` CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`213051Orig1s000
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`LABELING
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` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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` Personal or family history of medullary thyroid carcinoma or in patients
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`•
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` with Multiple Endocrine Neoplasia syndrome type 2 (4).
` Known hypersensitivity to semaglutide or any of the components in
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` RYBELSUS (4).
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`See 17 for PATIENT COUNSELING INFORMATION and
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`Medication Guide.
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`Revised: 09/2019
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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` Pancreatitis: Has been reported in clinical trials. Discontinue promptly if
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`•
` pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2).
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` Diabetic Retinopathy Complications: Has been reported in a cardiovascular
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` outcomes trial with semaglutide injection. Patients with a history of
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` diabetic retinopathy should be monitored (5.3).
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` Hypoglycemia: When RYBELSUS is used with an insulin secretagogue or
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` insulin, consider lowering the dose of the secretagogue or insulin to reduce
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` the risk of hypoglycemia (5.4).
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` Acute Kidney Injury: Monitor renal function in patients with renal
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` impairment reporting severe adverse gastrointestinal reactions (5.5).
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` Hypersensitivity Reactions: Discontinue RYBELSUS if suspected and
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`promptly seek medical advice (5.6).
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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`The most common adverse reactions, reported in ≥5% of patients treated with
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`RYBELSUS are: nausea, abdominal pain, diarrhea, decreased appetite, vomiting
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`and constipation (6.1).
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`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
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`Inc., at 1-833-457-7455 or FDA at 1-800-FDA-1088 or
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`www.fda.gov/medwatch.
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`------------------------------DRUG INTERACTIONS----------------------------------
`Oral Medications RYBELSUS delays gastric emptying. When coadministering
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`oral medications instruct patients to closely follow RYBELSUS administration
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`instructions. Consider increased clinical or laboratory monitoring for
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`medications that have a narrow therapeutic index or that require clinical
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`monitoring (7.2).
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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`Pregnancy: May cause fetal harm (8.1).
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`Lactation: Breastfeeding not recommended (8.2).
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`Females and Males of Reproductive Potential: Discontinue RYBELSUS in
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`women at least 2 months before a planned pregnancy due to the long
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`washout period for semaglutide (8.3).
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
` RYBELSUS® safely and effectively. See full prescribing information
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`for RYBELSUS.
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`RYBELSUS (semaglutide) tablets, for oral use
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`Initial U.S. Approval: 2017
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` WARNING: RISK OF THYROID C-CELL TUMORS
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` See full prescribing information for complete boxed warning.
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` In rodents, semaglutide causes thyroid C-cell tumors. It is
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` unknown whether RYBELSUS causes thyroid C-cell tumors,
` including medullary thyroid carcinoma (MTC), in humans as
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`the human relevance of semaglutide-induced rodent thyroid C-
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`cell tumors has not been determined (5 1, 13 1).
`RYBELSUS is contraindicated in patients with a personal or
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`family history of MTC or in patients with Multiple Endocrine
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`Neoplasia syndrome type 2 (MEN 2). Counsel patients
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`regarding the potential risk of MTC and symptoms of thyroid
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` tumors (4, 5.1).
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` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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` RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist
` indicated as an adjunct to diet and exercise to improve glycemic control
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` in adults with type 2 diabetes mellitus (1).
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` Limitations of Use
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`• Not recommended as first-line therapy for patients inadequately
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`controlled on diet and exercise (1, 5.1).
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`• Has not been studied in patients with a history of pancreatitis (1, 5.2).
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`• Not indicated for use in patients with type 1 diabetes mellitus or
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`treatment of diabetic ketoacidosis (1).
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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`• Instruct patients to take RYBELSUS at least 30 minutes before the
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`first food, beverage, or other oral medications of the day with no more
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`than 4 ounces of plain water only. Waiting less than 30 minutes, or
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`taking with food, beverages (other than plain water) or other oral
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`medications will lessen the effect of RYBELSUS. Waiting more than
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`30 minutes to eat may increase the absorption of RYBELSUS (2.1).
