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.

LUPRON DEPOT (NDA-019732)

(LEUPROLIDE ACETATE)

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

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03/21/2024 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Tumor Flare

Additions and/or revisions underlined:

Initially, LUPRON DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approximately 50% above baseline during the first weeks of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, hematuria, or bladder outlet obstruction.

Spinal cord compression may contribute to paralysis with or without fatal complications.

Monitor patients for tumor flare symptoms during the first few weeks of treatment with LUPRON DEPOT. Closely monitor patients with metastatic vertebral lesions and/or with urinary tract obstruction for new or worsening symptoms.

5.6 Severe Cutaneous Adverse Reactions

Newly added subsection:

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), occurred in patients receiving LUPRON DEPOT; including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions (6.5)].

Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).

If a SCAR is suspected, interrupt LUPRON DEPOT until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue LUPRON DEPOT.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.6)]

6.5 Postmarketing

Additions and/or revisions underlined:

Symptoms consistent with an anaphylactoid or asthmatic process have occurred (incidence rate of about 0.002%).

…

Skin reactions – rash, urticaria, photosensitivity, erythema multiforme, bullous dermatitis, dermatitis exfoliative, DRESS, SJS/ TEN, and AGEP

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hypersensitivity Reactions

Inform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like LUPRON DEPOT, LUPRON DEPOT is contraindicated [see Contraindications (4)].

Tumor Flare

Inform patients that LUPRON DEPOT can cause tumor flare during the first weeks of treatment. Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if bone pain, neuropathy, hematuria, bladder outlet obstruction, spinal cord compression, or new or worsened symptoms occur after beginning LUPRON DEPOT treatment [see Warnings and Precautions (5.1)].

…

Severe Cutaneous Adverse Reactions

Inform patients that severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life threatening or fatal, may occur during treatment with LUPRON DEPOT.
Urogenital Disorders
Advise patients that LUPRON DEPOT may cause impotence [see Adverse Reactions (6)].

12/04/2023 (SUPPL-48)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Metabolic Syndrome

Subsection title revised

Additions and/or revisions underlined:

The use of GnRH agonists may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) in patients receiving a GnRH agonist, and manage according to current treatment guidelines.

5.3 Cardiovascular Diseases

Additions and/or revisions underlined:

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to institutional guidelines.

5.5 Convulsions

Additions and/or revisions underlined:

Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above. Patients receiving a GnRH agonist who experience convulsion should be managed according to institutional guidelines.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Metabolic Syndrome [see Warnings and Precautions (5.2)]

6.5 Postmarketing

Additions and/or revisions underlined:

…

Patients should be counseled on the possibility of development or worsening of depression during treatment with LUPRON DEPOT.

…

Hepato-biliary disorder - serious drug-induced liver injury, non-alcoholic fatty liver disease

Blood and Lymphatic System - decreased WBC

Central/Peripheral Nervous System - convulsion, peripheral neuropathy, spinal fracture/paralysis

Endocrine System - diabetes mellitus

Musculoskeletal System - tenosynovitis-like symptoms

Urogenital System - prostate pain

See other LUPRON DEPOT and LUPRON Injection prescribing information for other reactions reported in women and pediatric populations.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Metabolic Syndrome

Advise patients that there is an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease with LUPRON DEPOT therapy. Inform patients that periodic monitoring for metabolic changes is required when being treated with LUPRON DEPOT [see Warnings and Precautions (5.2)].

03/04/2019 (SUPPL-44)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

(addition underlined)

…

Continuation of LUPRON DEPOT Treatment

Inform patients that LUPRON DEPOT is usually continued, often with additional medication, after the development of non-metastatic and metastatic castration-resistant prostate cancer.

12/10/2018 (SUPPL-43)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.7 Embryo-Fetal Toxicity

Based on findings in animal studies, LUPRON DEPOT may cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, administration of the monthly formulation of leuprolide acetate on day 6 of pregnancy (sustained exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose, based on body surface area, using an estimated daily dose. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

6 Adverse Reactions

Addition of the following bulleted line listing:

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

Tumor Flare
Hyperglycemia and Diabetes
Cardiovascular Disease
Effect on QT/QTc Interval
Convulsions

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

PLLR conversion; extensive changes. Please refer to label for complete information.

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

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label for complete information.

06/06/2016 (SUPPL-42)

Approved Drug Label (PDF)

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

PCI - Patients should be informed that:

LUPRON DEPOT is usually continued, often with additional medication, after the development of metastatic castration-resistant prostate cancer. (addition)