Oral Semaglutide

1 INDICATIONS AND USAGE RYBELSUS and OZEMPIC tablets are 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 and OZEMPIC tablets are glucagon-like peptide-1 (GLP-1) receptor agonists 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 )

2 DOSAGE AND ADMINISTRATION • RYBELSUS and OZEMPIC tablets are not substitutable on a mg-to-mg basis. • Take RYBELSUS or OZEMPIC tablets orally once daily on an empty stomach in the morning with water (up to 4 ounces of water); do not take with other liquids besides water. ( 2.1 ) • Swallow tablets whole. Do not split, crush, chew or dissolve in any solution. ( 2.1 ) • After taking RYBELSUS or OZEMPIC tablets, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications. ( 2.1 ) • See the Full Prescribing Information for instructions on switching between RYBELSUS and OZEMPIC tablets ( 2.3 ) and from OZEMPIC injections to RYBELSUS or OZEMPIC tablets. ( 2.4 ) Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS and OZEMPIC Tablets ( 2.2 ) RYBELSUS ( 2.2 ) • 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: ( 2.2 ) 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. OZEMPIC Tablets ( 2.2 ) • 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: ( 2.2 ) 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 Important Administration Instructions • RYBELSUS and OZEMPIC tablets are not substitutable on a mg-to-mg basis. • Take one RYBELSUS or OZEMPIC tablet orally once daily on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS or OZEMPIC tablets with other liquids besides water [see Clinical Pharmacology ( 12.3 )] . • Do not take more than one tablet per day. • Swallow tablets whole. Do not split, crush, chew or dissolve in any solution. • After taking RYBELSUS or OZEMPIC tablets, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications [see Clinical Pharmacology ( 12.3 )] . • If a dose is missed, skip the missed dose and take the next dose the following day. 2.2 Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS and OZEMPIC Tablets RYBELSUS: Recommended Dosage Follow the RYBELSUS starting, escalation, and maintenance dosage described below to reduce the risk of gastrointestinal (GI) 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. OZEMPIC Tablets: Recommended Dosage Follow the OZEMPIC tablets starting, escalation, and maintenance dosage described below to reduce the risk of GI 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. 2.3 Switching Between RYBELSUS and OZEMPIC Tablets • Do not switch between RYBELSUS and OZEMPIC tablets during the initiation phase (Days 1 to 30) [see Dosage and Administration ( 2.2 )] . • After 30 days of RYBELSUS or OZEMPIC tablet treatment (after the initiation phase) [see Dosage and Administration ( 2.2 )] , patients may switch between RYBELSUS and OZEMPIC tablet products (see Table 1 ). • When switching between RYBELSUS and OZEMPIC tablets, initiate the other semaglutide tablet product the day after discontinuing the previous semaglutide tablet product. Table 1. Switching Between Escalation or Maintenance Dosage of RYBELSUS and OZEMPIC Tablets RYBELSUS OZEMPIC Tablets 7 mg orally once daily 4 mg orally once daily 14 mg orally once daily 9 mg orally once daily 2.4 Switching from OZEMPIC Injection to RYBELSUS or OZEMPIC Tablets Switching from OZEMPIC Injection to RYBELSUS Tablets • Patients taking the 0.5 mg dose of OZEMPIC injection may switch to RYBELSUS tablets. • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC injection, start 7 mg or 14 mg of RYBELSUS orally once daily. Switching from OZEMPIC Injection to OZEMPIC Tablets • Patients taking the 0.5 mg dose of OZEMPIC injection may switch to OZEMPIC tablets. • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC injection, start 4 mg or 9 mg of OZEMPIC tablets orally once daily.

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/1.73m 2 ) in 5.4% of the patients. Common Adverse Reactions Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of semaglutide tablets in adult patients with type 2 diabetes mellitus in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on semaglutide tablets than on placebo and occurred in at least 5% of patients treated with semaglutide tablets. Table 2. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of Semaglutide Tablets-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=362) % Semaglutide Tablets 7 mg (N=356) % Semaglutide Tablets 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 semaglutide tablets 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 semaglutide tablets-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 semaglutide tablets than placebo: semaglutide tablets 14 mg once daily (41%), semaglutide tablets 7 mg once daily (32%) and placebo (21%), including severe reactions (semaglutide tablets 14 mg 2.0%, semaglutide tablets 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 semaglutide tablets 14 mg once daily (8%) and semaglutide tablets 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 semaglutide tablets -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 semaglutide tablets, pancreatitis was reported as a serious adverse event in 6 semaglutide tablets -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 semaglutide tablets, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with semaglutide tablets 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 Semaglutide Tablets 7 mg Semaglutide Tablets 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 semaglutide tablets were used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Increases in Amylase and Lipase : In placebo-controlled trials, patients exposed to semaglutide tablets 7 mg and 14 mg tablets 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 semaglutide tablets 7 mg. In a 4-year CV outcomes trial (Trial 7), cholelithiasis was reported in 1.1% of patients treated with semaglutide 14 mg tablets and in 0.9% of placebo-treated patients. In Trial 7, cholecystitis was reported in 1.1% of patients treated with semaglutide14 mg tablets and in 0.7% of placebo-treated patients. Increases in Heart Rate : In placebo-controlled trials, semaglutide tablets 7 mg and 14 mg tablets 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 in RYBELSUS and OZEMPIC tablets. 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