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`• Swallow tablets whole. Do not cut, crush, or chew tablets (2.1).
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`• Start RYBELSUS with 3 mg once daily for 30 days. After 30 days on
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`the 3 mg dose, increase the dose to 7 mg once daily (2.2).
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`• Dose may be increased to 14 mg once daily if additional glycemic
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`control is needed after at least 30 days on the 7 mg dose (2.2).
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`• See the Full Prescribing Information for instructions on switching
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`between OZEMPIC® and RYBELSUS (2 3).
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
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`Tablets: 3 mg, 7 mg and 14 mg (3).
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`Reference ID: 4494169Reference ID: 4497378
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`8.5 Geriatric Use
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`8.6 Renal Impairment
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`8.7 Hepatic Impairment
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`13.2 Animal Toxicology and/or Pharmacology
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`14 CLINICAL STUDIES
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`14.1 Overview of Clinical Studies
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`14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes
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`Mellitus
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`14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2
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`Diabetes Mellitus
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`14.4 Cardiovascular Outcomes Trial of RYBELSUS in Patients with
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`Type 2 Diabetes Mellitus
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the full prescribing information are not
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`listed.
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` FULL PRESCRIBING INFORMATION: CONTENTS*
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` WARNING: RISK OF THYROID C-CELL TUMORS
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` 1
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` 2
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` INDICATIONS AND USAGE
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` DOSAGE AND ADMINISTRATION
` Important Administration Instructions
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` 2.1
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` 2.2 Recommended Dosage
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` 2.3
` Switching Patients between OZEMPIC and RYBELSUS
` DOSAGE FORMS AND STRENGTHS
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` 3
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` 4
` CONTRAINDICATIONS
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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Risk of Thyroid C-Cell Tumors
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` 5.2
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` Pancreatitis
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`5.3
` Diabetic Retinopathy Complications
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` 5.4 Hypoglycemia with Concomitant Use of Insulin
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` Secretagogues or Insulin
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`5.5
` Acute Kidney Injury
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` 5.6 Hypersensitivity
` ADVERSE REACTIONS
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` 6.1 Clinical Trials Experience
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` 6.2 Immunogenicity
` DRUG INTERACTIONS
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` 7.1 Concomitant Use with an Insulin Secretagogue (e.g.,
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` Sulfonylurea) or with Insulin
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` 7.2 Oral Medications
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` USE IN SPECIFIC POPULATIONS
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` 8.1 Pregnancy
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` 8.2 Lactation
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` 8.3 Females and Males of Reproductive Potential
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` 8.4 Pediatric Use
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` 6
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` 7
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` 8
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`Reference ID: 4494169Reference ID: 4497378
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` FULL PRESCRIBING INFORMATION
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`•
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` WARNING: RISK OF THYROID C-CELL TUMORS
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`In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid
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`
` 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
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`Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
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`• RYBELSUS is contraindicated in patients with a personal or family history of MTC or in
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`patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications
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`(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,
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` 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
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` Contraindications (4) and Warnings and Precautions (5.1)].
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`INDICATIONS AND USAGE
`1
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`RYBELSUS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2
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`diabetes mellitus [see Clinical Studies (14.1)].
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`Limitations of Use
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`• RYBELSUS is not recommended as a first-line therapy for patients who have inadequate glycemic control
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`on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans [see
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`Warnings and Precautions (5.1)].
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`• RYBELSUS has not been studied in patients with a history of pancreatitis. Consider other antidiabetic
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`therapies in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
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`• RYBELSUS is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of patients
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`with diabetic ketoacidosis, as it would not be effective in these settings.
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`DOSAGE AND ADMINISTRATION
`2
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`Important Administration Instructions
`2.1
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`Instruct patients to take RYBELSUS at least 30 minutes before the first food, beverage, or other oral
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`medications of the day with no more than 4 ounces of plain water only [see Clinical Pharmacology (12.3)].
