Drug Safety-related Labeling Changes (SrLC)

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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)

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01/24/2024 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Nervous system disorders: dizziness, dysgeusia

01/12/2023 (SUPPL-12)

Approved Drug Label (PDF)

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 Use

Additions 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)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Acute Gallbladder Disease

Newly 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)]

6.3 Postmarketing Experience

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

…

PATIENT COUNSELING INFORMATION

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)

Approved Drug Label (PDF)

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.

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. 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)

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.

Patient Counseling Information

(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)].