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.

TRELSTAR (NDA-021288)

(TRIPTORELIN PAMOATE)

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

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04/12/2024 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions

Additions and/or revisions underlined:

Anaphylactic shock, hypersensitivity, and angioedema related to TRELSTAR administration have been reported. In the event of a hypersensitivity reaction, discontinue TRELSTAR immediately and administer the appropriate supportive and symptomatic care.

5.2 Tumor Flare

Additions and/or revisions underlined:

Initially, triptorelin (TRELSTAR), like other GnRH agonists, causes a transient increase in serum testosterone levels [see Clinical Pharmacology (12.2)]. As a result, worsening signs and symptoms of prostate cancer during the first weeks of treatment have been reported with GnRH agonists. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction.
Closely monitor patients with metastatic vertebral lesions and/or with urinary tract obstruction during the first few weeks of therapy.

5.3 Metabolic Syndrome

Additions and/or revisions underlined:

The use of GnRH agonists (including TRELSTAR) 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 of 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) periodically in patients receiving TRELSTAR and manage according to institutional guidelines.

5.4 Cardiovascular Diseases

Additions and/or revisions underlined:

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with the use of GnRH agonists (including TRELSTAR) 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. Monitor patients receiving TRELSTAR for symptoms and signs suggestive of development of cardiovascular disease and manage according to current institutional guidelines.

5.5 Convulsions

Newly added subsection:

Convulsions have occurred in patients treated with GnRH analog (including TRELSTAR). These events included patients with risk factors for seizures such as a history of epilepsy, intracranial tumors or co- medication with other drugs known to present a risk of seizure reactions. Convulsions have also been reported in patients in the absence of known risk factors. Manage patients receiving TRELSTAR who experience convulsion according to institutional guidelines.

5.6 Effect on QT/QTc Interval

Additions and/or revisions underlined:

Androgen deprivation therapy with TRELSTAR may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

5.8 Laboratory Test Interactions

Additions and/or revisions underlined:

Chronic or continuous administration of TRELSTAR in therapeutic doses results in suppression of pituitary- gonadal axis. Diagnostic tests of the pituitary-gonadal function conducted during treatment and after cessation of therapy may therefore be misleading.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Convulsions [see Warnings and Precautions (5.5)].

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Adverse reactions reported for each of the three TRELSTAR formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4. The majority of adverse reactions related to TRELSTAR are a result of its pharmacological action, i.e., the induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved. Local reactions at the injection site or allergic reactions may occur.

…

7 Drug Interactions

Additions and/or revisions underlined:

No drug-drug interaction studies involving TRELSTAR have been conducted.
Human pharmacokinetic data with triptorelin suggest that C-terminal fragments produced by tissue degradation are either degraded completely within tissues, are rapidly degraded further in plasma, or cleared by the kidneys. Therefore, hepatic microsomal enzymes are unlikely to be involved in triptorelin metabolism. However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with TRELSTAR since hyperprolactinemia reduces the number of pituitary GnRH receptors.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of TRELSTAR in pediatric patients have not been established.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Convulsions

Inform patients that there is an increased risk of convulsions with TRELSTAR treatment. Advise patients to immediately contact their healthcare provider if they experience convulsions [see Warnings and Precautions (5.5)].

…

11/17/2023 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Metabolic Syndrome

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 of 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 institutional guidelines.

5.6 Laboratory Tests

Additions and/or revisions underlined:

Monitor serum levels of testosterone following injection of TRELSTAR In the majority of patients, testosterone levels increased above baseline, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks [see Clinical Studies (14) and Adverse Reactions

6 Adverse Reactions

Addition and/or revisions underlined:

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

Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
Tumor Flare [see Warnings and Precautions (5.2)].
Metabolic Syndrome [see Warnings and Precautions (5.3)]
Cardiovascular Diseases [see Warnings and Precautions (5.4)].
Effect of QT/QTc Interval [see Warnings and Precautions (5.5)].
6.2 Postmarketing Experience
Additions and/or revisions underlined:
…
Cardiovascular System – cerebrovascular accident, myocardial infarction, pulmonary emboli, thromboembolic events (including deep venous thrombosis, transient ischemic attack, and thrombophlebitis)
Central/Peripheral Nervous System – convulsions
Hepatobiliary Disorder – non-alcoholic fatty liver disease
Respiratory, Thoracic, and Mediastinal Disorder – interstitial lung disease

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 TRELSTAR therapy. Inform patients that periodic monitoring for hyperglycemia and diabetes is required when being treated with TRELSTAR [see Warnings and Precautions (5.5)].
…

12/14/2018 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.9 Embryo-Fetal Toxicity

Based on findings from animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

During postmarketing experience, convulsions, interstitial lung disease, and thromboembolic events …

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

Extensively changed; please refer to label for complete information.