Drug Safety-related Labeling Changes (SrLC)

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RYBELSUS (NDA-213051)

(SEMAGLUTIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/30/2026 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Acute Pancreatitis

Additions and/or revisions underlined:

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 accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue RYBELSUS or OZEMPIC tablets and initiate appropriate management.

5.8 Acute Gallbladder Disease

Additions and/or revisions underlined:

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials to improve glycemic control, cholelithiasis was reported in 1% of patients treated with semaglutide tablets (7 mg once daily). In a 4-year CV outcomes trial (Trial 7), cholelithiasis was reported in 1.1% of patients treated with semaglutide tablets (14 mg once daily) and in 0.9% of placebo-treated patients. In Trial 7, cholecystitis was reported in 1.1% of patients treated with semaglutide tablets (14 mg once daily) and in 0.7% of placebo-treated patients [see Adverse Reactions (6.1)]. If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

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 HbA1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR greater than or equal to 90 mL/min/1.73m2) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 1.4% of patients.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Medication Guide has undergone extensive changes; please refer to label for complete information.

Other

The name of the product was changed from Rybelsus (formulation R2) to Ozempic (semaglutide) throughout the label.

10/17/2025 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Acute Gallbladder Disease

Additions and/or revisions underlined:

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. 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 [see Adverse Reactions (6.1)]. If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

Common Adverse Reactions

. . .

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.

. . .

Other Adverse Reactions

. . .

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.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

What is RYBELSUS?

RYBELSUS is a prescription medicine used:

• along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes mellitus.
• to reduce the risk of major cardiovascular events such as heart attack, stroke or death in adults with type 2 diabetes mellitus who are at high risk for these events.

It is not known if RYBELSUS is safe and effective for use in children.

. . .

10/17/2025 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Acute Pancreatitis

Additions and/or revisions underlined:

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS [see Adverse Reactions (6)].

After initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back), and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue RYBELSUS and initiate appropriate management.

5.5 Acute Kidney Injury Due to Volume Depletion

Subsection title revised

Additions and/or revisions underlined:

There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with semaglutide. The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6)].

Monitor renal function in patients reporting adverse reactions to RYBELSUS that could lead to volume depletion, especially during dosage initiation and escalation of RYBELSUS.

5.6 Severe Gastrointestinal Adverse Reactions

Additions and/or revisions underlined:

Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6)]. In RYBELSUS clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving RYBELSUS (7 mg 0.6%, 14 mg 2%) than placebo (0.3%). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists.

RYBELSUS is not recommended in patients with severe gastroparesis.

6 Adverse Reactions

Additions and/or revisions underlined:

The following serious adverse reactions are described below or elsewhere in the prescribing information:

. . .

• Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.5)]

. . .

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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

. . .

• Renal: acute kidney injury

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

What are the possible side effects of RYBELSUS? RYBELSUS may cause serious side effects, including:

• See “What is the most important information I should know about RYBELSUS?”
• inflammation of your pancreas (pancreatitis). Stop using RYBELSUS and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without nausea or vomiting. You may feel the pain from your abdomen to your back.

. . .

• dehydration leading to kidney problems. Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Tell your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Acute Pancreatitis

Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by nausea or vomiting. Instruct patients to discontinue RYBELSUS promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)].

. . .

Acute Kidney Injury Due to Volume Depletion

Inform patients of the potential risk of acute kidney injury due to dehydration associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider [see Warnings and Precautions (5.5)].

. . .

10/17/2025 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

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.

. . .

• Nervous system disorders: dizziness, dysesthesia, dysgeusia, headache

. . .

12/09/2024 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Acute Pancreatitis

Subsection title revised

Additions and revisions underlined:

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS [see Adverse Reactions (6.1)].

5.6 Severe Gastrointestinal Adverse Reactions

Newly added subsection:

Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In RYBELSUS clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving RYBELSUS (7 mg 0.6%, 14 mg 2%) than placebo (0.3%).

RYBELSUS is not recommended in patients with severe gastroparesis.

5.8 Acute Gallbladder Disease

Additions and revisions underlined:

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients [see Adverse Reactions (6.1)]. If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)].

6 Adverse Reactions

Additions and revisions underlined:

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 [see Warnings and Precautions (5.5)]

• Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label

6.2 Postmarketing Experience

Additions and revisions underlined:

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: ileus

·       Hypersensitivity: anaphylaxis, angioedema, rash, urticaria

·       Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy

·       Nervous system disorders: dizziness, dysesthesia, dysgeusia

·       Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation

·       Skin and Subcutaneous Tissue: alopecia

8 Use in Specific Populations

8.2 Lactation

Additions and revisions underlined:

Risk Summary

A clinical lactation study reported semaglutide concentrations below the lower limit of quantification in human breast milk. However, salcaprozate sodium (SNAC) and/or its metabolites are present in human milk. Since the activity of enzymes involved in SNAC clearance may be lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC, and because there are alternative formulations of semaglutide that do not contain SNAC that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS.

. . .

8.6 Renal Impairment

Newly added information:

The recommended dosage of RYBELSUS in patients with renal impairment is the same as those with normal renal function.

8.7 Hepatic Impairment

Newly added information:

The recommended dosage in patients with hepatic impairment is the same as those with normal hepatic function.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Newly added information:

·       Do not take more than 1 tablet each day.

. . .

·       Do not take RYBELSUS with any other liquids besides water.

. . .

·       If you take too much RYBELSUS, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.

. . .

·       severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use RYBELSUS. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

. . .

PATIENT COUNSELING INFORMATION

Newly added information:

Severe Gastrointestinal Adverse Reactions

Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)].

