1 INDICATIONS AND USAGE KYZATREX® is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals.

These men usually have low serum testosterone concentrations and gonadotropins (folliclestimulating hormone (FSH), luteinizing hormone (LH)) above the normal range.

Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, pituitary-hypothalamic injury from tumors, trauma, or radiation.

These men have low serum testosterone concentrations but have gonadotropins in the normal or low range.

KYZATREX® is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone ( 1 ).

Limitations of Use: Safety and efficacy of KYZATREX® in males less than 18 years old have not been established ( 1 , 8.4 ).

Safety and efficacy of KYZATREX® in men with “age-related hypogonadism” have not been established (1) .

Limitations of Use Safety and efficacy of KYZATREX® in males less than 18 years old have not been established [see Use in Specific Populations (8.4) ] .

Safety and efficacy of KYZATREX® in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Polycythemia [see Warnings and Precautions (5.1) ] Venous Thromboembolism [see Warnings and Precautions (5.2) ] Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer [ see Warnings and Precautions (5.3) ] Blood Pressure Increases [see Warnings and Precautions (5.4) ] Hepatic Adverse Effects [see Warnings and Precautions (5.8) ] Edema [see Warnings and Precautions (5.9) ] Sleep Apnea [see Warnings and Precautions (5.10) ] Gynecomastia [see Warnings and Precautions (5.11) ] Lipid Changes [see Warnings and Precautions (5.12) ] Hypercalcemia [see Warnings and Precautions (5.13) ] Decreased Thyroxine-binding Globulin [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence ≥ 2%): hypertension ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Marius Pharmaceuticals at 1-833-949-5040 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of KYZATREX® was evaluated in Study MRS-TU-2019EXT in 155 hypogonadal males [see Clinical Studies (14) ].

All patients initially received KYZATREX® 200 mg orally twice daily.

If needed, the dosage was titrated to 100 mg once daily in the morning or 100 mg, 300 mg, or 400 mg twice daily to achieve testosterone concentrations in the normal range .

After the dosage titration period, patients continued their optimized dose for the remainder of the duration of the 6-month study.

The mean duration of exposure was 168 days (range: 1 to 180 days).

The median age was 52 years (range: 22 to 66 years); 77% were White, 19% were Black, 3% were Asian, and 2% were American Indian, Alaskan Native or Other.

Table 2 summarizes adverse reactions reported in ≥2% of patients in this 6-month study.

Table 2: Adverse Reactions in ≥ 2% of Patients Receiving KYZATREX® in STUDY MRS-TU-2019EXT Adverse Reaction N = 155 n (%) Hypertensión Based upon blood pressure cuff measurements 4 (2.6) One (0.8%) patient who received KYZATREX® experienced an adverse reaction (acne) that lead to premature discontinuation from the study.

In a 12-month, open-label study in hypogonadal adult males (N=212) who received KYZATREX® 200 mg once daily to 400 mg twice daily (n=202) the following additional adverse reactions were reported: headache, arthralgia, diarrhea, hemoglobin increased, anxiety, constipation, peripheral edema, and PSA increased.

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 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) 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 Table 3: Blood Pressure Increases Blood Pressure Change from Baseline (95% CI) mm Hg Systolic Diastolic 24-Hour Ambulatory 4 Month 1.7 (0.3 to 3.1) 0.6 (-0.3 to 1.6) 6 Month 1.8 (0.3 to 3.2) 0.6 (-0.4 to 1.6) A history of antihypertensive treatment and diabetes mellitus at baseline were significant factors related to ambulatory SBP increases.

Table 4 presents the Least Squares Mean estimates of Change from Baseline, with 95% CI’s, for sub-populations of subjects at study start either with or without hypertensive treatment or with or without diabetes mellitus.

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 (±SD) was 63.3 (7.9) years, with 2452 patients ages 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 2 .

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 Reproted 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 Table 4 Heart Rate Increases KYZATREX® increased mean (95%CI) 24-hour ambulatory heart rate by an average of 0.7 (-0.5 to 1.9) beats per minute (bpm) at 4 months and 1.9 (0.6 to 3.1) bpm at 6 months in Study MRS-TU-2019EXT.

Changes in heart rate were similar between patients with or without hypertension or diabetes.

Changes in heart rate with treatment were most prominent in the evening, 12 to 17 hours after the morning dose.

Increases in Hemoglobin Increases in hemoglobin were reported in 7 out of 155 patients (4.5%) in Study MRS-TU2019EXT.

None of these increases led to premature discontinuation of KYZATREX®.

Hematocrit was not assessed in this study.

Headaches Headaches were reported in 3 of 155 patients (1.9%) receiving KYZATREX® in Study MRSTU-2019EXT.

Increases in Serum PSA Four out of 155 patients (2.6%) receiving KYZATREX® in Study MRS-TU-2019EXT had an increase in PSA from baseline greater than 1.4 ng/mL and two out of 155 patients (1.3%) had a PSA of at least 4.0 ng/mL during Study MRS-TU-2019EXT.

The mean (SE) increase in PSA from baseline was 0.15 (±0.04) ng/mL at 6 months (n=135).

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of testosterone.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular Disorders: myocardial infarction, stroke Vascular Disorders: Venous thromboembolism