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.

FORTESTA (NDA-021463)

(TESTOSTERONE)

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

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07/11/2025 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Lipid Changes

Additions and/or revisions underlined:

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as FORTESTA. Monitor the lipid profile periodically, particularly after starting testosterone therapy.

5.3 Venous Thromboembolism (VTE)

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)].

…

5.5 Blood Pressure Increases

Newly added subsection:

FORTESTA can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, FORTESTA increased the mean systolic/diastolic blood pressure by 3.1/1.2 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, FORTESTA increased the mean systolic/diastolic BP by 4.0/1.3 mm Hg from baseline. 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 blood pressure periodically in men using FORTESTA, especially men with hypertension. FORTESTA is not recommended for use in patients with hypertension.

5.7 Not for Use in Women

Subsection title revised:

Due to the lack of controlled evaluations in women and potential virilizing effects, FORTESTA is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.2)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Blood Pressure Increases

In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 223 patients. ABPM was conducted at baseline and at Week 16 of FORTESTA therapy. A total of 92 patients had acceptable ABPM recordings at both baseline and Week 16 and were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic blood pressure (BP) and diastolic BP from baseline to end-of-treatment at Week 16 (n=92) was 3.1 mm Hg (95% CI 0.9, 5.3) and 1.2 mm Hg (95% CI -0.1, 2.5), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 4.0 mm Hg [95% CI 0.3, 7.8] and 1.3 mm Hg [95% CI -0.9, 3.4], respectively [n=42]). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 1.5 mm Hg [95% CI -1.1, 4.1] and 0.6 mm Hg [95% CI -1.0, 2.1], respectively [n=45].

One patient (1.1 %) on FORTESTA, who was receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=1) or had their antihypertensive medication regimen adjusted (n=0) during the ABPM study.

Of the 223 patients in the ABPM study who used FORTESTA, 7 patients (3.1%) were reported to have either an adverse reaction of hypertension (5 patients, 2.2%) or increased blood pressure (2 patients, 0.9%).

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 (±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/m2.

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 >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

17.3 Potential Adverse Reactions with Androgens

Additions and/or revisions underlined:

…

Venous thromboembolism, the signs and symptoms of which may include lower limb pain, edema, or erythema; dyspnea; or chest pain.

Increased blood pressure that can increase cardiovascular risk over time

17.4 Patients Should Be Advised of the Following Instructions for Use

Additions and/or revisions underlined:

Report any changes in their state of health, such as signs and symptoms of venous thromboembolism, changes in urinary habits, breathing, sleep, and mood.
Be aware of the importance of monitoring BP periodically while on FORTESTA. If BP increases while on FORTESTA, antihypertensive medications may need to be started, added, or adjusted, or FORTESTA may need to be discontinued.

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Before using FORTESTA, tell your healthcare provider about all of your medical conditions including if you:

…

have high blood pressure or are being treated for high blood pressure.
…

What are the possible side effects of FORTESTA?
FORTESTA can cause serious side effects including:
…

Increased blood pressure. FORTESTA can increase your blood pressure, which can increase your risk of having a heart attack or stroke over time. Your risk may be greater if you have already had a heart attack or stroke or if you have other risk factors for heart attack or stroke. You may need to start new medicines or have medicines changed for high blood pressure while on FORTESTA. If your blood pressure cannot be controlled, FORTESTA may need to be stopped. Your healthcare provider should check your blood pressure while you use FORTESTA.
…

03/13/2020 (SUPPL-22)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

FORTESTA is contraindicated in women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman [see Use in Specific Populations (8.1, 8.2)].

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:
Risk Summary

FORTESTA is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm based on data from animal studies and its mechanism of action [see Contraindications (4) and Clinical Pharmacology (12.1)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies.

Data

Animal Data

In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased anogenital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes.

Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

8.2 Lactation

PLLR conversion; newly added information:
Risk Summary

FORTESTA is not indicated for use in females.

8.3 Females and Males of Reproductive Potential

PLLR conversion; newly added information:

Infertility

During treatment with large doses of exogenous androgens, including FORTESTA, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions (5.8)], possibly leading to adverse effects on semen parameters including sperm count. Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence (9.2)]. With either type of use, the impact on fertility may be irreversible.

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

MEDICATION GUIDE

Removed from label.

10/25/2016 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations (subsection added)

Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions.

If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.