1 INDICATIONS AND USAGE OZEMPIC 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 events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.

• 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.

OZEMPIC 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 in adults with type 2 diabetes mellitus and established cardiovascular disease.

( 1 ) • 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.

( 1 )

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 ( 5.5 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.6 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.7 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.9 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.10 )] The most common adverse reactions reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or http://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.

Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] .

These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks.

Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male.

In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity.

At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%.

At baseline, 8.9% of the population reported retinopathy.

Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients.

Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin.

In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks.

Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male.

In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity.

At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%.

At baseline, 7.8% of the population reported retinopathy.

Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients.

Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials.

These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC.

Table 1.

Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5 3.1 In the pool of placebo- and active-controlled trials and in the 2-year cardiovascular outcomes trial, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 .

In a clinical trial with 959 patients treated with OZEMPIC 1 mg or OZEMPIC 2 mg as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified.

In the FLOW trial [see Clinical Studies ( 14.3 )] in patients with type 2 diabetes mellitus and chronic kidney disease, safety data collection was limited to serious adverse events and selected predefined categories of adverse events regardless of seriousness.

There were no new serious or severe adverse reactions identified in this trial.

Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%, OZEMPIC 1 mg 36.4%).

The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation.

More patients receiving OZEMPIC 0.5 mg (3.1%) and OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%).

In the trial with OZEMPIC 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC 2 mg (34%) vs OZEMPIC 1 mg (30.8%).

In addition to the reactions in Table 1 , the following gastrointestinal adverse reactions with a frequency of <5% were associated with OZEMPIC (frequencies listed, respectively, as: placebo; 0.5 mg; 1 mg): dyspepsia (1.9%, 3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulence (0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%, 1.9%, 1.5%), and gastritis (0.8%, 0.8%, 0.4%).

Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of events related to hypoglycemia by various definitions in the placebo-controlled trials.

Table 2.

Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Monotherapy (30 weeks) N=129 N=127 N=130 Severe † 0% 0% 0% Documented symptomatic (≤70 mg/dL glucose threshold) 0% 1.6% 3.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 1.6% 0% 0% Add-on to Basal Insulin with or without Metformin (30 weeks) N=132 N=132 N=131 Severe † 0% 0% 1.5% Documented symptomatic (≤70 mg/dL glucose threshold) 15.2% 16.7% 29.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 5.3% 8.3% 10.7% † “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person.

Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea [see Warnings and Precautions ( 5.5 ), Clinical Studies ( 14 )].

Severe hypoglycemia occurred in 0.8% and 1.2% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea.

Documented symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea.

Severe or blood glucose confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea.

Injection Site Reactions In placebo-controlled trials, injection site reactions (e.g., injection-site discomfort, erythema) were reported in 0.2% of OZEMPIC-treated patients.

Increases in Amylase and Lipase In placebo-controlled trials, patients exposed to OZEMPIC had a mean increase from baseline in amylase of 13% and lipase of 22%.

These changes were not observed in placebo-treated patients.

Acute Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years).

Cholelithiasis In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively.

Cholelithiasis was not reported in placebo-treated patients.

Increases in Heart Rate In placebo-controlled trials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute.

There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients.

Fatigue, Dysgeusia and Dizziness Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC include fatigue, dysgeusia and dizziness.

6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of OZEMPIC.

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, cholecystectomy Neurologic : dysesthesia, 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
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.

Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] .

These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks.

Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male.

In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity.

At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%.

At baseline, 8.9% of the population reported retinopathy.

Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients.

Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin.

In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks.

Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male.

In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity.

At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%.

At baseline, 7.8% of the population reported retinopathy.

Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients.

Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials.

These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC.

Table 1.

Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5 3.1 In the pool of placebo- and active-controlled trials and in the 2-year cardiovascular outcomes trial, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 .

In a clinical trial with 959 patients treated with OZEMPIC 1 mg or OZEMPIC 2 mg as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified.

In the FLOW trial [see Clinical Studies ( 14.3 )] in patients with type 2 diabetes mellitus and chronic kidney disease, safety data collection was limited to serious adverse events and selected predefined categories of adverse events regardless of seriousness.

There were no new serious or severe adverse reactions identified in this trial.

Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%, OZEMPIC 1 mg 36.4%).

The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation.

More patients receiving OZEMPIC 0.5 mg (3.1%) and OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%).

In the trial with OZEMPIC 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC 2 mg (34%) vs OZEMPIC 1 mg (30.8%).

In addition to the reactions in Table 1 , the following gastrointestinal adverse reactions with a frequency of <5% were associated with OZEMPIC (frequencies listed, respectively, as: placebo; 0.5 mg; 1 mg): dyspepsia (1.9%, 3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulence (0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%, 1.9%, 1.5%), and gastritis (0.8%, 0.8%, 0.4%).

Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of events related to hypoglycemia by various definitions in the placebo-controlled trials.

Table 2.

Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Monotherapy (30 weeks) N=129 N=127 N=130 Severe † 0% 0% 0% Documented symptomatic (≤70 mg/dL glucose threshold) 0% 1.6% 3.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 1.6% 0% 0% Add-on to Basal Insulin with or without Metformin (30 weeks) N=132 N=132 N=131 Severe † 0% 0% 1.5% Documented symptomatic (≤70 mg/dL glucose threshold) 15.2% 16.7% 29.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 5.3% 8.3% 10.7% † “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person.

Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea [see Warnings and Precautions ( 5.5 ), Clinical Studies ( 14 )].

Severe hypoglycemia occurred in 0.8% and 1.2% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea.

Documented symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea.

Severe or blood glucose confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea.

Injection Site Reactions In placebo-controlled trials, injection site reactions (e.g., injection-site discomfort, erythema) were reported in 0.2% of OZEMPIC-treated patients.

Increases in Amylase and Lipase In placebo-controlled trials, patients exposed to OZEMPIC had a mean increase from baseline in amylase of 13% and lipase of 22%.

These changes were not observed in placebo-treated patients.

Acute Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years).

Cholelithiasis In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively.

Cholelithiasis was not reported in placebo-treated patients.

Increases in Heart Rate In placebo-controlled trials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute.

There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients.

Fatigue, Dysgeusia and Dizziness Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC include fatigue, dysgeusia and dizziness.

6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of OZEMPIC.

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, cholecystectomy Neurologic : dysesthesia, 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