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.

OZEMPIC (NDA-209637)

(SEMAGLUTIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/22/2023 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of OZEMPIC. 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 Disorders: Ileus

Hypersensitivity: anaphylaxis, angioedema, rash, urticaria.

Hepatobiliary: cholecystitis, cholecystectomy

7 Drug Interactions

7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

Additions and/or revisions underlined:

OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5) and Adverse Reactions (6)].

09/22/2023 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

7 Drug Interactions

7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

Additions and/or revisions underlined:

10/06/2022 (SUPPL-12)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

There are limited data with semaglutide use in pregnant women to inform a drug-associated risk for adverse developmental 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 semaglutide during pregnancy. OZEMPIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

were observed at clinical exposure (rabbit) and ?2-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data).

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. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/fetal Risk

Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. 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.

03/28/2022 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Acute Gallbladder Disease

New subsection added

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 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in 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 (5.8)]
6.1 Clinical Trials Experience
Additions underlined
…
In a clinical trial with 959 patients treated with OZEMPIC 1 mg or OZEMPIC 2 mg once weekly as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified.
…
In the trial with OZEMPIC 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC 2 mg (34.0%) vs OZEMPIC 1 mg (30.8%).
…
6.3 Postmarketing Experience
Additions underlined
…
Hepatobiliary: cholecystitis, cholecystectom

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

Risk Summary

…

In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal clinical exposure based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses or structural abnormalitieswere observed at clinical exposure (rabbit) and ?2-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data).

…

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 (0.06-, 0.2-, and 0.6-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 an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.02-, 0.2-, and 1.2-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 greater than or equal to 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 (0.5-, 3-, and 8-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 greater than or equal to 0.075 mg/kg twice weekly (greater than or equal to 3X 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 (0.3-, 2-, and 4-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 greater than or equal to 0.075 mg/kg twice weekly (greater than or equal to 2X human exposure).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

…

Your dose of OZEMPIC and other diabetes medicines may need to change because of:

change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, fever, trauma, infection, surgery or because of other medicines you take.
If you take too much OZEMPIC, call your healthcare provider or go to the nearest hospital emergency room right away.

…

What are the possible side effects of OZEMPIC?

OZEMPIC may cause serious side effects, including:

…

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

pain in your upper stomach (abdomen)
fever
yellowing of skin or eyes (jaundice)
clay-colored stools

…

PATIENT COUNSELING INFORMATION

Additions 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 (5.8)].

04/12/2021 (SUPPL-8)

Approved Drug Label (PDF)

4 Contraindications

Additions underlined

…

A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in OZEMPIC. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with OZEMPIC [see Warnings and Precautions (5.7)].

5 Warnings and Precautions

5.5 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Additions underlined

Patients receiving OZEMPIC 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.

6 Adverse Reactions

6.3 Postmarketing Experience

New subsection added

Hypersensitivity:anaphylaxis, angioedema, rash, urticaria.

7 Drug Interactions

7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

Additions underlined

When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sufonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5) and Adverse Reactions (6)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

…

What is OZEMPIC?

…

OZEMPIC is not for use in people with type 1 diabetes.

…

Do not use OZEMPIC 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 OZEMPIC. See the end of this Medication Guide for a complete list of ingredients in OZEMPIC. 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

…

What are the possible side effects of OZEMPIC?

OZEMPIC may cause serious side effects, including:

…

serious allergic reactions. Stop using OZEMPIC 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.
  …

PATIENT COUNSELING INFORMATION

Additions underlined

…

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Inform patients that the risk of hypoglycemia is increased when OZEMPIC 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 (5.5)].

…

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of OZEMPIC. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking OZEMPIC and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.7)].

…

01/16/2020 (SUPPL-3)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

…

What is OZEMPIC?

OZEMPIC is an injectable prescription medicine used:

…

to reduce the risk of major cardiovascular events such as heart attack, stroke or death in adults with type 2 diabetes mellitus with known heart disease.

…