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 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:
JATENZO can increase blood pressure. Ambulatory
blood pressure monitoring (ABPM) demonstrated JATENZO increased systolic
/diastolic BP by an average of 4.9/2.5 mm Hg from baseline after 4 months of
treatment in a clinical trial [see
Adverse Reactions (6.1)]. In patients with hypertension on antihypertensive
therapy, JATENZO increased the mean systolic/diastolic BP by 5.4/3.2 mm Hg from
baseline. Average blood pressures had not plateaued at the end of the trial.
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
JATENZO, especially men with hypertension. JATENZO is not recommended for use
in patients with uncontrolled hypertension.
5.12 Lipid Changes
Subsection title revised
6.1 Clinical Trial
Experience
Additions and/or revisions underlined:
. . .
BP Increases
In the 4-month clinical study, 24-hour ABPM was
conducted on 166 patients. ABPM was conducted at baseline and at Day 139 of
JATENZO therapy. A total of 135 patients had acceptable ABPM recordings at both
time periods and were at least 85% compliant with study drug. In that
group, the mean change in 24-hour systolic BP and diastolic BP from baseline to
final on-treatment visit on Day 139 (n=135) was +4.9 mm Hg (95% CI 3.5, 6.4)
and +2.5 mm Hg (95% CI 1.5, 3.6), respectively. In patients with a history of
hypertension who were receiving antihypertensive therapy, the mean ABPM
systolic and diastolic BP increased by 5.4 mm Hg [95% CI 3.3, 7.6] and 3.2 mm
Hg [95% CI 1.7, 4.7], respectively [n=67]. In patients with no history of
hypertension, the mean ABPM systolic and diastolic blood pressure increased by
4.4 mm Hg [95% CI 2.3, 6.4] and 1.8 mm Hg [95% CI 0.2, 3.3], respectively
[n=63].
. . .
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.
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