12.3 Pharmacokinetics Semaglutide estimated mean steady-state concentration was 6.7 nmol/L and 14.6 nmol/L following once daily oral administration of 7 mg and 14 mg of RYBELSUS, respectively, in patients with type 2 diabetes mellitus. Semaglutide exposures increased in a dose-proportional manner. Steady-state exposure was achieved following 4 to 5 weeks of semaglutide tablets oral administration. Absorption RYBELSUS and OZEMPIC tablets are co-formulated with SNAC which facilitates the absorption of semaglutide after oral administration. The absorption of semaglutide predominantly occurs in the stomach. Semaglutide estimated absolute bioavailability was approximately: • 0.4% to 1% after oral administration of 3 mg, 7 mg and 14 mg of RYBELSUS. • 1% to 2% after oral administration of 1.5 mg, 4 mg and 9 mg of OZEMPIC tablets. Semaglutide maximum concentration was reached approximately 1-hour after oral administration of semaglutide tablets. Effect of Semaglutide Tablet Formulations : There were no clinically significant differences observed in the mean steady state AUC 0-24h,SS and C max,SS between the 3 mg, 7 mg and 14 mg doses of RYBELSUS and the 1.5 mg, 4 mg and 9 mg doses of OZEMPIC tablets, respectively, in a clinical study conducted in healthy subjects. Effect of Volume and Timing of Water Consumption : Single oral doses of semaglutide tablets were administered with 50 mL or 240 mL of water after an 8-hour overnight fast and a continued fast of 4 hours post-dose in healthy subjects. Semaglutide absorption (i.e., area under the curve (AUC) and peak concentrations (C max ) were higher following dosing with 50 mL water compared to that of 240 mL water. For 10 days, healthy subjects received semaglutide tablets once daily doses orally with 50 mL or 120 mL of water under fasting conditions with post-dose fasting period of 15, 30, 60 or 120 minutes. In this study, semaglutide absorption (i.e., AUC and C max ) was higher after a longer post-dose fasting period. There were no clinically significant differences in semaglutide absorption with administration of 50 mL or 120 mL of water. Distribution Semaglutide absolute volume of distribution is approximately 8 L in patients with type 2 diabetes. Semaglutide is >99% bound to plasma albumin. Elimination Semaglutide elimination half-life is approximately one week with an absolute clearance of approximately 0.04 L/hour in patients with type 2 diabetes. Semaglutide is present in the circulation for about five weeks after the last semaglutide tablet dose. Metabolism : The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. Excretion : The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine as intact semaglutide. Specific Populations No clinically significant differences in semaglutide pharmacokinetics were observed based on age (≥18 years old), sex, race (White, Asian or Black or African American), ethnicity, body weight (40 to 188 kg), upper GI disease (i.e., chronic gastritis and/or gastroesophageal reflux disease), hepatic impairment (i.e., mild, moderate, severe based on the Child-Pugh system) and renal impairment (i.e., mild, moderate, severe, end staged renal disease). Drug Interaction Studies Clinical Studies and Model-Informed Approaches : The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral drugs. Trials were conducted to study the potential effect of semaglutide on the absorption of oral drugs taken with semaglutide administered orally at steady-state exposure. Levothyroxine : Total thyroxine (i.e., adjusted for endogenous levels) AUC was increased by 33% following administration of a single dose of levothyroxine 600 mcg concomitantly administered with semaglutide tablets. Maximum exposure (C max ) was unchanged. Other Drugs : No clinically significant differences in semaglutide pharmacokinetics were observed when used concomitantly with omeprazole. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with semaglutide: lisinopril, S-warfarin, R-warfarin, metformin, digoxin, ethinyl estradiol, levonorgestrel, furosemide or rosuvastatin. In Vitro Studies : Semaglutide has very low potential to inhibit or induce CYP enzymes, and to inhibit drug transporters.