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.

XTANDI (NDA-213674)

(ENZALUTAMIDE)

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

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12/11/2025 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Interference with Immunoassay Measurement of Digoxin

Newly added subsection:

XTANDI can interfere with certain digoxin immunoassays (e.g., Chemiluminescent Microparticle Immunoassays), resulting in falsely elevated digoxin plasma concentration results. Notify the laboratory conducting the digoxin plasma concentration assay to use an appropriate method in patients receiving XTANDI and digoxin [see Drug Interactions (7.3)].

7 Drug Interactions

7.3 Laboratory Test Interference

Newly added subsection:

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products [see Drug Interactions (7.1, 7.2, 7.3)].

…

03/21/2025 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

EMBARK: XTANDI versus Placebo in Non-metastatic CSPC Patients with High-Risk BCR

. . .

Table 6. Drug Treatment and Suspension in EMBARK

Revision to the duration of suspension from drug treatment section of table; please refer to label for complete information

. . .

01/22/2025 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Dysphagia or Choking

Newly added section

Severe dysphagia or choking, including events that could be life-threatening requiring medical intervention or fatal, can occur due to XTANDI product size. Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. Consider use of a smaller tablet size of XTANDI in patients who have difficulty swallowing. Discontinue XTANDI for patients who cannot swallow capsules or tablets.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

…

Dysphagia or Choking [see Warnings and Precautions (5.7)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Gastrointestinal Disorders: vomiting, dysphagia (including choking related to XTANDI product size)

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Dysphagia or Choking

Inform patients that the size of XTANDI capsules and tablets has been associated with severe dysphagia or choking.
Advise patients to take each capsule or tablet as instructed in Dosage and Administration.

Advise patients to inform their healthcare provider if experiencing difficulty swallowing XTANDI [see Warnings and Precautions (5.7)].

…

Dosage and Administration

Inform patients who have not undergone bilateral orchiectomy and are receiving GnRH therapy that they need to maintain this treatment during the course of treatment with XTANDI.
Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets [see Warnings and Precautions (5.7)].

PATIENT INFORMATION

Additions and/or revisions underlined:

How should I take XTANDI?

Take XTANDI exactly as your healthcare provider tells you.
Take your prescribed dose of XTANDI 1 time a day, at the same time each day.
Your healthcare provider may change your dose if needed.
Do not change or stop taking your prescribed dose of XTANDI without talking with your healthcare provider first.
XTANDI can be taken with or without food.

Swallow each XTANDI capsule or tablet whole with enough water to make sure that you can swallow all of the medicine successfully. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets. Your healthcare provider may change your treatment to a smaller tablet size or stop your treatment with XTANDI if you have swallowing problems with capsules or tablets.

…

What are the possible side effects of XTANDI?

XTANDI may cause serious side effects including:

…

Swallowing problems or choking. Severe swallowing problems or choking, including life-threatening problems or death can happen in people during treatment with XTANDI because of the size of the XTANDI capsules and tablets. Swallow each XTANDI capsule or tablet whole with enough water to make sure that you can swallow all of the medicine successfully. See “How should I take XTANDI?”

…

11/16/2023 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Seizure

Additions and/or revisions underlined:

Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In these trials, patients with predisposing factors for seizure were generally excluded. Seizure occurred from 13 to 2250 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy, and all seizure events resolved.

…

5.3 Hypersensitivity

Additions and/or revisions underlined:

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with enzalutamide in eight randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

5.4 Ischemic Heart Disease

Additions and/or revisions underlined:

In the combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on the XTANDI arm compared to 1.1% on the placebo arm. Ischemic events led to death in 0.4% of patients on the XTANDI arm compared to 0.1% on the placebo arm.

…

5.5 Falls and Fractures

Additions and/or revisions underlined:

…

In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo. Grade 3-4 fractures occurred in 3.4% of patients treated with XTANDI and in 1.9% of patients treated with placebo. The median time to onset of fracture was 420 days (range: 1 to 2348 days) for patients treated with XTANDI. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and/or revisions, please refer to label.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of 5110 patients who received XTANDI in eight randomized, controlled clinical trials, 78% were 65 and over, while 33% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

What is XTANDI®?

XTANDI is a prescription medicine used to treat men with prostate cancer that:

…

has not spread to other parts of the body and responds to a hormone therapy or surgical treatment to lower testosterone, and who are at high risk of cancer spreading to other parts of the body
…
What are the possible side effects of XTANDI?
XTANDI may cause serious side effects including:
…
The most common side effects of XTANDI include:

muscle and joint pain
feeling more tired than usual
high blood pressure
bleeding problems
hot flashes
falls
constipation
bone fractures
decreased appetite
headache
Diarrhea
…

01/13/2022 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Experience

Additions and/or revisions underlined:

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusia

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Effect of Other Drugs on XTANDI

Strong CYP2C8 Inhibitors

The coadministration of XTANDI with gemfibrozil (a strong CYP2C8 inhibitor) increases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may increase the incidence and severity of adverse reactions of XTANDI. Avoid the coadministration of XTANDI with strong CYP2C8 inhibitors. If the coadministration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of XTANDI [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

Strong CYP3A4 Inducers

The coadministration of XTANDI with rifampin (a strong CYP3A4 inducer and a moderate CYP2C8 inducer) decreases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may decrease the efficacy of XTANDI. Avoid the coadministration of XTANDI with strong CYP3A4 inducers. If the coadministration of XTANDI with a strong CYP3A4 inducer cannot be avoided, increase the dosage of XTANDI [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

7.2 Effect of XTANDI on Other Drugs

Certain CYP3A4, CYP2C9, or CYP2C19 Substrates

XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. The coadministration of XTANDI decreases the concentrations of certain CYP3A4, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid the coadministration of XTANDI with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. If the coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.6 Renal Impairment

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] greater than or equal to 30 mL/min). XTANDI has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage modification is recommended for patients with mild, moderate, or severe hepatic impairment [see Clinical Pharmacology (12.3)].

05/24/2021 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

The following is discussed in more detail in other sections of the labeling:

Seizure [see Warnings and Precautions (5.1)]
Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.2)]
Hypersensitivity [see Warnings and Precautions (5.3)]
Ischemic Heart Disease [see Warnings and Precautions (5.4)]
Falls and Fractures [see Warnings and Precautions (5.5)]

6.2 Post-Marketing Experience

(Additions and/or revisions underlined)

The following additional adverse reactions have been identified during post-approval use of XTANDI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: vomiting

Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx)

Neurological Disorders: posterior reversible encephalopathy syndrome (PRES)

Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))