RYBELSUS

RYBELSUS tablets, for oral use, contain semaglutide, a GLP-1 receptor agonist. The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C 187 H 291 N 45 O 59 and the molecular weight is 4113.58 g/mol. Structural formula: Semaglutide is a white to almost white hygroscopic powder. Each tablet of: • RYBELSUS (formulation R1) contains 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC). • RYBELSUS (formulation R2) contains 1.5 mg, 4 mg or 9 mg of semaglutide and the following inactive ingredients: SNAC and magnesium stearate. structural_formula

RYBELSUS is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. • to reduce the risk of major adverse cardiovascular (CV) events (CV death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus who are at high risk for these events. RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who are at high risk for these events. ( 1 )

• There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. ( 2.1 ) o These formulations are not substitutable on a mg per mg basis o Use either formulation but do not use both formulations at the same time. • Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water); do not take with other liquids besides water. ( 2.2 ) • After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications. ( 2.2 ) • Swallow tablets whole. Do not split, crush or chew tablets. ( 2.2 ) • See the Full Prescribing Information for instructions on switching from OZEMPIC to RYBELSUS and switching between the two different RYBELSUS formulations. ( 2.4 ) Recommended Dosage of Starting, Escalation and Maintenance Dosage of RYBELSUS Formulations R1 and R2 ( 2.3 ) RYBELSUS (formulation R1) ( 2.3 ) • Day 1 to 30: Recommended starting dosage is 3 mg orally once daily for 30 days (this dosage is not effective for glycemic control). • Days 31 to 60: Increase the dosage to 7 mg orally once daily. • On Day 61 or thereafter, if: ( 2.3 ) o No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 14 mg orally once daily. RYBELSUS (formulation R2) ( 2.3 ) • Day 1 to 30: Recommended starting dosage is 1.5 mg orally once daily for 30 days (this dosage is not effective for glycemic control). • Days 31 to 60: Increase the dosage to 4 mg orally once daily. • On Day 61 or thereafter, if: ( 2.3 ) o No additional glycemic control is needed, maintain the dosage at 4 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 9 mg orally once daily. 2.1 Overview of RYBELSUS Formulations • There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. Refer to recommendations on how to switch from one formulation to another formulation [see Dosage and Administration ( 2.3 , 2.4 )] . o RYBELSUS (formulation R1) includes strengths 3 mg, 7 mg and 14 mg. o RYBELSUS (formulation R2) includes strengths 1.5 mg, 4 mg and 9 mg. • These formulations are not substitutable on a mg per mg basis. • Use either RYBELSUS formulation R1 or formulation R2; do not use both formulations at the same time. • Do not take more than one tablet per day. 2.2 Important Administration Instructions • Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water. • After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications [see Clinical Pharmacology ( 12.3 )] . • Swallow tablets whole. Do not split crush or chew. • If a dose is missed, skip the missed dose and take the next dose the following day. 2.3 Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS Formulations R1 and R2 RYBELSUS (formulation R1) RYBELSUS (formulation R1) includes the following strengths: 3 mg, 7 mg and 14 mg. Recommend the following RYBELSUS (formulation R1) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 )]: • Starting Dosage (Initiation Phase) (Days 1 to 30) : The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond) : o Days 31 to 60: Increase the dosage to 7 mg orally once daily. o On Day 61 or thereafter, if: ▪ No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. ▪ Additional glycemic control is needed, increase the dosage to 14 mg orally once daily. RYBELSUS (formulation R2) RYBELSUS (formulation R2) includes the following strengths: 1.5 mg, 4 mg and 9 mg. Recommend the following RYBELSUS (formulation R2) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 )] : • Starting Dosage (Initiation Phase) (Days 1 through 30) : The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond) : o Days 31 to 60: Increase the dosage to 4 mg orally once daily. o On Day 61 or thereafter, if: ▪ No additional glycemic control is needed maintain the dosage at 4 mg orally once daily. ▪ Additional glycemic control is needed increase the dosage to 9 mg orally once daily. 2.4 Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS Switching Between RYBELSUS Formulations • Do not switch between RYBELSUS formulations during the initiation phase (Days 1-30) [see Dosage and Administration ( 2.3 )] . • After 30 days of RYBELSUS treatment (after the initiation phase) [see Dosage and Administration ( 2.3 )] , patients may switch between RYBELSUS formulations (see Table 1 ). • When switching between the formulations, initiate the other RYBELSUS formulation the day after discontinuing the previous RYBELSUS formulation. Table 1. Switching Between Escalation or Maintenance Dosage of RYBELSUS Formulations RYBELSUS (formulation R1) * RYBELSUS (formulation R2) * 7 mg orally once daily 4 mg orally once daily 14 mg orally once daily 9 mg orally once daily *Discontinue this formulation and initiate the alternate formulation the day after Switching from OZEMPIC to RYBELSUS (formulation R1) or RYBELSUS (formulation R2) Switching from OZEMPIC to RYBELSUS (formulation R1) • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 7 mg or 14 mg of RYBELSUS (formulation R1) orally once daily. • Switching recommendations for patients taking OZEMPIC 0.25 mg, 1 mg or 2 mg subcutaneously once weekly to RYBELSUS (formulation R1) are not available. Switching from OZEMPIC to RYBELSUS (formulation R2) • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 4 mg or 9 mg of RYBELSUS (formulation R2) orally once daily. • Switching recommendations for patients taking OZEMPIC 0.25 mg, 1 mg or 2 mg subcutaneously once weekly to RYBELSUS (formulation R2) are not available.

