FDA Clarifies Stance on Compounded GLP-1 Receptor Agonists Amid Supply Shortages

Introduction

The U.S. Food and Drug Administration (FDA) has issued critical guidance regarding the compounding of glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide (active ingredient in Ozempic, Wegovy) and tirzepatide (active ingredient in Mounjaro, Zepbound). This clarification comes amidst widespread interest in these medications for weight management and type 2 diabetes, coupled with intermittent supply shortages of the FDA-approved brand-name products. The FDA's statements underscore the strict limitations under which compounding pharmacies and outsourcing facilities may prepare these drugs, particularly warning against the use of unapproved salt forms.

Understanding FDA's Compounding Regulations

Compounding is the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual patient. This is typically done by a licensed pharmacist or physician in response to a valid prescription. The FDA distinguishes between two types of compounding facilities:

• 503A Compounding Pharmacies: These are traditional pharmacies that compound drugs for individual patients based on a prescription, typically for immediate use. They are regulated by state boards of pharmacy.
• 503B Outsourcing Facilities: These are facilities that compound sterile drugs in anticipation of future needs, without patient-specific prescriptions. They are subject to federal oversight by the FDA, including current Good Manufacturing Practice (cGMP) requirements.

The FDA's authority over compounding is primarily derived from sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act). A key provision in these sections allows for compounding of a drug that is essentially a copy of an FDA-approved drug only when the approved drug is on the FDA's drug shortage list, or if there is a clinical need for a compounded version that is different from the approved drug (e.g., different dosage form, allergen removal).

The GLP-1 Shortage and Compounding

Both Ozempic (semaglutide) and Mounjaro (tirzepatide) have experienced periods on the FDA's drug shortage list. During these periods, compounding of semaglutide and tirzepatide by licensed pharmacies or outsourcing facilities is permissible, provided they adhere to all other applicable compounding requirements. However, the FDA has emphasized several critical points:

1. Approved Active Pharmaceutical Ingredient (API): Compounded drugs must use an active pharmaceutical ingredient (API) that meets the requirements of an applicable USP monograph or is a component of an FDA-approved drug. The FDA has specifically warned against compounded versions of semaglutide that use salt forms, such as semaglutide sodium or semaglutide acetate. These salt forms are not the active ingredient in the approved Ozempic or Wegovy products, nor have they been evaluated by the FDA for safety or efficacy. The FDA's approved semaglutide is a base, not a salt.

   • Source: FDA Statement on Compounded Semaglutide, May 31, 2023. Available at: https://www.fda.gov/drugs/human-drug-compounding/compounding-and-glp-1-ags

2. Risk of Unapproved Products: The FDA has received adverse event reports related to compounded semaglutide products, highlighting the potential for patient harm when using unapproved and improperly compounded medications. These products have not undergone the rigorous safety, efficacy, and quality evaluations required for FDA approval.

   • Source: FDA Warns Consumers About Unapproved Compounded Drugs Represented as Semaglutide and Tirzepatide, October 17, 2023. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-about-unapproved-compounded-drugs-represented-semaglutide-and-tirzepatide

3. Cessation of Shortage: Once an FDA-approved drug is removed from the drug shortage list, compounding of that drug is generally no longer permissible as a copy of the approved drug. This means that the window for legally compounding these medications can close as supply issues resolve.

Specific Warnings Regarding Salt Forms

The FDA has been particularly vocal about the use of semaglutide salt forms. The agency's approved GLP-1 drugs for weight loss and diabetes, Ozempic, Wegovy, Mounjaro, and Zepbound, contain the active ingredients semaglutide (as a base) and tirzepatide (as a base), respectively. Manufacturers of compounded versions often use different salt forms, claiming they are chemically similar. However, the FDA has explicitly stated that these salt forms are not the active ingredients in the approved drugs and have not been proven safe or effective. This distinction is critical for prescribers and patients.

Regulatory Implications for Healthcare Businesses

For telehealth platforms, medspas, and other healthcare providers offering GLP-1 medications for weight loss, the FDA's guidance creates a complex regulatory landscape:

• Due Diligence on Compounding Pharmacies: Providers must exercise extreme caution and conduct thorough due diligence when partnering with compounding pharmacies or outsourcing facilities. It is essential to verify that these facilities are compliant with federal and state compounding laws, use appropriate APIs, and do not produce unapproved salt forms.
• Prescribing Practices: Clinicians must be aware of the specific regulatory status of the GLP-1 products they are prescribing. Prescribing compounded versions using unapproved salt forms or when the brand-name drug is not on the FDA shortage list could lead to regulatory action from state medical boards, federal agencies, and potential liability issues.
• Patient Safety and Communication: Healthcare providers have a responsibility to ensure patient safety. This includes transparently communicating with patients about the source and nature of their medication, especially if it is a compounded version. Patients should be informed that compounded drugs have not undergone the same rigorous FDA review as approved drugs.
• Advertising and Marketing: Marketing compounded GLP-1s must be truthful and not misleading. Claims about efficacy or safety must be substantiated and not imply FDA approval for compounded versions.

Conclusion

The FDA's consistent messaging on compounded GLP-1 receptor agonists serves as a clear warning to the healthcare industry. While compounding plays a vital role in patient care, it is subject to stringent federal and state regulations designed to ensure drug quality and patient safety. Healthcare businesses, particularly those leveraging telehealth for weight loss programs, must prioritize compliance with these regulations. Failure to do so not only risks regulatory enforcement actions but also jeopardizes patient trust and safety. Staying informed about the FDA's drug shortage list and specific guidance on compounding is paramount for any practice involved in prescribing or dispensing these highly sought-after medications.

References

• FDA Statement on Compounded Semaglutide, May 31, 2023. Available at: https://www.fda.gov/drugs/human-drug-compounding/compounding-and-glp-1-ags
• FDA Warns Consumers About Unapproved Compounded Drugs Represented as Semaglutide and Tirzepatide, October 17, 2023. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-about-unapproved-compounded-drugs-represented-semaglutide-and-tirzepatide