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`Waiting less than 30 minutes, or taking RYBELSUS with food, beverages (other than plain water) or other
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`oral medications will lessen the effect of RYBELSUS by decreasing its absorption. Waiting more than 30
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`minutes to eat may increase the absorption of RYBELSUS.
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`Swallow tablets whole. Do not split, crush, or chew tablets.
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`2.2
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`Recommended Dosage
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`Start RYBELSUS with 3 mg once daily for 30 days. The 3 mg dose is intended for treatment initiation and
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`is not effective for glycemic control.
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`• After 30 days on the 3 mg dose, increase the dose to 7 mg once daily.
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`• Dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days
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`on the 7 mg dose.
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`• Taking two 7 mg RYBELSUS tablets to achieve a 14 mg dose is not recommended.
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`If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day.
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`Switching Patients Between OZEMPIC and RYBELSUS
`2.3
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`Patients treated with RYBELSUS 14 mg daily can be transitioned to OZEMPIC subcutaneous injection
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`0.5 mg once weekly. Patients can start OZEMPIC the day after their last dose of RYBELSUS.
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`Reference ID: 4494169Reference ID: 4497378
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` 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
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` OZEMPIC. There is no equivalent dose of RYBELSUS for OZEMPIC 1 mg.
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`DOSAGE FORMS AND STRENGTHS
`3
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`RYBELSUS tablets are available as:
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`3 mg: white to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side.
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`7 mg: white to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side.
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`14 mg: white to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side.
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`CONTRAINDICATIONS
`4
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`RYBELSUS is contraindicated in patients with:
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`• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine
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`Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].
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`• Known hypersensitivity to semaglutide or to any of the components in RYBELSUS [see Warnings and
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`Precautions (5.6)].
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`WARNINGS AND PRECAUTIONS
`5
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`Risk of Thyroid C-Cell Tumors
`5.1
`In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the
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`incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant
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`plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether RYBELSUS causes thyroid C-
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`cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide
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`induced rodent thyroid C-cell tumors has not been determined.
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`Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the
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`postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship
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`between MTC and GLP-1 receptor agonist use in humans.
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`RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.
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`Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of
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`symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
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`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of
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`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.
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`Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin
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`values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further
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`evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further
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`evaluated.
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`Pancreatitis
`5.2
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`In glycemic control trials, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients
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`(0.1 events per 100 patient years) versus 1 in comparator-treated patients (<0.1 events per 100 patient years).
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`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
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`by vomiting). If pancreatitis is suspected, RYBELSUS should be discontinued and appropriate management
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`initiated; if confirmed, RYBELSUS should not be restarted.
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`Reference ID: 4494169Reference ID: 4497378
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`
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`Diabetic Retinopathy Complications
`5.3
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`In a pooled analysis of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy related
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`adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator).
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`In a 2-year cardiovascular outcomes trial with semaglutide injection involving patients with type 2 diabetes and
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`high cardiovascular risk, diabetic retinopathy complications (which was a 4 component adjudicated endpoint)
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`occurred in patients treated with semaglutide injection (3.0%) compared to placebo (1.8%). The absolute risk
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`increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy
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`at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic
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`retinopathy (semaglutide injection 0.7%, placebo 0.4%).
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`Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.
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`The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been
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`studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic
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`retinopathy.
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`5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
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`The risk of hypoglycemia is increased when RYBELSUS is used in combination with insulin secretagogues
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`(e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the
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`risk of hypoglycemia in this setting [see Adverse Reactions (6.1), Drug Interactions (7.1)].
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`Acute Kidney Injury
`5.5
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`There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which
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`may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide.
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`Some of these events have been reported in patients without known underlying renal disease. A majority of the
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`reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor
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`renal function when initiating or escalating doses of RYBELSUS in patients reporting severe adverse
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`gastrointestinal reactions.
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`5.6 Hypersensitivity
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`Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor
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`agonists, including semaglutide. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat
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`promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a
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`previous hypersensitivity to RYBELSUS [see Contraindications (4)].
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`Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in a patient with a
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`history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such
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`patients will be predisposed to anaphylaxis with RYBELSUS.
