FDA prescribing information: OZEMPIC, RYBELSUS (ORAL SEMAGLUTIDE) - label effective 2026-01-30

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Abstract

[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS and OZEMPIC tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . • RYBELSUS and OZEMPIC tablets are contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of RYBELSUS or OZEMPIC tablets and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS or OZEMPIC tablets [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether RYBELSUS and OZEMPIC tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). • RYBELSUS and OZEMPIC tablets are contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ). [WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS or OZEMPIC tablets. Discontinue if pancreatitis is suspected. ( 5.2 ) • Diabetic Retinopathy Complications : Has been reported in a cardiovascular outcomes trial with semaglutide injection. Patients with a history of diabetic retinopathy should be monitored. ( 5.3 ) • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin : May increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dosage of insulin secretagogue or insulin may be necessary. ( 5.4 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) • Severe Gastrointestinal Adverse Reactions : Use of RYBELSUS or OZEMPIC tablets has been associated with gastrointestinal adverse reactions, sometimes severe. RYBELSUS and OZEMPIC tablets are not recommended in patients with severe gastroparesis. ( 5.6 ) • Hypersensitivity Reactions : Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue RYBELSUS or OZEMPIC tablets if hypersensitivity reactions occur and monitor until signs and symptoms resolve. ( 5.7 ) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether RYBELSUS and OZEMPIC tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. RYBELSUS and OZEMPIC tablets are contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS or OZEMPIC tablets and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS or OZEMPIC tablets. Such monitoring may increase the risk of unnecessary procedures, due to the low-test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including semaglutide tablets [see Adverse Reactions ( 6 )] . After initiation of RYBELSUS or OZEMPIC tablets, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back), and which may or may not be ac [ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Diabetic Retinopathy Complications [see Warnings and Precautions ( 5.3 )] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.4 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-457-7455 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OZEMPIC tablets (1.5 mg, 4 mg and 9 mg strengths) [see Dosage and Administration ( 2.2 )] and RYBELSUS (3 mg, 7, mg and 14 mg strengths) [see Dosage and Administration ( 2.2 )] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . Below is a display of the safety results of the adequate and well-controlled studies of RYBELSUS (referred to below as semaglutide tablets) in adult patients with type 2 diabetes mellitus. Pool of Placebo-Controlled Trials The data in Table 2 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes mellitus [see Clinical Studies ( 14 )] . These data reflect exposure of 1,071 patients to semaglutide tablets (3 mg, 7, mg or 14 mg orally once daily) with a mean duration of exposure of 41.8 weeks. The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these trials, 63% were White, 6% were Black or African American and 27% were Asian; 19% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 mellitus diabetes for an average of 9.4 years and had a mean HbA 1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 1.4% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in 9 placebo- and active-controlled trials [see Clinical Studies ( 14 )] . In this pool, 4,116 patients with type 2 diabetes mellitus were treated with semaglutide tablets for a mean duration of 59.8 weeks. The mean age of patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, 65% were White, 6% were Black or African American and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 16.6% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 28.5% and moderately impaired (eGFR 30 to 60 mL/min/1.73 [DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Other Oral Drugs : RYBELSUS and OZEMPIC tablets delay gastric emptying. Consider increased clinical or laboratory monitoring when co-administered with other oral medications that have a narrow therapeutic index or that require clinical monitoring. ( 7.2 ) 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Semaglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS or OZEMPIC tablets in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating RYBELSUS or OZEMPIC tablets, consider reducing the dosage of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )] . 7.2 Other Oral Drugs Semaglutide cause a delay of gastric emptying and thereby has the potential to impact the absorption of other oral drugs. Levothyroxine exposure was increased 33% (90% CI: 1.25 to 1.42) when administered with semaglutide tablets in a drug interaction study [see Clinical Pharmacology ( 12.3 )] . When using RYBELSUS or OZEMPIC tablets concomitantly with other oral drugs that have a narrow therapeutic index or that require clinical monitoring, consider increased clinical or laboratory monitoring [see Dosage and Administration ( 2 )] . [CONTRAINDICATIONS] 4 CONTRAINDICATIONS RYBELSUS and OZEMPIC tablets are contraindicated in patients with: • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS or OZEMPIC tablets. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with semaglutide tablets [see Warnings and Precautions ( 5.7 )] . • Personal or family history of MTC or in patients with MEN 2 syndrome type 2 ( 4 ) • Prior serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC ( 4 )

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