RYBELSUS is 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. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS [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 RYBELSUS. ( 4 )

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 RYBELSUS (formulation R2 - 1.5 mg, 4 mg and 9 mg strengths) [see Dosage and Administration ( 2.2 )] and RYBELSUS (formulation R1 - 3 mg, 7, mg and 14 mg strengths) [see Dosage and Administration ( 2.3 )] 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 (formulation R1) 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 (formulation R1) 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 RYBELSUS 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/1.73 m 2 ) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73 m 2 ) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73 m 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 RYBELSUS 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/1.73 m 2 ) in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73 m 2 ) in 28.5% and moderately impaired (eGFR 30 to 60 mL/min/1.73 m 2 ) in 5.4% of the patients. Common Adverse Reactions Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in adult patients with type 2 diabetes mellitus in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on RYBELSUS than on placebo and occurred in at least 5% of patients treated with RYBELSUS. Table 2. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of RYBELSUS-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=362) % RYBELSUS 7 mg (N=356) % RYBELSUS 14 mg (N=356) % Nausea 6 11 20 Abdominal Pain 4 10 11 Diarrhea 4 9 10 Decreased appetite 1 6 9 Vomiting 3 6 8 Constipation 2 6 5 In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 2 . In a 4-year CV outcomes trial (Trial 7), 4,825 patients were randomized to RYBELSUS for a median follow-up of 49.6 months and 4,825 patients were randomized to placebo for a median follow-up of 49.4 months [see Clinical Studies ( 14.4 )]. Safety data collection was limited to serious adverse events (including death), adverse events leading to discontinuation, and adverse events of special interest. Study drug was permanently discontinued due to an adverse event in 15.5% of RYBELSUS-treated patients and 11.6% of placebo-treated patients. Additional information from this trial is included in subsequent sections below, when relevant. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients who received RYBELSUS than placebo: RYBELSUS 14 mg once daily (41%), RYBELSUS 7 mg once daily (32%) and placebo (21%), including severe reactions (RYBELSUS 14 mg 2.0%, RYBELSUS 7 mg 0.6%, placebo 0.3%). The majority of reports of nausea, vomiting and/or diarrhea occurred during dose escalation. A greater percentage of patients who received RYBELSUS 14 mg once daily (8%) and RYBELSUS 7 mg once daily (4%) discontinued treatment due to gastrointestinal adverse reactions than patients who received placebo (1%). In addition to the reactions in Table 2 , the following gastrointestinal adverse reactions with a frequency of <5% occurred in RYBELSUS-treated patients (frequencies listed, respectively, as 14 mg once daily, 7 mg once daily and placebo): abdominal distension (3%, 2% and 1%), dyspepsia (0.6%, 3%, 0.6%), eructation (2%, 0.6%, 0%,), flatulence (1%, 2%, 0%), gastroesophageal reflux disease (2%, 2%, 0.3%) and gastritis (2%, 2%, 0.8%). Other Adverse Reactions Pancreatitis: In the pool of placebo- and active-controlled trials with RYBELSUS, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patient years) versus 1 in comparator-treated patients (<0.1 events per 100 patient years). Diabetic Retinopathy Complications: In the pool of placebo- and active-controlled trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Hypoglycemia: Table 3 summarizes the incidence of hypoglycemia by various definitions in the placebo-controlled trials. Table 3. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus Placebo RYBELSUS 7 mg RYBELSUS 14 mg Monotherapy (26 weeks) N=178 N=175 N=175 Severe* 0% 1% 0% Plasma glucose <54 mg/dL 1% 0% 0% Add-on to metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin in patients with moderate renal impairment (26 weeks) N=161 - N=163 Severe* 0% - 0% Plasma glucose <54 mg/dL 3% - 6% Add-on to insulin with or without metformin (52 weeks) N=184 N=181 N=181 Severe* 1% 0% 1% Plasma glucose <54 mg/dL 32% 26% 30% * “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when RYBELSUS was used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin . Increases in Amylase and Lipase: In placebo-controlled trials, patients exposed to RYBELSUS 7 mg and 14 mg had a mean increase from baseline in amylase of 10% and 13%, respectively and lipase of 30% and 34%, respectively. These changes were not observed in placebo-treated patients. Cholelithiasis: In placebo-controlled trials to improve glycemic control, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. In a 4-year CV outcomes trial (Trial 7), cholelithiasis was reported in 1.1% of patients treated with RYBELSUS 14 mg and in 0.9% of placebo-treated patients. In Trial 7, cholecystitis was reported in 1.1% of patients treated with RYBELSUS 14 mg and in 0.7% of placebo-treated patients. Increases in Heart Rate: In placebo-controlled trials, RYBELSUS 7 mg and 14 mg resulted in a mean increase in heart rate of 1 to 3 beats per minute. There was no change in heart rate in placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Gastrointestinal: acute pancreatitis and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction • Hypersensitivity: anaphylaxis, angioedema, rash, urticaria • Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy • Nervous system disorders: dizziness, dysesthesia, dysgeusia, headache • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation • Renal: acute kidney injury • Skin and Subcutaneous Tissue: alopecia

Other Oral Drugs: RYBELSUS delays 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 RYBELSUS stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating RYBELSUS, consider reducing the dose 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 RYBELSUS causes 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: 1.25-1.42) when administered with RYBELSUS in a drug interaction study [see Clinical Pharmacology ( 12.3 )] . When coadministering RYBELSUS 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 )] .