b'RYBELSUS (semaglutide) tablets treated with GLP-1 receptor agonists, including semaglutide. Some of these events have Rx Only been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or BRIEF SUMMARY: Please consult package insert for full prescribingdehydration. Monitor renal function when initiating or escalating doses of RYBELSUS in information. patients reporting severe adverse gastrointestinal reactions. Hypersensitivity: Serious WARNING: RISK OF THYROID C-CELL TUMORS: In rodents, semaglutidehypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 causesdose-dependentandtreatment-duration-dependentthyroidreceptor agonists, including semaglutide. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symp-C-cell tumors at clinically relevant exposures. It is unknown whetherRYBELSUS causes thyroid C-cell tumors, including medullary thyroidtoms resolve. Do not use in patients with a previous hypersensitivity to RYBELSUS[see carcinoma (MTC), in humans as human relevance of semaglutide-inducedContraindications]. Anaphylaxis and angioedema have been reported with GLP-1 receptor rodent thyroid C-cell tumors has not been determined [see Warnings andagonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed Precautions]. to anaphylaxis with RYBELSUS.RYBELSUSiscontraindicatedinpatientswithapersonalorfamilyADVERSE REACTIONS: The following serious adverse reactions are described below history of MTC or in patients with Multiple Endocrine Neoplasia syndromeor elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warn-type 2 (MEN 2) [see Contraindications]. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them ofings and Precautions]; Pancreatitis [see Warnings and Precautions]; Diabetic Retinopathy symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea,Complications [see Warnings and Precautions]; Hypoglycemia with Concomitant Use of persistent hoarseness). Routine monitoring of serum calcitonin or usingInsulin Secretagogues or Insulin [see Warnings and Precautions]; Acute Kidney Injury [see thyroid ultrasound is of uncertain value for early detection of MTC inWarnings and Precautions]; Hypersensitivity [see Warnings and Precautions]. Clinical patients treated with RYBELSUS [see Contraindications and WarningsTrials Experience: Because clinical trials are conducted under widely varying condi-and Precautions]. tions, 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 INDICATIONS AND USAGE: RYBELSUS is indicated as an adjunct to diet and exercisein practice. Pool of Placebo-Controlled Trials: The data in Table 1 are derived from 2 to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use:placebo-controlled trials in patients with type 2 diabetes. These data reflect exposure of RYBELSUS is not recommended as a first-line therapy for patients who have inadequate1071 patients to RYBELSUS with a mean duration of exposure of 41.8 weeks. The mean glycemic control on diet and exercise because of the uncertain relevance of rodent C-cellage of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these tumor findings to humans [see Warnings and Precautions]. RYBELSUS has not beentrials, 63% were White, 6% were Black or African American, and 27% were Asian; 19% studied in patients with a history of pancreatitis. Consider other antidiabetic therapies inidentified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an patients with a history of pancreatitis [see Warnings and Precautions]. RYBELSUS is notaverage of 9.4 years and had a mean HbA 1cof 8.1%. At baseline, 20.1% of the popula-indicated for use in patients with type 1 diabetes mellitus or for the treatment of patientstion reported retinopathy. Baseline estimated renal function was normal (eGFR 90 mL/with diabetic ketoacidosis, as it would not be effective in these settings. min/1.73m 2 ) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 32.4% and CONTRAINDICATIONS: RYBELSUS is contraindicated in patients with: A personal ormoderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 1.4% of patients. Pool of Placebo- family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrineand Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 9 placebo- and active-controlled Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions]. Known hypersen- trials. In this pool, 4116 patients with type 2 diabetes were treated with RYBELSUS for a sitivity to semaglutide or to any of the components in RYBELSUS [see Warnings andmean duration of 59.8 weeks. The mean age of patients was 58 years, 5% were 75 years Precautions]. or older and 55% were male. In these trials, 65% were White, 6% were Black or African WARNINGS AND PRECAUTIONS: Risk of Thyroid C-Cell Tumors: In mice and rats,American, and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline, semaglutide caused a dose-dependent and treatment-duration-dependent increase inpatients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1cof 8.2%. At the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime expo- baseline, 16.6% of the population reported retinopathy. Baseline estimated renal function sure at clinically relevant plasma exposures. It is unknown whether RYBELSUS causeswas normal (eGFR 90 mL/min/1.73m 2 ) in 65.9%, mildly impaired (eGFR 60 to 90 mL/thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as humanmin/1.73m 2 ) in 28.5%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 5.4% relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined.of the patients. Common Adverse Reactions: Table 1 shows common adverse reactions, Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, haveexcluding hypoglycemia, associated with the use of RYBELSUS in the pool of placebo-been reported in the postmarketing period; the data in these reports are insufficient tocontrolled trials. These adverse reactions occurred more commonly on RYBELSUS than establish or exclude a causal relationship between MTC and GLP-1 receptor agonist useon placebo and occurred in at least 5% of patients treated with RYBELSUS.in humans. RYBELSUS is contraindicated in patients with a personal or family historyTable 1. Adverse Reactions in Placebo-Controlled Trials Reported in 5% of of MTC or in patients with MEN 2. Counsel patients regarding the potential risk forRYBELSUS-Treated Patients with Type 2 Diabetes MellitusMTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g.Adverse Reaction PlaceboRYBELSUS 7 mgRYBELSUS 14 mg a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring(N=362) % (N=356) % (N=356) %of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS. Such monitoring may increase the risk ofNausea 6 11 20unnecessary procedures, due to the low test specificity for serum calcitonin and a highAbdominal Pain 4 10 11background incidence of thyroid disease. Significantly elevated serum calcitonin value mayDiarrhea4 9 10indicate 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.Decreased appetite1 6 9Patients with thyroid nodules noted on physical examination or neck imaging should alsoVomiting 3 6 8be further evaluated. Pancreatitis: In glycemic control trials, pancreatitis was reportedConstipation 2 6 5as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patientIn the pool of placebo- and active-controlled trials, the types and frequency of common years) versus 1 in comparator-treated patients (0.1 events per 100 patient years). After initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitisadverse reactions, excluding hypoglycemia, were similar to those listed in Table 1.(including persistent severe abdominal pain, sometimes radiating to the back and whichGastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinal may or may not be accompanied by vomiting). If pancreatitis is suspected, RYBELSUSadverse reactions occurred more frequently among patients receiving RYBELSUS than should be discontinued and appropriate management initiated; if confirmed, RYBELSUSplacebo (placebo 21%, RYBELSUS 7 mg 32%, RYBELSUS 14 mg 41%). The majority should not be restarted. Diabetic Retinopathy Complications: In a pooled analysisof reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy relatedpatients receiving RYBELSUS 7 mg (4%) and RYBELSUS 14 mg (8%) discontinued adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Intreatment due to gastrointestinal adverse reactions than patients receiving placebo (1%). a 2-year cardiovascular outcomes trial with semaglutide injection involving patients withIn addition to the reactions in Table 1, the following gastrointestinal adverse reactions with type 2 diabetes and high cardiovascular risk, diabetic retinopathy complications (whicha frequency of 5% were associated with RYBELSUS (frequencies listed, respectively, was a 4 component adjudicated endpoint) occurred in patients treated with semaglutideas placebo; 7 mg; 14 mg): abdominal distension (1%, 2%, 3%), dyspepsia (0.6%, 3%, injection (3.0%) compared to placebo (1.8%). The absolute risk increase for diabetic reti- 0.6%), eructation (0%, 0.6%, 2%), flatulence (0%, 2%, 1%), gastroesophageal reflux nopathy complications was larger among patients with a history of diabetic retinopathydisease (0.3%, 2%, 2%), and gastritis (0.8%, 2%, 2%). Other Adverse Reactions: Hypo-at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without aglycemia: Table 2 summarizes the incidence of hypoglycemia by various definitions in the known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). Rapidplacebo-controlled trials.improvement in glucose control has been associated with a temporary worsening ofTable 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials In diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabeticPatients with Type 2 Diabetes Mellitusretinopathy complications has not been studied. Patients with a history of diabetic retinop- Placebo RYBELSUS 7 mg RYBELSUS 14 mgathy should be monitored for progression of diabetic retinopathy. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemiaMonotherapyis increased when RYBELSUS is used in combination with insulin secretagogues (e.g.,(26 weeks) N=178 N=175 N=175sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin Severe* 0% 1% 0%to reduce the risk of hypoglycemia in this setting [see Adverse Reactions, Drug Interactions]. Plasma glucose 1% 0% 0%Acute Kidney Injury: There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients54 mg/dL'