∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Personal or family history of medullary thyroid carcinoma or in patients
`
`with Multiple Endocrine Neoplasia syndrome type 2 (4).
`Prior serious hypersensitivity reaction to semaglutide or any of the
`excipients in RYBELSUS (4).
`
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Pancreatitis: Has been reported in clinical trials. Discontinue promptly if
`
`pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2).
`Diabetic Retinopathy Complications: Has been reported in a cardiovascular
`outcomes trial with semaglutide injection. Patients with a history of
`diabetic retinopathy should be monitored (5.3).
`Hypoglycemia: Concomitant use with an insulin secretagogue or insulin
`may increase the risk of hypoglycemia, including severe hypoglycemia.
`Reducing dose of insulin secretagogue or insulin may be necessary (5.4).
`Acute Kidney Injury: Monitor renal function in patients with renal
`impairment reporting severe adverse gastrointestinal reactions (5.5).
`Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
`anaphylaxis and angioedema) have been reported. Discontinue
`RYBELSUS if suspected and promptly seek medical advice (5.6).
`Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected,
`gallbladder studies are indicated (5.7)
`
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`The most common adverse reactions, reported in ≥5% of patients treated with
`RYBELSUS 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.
`
`------------------------------DRUG INTERACTIONS-----------------------------------
`Oral Medications: RYBELSUS delays gastric emptying. When coadministering
`oral medications instruct patients to closely follow RYBELSUS administration
`instructions. Consider increased clinical or laboratory monitoring for
`medications that have a narrow therapeutic index or that require clinical
`monitoring (7.2).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Pregnancy: May cause fetal harm (8.1).
`
`Lactation: Breastfeeding not recommended (8.2).
`
`Females and Males of Reproductive Potential: Discontinue RYBELSUS in
`
`women at least 2 months before a planned pregnancy due to the long
`washout period for semaglutide (8.3).
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide.
`
` Revised: 06/2022
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`RYBELSUS® safely and effectively. See full prescribing information
`for RYBELSUS.
`
`RYBELSUS (semaglutide) tablets, for oral use
`Initial U.S. Approval: 2017
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`In rodents, semaglutide causes thyroid C-cell tumors. It is
`unknown whether RYBELSUS causes thyroid C-cell tumors,
`including medullary thyroid carcinoma (MTC), in humans as
`the human relevance of semaglutide-induced rodent thyroid C-
`cell tumors has not been determined (5.1, 13.1).
`RYBELSUS is contraindicated in patients with a personal or
`family history of MTC or in patients with Multiple Endocrine
`Neoplasia syndrome type 2 (MEN 2). Counsel patients
`regarding the potential risk of MTC and symptoms of thyroid
`tumors (4, 5.1).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Warning and Precautions, Acute Gallbladder Disease (5.7)……06/2022
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`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).
`
`Limitations of Use
` Not recommended as first-line therapy for patients inadequately
`controlled on diet and exercise (1, 5.1).
` Has not been studied in patients with a history of pancreatitis (1, 5.2).
` Not for treatment of type 1 diabetes mellitus (1).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
` Instruct patients to take RYBELSUS at least 30 minutes before the
`first food, beverage, or other oral medications of the day with no more
`than 4 ounces of plain water only. Waiting less than 30 minutes, or
`taking with food, beverages (other than plain water) or other oral
`medications will lessen the effect of RYBELSUS. Waiting more than
`30 minutes to eat may increase the absorption of RYBELSUS (2.1).
` Swallow tablets whole. Do not cut, crush, or chew tablets (2.1).
` Start RYBELSUS with 3 mg once daily for 30 days. After 30 days on
`the 3 mg dose, increase the dose to 7 mg once daily (2.2).
` Dose may be increased to 14 mg once daily if additional glycemic
`control is needed after at least 30 days on the 7 mg dose (2.2).
` See the Full Prescribing Information for instructions on switching
`between OZEMPIC® and RYBELSUS (2.3).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Tablets: 3 mg, 7 mg and 14 mg (3).
`
`Reference ID: 4997051
`
`