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`ADVERSE REACTIONS
`6
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`The following serious adverse reactions are described below or elsewhere in the prescribing information:
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`• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
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`• Pancreatitis [see Warnings and Precautions (5.2)]
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`• Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)]
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`• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions
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`(5.4)]
`• Acute Kidney Injury [see Warnings and Precautions (5.5)]
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`• Hypersensitivity [see Warnings and Precautions (5.6)]
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`Reference ID: 4494169Reference ID: 4497378
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` 6.1
`Clinical Trials Experience
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` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
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` 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.
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`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
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`41.8 weeks. The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these
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`trials, 63% were White, 6% were Black or African American, and 27% were Asian; 19% identified as Hispanic
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`or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 9.4 years and had a mean HbA1c
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`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
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`moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 1.4% of patients.
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`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
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`participating in 9 placebo- and active-controlled trials [see Clinical Studies (14)]. In this pool, 4116 patients
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`with type 2 diabetes were treated with RYBELSUS for a mean duration of 59.8 weeks. The mean age of
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`patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, 65% were White, 6% were
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`Black or African American, and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline,
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`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
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`the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2)
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`in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 28.5%, and moderately impaired (eGFR 30 to 60
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`mL/min/1.73m2) in 5.4% of the patients.
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`Common Adverse Reactions
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`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in
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`the pool of placebo-controlled trials. These adverse reactions occurred more commonly on RYBELSUS than on
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`placebo and occurred in at least 5% of patients treated with RYBELSUS.
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`Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of RYBELSUS-Treated
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`Patients with Type 2 Diabetes Mellitus
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` Placebo
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` Adverse Reaction
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` (N=362)
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` %
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` 6
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` 4
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` 4
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` 1
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` 3
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` 2
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` RYBELSUS 14 mg
` (N=356)
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` %
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` 20
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` 11
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` 10
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` 9
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` 8
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` 5
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`Reference ID: 4494169Reference ID: 4497378
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` RYBELSUS 7 mg
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` (N=356)
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` %
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` 11
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` 10
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` 9
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` 6
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` 6
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` 6
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` Nausea
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` Abdominal Pain
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`Diarrhea
`Decreased appetite
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` Vomiting
` Constipation
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` In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions,
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` excluding hypoglycemia, were similar to those listed in Table 1.
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` Gastrointestinal Adverse Reactions
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` 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%).
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` The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients
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` receiving RYBELSUS 7 mg (4%) and RYBELSUS 14 mg (8%) discontinued treatment due to gastrointestinal
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` adverse reactions than patients receiving placebo (1%).
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`In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5%
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`were associated with RYBELSUS (frequencies listed, respectively, as placebo; 7 mg; 14 mg): abdominal
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`distension (1%, 2%, 3%), dyspepsia (0.6%, 3%, 0.6%), eructation (0%, 0.6%, 2%), flatulence (0%, 2%, 1%),
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`gastroesophageal reflux disease (0.3%, 2%, 2%), and gastritis (0.8%, 2%, 2%).
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`Other Adverse Reactions
`Hypoglycemia
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`Table 2 summarizes the incidence of hypoglycemia by various definitions in the placebo-controlled trials.
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` Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials In Patients with Type 2 Diabetes
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` Mellitus
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` Placebo
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` RYBELSUS
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` 7 mg
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` RYBELSUS
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` 14 mg
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` N=178
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` 0%
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` 1%
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` Monotherapy
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` (26 weeks)
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` Severe*
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` Plasma glucose
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` <54 mg/dL
`Add-on to metformin and/or sulfonylurea, basal insulin alone or metformin in combination with
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` basal insulin in patients with moderate renal impairment
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` (26 weeks)
` N=161
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` 0%
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` 3%
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` N=175
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` 1%
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` 0%
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` -
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` -
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` -
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` N=175
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` 0%
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` 0%
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` N=163
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` 0%
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` 6%
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` Severe*
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` Plasma glucose
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` <54 mg/dL
` Add-on to insulin with or without metformin
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` (52 weeks)
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` N=184
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` 1%
` 32%
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` N=181
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` 0%
` 26%
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` N=181
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` 1%
` 30%
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` Severe*
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` Plasma glucose
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` <54 mg/dL
` *“Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person.
