Clinicians who prescribe semaglutide for adults with type 2 diabetes mellitus and other prescribers of GLP-1 receptor agonists should note the FDA’s proposal to exclude semaglutide (and two other incretin-related agents) from the 503B bulks list ^[3][1][2]. The FDA’s proposal reiterates that outsourcing facilities generally cannot compound using bulk drug substances when FDA-approved drugs are available unless the substance appears on the 503B bulks list or the compounded drug is on the FDA drug shortage list at the time of compounding, distribution, and dispensing ^[3]. How will the final FDA determination affect the availability or use of compounded formulations for these agents in your practice or institution?

Q1 What is semaglutide approved for?

Semaglutide (OZEMPIC injection; RYBELSUS and OZEMPIC tablets) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. OZEMPIC injection is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease and to reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes mellitus and chronic kidney disease.

Q2 How does semaglutide work?

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that acts as a GLP-1 receptor agonist; it binds to and activates the GLP-1 receptor and reduces blood glucose by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner. Semaglutide’s prolonged action is attributed in part to albumin binding, which decreases renal clearance and protects against metabolic degradation.

Q3 What is the dose?

For OZEMPIC injection the labeling recommends once-weekly subcutaneous administration, initiating at 0.25 mg once weekly for 4 weeks then increasing to 0.5 mg once weekly, with further escalation to 1 mg and then 2 mg once weekly as specified in the prescribing information; the injection is administered subcutaneously in the abdomen, thigh, or upper arm. For oral semaglutide tablets, RYBELSUS tablets start at 3 mg orally once daily for 30 days then escalate to 7 mg and, if needed, to 14 mg; OZEMPIC tablets are dosed starting at 1.5 mg once daily for 30 days then increase to 4 mg and, if needed, to 9 mg once daily as described in the tablet labeling. Clinicians should consult current prescribing information for full dosing guidance.

Q4 What are the side effects?

The semaglutide labeling includes a boxed warning about a risk of thyroid C-cell tumors observed in rodents; other labeled warnings and precautions include acute pancreatitis, diabetic retinopathy complications, hypoglycemia with concomitant use of insulin secretagogues or insulin, acute kidney injury due to volume depletion, severe gastrointestinal adverse reactions, hypersensitivity reactions (including anaphylaxis and angioedema), acute gallbladder disease, and pulmonary aspiration during general anesthesia or deep sedation. The most common adverse reactions reported in ≥5% of patients treated with OZEMPIC injection include nausea, vomiting, diarrhea, abdominal pain and constipation, and semaglutide tablets list nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation among the most common adverse reactions.

Clinicians should consult current prescribing information for complete dosing guidance.