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.

ENHERTU (BLA-761139)

(FAM-TRASTUZUMAB DERUXTECAN-NXKI)

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

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02/15/2024 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 6 months (range: 0.9 to 32).

5.2 Neutropenia

Additions and/or revisions underlined:

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 0.9% of patients.

5.3 Left Ventricular Dysfunction

Additions and/or revisions underlined:

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.9% of patients, of which 0.4% were Grade 3.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 1287 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 22% were 65 years or older and 3.8% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients greater than or equal to 65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (59%) as compared to younger patients (49%).

08/05/2022 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

…

Metastatic Breast Cancer and HER2-Mutant Solid Tumors (5.4 mg/kg)

In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

5.2 Neutropenia

Additions and/or revisions underlined:

…

Metastatic Breast Cancer and HER2-Mutant Solid Tumors (5.4 mg/kg)

In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

5.3 Left Ventricular Dysfunction

Additions and/or revisions underlined:

…

Metastatic Breast Cancer and HER2-Mutant Solid Tumors (5.4 mg/kg)

In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 883 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 22% were 65 years or older and 3.6% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients greater or equal to 65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (60%) as compared to younger patients (48%).

…

8.6 Renal Impairment

Additions and/or revisions underlined:

No dose adjustment of ENHERTU is required in patients with mild (creatinine clearance [CLcr] greater than or equal to 60 and <90 mL/min) or moderate (CLcr greater than or equal to 30 and <60 mL/min) renal impairment [see Clinical Pharmacology (12.3)]. Limited data are available in patients with severe renal impairment. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate or severe renal impairment [see Warnings and Precautions (5.1)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is ENHERTU?

ENHERTU is a prescription medicine used to treat adults who have:

human epidermal growth factor receptor 2 (HER2)-positive breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received a prior anti-HER2 breast cancer treatment:
- for metastatic disease, or
- have breast cancer that has come back during or within 6 months of completing treatment for their early-stage breast cancer.

HER2-low breast cancer that cannot be removed by surgery or that has spread to other parts of your body (metastatic), and who have received a prior chemotherapy
- for metastatic disease, or
- your disease has returned during or within 6 months of completing adjuvant chemotherapy (after surgery). Your healthcare provider will perform a test to make sure ENHERTU is right for you.

stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that is HER2-positive and has spread to areas near your stomach (locally advanced) or that has spread to other parts of your body (metastatic), and who have received a prior trastuzumab-based regimen.

It is not known if ENHERTU is safe and effective in children.

…

What are the possible side effects of ENHERTU?

ENHERTU can cause serious side effects. See "What is the most important information I should know about ENHERTU?"

The most common side effects of ENHERTU, when used in people with metastatic breast cancer and HER2- mutant solid tumors include:

nausea
constipation
low white blood cell counts
muscle or bone pain
low red blood cell counts
decreased appetite
feeling tired
diarrhea
low platelet counts
low levels of blood potassium
increased liver function tests
cough
vomiting

hair loss

The most common side effects of ENHERTU, when used in people with HER-2 positive gastric or GEJ adenocarcinoma, include:

…

05/04/2022 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and revisions underlined:

Metastatic Breast Cancer

In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 13% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.4% of patients treated with ENHERTU. Median time to first onset was 5.5 months (range: 1.1 to 20.8).

Additions and revisions underlined:

Metastatic Breast Cancer

In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU

5.4 mg/kg, ILD occurred in 13% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.4% of patients

treated with ENHERTU. Median time to first onset was 5.5 months (range: 1.1 to 20.8).

5.2 Neutropenia

Additions and revisions underlined:

Metastatic Breast Cancer

In clinical studies, of the 491 patients with unresectable or metastatic HER2-positive breast cancer who received

ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 68% of patients. Eighteen percent had Grade 3 or 4

decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 6 to 664).

Febrile neutropenia was reported in 1.2% of patients.

5.3 Left Ventricular Dysfunction

Newly added subsections:

Additions and revisions underlined:

Metastatic Breast Cancer

In the 491 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4 mg/kg, 13 cases (2.6%) of asymptomatic LVEF decrease were reported.

