Increased Demand and Shortages of GLP-1 Receptor Agonists Contributes to Patient Harm

Problem: Many people struggle to maintain a healthy body weight. In fact, the Centers for Disease Control and Prevention (CDC) has estimated that more than 40% of adults in the United States are obese.¹ Even though they may try new diets or exercise programs, many people struggle to adhere to these lifestyle changes to maintain any weight loss. To help with their efforts, some people have turned to prescription medications, but, until more recently approved drugs, most of these therapies did not always prove to be significantly effective.

Glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide [OZEMPIC], liraglutide [VICTOZA]) were originally developed and approved to treat patients with type 2 diabetes by improving glycemic control, along with diet and exercise. They are available primarily in prefilled pen devices; however, MOUNJARO (tirzepatide) is also approved to be manufactured in single-dose vials, and RYBELSUS (semaglutide) is an oral tablet. Clinicians and researchers observed that these medications also helped patients lose weight. So, the pharmaceutical manufacturers developed products (e.g., WEGOVY [semaglutide], SAXENDA [liraglutide], ZEPBOUND [tirzepatide]) indicated specifically for chronic weight management. In conjunction with lifestyle changes (e.g., diet and exercise), these medications have been found to help patients achieve clinically significant weight loss.² With this news and the power of social media, the interest in these medications has exploded. At one point semaglutide was known as the “hottest drug in Hollywood.” All of this interest led to a dramatic increase in the demand for the products and has resulted in long-lasting drug shortages for semaglutide (since March 2022), liraglutide (since July 2023), and tirzepatide (since December 2022).^3,4 In addition, Novo Nordisk, the manufacturer of Ozempic, discontinued Ozempic 0.25 mg and 0.5 mg dose strengths in the 2 mg/1.5 mL presentations further impacting the availability of these drugs.

Errors and Adverse Effects with Compounded Weight-Loss Drugs

Due to these drug shortages, compounding pharmacies and others have been preparing compounded versions of the drugs. However, both the US Food and Drug Administration (FDA) and America’s Poison Centers have reported receiving cases of patients experiencing medication errors and adverse events following the use of compounded semaglutide products.^5,6 The Utah Poison Control Center described three cases of adverse events. The patients had received the medications from compounding pharmacies and an aesthetic spa. Two patients administered 10 times the amount of drug to themselves. One of the patients reported receiving a vial of medication from the compounding pharmacy. Another one of the patients reported that their medication had been co-formulated with catecholamine (synthetic vitamin B12). All three patients experienced symptoms such as nausea, vomiting, and abdominal pain. One patient required treatment in an emergency department (ED). The Poison Control Center noted that the patients had not received counseling from a pharmacist. 

ISMP has also been receiving reports of patients experiencing medication errors and adverse events after receiving compounded semaglutide and tirzepatide. Some of the products were not labeled. In one case, a hospital reported having three patients requiring admission to the intensive care unit (ICU) in less than a week due to hypoglycemia from compounded semaglutide. The patients reported receiving multiple pens without a prescription from people they identified as “nurses” in a hotel room or a gathering akin to a “Botox party.”

In a second case, a patient was prescribed semaglutide injection for weight loss. The patient received the compounded medication in a vial with instructions to inject 0.05 mL (5 units) using an insulin syringe. The patient did not understand the instructions and injected 0.5 mL (50 units). Later, they presented to an ED with severe abdominal pain, nausea, vomiting, and diarrhea. The patient was unable to verify the product’s concentration. The reporter also noted that there had been an increase in ED visits by patients experiencing accidental overdoses after using insulin syringes to prepare their own doses of semaglutide from compounded vials.

A patient also reported to ISMP that they had been undergoing weight-management therapy with a provider at a weight-loss clinic. They reported receiving 12 clinic-prepared syringes containing tirzepatide and L-arginine in an unlabeled plastic bag. The patient noted that the volumes in the syringes (the syringes contained 1 to 1.5 mL) were different than the volume (2.5 mL) contained in syringes obtained from a previous provider. The patient was concerned about the risk of being underdosed, especially because they did not lose the anticipated amount of weight in a little more than a month. When the patient questioned the clinic staff about the compounded product and requested a refund for the next batch of syringes, the clinic staff became upset and called the police.

While the Federal Food Drug and Cosmetic (FD&C) Act prohibits pharmacies from compounding drug products that are essentially copies of a commercially available drug product, compounding pharmacies may prepare compounded versions of a drug if it appears on the FDA’s drug shortage list and is thus not considered to be “commercially available.” The compounders must also ensure that they meet certain conditions in the FD&C Act. Community pharmacies, licensed pharmacists, and licensed physicians are allowed to compound versions of an approved drug product that is not commercially available using bulk drug substances if the substances:⁷

• Comply with the standards of an applicable USP or National Formulary (NF) monograph, if a monograph exists; and the USP chapter on pharmacy compounding;

• If a monograph does not exist, components of drugs must be approved by FDA; or 

• If a monograph does not exist and the bulk drug substances are not components of a drug approved by FDA, they must appear on a list developed by FDA through regulations (the 503A Bulks List). 

