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.

NUBEQA (NDA-212099)

(DAROLUTAMIDE)

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

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06/03/2025 (SUPPL-8)

Approved Drug Label (PDF)

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 954 patients who received NUBEQA in ARAMIS, 88% of patients were 65 years and over, and 49% were 75 years and over. Of the 445 patients who received NUBEQA in ARANOTE, 74% of patients were 65 years and over, and 30% were 75 years and over. Of the 652 patients who received NUBEQA in ARASENS, 63% of patients were 65 years and over, and 16% were 75 years and over. No overall differences in safety or efficacy were observed between these patients and younger patients in both studies.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Dosage and Administration

Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) agonist or antagonist therapy that they need to maintain this treatment during the course of treatment with NUBEQA.

. . .

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

NUBEQA is a prescription medicine used to treat adults with prostate cancer:

that has not spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone
that has spread to other parts of the body and responds to a medical or surgical treatment that lowers testosterone
that has spread to other parts of the body and responds to a medical or surgical treatment that lowers testosterone in combination with docetaxel.

It is not known if NUBEQA is safe and effective in females or children.

. . .

Seizure. Treatment with NUBEQA may increase your risk of having a seizure. You should avoid activities where a sudden loss of consciousness could cause serious harm to yourself or others. Tell your healthcare provider right away if you have loss of consciousness or seizure during treatment with NUBEQA.

10/13/2023 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ischemic Heart Disease

Additions and/or revisions underlined:

…

In a randomized study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel and 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% and 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel and 0% receiving placebo with docetaxel.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Table 3: Adverse Reactions (greater than or equal to 10% with a greater than or equal to 2% increase compared to placebo with docetaxel) in ARASENS

updates to Table 3, please refer to label for complete information.

Clinically relevant adverse reactions in < 10% of patients who received NUBEQA with docetaxel included fractures (8%), ischemic heart disease (3.2%), seizures (0.6%), and drug-induced liver injury (0.3%).

…

08/05/2022 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ischemic Heart Disease

Newly added subsection:

Ischemic heart disease, including fatal cases, occurred in patients receiving NUBEQA.

In a randomized study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA and 2.5% receiving placebo, including Grade 3-4 events in 1.7% and 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA and 0.2% receiving placebo.

In a randomized study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 2.9% of patients receiving NUBEQA with docetaxel and 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% and 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel and 0.1% receiving placebo with docetaxel.

Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.

5.2 Seizure

Newly added subsection:

Seizure occurred in patients receiving NUBEQA.

In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA and 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA.

In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, and 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA.

It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.

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 954 patients who received NUBEQA in ARAMIS, 88% of patients were 65 years and over, and 49% were 75 years and over. Of the 652 patients who received NUBEQA in ARASENS, 63% of patients were 65 years and over, and 16% were 75 years and over. No overall differences in safety or efficacy were observed between these patients and younger patients in both studies.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Ischemic Heart Disease

Inform patients that NUBEQA has been associated with an increased risk of ischemic heart disease. Advise patients to seek immediate medical attention if any symptoms suggestive of an ischemic heart disease event occur [see Warnings and Precautions (5.1)].

Seizure

Inform patients that NUBEQA has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they have loss of consciousness or seizure [see Warnings and Precautions (5.2)].

…

PATIENT INFORMATION

Extensive changes; please refer to label

01/07/2021 (SUPPL-1)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Effects of NUBEQA on Other Drugs

(Additions and/or revisions underlined)

Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3 Substrates

NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and Cmax of BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of BCRP substrate-related toxicities.

Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug.

NUBEQA is an inhibitor of OATP1B1 and OATP1B3 transporters. Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor patients more frequently for adverse reactions of these drugs and consider dose reduction while patients are taking NUBEQA [see Clinical Pharmacology (12.3)],

Review the prescribing information of the BCRP, OATP1B1 and OATP1B3 substrates when used concomitantly with NUBEQA.