PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL – 14 mg Bottle

NDC 0169-4314-30List 431430

RYBELSUS**®**** 14 mg**

(semaglutide) Tablets

14 mg

Once daily

Oral use only

Rx only

DISPENSE WITH MEDICATION GUIDE

30 tablets

DESCRIPTION SECTION

11 DESCRIPTION

RYBELSUS tablets, for oral use, contain semaglutide, a GLP-1 receptor agonist. The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol.

Structural formula:

Semaglutide is a white to almost white hygroscopic powder. Each tablet of RYBELSUS contains 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC).

INDICATIONS & USAGE SECTION

Highlight: 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

•

Has not been studied in patients with a history of pancreatitis (1, 5.2).

•

Not for treatment of type 1 diabetes mellitus (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.

Limitations of Use

•

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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Tablets: 3 mg, 7 mg and 14 mg (3).

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 SECTION

Highlight: •

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).

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 (5.6)].

Boxed Warning section

WARNING: RISK OF THYROID C-CELL TUMORS

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Overview of Clinical Studies

RYBELSUS has been studied as monotherapy and in combination with metformin, sulfonylureas, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, insulins, and thiazolidinediones in patients with type 2 diabetes. The efficacy of RYBELSUS was compared with placebo, empagliflozin, sitagliptin, and liraglutide. RYBELSUS has also been studied in patients with type 2 diabetes with mild and moderate renal impairment.

In patients with type 2 diabetes, RYBELSUS produced clinically significant reduction from baseline in HbA1c compared with placebo.

The efficacy of RYBELSUS was not impacted by baseline age, gender, race, ethnicity, BMI, body weight, diabetes duration and level of renal impairment.

14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus

In a 26-week double-blind trial (NCT02906930), 703 adult patients with type 2 diabetes inadequately controlled with diet and exercise were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg or RYBELSUS 14 mg once daily or placebo. Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes was 3.5 years, and the mean BMI was 32 kg/m2. Overall, 75% were White, 5% were Black or African American, and 17% were Asian; 26% identified as Hispanic or Latino ethnicity.

Monotherapy with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (seeTable 3).

Table 3. Results at Week 26 in a Trial of RYBELSUS as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise

Baseline (mean)

Change at week 26b

Difference from placebob
[95% CI]

Baseline (mean)

Change at week 26b

a The intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 8.6% and 8.6% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 15%, 2% and 1% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively.

b Estimated using an ANCOVA model based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 88.6 kg, 89.0 kg and 88.1 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -1.4 kg, -2.3 kg and -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -0.9 kg (-1.9, 0.1) and for RYBELSUS 14 mg was -2.3 kg (-3.1, -1.5).

14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes

Mellitus

Combination with Metformin

In a 26-week trial (NCT02863328), 822 adult patients with type 2 diabetes were randomized to RYBELSUS 14 mg once daily or empagliflozin 25 mg once daily, all in combination with metformin. Patients had a mean age of 58 years and 50% were men. The mean duration of type 2 diabetes was 7.4 years, and the mean BMI was 33 kg/m2. Overall, 86% were White, 7% were Black or African American, and 6% were Asian; 24% identified as Hispanic or Latino ethnicity.

Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to empagliflozin 25 mg once daily (seeTable 4).

Table 4. Results at Week 26 in a Trial of RYBELSUS Compared to Empagliflozin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin

Baseline (mean)

Change at week 26b

Difference from empagliflozinb
[95% CI]

Baseline (mean)

Change at week 26b

a The intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.6% and 3.7% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 91.9 kg and 91.3 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to week 26 were -3.8 kg and -3.7 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for RYBELSUS 14 mg was -0.1 kg (-0.7, 0.5).

Combination with Metformin or Metformin with Sulfonylurea

In a 26-week, double-blind trial (NCT02607865), 1864 adult patients with type 2 diabetes on metformin alone or metformin with sulfonylurea were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg, RYBELSUS 14 mg or sitagliptin 100 mg once daily. Patients had a mean age of 58 years and 53% were men. The mean duration of type 2 diabetes was 8.6 years, and the mean BMI was 32 kg/m2. Overall, 71% were White, 9% were Black or African American, and 13% were Asian; 17% identified as Hispanic or Latino ethnicity.

Treatment with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin 100 mg once daily (seeTable 5).