Similarly, licensed compounding or outsourcing facilities are allowed to compound versions of an approved drug product that is not commercially available using bulk drug substances or active pharmaceutical ingredients (APIs) as long as the bulk substance meets the following criteria:⁷

• It appears on a list established by FDA identifying bulk drug substances for which there is a clinical need (the 503B Bulks List); or 

• The drug compounded from such bulk drug substances appears on FDA’s drug shortage list at the time of compounding, distribution, and dispensing.

FDA has informed the public and ISMP has seen reports in the media and on social media that some compounders are not using the same bulk drug substance that Novo Nordisk uses for its commercially available semaglutide products. Both Ozempic and Wegovy are produced using the base form of semaglutide. However, some compounders appear to be using a salt form of semaglutide, including semaglutide sodium and semaglutide acetate.⁵ The use of the salt formulations of semaglutide may contribute to the compounded products having different strengths or concentrations than commercially available products. Also, compounded preparations produced using the semaglutide salts have not been shown to be safe and/or effective. Furthermore, semaglutide salts are not the subject of an applicable USP or NF monograph; are not components of an FDA-approved drug product currently on the FDA’s drug shortage list; and do not appear on either the 503A Bulks List or 503B Bulks List.⁷ Therefore, compounded products using semaglutide salts are not exempt from certain sections of the FD&C Act, including the requirements of premarket approval and labeling with adequate directions for use, and therefore should not be marketed.^7,8

Counterfeit Semaglutide Products

There have also been reports of counterfeit semaglutide products being distributed in the United States and globally. The FDA has reported they have seized thousands of units of suspected counterfeit Ozempic 1 mg packages.9 FDA and Novo Nordisk are evaluating the seized products to determine the identity of the contents. Australian, Belgian, and Lebanese regulators have also reported counterfeit semaglutide products that were found to contain or were thought to have contained insulin.¹⁰ Some patients who received these counterfeit products developed hypoglycemia and required hospitalization. 

Wrong Strength Errors

When beginning therapy with approved GLP-1 receptor agonists, whether it is to treat type 2 diabetes or for chronic weight management, patients are started on a low dose and then titrated up to a maintenance dose over several months. For example, patients begin Wegovy treatment by injecting 0.25 mg subcutaneously once a week for 4 weeks. They then go through an escalation phase using 0.5 mg, 1 mg, and 1.7 mg for 4 weeks each before entering the maintenance phase of treatment at week 17 where they will inject 2.4 mg (or 1.7 mg) weekly.

ISMP has learned from practicing pharmacists that some prescribers order multiple strengths of a GLP-1 receptor agonists at one time anticipating a smooth titration of the drug. Sometimes these are sent as separate prescriptions and sometimes all are included in a single prescription. Unfortunately, there have been cases where the pharmacy has accidentally dispensed the wrong strength (e.g., an escalation strength instead of the starting strength) at the wrong time. This can increase the risks of adverse reactions such as nausea, diarrhea, vomiting, and abdominal pain.

Safe Practice Recommendations: Pharmacists and providers are in a position to help patients navigate the complexities of the current drug shortages of semaglutide, liraglutide, and tirzepatide. Consider the following recommendations when you are addressing the drug shortage situation with staff and patients, and if you are considering preparing compounded versions of these drugs. 

Providers and Pharmacies

Provide one prescription for one strength at a time. While it may be convenient to issue prescriptions for multiple strengths at the same time, the safety of this practice is concerning. Ideally, only one prescription for the current dosage strength should be sent to a licensed pharmacy. This will help reduce the risk of the pharmacy dispensing the wrong strength for the patient’s current stage of therapy or potentially dispensing all escalating strengths at the same time. Also, practitioners should provide clear directions to the patient when their prescribed dose changes and ensure those directions are understood. For example, with Rybelsus, prescribers should include instructions for the 7 mg tablets to begin after the 3 mg tablet prescription supply is exhausted (after 30 days). If prescriptions for both Rybelsus 3 mg and 7 mg must be provided at the same time, the statement, “Begin taking after [date]” should be included in the Rybelsus 7 mg directions. Pharmacists should make sure the patient has received these explicit instructions verbally and in writing. Use the teach-back method to verify that the patient understands, and can demonstrate, how to properly administer oral and injectable GLP-1 receptor agonists and manage dose changes.