Locally Advanced or Metastatic Gastric Cancer

6 Adverse Reactions

6.1 Clinical Trials Experience

Metastatic Breast Cancer section extensively revised; please refer to label

6.2 Immunogenicity

Additions and revisions underlined:

Treatment-emergent anti-fam-trastuzumab deruxtecan-nxki antibodies (ADA) developed in 2.1% (27/1311) patients who received ENHERTU across all doses. The incidence of neutralizing antibodies against fam-trastuzumab deruxtecan-nxki was 0.1% (1/1311). Due to the limited number of patients who tested positive for ADA, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

Of the 491 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 22% were 65 years or older and 4% were 75 years or older. No overall differences in efficacy within clinical studies were observed between patients greater than or = 65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years or older (60%) as compared to younger patients (49%).

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

Medication Guide

Additions and revisions underlined:

What is ENHERTU?

ENHERTU is a prescription medicine used in adults to treat human epidermal growth factor receptor 2 (HER2)-positive:

• breast cancer that cannot be removed by surgery or that has spread to other parts of the body (metastatic), and who have received a prior anti-HER2 breast cancer treatment:

o for metastatic disease, or

o have breast cancer that has come back during or within 6 months of completing treatment for their early-stage breast cancer.

• Your healthcare provider will give you medicines before your infusion to help prevent nausea and vomiting.

The most common side effects of ENHERTU, when used in people with breast cancer, include:

• nausea

• low white blood cell counts

• low red blood cell counts

• increased liver function tests

• feeling tired

• vomiting

• low platelet counts

• hair loss

• constipation

• low levels of blood potassium

• decreased appetite

• diarrhea

• pain in muscles and bones

• infections of the respiratory tract

• headache

• stomach-area (abdominal) pain

01/15/2021 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

(Additions and/or revisions underlined)

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU [see Adverse Reactions (6.1)]. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic (Grade 1) ILD, consider corticosteroid treatment (e.g., =0.5 mg/kg/day prednisolone or equivalent).

Withhold ENHERTU until recovery [see Dosage and Administration (2.3)]. In cases of symptomatic ILD (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g., =1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Permanently discontinue ENHERTU in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD [see Dosage and Administration (2.3)].

Metastatic Breast Cancer

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU

5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

5.3 Left Ventricular Dysfunction

(Additions and/or revisions underlined)

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic

HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.2 Immunogenicity

(Additions and/or revisions underlined)

Treatment-induced anti-fam-trastuzumab deruxtecan-nxki antibodies (ADA) developed in 1.7% (14/807) patients who received ENHERTU across all doses.

8 Use in Specific Populations

8.5 Geriatric Use

(Newly added information)

Of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years or older and 14% were 75 years or older. No overall differences in efficacy or safety were observed between patients > or equal to 65 years of age compared to younger patients.

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

Medication Guide

(Additions and/or revisions underlined)

What is ENHERTU?

ENHERTU is a prescription medicine used in adults to treat human epidermal growth factor receptor 2 (HER2)-positive

- breast cancer that cannot be removed by surgery or that has spread to other parts of your body (metastatic), and

who have received two or more prior anti-HER2 breast cancer treatments.

- stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that has spread to areas near

your stomach (locally advanced) or that has spread to other parts of your body (metastatic), and who have received

a prior trastuzumab-based regimen.

The most common side effects of ENHERTU, when used in people with breast cancer, include:

- nausea

- low white blood cell counts

- low red blood cell counts

- feeling tired

- vomiting

- hair loss

- increased liver function tests

- low platelet counts

- constipation

- decreased appetite

- diarrhea

- low levels of blood potassium

- cough

The most common side effects of ENHERTU, when used in people with stomach cancer, include:

- low red blood cell counts

- low white blood cell counts

- low platelet counts

- nausea

- decreased appetite

- increased liver function tests

- feeling tired

- diarrhea

- low levels of blood potassium

- vomiting

- constipation

- fever

- hair loss