Table 5. Results at Week 26 in a Trial of RYBELSUS Compared to Sitagliptin 100 mg Once Daily in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea

Baseline (mean)

Change at week 26b

Difference from sitagliptinb
[95% CI]

Baseline (mean)

Change at week 26b

a The intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.8%, 6.2% and 4.5% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1% and 2.8% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 91.3 kg, 91.2 kg and 90.9 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The mean changes from baseline to week 26 were -2.2 kg, -3.1 kg and -0.6 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for RYBELSUS 7 mg was -1.6 kg (-2.0, -1.1) and RYBELSUS 14 mg was -2.5 kg (-3.0, -2.0).

Combination with Metformin or Metformin with SGLT-2 Inhibitors

In a 26-week, double-blind, double-dummy trial (NCT02863419), 711 adult patients with type 2 diabetes on metformin alone or metformin with SGLT-2 inhibitors were randomized to RYBELSUS 14 mg once daily, liraglutide 1.8 mg s.c. injection once daily or placebo. Patients had a mean age of 56 years and 52% were men. The mean duration of type 2 diabetes was 7.6 years, and the mean BMI was 33 kg/m2. Overall, 73% were White, 4% were Black or African American, and 13% were Asian; 6% identified as Hispanic or Latino ethnicity.

Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in statistically significant reductions in HbA1c compared to placebo. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in non-inferior reductions in HbA1c compared to liraglutide 1.8 mg (seeTable 6).

Table 6. Results at Week 26 in a Trial of RYBELSUS Compared to Liraglutide and Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with SGLT-2i

Baseline (mean)

Change at week 26b

Difference from placebob
[95% CI]

Difference from liraglutideb
[95% CI]

Baseline (mean)

Change at week 26b

a The intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 4.2% and 2.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2% and 3.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 93.2 kg, 95.5 kg and 92.9 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.5 kg, -3.1 kg and -4.4 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -3.8 kg (-4.7, -3.0). The difference from liraglutide 1.8 mg for RYBELSUS 14 mg was -1.2 (-1.9, -0.6).

Combination in patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment with Metformin alone, Sulfonylurea alone, Basal Insulin alone, or Metformin in Combination with either Sulfonylurea or Basal Insulin

In a 26-week, double-blind trial (NCT02827708), 324 adult patients with moderate renal impairment (eGFRCKD-EPI 30−59 mL/min/1.73m2) were randomized to RYBELSUS 14 mg or placebo once daily. RYBELSUS was added to the patient’s stable pre-trial antidiabetic regimen. The insulin dose was reduced by 20% at randomization for patients on basal insulin. Dose reduction of insulin and sulfonylurea was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose.

Patients had a mean age of 70 years and 48% were men. The mean duration of type 2 diabetes was 14 years, and the mean BMI was 32 kg/m2. Overall, 96% were White, 4% were Black or African American, and 0.3% were Asian; 6.5% identified as Hispanic or Latino ethnicity. 39.5% of patients had an eGFR value of 30 to 44 mL/min/1.73m2.

Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo (seeTable 7).

Table 7. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Patients with Moderate Renal Impairment

Baseline (mean)

Change at week 26b

Difference from placebob
[95% CI]

Baseline (mean)

Change at week 26b

a The intent-to-treat population includes all randomized patients including patients on rescue medication. At week 26, the primary HbA1c endpoint was missing for 3.7% and 5.5% of patients randomized to placebo and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 10% and 4.3% of patients randomized to placebo and RYBELSUS 14 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, renal status and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 90.4 kg and 91.3 kg in the placebo and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.9 kg and -3.4 kg in the placebo and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -2.5 kg (-3.2, -1.8).

Combination with Insulin with or without Metformin

In a 26-week double blind trial (NCT03021187), 731 adult patients with type 2 diabetes inadequately controlled on insulin (basal, basal/bolus or premixed) with or without metformin, were randomized to RYBELSUS 3 mg, 7 mg and 14 mg once daily or placebo once daily. All patients reduced their insulin dose by 20% at randomization to reduce the risk of hypoglycemia. Patients were allowed to increase the insulin dose only up to the starting insulin dose prior to randomization.

Patients had a mean age of 61 years and 54% were men. The mean duration of type 2 diabetes was 15 years, and the mean BMI was 31 kg/m2. Overall, 51% were White, 7% were Black or African American, and 36% were Asian; 13% identified as Hispanic or Latino ethnicity.

Treatment with RYBELSUS 7 mg and 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo once daily (seeTable 8).

Table 8. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Insulin alone or with Metformin

Baseline (mean)

Change at week 26b

Difference from placebob 
[95% CI]

Baseline (mean)

Change at week 26b

a The intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.3%, 4.4%, and 4.4% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 4.9%, 1.1 % and 2.2% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 86.0 kg, 87.1 kg and 84.6 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.4 kg, -2.4 kg and -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -2.0 kg (-3.0, -1.0), and for RYBELSUS 14 mg was -3.3 kg (-4.2, -2.3).