`

`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Overview of Clinical Studies
`14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes
`Mellitus
`14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2
`Diabetes Mellitus
`14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes
`Mellitus and Cardiovascular Disease
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`1
`2
`
`6
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Instructions
`2.2 Recommended Dosage
`2.3 Switching Patients between OZEMPIC and RYBELSUS
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Thyroid C-Cell Tumors
`5.2
`Pancreatitis
`5.3
` Diabetic Retinopathy Complications
`5.4
` Hypoglycemia with Concomitant Use of Insulin
`Secretagogues or Insulin
` Acute Kidney Injury
`5.5
` Hypersensitivity
`5.6
` Acute Gallbladder Disease
`5.7
`ADVERSE REACTIONS
`6.1
` Clinical Trials Experience
`6.2
` Immunogenicity
`6.3
` Postmarketing Experience
`DRUG INTERACTIONS
`7.1
` Concomitant Use with an Insulin Secretagogue (e.g.,
`Sulfonylurea) or with Insulin
` Oral Medications
`7.2
`USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2
` Lactation
`8.3
` Females and Males of Reproductive Potential
`8.4
` Pediatric Use
`
`7
`
`8
`
`Reference ID: 4997051
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid
`C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS causes
`thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human
`relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see
`Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
` RYBELSUS is contraindicated in patients with a personal or family history of MTC or in
`patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications
`(4)]. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and
`inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea,
`persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is
`of uncertain value for early detection of MTC in patients treated with RYBELSUS [see
`Contraindications (4) and Warnings and Precautions (5.1)].
`
`1
`INDICATIONS AND USAGE
`RYBELSUS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus [see Clinical Studies (14.1)].
`
`Limitations of Use
`RYBELSUS is not recommended as a first-line therapy for patients who have inadequate glycemic control
`
`on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans [see
`Warnings and Precautions (5.1)].
`RYBELSUS has not been studied in patients with a history of pancreatitis. Consider other antidiabetic
`therapies in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
`RYBELSUS is not indicated for use in patients with type 1 diabetes mellitus.
`
`
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`2.1 Important Administration Instructions
`Instruct patients to take RYBELSUS at least 30 minutes before the first food, beverage, or other oral
`
`medications of the day with no more than 4 ounces of plain water only [see Clinical Pharmacology (12.3)].
`Waiting less than 30 minutes, or taking RYBELSUS with food, beverages (other than plain water) or other
`oral medications will lessen the effect of RYBELSUS by decreasing its absorption. Waiting more than 30
`minutes to eat may increase the absorption of RYBELSUS.
`Swallow tablets whole. Do not split, crush, or chew tablets.
`
`
`
`2.2 Recommended Dosage
`Start RYBELSUS with 3 mg once daily for 30 days. The 3 mg dose is intended for treatment initiation and
`
`is not effective for glycemic control.
` After 30 days on the 3 mg dose, increase the dose to 7 mg once daily.
` Dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days
`on the 7 mg dose.
`Taking two 7 mg RYBELSUS tablets to achieve a 14 mg dose is not recommended.
`If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day.
`
`
`
`
`2.3 Switching Patients between OZEMPIC and RYBELSUS
`Patients treated with RYBELSUS 14 mg daily can be transitioned to OZEMPIC subcutaneous injection
`
`0.5 mg once weekly. Patients can start OZEMPIC the day after their last dose of RYBELSUS.
`
`Reference ID: 4997051
`
`

`

`
`
`Patients treated with once weekly OZEMPIC 0.5 mg subcutaneous injection can be transitioned to
`RYBELSUS 7 mg or 14 mg. Patients can start RYBELSUS up to 7 days after their last injection of
`OZEMPIC. There is no equivalent dose of RYBELSUS for OZEMPIC 1 mg.
`
`3
`DOSAGE FORMS AND STRENGTHS
`RYBELSUS tablets are available as:
`
`
`
`
`
`3 mg: white to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side.
`7 mg: white to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side.
`14 mg: white to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side.
`
`CONTRAINDICATIONS
`4
`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)].
`
`WARNINGS AND PRECAUTIONS
`5
`Risk of Thyroid C-Cell Tumors
`5.1
`In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the
`incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant
`plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether RYBELSUS causes thyroid C-
`cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-
`induced rodent thyroid C-cell tumors has not been determined.
`
`Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the
`postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship
`between MTC and GLP-1 receptor agonist use in humans.
`
`RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.
`Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of
`symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
`
`Routine monitoring 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 of unnecessary procedures,
`due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease.
`Significantly elevated serum calcitonin value may indicate 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. Patients with thyroid nodules noted on physical examination or neck imaging should also be further
`evaluated.
`
`Pancreatitis
`5.2
`In glycemic control trials, 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).
`
`After initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitis (including
`persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied
`
`Reference ID: 4997051
`
`