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`Hypoglycemia was more frequent when RYBELSUS was used in combination with insulin secretagogues (e.g.,
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`sulfonylureas) or insulin.
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`Increases in Amylase and Lipase
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` In placebo-controlled trials, patients exposed to RYBELSUS 7 mg and 14 mg had a mean increase from
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` baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%, respectively. These changes
` were not observed in placebo-treated patients.
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` Cholelithiasis
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`In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg.
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`Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients.
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`Reference ID: 4494169Reference ID: 4497378
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` Increases in Heart Rate
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`In placebo-controlled trials, RYBELSUS 7 mg and 14 mg resulted in a mean increase in heart rate of 2 to 3
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`beats per minute. There was no change in heart rate in placebo-treated patients.
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` Immunogenicity
` 6.2
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`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
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`dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody
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`(including neutralizing antibody) positivity in an assay may be influenced by several factors including assay
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`methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
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`For these reasons, the incidence of antibodies to semaglutide in the studies described below cannot be directly
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`compared with the incidence of antibodies in other studies or to other products.
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` Across the placebo- and active-controlled glycemic control trials with antibody measurements, 14 (0.5%)
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` RYBELSUS-treated patients developed anti-drug antibodies (ADAs) to the active ingredient in RYBELSUS
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` (i.e., semaglutide). Of the 14 semaglutide-treated patients that developed semaglutide ADAs, 7 patients (0.2%
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` of the overall population) developed antibodies cross-reacting with native GLP-1. The neutralizing activity of
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` the antibodies is uncertain at this time.
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` 7
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` DRUG INTERACTIONS
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` 7.1
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` Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
` The risk of hypoglycemia is increased when RYBELSUS is used in combination with insulin secretagogues
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` (e.g., sulfonylureas) or insulin. The risk of hypoglycemia may be lowered by a reduction in the dose of
` sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin [see Warnings and
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` Precautions (5.4)].
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` 7.2 Oral Medications
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` RYBELSUS causes a delay of gastric emptying, and thereby has the potential to impact the absorption of other
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` oral medications. Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered with
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` RYBELSUS in a drug interaction study.
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` When coadministering oral medications instruct patients to closely follow RYBELSUS administration
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`instructions. Consider increased clinical or laboratory monitoring for medications that have a narrow therapeutic
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` index or that require clinical monitoring [see Dosage and Administration (2)].
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` 8
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` USE IN SPECIFIC POPULATIONS
` 8.1
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` Pregnancy
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` Risk Summary
`Available data with RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated risk
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`of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations
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`regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal
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`reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy.
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`RYBELSUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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`In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities
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`and alterations to growth occurred at maternal exposures below the maximum recommended human dose
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`(MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis,
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`early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and
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`≥10-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both
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`animal species (see Data).
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`Reference ID: 4494169Reference ID: 4497378
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` The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an
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` 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
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`pregnancies is 2-4% and 15-20%, respectively.
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`Clinical Considerations
`Disease associated maternal and fetal risk
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`Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre
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`eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes
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`increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
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` Data
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`Animal Data
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`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
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`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
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`observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and
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`skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure.
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`In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075
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`mg/kg/day (0.06-, 0.6-, and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation
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`Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were
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`observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver)
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`and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant
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`exposures.
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`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
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`reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities
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`(vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (>9X human exposure).
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`In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015,
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`0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-, and 14-fold the MRHD) were administered from Gestation Day
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`16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight
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`gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly
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`smaller offspring at ≥0.075 mg/kg twice weekly (>6X human exposure).
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`Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the placenta and reaches fetal
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`tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was
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`administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through
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`lactation day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup
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`viability were observed.
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`Lactation
`8.2
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`Risk Summary
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`There are no data on the presence of