin B12 or relying exclusively on small-scale compounders, which are subject to fewer restrictions on copying FDA-approved products than larger compounding facilities.[14] The matter may be settled in court.

Notably, because of safety concerns, Australia has banned compounding of all medications containing GLP-1 products, regardless of dosage form, as of October 2024.[15]

What You Can Do

Public Citizen’s Health Research Group recommends that you do not use compounded injectable semaglutide or tirzepatide products or any such products that are purchased without a prescription. In addition to the safety concerns, compounded drugs have no advantages in meeting the medical needs of patients who may be prescribed GLP-1 receptor agonists or GIP/GLP-1 receptor agonists.
 

References

[1] Food and Drug Administration. FDA alerts health care providers, compounders and patients of dosing errors associated with compounded injectable semaglutide products. July 26, 2024. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded. Accessed September 24, 2024.

[2] Public Citizen. Comments on the FDA’s proposal to exclude four bulk drug substances from the 503B bulks list for pharmacy compounding by outsourced facilities. May 24, 2021. https://www.citizen.org/article/comments-on-the-fdas-proposal-to-exclude-four-bulk-drug-substances-from-the-503b-bulks-list-for-pharmacy-compounding-by-outsourced-facilities/. Accessed September 24, 2024.

[3] FDA drug shortages. https://dps.fda.gov/drugshortages. Accessed September October 5, 2024.

[4] Wegovy prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215256s011lbl.pdf. Accessed September 24, 2024.

[5] Ozempic prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209637s020s021lbl.pdf. Accessed September 24, 2024.

[6] Zepbound prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217806s003lbl.pdf. Accessed September 24, 2024.

[7] Mounjaro prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf. Accessed September 24, 2024.

[8] Food and Drug Administration. FDA alerts health care providers, compounders and patients of dosing errors associated with compounded injectable semaglutide products. July 26, 2024. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded. Accessed September 24, 2024.

[9] America’s Poison Centers. Glucagon-like peptide-1 (GLP-1) agonists. https://poisoncenters.org/track/GLP-1#:~:text\=As%20of%20August%2031%2C%202024,1%20agonist%20related%20exposure%20cases. Accessed September 24, 2024.

[10] Food and Drug Administration. FDA alerts health care providers, compounders and patients of dosing errors associated with compounded injectable semaglutide products. July 26, 2024. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded. Accessed September 24, 2024.

[11] Food and Drug Administration. Medications containing semaglutide marketed for type 2 diabetes or weight loss. January 10, 2024. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss. Accessed September 24, 2024.

[12] World Health Organization. WHO issues warning on falsified medicines used for diabetes treatment and weight loss. News Release. June 20, 2024. https://www.who.int/news/item/20-06-2024-who-issues-warning-on-falsified-medicines-used-for-diabetes-treatment-and-weight-loss. Accessed September 19, 2024.

[13] Ashraf AR, Mackey TK, Schmidt J, et al. Safety and risk assessment of no-prescription online semaglutide purchases. JAMA Network Open. 2024;7(8):e2428280. doi:10.1001/jamanetworkopen.2024.28280. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2821882. Accessed September 24, 2024.

[14] Palmer K, Florko N. The weight loss drug shortage is driving patients to Hims. What happens when the shortage ends. STAT News. August 29, 2024. https://www.statnews.com/2024/08/29/telehealth-hims-hers-glp-1-compounded-weight-loss-drugs-hurdles/. Accessed September 24, 2024.

[15] Australian Government Department of Health and Aged Care. Update on the glucagon-like peptide-1 receptor agonists (GLP-1 Ras) pharmacy compounding changes. June 18, 2024. https://www.tga.gov.au/news/media-releases/update-glucagon-peptide-1-receptor-agonists-glp-1-ras-pharmacy-compounding-changes. Accessed September 24, 2024.