`

`by vomiting). If pancreatitis is suspected, RYBELSUS should be discontinued and appropriate management
`initiated; if confirmed, RYBELSUS should not be restarted.
`
`Diabetic Retinopathy Complications
`5.3
`In a pooled analysis of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy related
`adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator).
`
`In a 2-year cardiovascular outcomes trial with semaglutide injection involving patients with type 2 diabetes and
`high cardiovascular risk, diabetic retinopathy complications (which was a 4 component adjudicated endpoint)
`occurred in patients treated with semaglutide injection (3.0%) compared to placebo (1.8%). The absolute risk
`increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy
`at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic
`retinopathy (semaglutide injection 0.7%, placebo 0.4%).
`
`Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.
`The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been
`studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic
`retinopathy.
`
`5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
`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.
`
`Acute Kidney Injury
`5.5
`There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which
`may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide.
`Some of these events have 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 dehydration. Monitor
`renal function when initiating or escalating doses of RYBELSUS in patients reporting severe adverse
`gastrointestinal reactions.
`
`5.6 Hypersensitivity
`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)].
`
`Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. 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 to anaphylaxis with RYBELSUS.
`
`Acute Gallbladder Disease
`5.7
`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.
`
`Reference ID: 4997051
`
`

`

`ADVERSE REACTIONS
`6
`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)]
`• 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)]
`• Hypersensitivity [see Warnings and Precautions (5.6)]
`• Acute Gallbladder Disease [see Warnings and Precautions (5.7)]
`
`Clinical Trials Experience
`6.1
`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 in patients with type 2 diabetes [see Clinical
`Studies (14)]. These data reflect exposure of 1071 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 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 ≥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.
`
`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 9 placebo- and active-controlled trials [see Clinical Studies (14)]. In this pool, 4116 patients
`with type 2 diabetes 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 for an average of 8.8 years and had a mean HbA1c of 8.2%. At baseline, 16.6% of
`the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2)
`in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 28.5%, and moderately impaired (eGFR 30 to 60
`mL/min/1.73m2) in 5.4% of the patients.
`
`Common Adverse Reactions
`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS 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 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of RYBELSUS-Treated
`Patients with Type 2 Diabetes Mellitus
`Adverse Reaction
`Placebo
`(N=362)
`%
`6
`4
`
`RYBELSUS 7 mg
`(N=356)
`%
`11
`10
`
`RYBELSUS 14 mg
`(N=356)
`%
`20
`11
`
`Nausea
`Abdominal Pain
`
`Reference ID: 4997051
`
`

`

`Diarrhea
`Decreased appetite
`Vomiting
`Constipation
`
`4
`1
`3
`2
`
`9
`6
`6
`6
`
`10
`9
`8
`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 1.
`
`Gastrointestinal Adverse Reactions
`In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among
`patients receiving RYBELSUS than placebo (placebo 21%, RYBELSUS 7 mg 32%, RYBELSUS 14 mg 41%).
`The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients
`receiving RYBELSUS 7 mg (4%) and RYBELSUS 14 mg (8%) discontinued treatment due to gastrointestinal
`adverse reactions than patients receiving placebo (1%).
`
`In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5%
`were associated with RYBELSUS (frequencies listed, respectively, as placebo; 7 mg; 14 mg): abdominal
`distension (1%, 2%, 3%), dyspepsia (0.6%, 3%, 0.6%), eructation (0%, 0.6%, 2%), flatulence (0%, 2%, 1%),
`gastroesophageal reflux disease (0.3%, 2%, 2%), and gastritis (0.8%, 2%, 2%).
`
`Other Adverse Reactions
`Hypoglycemia
`
`Table 2 summarizes the incidence of 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
`
`RYBELSUS
`7 mg
`
`RYBELSUS
`14 mg
`
`Monotherapy
` (26 weeks)
` Severe*
`Plasma glucose
`<54 mg/dL
`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=175
`1%
`0%
`
`-
`
`N=175
`0%
`0%
`
`N=163
`
`N=178
`0%
`1%
`
` Severe*
`Plasma glucose
`<54 mg/dL
`Add-on to insulin with or without metformin
` (52 weeks)
`N=184
`
`0%
`3%
`
`-
`-
`
`N=181
`
` Severe*
`Plasma glucose
`<54 mg/dL
`*“Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person.
`
`1%
`32%
`
`0%
`26%
`
`0%
`6%
`
`N=181
`
`1%
`30%
`
`Hypoglycemia was more frequent when RYBELSUS was used in combination with insulin secretagogues (e.g.,
`sulfonylureas) or insulin.
`
`Reference ID: 4997051
`
`