. . .

RYBELSUS passes into breast milk, and it is not known how it affects your baby.

11/01/2024 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Pulmonary Aspiration During General Anesthesia or Deep Sedation

Newly added subsection:

RYBELSUS delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations.

Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking RYBELSUS, including whether modifying preoperative fasting recommendations or temporarily discontinuing RYBELSUS could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS.

6 Adverse Reactions

Additions and revisions underlined:

The following serious adverse reactions are described below or elsewhere in the prescribing information:

. . .

• Hypersensitivity Reactions [see Warnings and Precautions (5.6)]

• Acute Gallbladder Disease [see Warnings and Precautions (5.7)]

• Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.8)]

6.1 Postmarketing Experience

Newly added information:

Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

. . .

Before using RYBELSUS, tell your healthcare provider if you have any other medical conditions, including if you:

• have or have had problems with your pancreas or kidneys.

• have a history of vision problems related to your diabetes.

• are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).

. . .

RYBELSUS may cause serious side effects, including:

. . .

• food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). RYBELSUS may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking RYBELSUS before you are scheduled to have surgery or other procedures.

PATIENT COUNSELING INFORMATION

Newly added information:

Pulmonary Aspiration During General Anesthesia or Deep Sedation

Inform patients that RYBELSUS may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS [see Warnings and Precautions (5.8)].

01/24/2024 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Nervous system disorders: dizziness, dysgeusia       

01/12/2023 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Hypersensitivity

Additions and/or revisions underlined:

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. RYBELSUS is contraindicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. [see Adverse Reactions (6.2)].

Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists …

5.7 Acute Gallbladder Disease

[see Adverse Reactions (6.2)]. is added to end of subsection.

6 Adverse Reactions

6.1 Clinical Trials Experience

Pool of Placebo-Controlled Trials

Addition of ‘adult’ in front of patients in the first sentence of the paragraph.

Pool of Placebo- and Active-Controlled Trials

Addition of ‘adult’ in front of patients in the first sentence of the paragraph.

Common Adverse Reactions

Additions and/or revisions underlined:

Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in adult patients with type 2 diabetes in the pool of placebo-controlled trials.

Other Adverse Reactions

Additions and/or revisions underlined:

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 2 summarizes the incidence of hypoglycemia by various definitions in the placebo-controlled trials …

6.2 Postmarketing Experience

Newly added information:

Gastrointestinal: ileus

7 Drug Interactions

7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

Additions and/or revisions underlined:

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) and Adverse Reactions (6.1)].

7.2 Oral Medications

‘[see Clinical Pharmacology (12.3)]’ added to the end of the first paragraph in the subsection.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

In the pool of glycemic control trials, 1229 (30%) RYBELSUS-treated patients were 65 years of age and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over [see Clinical Studies (14)]. In PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS-treated patients were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of age and over.

No overall differences in safety or effectiveness for RYBELSUS have been observed between patients 65 years of age and older and younger adult patients.

06/10/2022 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Acute Gallbladder Disease

Newly added subsection:

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Acute Gallbladder Disease [see Warnings and Precautions (5.7)]

6.3 Postmarketing Experience

Additions and/or revisions underlined:

…

Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What are the possible side effects of RYBELSUS?

• gallbladder problems. Gallbladder problems have happened in some people who take RYBELSUS. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include:

• pain in your upper stomach (abdomen)     

• yellowing of skin or eyes (jaundice)

• fever

• clay-colored stools

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.7)].

…

04/30/2021 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

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 (5.6)].

5 Warnings and Precautions

5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

(Additions and/or revisions underlined)

Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)].

The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 Hypersensitivity

(Additions and/or revisions underlined)

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity to RYBELSUS [see Contraindications (4) and Adverse Reactions (6.3)].

6 Adverse Reactions

6.3 Postmarketing Experience

(Newly added section)

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.

Hypersensitivity: anaphylaxis, angioedema, rash, urticaria

7 Drug Interactions

7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

(Additions and/or revisions underlined)

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) and Adverse Reactions (6.1)].

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

In the pool of glycemic control trials, 1229 (29.9%) RYBELSUS-treated patients were 65 years of age and over and 199 (4.8%) RYBELSUS-treated patients were 75 years of age and over. In PIONEER 6, the cardiovascular outcomes trial, 891 (56.0%) RYBELSUS-treated patients were 65 years of age and over and 200 (12.6%) RYBELSUS-treated patients were 75 years of age and over.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions underlined)

Do not use RYBELSUS if:

• you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you

have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

• you have had a serious allergic reaction to semaglutide or any of the ingredients in RYBELSUS. See the end of this

Medication Guide for a complete list of ingredients in RYBELSUS. Symptoms of a serious allergic reaction include:

o swelling of your face, lips, tongue or throat

o problems breathing or swallowing

o severe rash or itching

o fainting or feeling dizzy

o very rapid heartbeat

Stop using RYBELSUS and get medical help right away, if you have any symptoms of

a serious allergic reaction including:

o swelling of your face, lips, tongue or throat

o problems breathing or swallowing

o severe rash or itching

o fainting or feeling dizzy

o very rapid heartbeat

How should I store RYBELSUS?

• Store RYBELSUS at room temperature between 68°F and 77°F (20°C to 25°C).

• Store in a dry place away from moisture.

• Store tablets in the original closed RYBELSUS bottle until you are ready to take one. Do not store in any other

container.

Patient Counseling Information

(Additions and/or revisions underlined)

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Inform patients that the risk of hypoglycemia is increased when RYBELSUS is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of RYBELSUS. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking RYBELSUS and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)].