14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes

Mellitus and Cardiovascular Disease

PIONEER 6 (NCT02692716) was a multi-center, multi-national, placebo- controlled, double-blind trial. In this trial, 3,183 adult patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to RYBELSUS 14 mg once daily or placebo for a median observation time of 16 months. The trial compared the risk of a major adverse cardiovascular event (MACE) between RYBELSUS 14 mg and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

Patients eligible to enter the trial were 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for cardiovascular disease. In total, 1,797 patients (56.5%) had established cardiovascular disease without chronic kidney disease, 354 patients (11.1%) had chronic kidney disease only, and 544 patients (17.1%) had both cardiovascular disease and kidney disease; 488 patients (15.3%) had cardiovascular risk factors without established cardiovascular disease or chronic kidney disease. The mean age at baseline was 66 years, and 68% were men. The mean duration of diabetes was 14.9 years, and mean BMI was 32 kg/m2. Overall, 72% were White, 6% were Black or African American, and 20% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (12%), history of ischemic stroke (8%) and history of a myocardial infarction (36%). In total, 99.7% of the patients completed the trial and the vital status was known at the end of the trial for 100%.

For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of RYBELSUS 14 mg to placebo for time to first MACE using a risk margin of 1.3. Type-1 error was controlled across multiple tests using a hierarchical testing strategy. Non‑inferiority to placebo was established, with a hazard ratio equal to 0.79 (95% CI: 0.57, 1.11) over the median observation time of 16-months. The proportion of patients who experienced at least one MACE was 3.8% (61/1591) for RYBELSUS 14 mg and 4.8% (76/1592) for placebo.

OVERDOSAGE SECTION

10 OVERDOSAGE

In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of RYBELSUS of approximately 1 week.

SPL MEDGUIDE SECTION

Medication Guide

**Possible thyroid tumors, including cancer.** Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, RYBELSUS and medicines that work like RYBELSUS caused thyroid tumors, including thyroid cancer. It is not known if RYBELSUS will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.

Do not use RYBELSUS if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

It is not known if RYBELSUS can be used in people who have had pancreatitis.

RYBELSUS is not for use in patients with type 1 diabetes.

you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

you have had a serious allergic reaction to semaglutide or any of the ingredients in RYBELSUS. See the end of this Medication Guide for a complete list of ingredients in RYBELSUS. Symptoms of a serious allergic reaction include:

swelling of your face, lips, tongue or throat

problems breathing or swallowing

severe rash or itching

fainting or feeling dizzy

very rapid heartbeat

have or have had problems with your pancreas or kidneys. 

have a history of vision problems related to your diabetes.

are pregnant or plan to become pregnant. It is not known if RYBELSUS will harm your unborn baby. You should stop using RYBELSUS 2 months before you plan to become pregnant. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant. 

are breastfeeding or plan to breastfeed. Breastfeeding is not recommended during treatment with RYBELSUS.

Take RYBELSUS exactly as your healthcare provider tells you to. 

Take RYBELSUS by mouth on an empty stomach when you first wake up.

Take RYBELSUS with a sip of plain water (no more than 4 ounces). 

Do not split, crush or chew. Swallow RYBELSUS whole. 

After 30 minutes, you can eat, drink, or take other oral medicines. 

If you miss a dose of RYBELSUS, skip the missed dose and go back to your regular schedule. 

**See “What is the most important information I should know about RYBELSUS?”**

**inflammation of your pancreas (pancreatitis).**Stop using RYBELSUS and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. 

**changes in vision.** Tell your healthcare provider if you have changes in vision during treatment with RYBELSUS.

**low blood sugar (hypoglycemia).** Your risk for getting low blood sugar may be higher if you use RYBELSUS with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin.**Signs and symptoms of low blood sugar may include:**

dizziness or light-headedness

blurred vision 

anxiety, irritability, or mood changes 

sweating

slurred speech

hunger

confusion or drowsiness

shakiness

weakness 

headache

fast heartbeat

feeling jittery

**kidney problems (kidney failure).** In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.

**serious allergic reactions.** Stop using RYBELSUS and get medical help right away, if you have any symptoms of a serious allergic reaction including:

swelling of your face, lips, tongue or throat

problems breathing or swallowing

severe rash or itching

fainting or feeling dizzy

very rapid heartbeat

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

pain in your upper stomach (abdomen)

yellowing of skin or eyes (jaundice)

fever

clay-colored stools

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

Store in a dry place away from moisture.

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

**Keep RYBELSUS and all medicines out of the reach of children.**

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 01/2023