`

`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, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg.
`Cholelithiasis was not reported in RYBELSUS 14 mg or 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.
`
`Immunogenicity
`6.2
`Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated
`with RYBELSUS may develop anti-semaglutide antibodies. The detection of antibody formation is highly
`dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody
`(including neutralizing antibody) positivity in an assay may be influenced by several factors including assay
`methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
`For these reasons, the incidence of antibodies to semaglutide in the studies described below cannot be directly
`compared with the incidence of antibodies in other studies or to other products.
`
`Across the placebo- and active-controlled glycemic control trials with antibody measurements, 14 (0.5%)
`RYBELSUS-treated patients developed anti-drug antibodies (ADAs) to the active ingredient in RYBELSUS
`(i.e., semaglutide). Of the 14 semaglutide-treated patients that developed semaglutide ADAs, 7 patients (0.2%
`of the overall population) developed antibodies cross-reacting with native GLP-1. The neutralizing activity of
`the antibodies is uncertain at this time.
`
`6.3 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.
`
`Hypersensitivity: anaphylaxis, angioedema, rash, urticaria
`Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy
`
`DRUG INTERACTIONS
`7
`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`7.1
`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
`RYBELSUS causes a delay of gastric emptying, and thereby has the potential to impact the absorption of other
`oral medications. Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered with
`RYBELSUS in a drug interaction study.
`
`Reference ID: 4997051
`
`

`

`When coadministering oral medications instruct patients to closely follow RYBELSUS administration
`instructions. Consider increased clinical or laboratory monitoring for medications that have a narrow therapeutic
`index or that require clinical monitoring [see Dosage and Administration (2)].
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`Available data with RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated risk
`of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations
`regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal
`reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy.
`RYBELSUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities
`and alterations to growth occurred at maternal exposures below the maximum recommended human dose
`(MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis,
`early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and
`≥10-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both
`animal species (see Data).
`
`The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an
`HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. In the U.S. general
`population, the estimated background risk of major birth defects and miscarriage in clinically recognized
`pregnancies is 2-4% and 15-20%, respectively.
`
`Clinical Considerations
`Disease associated maternal and fetal risk
`Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre-
`eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes
`increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
`
`Data
`Animal Data
`In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09
`mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout
`mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In
`parental animals, pharmacologically mediated reductions in body weight gain and food consumption were
`observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and
`skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure.
`
`In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075
`mg/kg/day (0.06-, 0.6-, and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation
`Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were
`observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver)
`and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant
`exposures.
`
`In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075,
`and 0.15 mg/kg twice weekly (1.9-, 9.9-, and 29-fold the MRHD) were administered throughout organogenesis,
`from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and
`reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities
`(vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (>9X human exposure).
`
`Reference ID: 4997051
`
`

`

`In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015,
`0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-, and 14-fold the MRHD) were administered from Gestation Day
`16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight
`gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly
`smaller offspring at ≥0.075 mg/kg twice weekly (>6X human exposure).
`
`Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the placenta and reaches fetal
`tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was
`administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through
`lactation day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup
`viability were observed.
`
`Lactation
`8.2
`Risk Summary
`There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the
`effects on milk production. Semaglutide was present in the milk of lactating rats. SNAC and/or its metabolites
`concentrated in the milk of lactating rats. When a substance is present in animal milk, it is likely that the
`substance will be present in human milk (see Data). There are no data on the presence of SNAC in human
`milk. Since the activity of UGT2B7, an enzyme involved in SNAC clearance, is 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 from breastfeeding
`and because there are alternative formulations of semaglutide that can be used during lactation, advise patients
`that breastfeeding is not recommended during treatment with RYBELSUS.
`
`Data
`In lactating rats, semaglutide was detected in milk at levels 3-12 fold lower than in maternal plasma. SNAC
`and/or its metabolites were detected in milk of lactating rats following a single maternal administration on
`lactation day 10. Mean levels of SNAC and/or its metabolites in milk were approximately 2-12 fold higher than
`in maternal plasma.
`
`Females and Males of Reproductive