Educate patients. Pharmacists should provide patient counseling when dispensing GLP-1 receptor agonists and verify with the patient their current stage of the dose escalation schedule. Also, for those patients already using a GLP-1 receptor agonist and for those who express interest in exploring their use, it is important for both providers and pharmacists to teach patients about the risk that some externally compounded products may pose. If the patient is interested in using the products for weight loss (and not management of diabetes), discuss the possibility of delaying treatment until commercially available products are readily available to reduce the risk posed by some externally compounded products. Educate patients that GLP-1 receptor agonists, even when used for weight loss, should only be obtained with a valid prescription, and their therapy should be managed closely by the prescribing provider. Advise them about the potential adverse effects of the drugs and when to follow up with providers for intervention. Encourage patients to obtain prescription drugs only from state-licensed pharmacies that are located in the United States. Share FDA’s BeSafeRx campaign with patients. This provides valuable information about how to safely buy prescription medicines online.

Educate staff. Provide education to providers, nurses, and pharmacy staff about the best clinical practices for managing GLP-1 receptor agonist therapy in patients who are obese and overweight.² Share information about the risk with compounded weight-loss products with staff. Update providers and pharmacy staff about the drug shortages identified on the FDA³ or American Society for Health-System Pharmacists⁴ drug shortage websites on a regular basis. Provide staff education and resources to help support patients looking for one of these medications by answering patient questions about the compounded products and providing strategies to identify valid or counterfeit products and manage therapy.

Report adverse events, counterfeit products, and errors. ealthcare practitioners, patients, and compounders should report adverse events and/or quality problems with these medications to FDA’s MedWatch Adverse Event Reporting program. Practitioners and consumers are also encouraged to report suspected counterfeit products to FDA by calling an FDA Consumer Complaint Coordinator or completing a report online. Also, please continue to report any errors to the ISMP.

Pharmacies Considering Compounding Versions of these Drugs

Utilize compounding technology. Implement technological safeguards (e.g., intravenous workflow management systems) to minimize opportunities for human error during the sterile compounding process. For additional information, review the ISMP Guidelines for Sterile Compounding and the Safe Use of Sterile Compounding Technology.

Verify current shortages and the legality of compounding the drug. Periodically check the FDA shortage list since compounding weight-loss medications will be prohibited if the FDA approved drug that was on shortage becomes listed as “currently available.” Review sections 503A and 503B of the FD&C Act and USP General Chapter <797> Pharmaceutical Compounding – Sterile Preparations to ensure your pharmacy and sterile compounding procedures meet current regulatory requirements and recommendations. 

Verify the bulk drug substance or API. If you are making compounded versions of drugs on the FDA drug shortage list, ensure that the API received is a pharmaceutical grade product, accompanied by a valid certificate of analysis, and is sourced from an establishment registered with the FDA. Also, ensure the product purchased is the intended formulation (e.g., using base rather than salt). Confirm that the API meets other state and federal requirements to be able to be used to compound a drug currently in shortage. Pharmacies should be aware that pharmaceutical manufacturers may initiate legal proceedings against prescribers and compounders who are producing illegal drug products.

References

1. Stierman B, Afful J, Carroll MD, et al. National Health and Nutrition Examination Survey 2017–March 2020 prepandemic data files—development of files and prevalence estimates for selected health outcomes. National Health Statistics Reports; no 158. Hyattsville, MD: National Center for Health Statistics. 2021.
2. ECRI. Clinical evidence assessment: Best clinical practices for managing obesity and overweight with GLP-1 receptor agonists. January 2024. 
3. FDA drug shortages. US Food and Drug Administration (FDA). Updated February 14, 2024. Accessed February 14, 2024.
4. Drug shortages list: current drug shortage bulletin. American Society for Health-System Pharmacists. Updated February 18, 2024. Accessed February 18, 2024.
5. Medications containing semaglutide marketed for type 2 diabetes or weight loss. US Food and Drug Administration (FDA). Updated January 10, 2024. Accessed February 14, 2024.
6. Lambson JE, Flegal SC, Johnson AR. Administration errors of compounded semaglutide reported to a poison control center-Case series. J Am Pharm Assoc (2003). 2023;63(5):1643-45.
7. US Food and Drug Administration (FDA). Letter to the National Association of Boards of Pharmacy. October 10, 2023. Accessed February 14, 2024.
8. North Carolina Board of Pharmacy. Statement Concerning Semaglutide Compounding. North Carolina Board of Pharmacy; published April 28, 2023. Accessed February 14, 2024.
9. FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in US drug supply change. US Food and Drug Administration (FDA). Published December 21, 2023. Updated January 10, 2024. Accessed February 14, 2024.
10. Wingrove P. Exclusive: Suspected fake Ozempic linked to three cases of hypoglycemia. Reuters. January 24, 2024. Accessed February 14, 2024.