
Drug Safety-related Labeling Changes (SrLC) Database
ANDA | Abbreviated New Drug Application |
BLA | Biologics License Application |
CDER | Center for Drug Evaluation and Research |
MG | Medication Guide |
NDA | New Drug Application |
PCI | Patient Counseling Information |
PI | Patient Information |
PLR | Physician Labeling Rule |
PLLR | Pregnancy and Lactation Labeling Rule |
Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
BW | Box Warning |
WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
RYBELSUS (NDA-213051)
(SEMAGLUTIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/09/2024 (SUPPL-21)
5 Warnings and Precautions
5.2 Acute PancreatitisSubsection title revised
Additions and revisions underlined:
Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS [see Adverse Reactions (6.1)].
Newly added subsection:
Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In RYBELSUS clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving RYBELSUS (7 mg 0.6%, 14 mg 2%) than placebo (0.3%).
RYBELSUS is not recommended in patients with severe gastroparesis.
Additions and revisions underlined:
Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients [see Adverse Reactions (6.1)]. If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)].
6 Adverse Reactions
Additions and revisions underlined:
The following serious adverse reactions are described below or elsewhere in the prescribing information:
• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
• Acute Pancreatitis [see Warnings and Precautions (5.2)]
• Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)]
• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.4)]
• Acute Kidney Injury [see Warnings and Precautions (5.5)]
• Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)]
Extensive changes; please refer to label
Additions and revisions underlined:
The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
· Gastrointestinal: ileus
· Hypersensitivity: anaphylaxis, angioedema, rash, urticaria
· Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy
· Nervous system disorders: dizziness, dysesthesia, dysgeusia
· Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation
· Skin and Subcutaneous Tissue: alopecia
8 Use in Specific Populations
8.2 LactationAdditions and revisions underlined:
Risk Summary
A clinical lactation study reported semaglutide concentrations below the lower limit of quantification in human breast milk. However, salcaprozate sodium (SNAC) and/or its metabolites are present in human milk. Since the activity of enzymes involved in SNAC clearance may be lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC, and because there are alternative formulations of semaglutide that do not contain SNAC that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS.
. . .
Newly added information:
The recommended dosage of RYBELSUS in patients with renal impairment is the same as those with normal renal function.
Newly added information:
The recommended dosage in patients with hepatic impairment is the same as those with normal hepatic function.17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideNewly added information:
· Do not take more than 1 tablet each day.
. . .
· Do not take RYBELSUS with any other liquids besides water.
. . .
· If you take too much RYBELSUS, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.
. . .
· severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use RYBELSUS. Tell your healthcare provider if you have stomach problems that are severe or will not go away.
. . .
Newly added information:
Severe Gastrointestinal Adverse Reactions
Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)].
. . .
RYBELSUS passes into breast milk, and it is not known how it affects your baby.
11/01/2024 (SUPPL-23)
5 Warnings and Precautions
5.8 Pulmonary Aspiration During General Anesthesia or Deep SedationNewly added subsection:
RYBELSUS delays gastric emptying
[see Clinical Pharmacology (12.2)].
There have been rare postmarketing reports of pulmonary
aspiration in patients receiving
GLP-1 receptor agonists undergoing
elective surgeries or procedures requiring general anesthesia or deep sedation
who had residual gastric contents despite reported adherence to preoperative
fasting recommendations.
Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking RYBELSUS, including whether modifying preoperative fasting recommendations or temporarily discontinuing RYBELSUS could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS.
6 Adverse Reactions
Additions and revisions underlined:
The following serious adverse reactions are described below or elsewhere in the prescribing information:
. . .
Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
Acute Gallbladder Disease [see Warnings and Precautions (5.7)]
Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.8)]
Newly added information:
Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideAdditions and revisions underlined:
. . .
Before using RYBELSUS, tell your healthcare provider if you have any other medical conditions, including if you:
have or have had problems with your pancreas or kidneys.
have a history of vision problems related to your diabetes.
are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).
. . .
RYBELSUS may cause serious side effects, including:
. . .
food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). RYBELSUS may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking RYBELSUS before you are scheduled to have surgery or other procedures.
Newly added information:
Pulmonary Aspiration During General Anesthesia or Deep Sedation
Inform patients that RYBELSUS may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS [see Warnings and Precautions (5.8)].
01/24/2024 (SUPPL-18)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and/or revisions underlined:
…
Nervous system disorders: dizziness, dysgeusia01/12/2023 (SUPPL-12)
5 Warnings and Precautions
5.6 Hypersensitivity
Additions and/or revisions underlined:
Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. RYBELSUS is contraindicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. [see Adverse Reactions (6.2)].
Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists …
5.7 Acute Gallbladder Disease
[see Adverse Reactions (6.2)]. is added to end of subsection.
6 Adverse Reactions
6.1 Clinical Trials Experience
Pool of Placebo-Controlled Trials
Addition of ‘adult’ in front of patients in the first sentence of the paragraph.
Pool of Placebo- and Active-Controlled Trials
Addition of ‘adult’ in front of patients in the first sentence of the paragraph.
Common Adverse Reactions
Additions and/or revisions underlined:
Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in adult patients with type 2 diabetes in the pool of placebo-controlled trials.
Other Adverse Reactions
Additions and/or revisions underlined:
Pancreatitis
In the pool of placebo- and active-controlled trials with RYBELSUS, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patient years) versus 1 in comparator- treated patients (<0.1 events per 100 patient years).
Diabetic Retinopathy Complications
In the pool of placebo- and active-controlled trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator).
Hypoglycemia
Table 2 summarizes the incidence of hypoglycemia by various definitions in the placebo-controlled trials …
6.2 Postmarketing Experience
Newly added information:
Gastrointestinal: ileus
7 Drug Interactions
7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
Additions and/or revisions underlined:
RYBELSUS stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.
When initiating RYBELSUS, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
7.2 Oral Medications
‘[see Clinical Pharmacology (12.3)]’ added to the end of the first paragraph in the subsection.
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
In the pool of glycemic control trials, 1229 (30%) RYBELSUS-treated patients were 65 years of age and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over [see Clinical Studies (14)]. In PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS-treated patients were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of age and over.
No overall differences in safety or effectiveness for RYBELSUS have been observed between patients 65 years of age and older and younger adult patients.
06/10/2022 (SUPPL-11)
5 Warnings and Precautions
5.7 Acute Gallbladder DiseaseNewly added subsection:
Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Acute Gallbladder Disease [see Warnings and Precautions (5.7)]
Additions and/or revisions underlined:
…
Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined:
…
What are the possible side effects of RYBELSUS?
gallbladder problems. Gallbladder problems have happened in some people who take RYBELSUS. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include:
pain in your upper stomach (abdomen)
yellowing of skin or eyes (jaundice)
fever
clay-colored stools
…
Additions and/or revisions underlined:
…
Acute Gallbladder Disease
Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.7)].
…
04/30/2021 (SUPPL-6)
4 Contraindications
(Additions and/or revisions underlined)
RYBELSUS is contraindicated in patients with:
A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].
A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS [see Warnings and Precautions (5.6)].
5 Warnings and Precautions
5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin(Additions and/or revisions underlined)
Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)].
The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
(Additions and/or revisions underlined)
Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity to RYBELSUS [see Contraindications (4) and Adverse Reactions (6.3)].
6 Adverse Reactions
6.3 Postmarketing Experience(Newly added section)
The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity: anaphylaxis, angioedema, rash, urticaria
7 Drug Interactions
7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin(Additions and/or revisions underlined)
When initiating RYBELSUS, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions underlined)
In the pool of glycemic control trials, 1229 (29.9%) RYBELSUS-treated patients were 65 years of age and over and 199 (4.8%) RYBELSUS-treated patients were 75 years of age and over. In PIONEER 6, the cardiovascular outcomes trial, 891 (56.0%) RYBELSUS-treated patients were 65 years of age and over and 200 (12.6%) RYBELSUS-treated patients were 75 years of age and over.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Additions and/or revisions underlined)
Do not use RYBELSUS if:
• you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you
have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• you have had a serious allergic reaction to semaglutide or any of the ingredients in RYBELSUS. See the end of this
Medication Guide for a complete list of ingredients in RYBELSUS. Symptoms of a serious allergic reaction include:
o swelling of your face, lips, tongue or throat
o problems breathing or swallowing
o severe rash or itching
o fainting or feeling dizzy
o very rapid heartbeat
Stop using RYBELSUS and get medical help right away, if you have any symptoms of
a serious allergic reaction including:
o swelling of your face, lips, tongue or throat
o problems breathing or swallowing
o severe rash or itching
o fainting or feeling dizzy
o very rapid heartbeat
How should I store RYBELSUS?
• Store RYBELSUS at room temperature between 68°F and 77°F (20°C to 25°C).
• Store in a dry place away from moisture.
• Store tablets in the original closed RYBELSUS bottle until you are ready to take one. Do not store in any other
container.
(Additions and/or revisions underlined)
Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
Inform patients that the risk of hypoglycemia is increased when RYBELSUS is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)].
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of RYBELSUS. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking RYBELSUS and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)].