Rybelsus (Oral Semaglutide)

• •
  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 Risk of Thyroid C-Cell Tumors

  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 ]

  . 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.

  ), Nonclinical Toxicology (

  13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

  In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day [9-, 33- and 113- fold the maximum recommended human dose (MRHD) of RYBELSUS 14 mg, based on AUC] were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (3-, 9- and 33-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (>3X human exposure).

  In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.8-, 1.8- and 11-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at ≥0.01 mg/kg/day, at clinically relevant exposures.

  Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies

  [see Boxed Warning, Warnings and Precautions ]

  .

  Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, rat bone marrow micronucleus).

  In a combined fertility and embryo-fetal 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 male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length was observed at all dose levels, together with a small reduction in numbers of corpora lutea at ≥0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight.

  )]

  .
• •
  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 CONTRAINDICATIONS

  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 ]
    .

  • •Personal or family history of MTC or in patients with MEN 2 syndrome type 2.
  • •Prior serious hypersensitivity reaction to semaglutide or any of the excipients in RYBELSUS.

  )]

  . 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 CONTRAINDICATIONS

  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 ]
    .

  • •Personal or family history of MTC or in patients with MEN 2 syndrome type 2.
  • •Prior serious hypersensitivity reaction to semaglutide or any of the excipients in RYBELSUS.

  ), Warnings and Precautions (

  5.1 Risk of Thyroid C-Cell Tumors

  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 ]

  . 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.

  )]

  .

Indications and Usage (

Dosage and Administration, Overview of RYBELSUS formulations (

Warning and Precautions

•  Acute Pancreatitis (
  5.2 Acute Pancreatitis

  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 ]

  .

  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.
  )………………………………..……….10/2025
•  Acute Kidney Injury Due to Volume Depletion (
  5.5 Acute Kidney Injury Due to Volume Depletion

  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 ].

  Monitor renal function in patients reporting adverse reactions to RYBELSUS that could lead to volume depletion, especially during dosage initiation and escalation of RYBELSUS.
  )………….10/2025
•  Severe Gastrointestinal Adverse Reactions (
  5.6 Severe Gastrointestinal Adverse Reactions

  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.
  )….……..…….10/2025
•  Acute Gallbladder Disease (
  5.8 Acute Gallbladder Disease

  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 ]

  . If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated

  [see Adverse Reactions ].

  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.
  ) ……………………………………………………..……...11/2024

RYBELSUS is indicated:

• •as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• •to reduce the risk of major adverse cardiovascular (CV) events (CV death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus who are at high risk for these events.

• •There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. (
  2.1 Overview of RYBELSUS Formulations

  • •There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. Refer to recommendations on how to switch from one formulation to another formulation
    [see Dosage and Administration ]
    .
  • oRYBELSUS (formulation R1) includes strengths 3 mg, 7 mg and 14 mg.
  • oRYBELSUS (formulation R2) includes strengths 1.5 mg, 4 mg and 9 mg.
  • •These formulations are not substitutable on a mg per mg basis.
  • •Use either RYBELSUS formulation R1 or formulation R2; do not use both formulations at the same time.
  • •Do not take more than one tablet per day.
  )
• oThese formulations are not substitutable on a mg per mg basis
• oUse either formulation but do not use both formulations at the same time.
• •Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water); do not take with other liquids besides water. (
  2.2 Important Administration Instructions

  • •Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water.
  • •After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications
    [see Clinical Pharmacology (
    12.3)]
    .
  • •Swallow tablets whole. Do not split crush or chew.
  • •If a dose is missed, skip the missed dose and take the next dose the following day.
  )
• •After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications. (
  2.2 Important Administration Instructions

  • •Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water.
  • •After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications
    [see Clinical Pharmacology (
    12.3)]
    .
  • •Swallow tablets whole. Do not split crush or chew.
  • •If a dose is missed, skip the missed dose and take the next dose the following day.
  )
• •Swallow tablets whole. Do not split, crush or chew tablets. (
  2.2 Important Administration Instructions

  • •Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water.
  • •After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications
    [see Clinical Pharmacology (
    12.3)]
    .
  • •Swallow tablets whole. Do not split crush or chew.
  • •If a dose is missed, skip the missed dose and take the next dose the following day.
  )
• •See the Full Prescribing Information for instructions on switching from OZEMPIC to RYBELSUS and switching between the two different RYBELSUS formulations. (
  2.4 Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS

  Switching Between RYBELSUS Formulations

  • •
    Do not switch between RYBELSUS formulations during the initiation phase (Days 1-30)

    [see Dosage and Administration (
    2.3

    )]
    .
  • •
    After 30 days of RYBELSUS treatment (after the initiation phase)

    [see Dosage and Administration (
    2.3

    )]
    , patients may switch between RYBELSUS formulations (see

    Table 1

    ).
  • •
    When switching between the formulations, initiate the other RYBELSUS formulation the day after discontinuing the previous RYBELSUS formulation.

  Table 1. Switching Between Escalation or Maintenance Dosage of RYBELSUS Formulations

  RYBELSUS (formulation R1) *	RYBELSUS (formulation R2) *
  7 mg orally once daily	4 mg orally once daily
  14 mg orally once daily	9 mg orally once daily

  • *Discontinue this formulation and initiate the alternate formulation the day after

  Switching from OZEMPIC to RYBELSUS (formulation R1) or RYBELSUS (formulation R2)

  Switching from OZEMPIC to RYBELSUS (formulation R1)

  • •
    One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 7 mg or 14 mg of RYBELSUS (formulation R1) orally once daily.
  • •
    Switching recommendations for patients taking OZEMPIC 0.25 mg, 1 mg or 2 mg subcutaneously once weekly to RYBELSUS (formulation R1) are not available.

