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.

KYZATREX (NDA-213953)

(TESTOSTERONE UNDECANOATE)

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

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07/11/2025 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Venous Thromboembolism

Additions and/or revisions underlined:

. . .

In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy Response in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, topical testosterone gel was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) [see Adverse Reactions (6.1)].

. . .

5.3 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer

Newly added subsection:

Patients with BPH who are treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.
Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications (4)].

5.4 Blood Pressure Increases

Newly added subsection:

KYZATREX can increase blood pressure. Based on ambulatory blood monitoring in Study MRS-TU- 2019EXT, KYZATREX increased mean systolic/diastolic blood pressure by 1.7/0.6 mm Hg from baseline after 4 months of treatment and 1.8/0.6 mm Hg from baseline after 6 months of treatment [see Adverse Reactions (6.1)]. In patients with hypertension on antihypertensive therapy, KYZATREX increased the mean systolic/diastolic BP by 3.4/0.7 mm Hg from baseline after 4 months of treatment and 3.1/1.0 mm Hg from baseline after 6 months of treatment [see Adverse Reactions (6.1)]. Blood pressure increases can increase cardiovascular (CV) risk over time.

The CV risk associated with topical testosterone gel was evaluated in TRAVERSE, a randomized,

double-blind, placebo controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, topical testosterone gel increased mean systolic blood pressure by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions (6.1)].

Monitor BP periodically in men using KYZATREX, especially men with hypertension.

KYZATREX is not recommended for use in patients with uncontrolled hypertension.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

. . .

Venous Thromboembolism [see Warnings and Precautions (5.2)]

. . .

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

. . .

Blood Pressure Increases

In Study MRS-TU-2019EXT, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 155 male patients, 135 of whom completed the study. ABPM was conducted at 3 distinct 24-hour time periods: at baseline and following approximately 4 months and 6 months weeks of treatment with KYZATREX. A total of 151 patients had acceptable 24-hour ABPM recordings at both time periods. In that group, the mean change in systolic BP from Baseline to 4 months and 6 months was + 1.7 mm Hg (95% CI 0.3, 3.1) and 1.8 mm Hg (95% CI 0.3, 3.2), respectively. In that group, the mean change in diastolic BP from Baseline to 4 months and 6 months was 0.6 mm Hg (95% CI -0.3, 1.6) and 0.6 mm Hg (95% CI -0.4, 1.6), respectively. In patients with a history of hypertension on antihypertensive therapy at baseline, the mean ABPM systolic blood pressure increased from Baseline to 4 months and 6 months by 3.4 mm Hg (95% CI 1.0, 5.9) and 3.1 mm Hg (95% CI 0.6, 5.6), respectively (n=49).

In patients with no history of hypertension at baseline, the mean systolic blood pressure from Baseline increased by 0.7 mm Hg (95% CI -1.0, 2.4) at 4 months and 1.0 mm Hg (95% CI -0.7, 2.8), at six months respectively (n =90). Ambulatory (24-hour) and in-clinic (cuff) blood pressure. Changes from Baseline for study MRS- TU-2019EXT are presented in Table 3 with 95% confidence intervals. No significant difference was observed between the 4-month and 6- month Changes from Baseline.

. . .

A total of 5 of 155 patients (3.2%) on KYZATREX in Study MRS-TU-2019EXT began taking new antihypertensive medications after study start. No patient had a dose increase in their antihypertensive medication by the end of treatment.

Of the 155 patients in Study MRS-TU-2019EXT who used KYZATREX, 4 patients (2.6%) were reported to have an adverse reaction of hypertension.

Cardiovascular Outcomes

TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non- fatal myocardial infarction (MI), and non-fatal stroke.

The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy.

The mean patient age (plus/minus SD) was 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35kg/m squared. Approximately 80% of

patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively.

The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was

220.4 ng/dL (n=2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving topical testosterone gel were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively.

For patients treated with topical testosterone gel, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]).

Additional Adverse Reactions Reported in TRAVERSE

Additional adverse reactions reported in TRAVERSE at an incidence rate greater than 2% in either treatment group and greater in topical testosterone gel versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.

. . .

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Venous Thromboembolism

Advise patients that KYZATREX can cause venous thromboembolism. Advise patients of the signs and symptoms of venous thromboembolism, which may include the following: lower limb pain, edema, or erythema; and dyspnea or chest pain. Advise patients to promptly report the signs and symptoms of venous thromboembolism, discontinue use of KYZATREX and seek urgent medical care.

. . .

Blood Pressure Increases

Inform patients that KYZATREX can increase blood pressure (BP) which can increase cardiovascular risk over time. Instruct patients about the importance of monitoring BP periodically while on KYZATREX. If BP increases while on KYZATREX, antihypertensive medications may need to be started, added, or adjusted to control BP, or KYZTREX may need to be discontinued [see Warnings and Precautions (5.4)].

. . .

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

What are the possible side effects of KYZATREX®? KYZATREX® may cause serious side effects including:

. . .

Increase in blood pressure. KYZATREX can increase your blood pressure. Increases in blood pressure can increase the risk of heart attack or stroke over time. If your blood pressure increases while on KYZATREX, blood pressure medicines may need to be started. If you are taking blood pressure medicines, new blood pressure medicines may need to be added or your current blood pressure medicines may need to be adjusted to control your blood pressure. If your blood pressure cannot be controlled, KYZATREX may need to be stopped. Your healthcare provider will monitor your blood pressure while you are being treated with KYZATREX.

. . .