  Switching from OZEMPIC to RYBELSUS (formulation R2)

  • •
    One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 4 mg or 9 mg of RYBELSUS (formulation R2) orally once daily.
  • •
    Switching recommendations for patients taking OZEMPIC 0.25 mg, 1 mg or 2 mg subcutaneously once weekly to RYBELSUS (formulation R2) are not available.
  )

• •Day 1 to 30: Recommended starting dosage is 3 mg orally once daily for 30 days (this dosage is not effective for glycemic control).
• •Days 31 to 60: Increase the dosage to 7 mg orally once daily.
• •On Day 61 or thereafter, if: (
  2.3 Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS Formulations R1 and R2

  RYBELSUS (formulation R1)

  RYBELSUS (formulation R1) includes the following strengths: 3 mg, 7 mg and 14 mg.

  Recommend the following RYBELSUS (formulation R1) dosage to reduce the risk of gastrointestinal adverse reactions

  [see Warnings and Precautions (

  5.6

  ), Adverse Reactions (

  6.1

  )]:

  • •
    Starting Dosage (Initiation Phase) (Days 1 to 30)

    : The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control).
  • •
    Escalation and Maintenance Dosage (Days 31 and beyond)

    :
  • o
    Days 31 to 60: Increase the dosage to 7 mg orally once daily.
  • o
    On Day 61 or thereafter, if:
    • ▪
      No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily.
    • ▪
      Additional glycemic control is needed, increase the dosage to 14 mg orally once daily.

  RYBELSUS (formulation R2)

  RYBELSUS (formulation R2) includes the following strengths: 1.5 mg, 4 mg and 9 mg.

  Recommend the following RYBELSUS (formulation R2) dosage to reduce the risk of gastrointestinal adverse reactions

  [see Warnings and Precautions (

  5.6

  ), Adverse Reactions (

  6.1

  )]

  :

  • •
    Starting Dosage (Initiation Phase) (Days 1 through 30)

    : The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control).
  • •
    Escalation and Maintenance Dosage (Days 31 and beyond)

    :
  • o
    Days 31 to 60: Increase the dosage to 4 mg orally once daily.
  • o
    On Day 61 or thereafter, if:
    • ▪
      No additional glycemic control is needed maintain the dosage at 4 mg orally once daily.
    • ▪
      Additional glycemic control is needed increase the dosage to 9 mg orally once daily.
  )
• oNo additional glycemic control is needed, maintain the dosage at 7 mg orally once daily.
• oAdditional glycemic control is needed, increase the dosage to 14 mg orally once daily.

• •Day 1 to 30: Recommended starting dosage is 1.5 mg orally once daily for 30 days (this dosage is not effective for glycemic control).
• •Days 31 to 60: Increase the dosage to 4 mg orally once daily.
• •On Day 61 or thereafter, if: (
  2.3 Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS Formulations R1 and R2

  RYBELSUS (formulation R1)

  RYBELSUS (formulation R1) includes the following strengths: 3 mg, 7 mg and 14 mg.

  Recommend the following RYBELSUS (formulation R1) dosage to reduce the risk of gastrointestinal adverse reactions

  [see Warnings and Precautions (

  5.6

  ), Adverse Reactions (

  6.1

  )]:

  • •
    Starting Dosage (Initiation Phase) (Days 1 to 30)

    : The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control).
  • •
    Escalation and Maintenance Dosage (Days 31 and beyond)

    :
  • o
    Days 31 to 60: Increase the dosage to 7 mg orally once daily.
  • o
    On Day 61 or thereafter, if:
    • ▪
      No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily.
    • ▪
      Additional glycemic control is needed, increase the dosage to 14 mg orally once daily.

  RYBELSUS (formulation R2)

  RYBELSUS (formulation R2) includes the following strengths: 1.5 mg, 4 mg and 9 mg.

  Recommend the following RYBELSUS (formulation R2) dosage to reduce the risk of gastrointestinal adverse reactions

  [see Warnings and Precautions (

  5.6

  ), Adverse Reactions (

  6.1

  )]

  :

  • •
    Starting Dosage (Initiation Phase) (Days 1 through 30)

    : The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control).
  • •
    Escalation and Maintenance Dosage (Days 31 and beyond)

    :
  • o
    Days 31 to 60: Increase the dosage to 4 mg orally once daily.
  • o
    On Day 61 or thereafter, if:
    • ▪
      No additional glycemic control is needed maintain the dosage at 4 mg orally once daily.
    • ▪
      Additional glycemic control is needed increase the dosage to 9 mg orally once daily.
  )
• oNo additional glycemic control is needed, maintain the dosage at 4 mg orally once daily.
• oAdditional glycemic control is needed, increase the dosage to 9 mg orally once daily.

RYBELSUS (semaglutide) tablets (formulation R1) 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.

RYBELSUS (semaglutide) tablets (formulation R2) are available as:

• •1.5 mg: white to light yellow, round shaped debossed with “1.5” on one side and “novo” on the other side.
• •4 mg: white to light yellow, round shaped debossed with “4” on one side and “novo” on the other side.
• •9 mg: white to light yellow, round shaped debossed with “9” on one side and “novo” on the other side.

• •
  Pregnancy:
  See
  Pregnancy
  subsection. (
  8.1 Pregnancy

  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 to 10% in women with pre-gestational diabetes with an HbA_1c>7 and has been reported to be as high as 20 to 25% in women with a HbA_1c>10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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).

  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:
  Breastfeeding not recommended. (
  8.2 Lactation

  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.
  )
• •
  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 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

  [see Use in Specific Populations ]

  .
  )