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.
Contraindications
KYZATREX® is contraindicated in: Patients with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.34) ] . 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) ]. Patients with known hypersensitivity to KYZATREX® or any of its ingredients [see Description (11) ] .
Carcinoma of the breast or known or suspected carcinoma of the prostate ( 5.4 ) Women who are pregnant. Testosterone may cause fetal harm ( 4 , 5.7 , 8.1 ) Hypersensitivity to KYZATREX® or any of its ingredients ( 4 )
Warnings and precautions
- Polycythemia : Monitor hemoglobin or hematocrit approximately every 3 months to detect increased red blood cell mass and polycythemia. Discontinue KYZATREX® if necessary ( 5.1 ). Venous thromboembolism (VTE) : VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone. Discontinue KYZATREX® if VTE is suspected and initiate appropriate workup and management (5.2) Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer : Monitor patients for worsening of signs and symptoms of BPH.
Evaluate patients for prostate cancer, including monitoring prostate specific antigen (PSA) prior to initiating and during treatment with androgens ( 5.3 ). Blood Pressure Increases: KYZATREX® can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.4 ) Abuse of Testosterone and Monitoring of Serum Testosterone : If testosterone use at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids is suspected, check serum testosterone concentration ( 5.5 ).
Potential for Adverse Effects on Spermatogenesis : KYZATREX® may cause azoospermia ( 5.7 ). Edema : Edema, with or without congestive heart failure (CHF), may occur in patients with pre-existing cardiac, renal, or hepatic disease. Discontinue KYZATREX® and initiate appropriate workup ( 5.9 ). Sleep Apnea : KYZATREX® may potentiate sleep apnea in those with risk factors ( 5.10 ) Lipid Changes : KYZATREX® may affect serum lipid profile.
Monitor patient lipid concentrations periodically; if necessary, adjust dosage of lipid lowering drug(s) or discontinue KYZATREX® ( 5.12 ).
5.1Polycythemia
Androgens, including KYZATREX®, can cause increase in hemoglobin or hematocrit, reflective of increase in red blood cell mass. Check hematocrit prior to initiating KYZATREX®. An increase in red blood cell mass may increase the risk of thromboembolic events [see Warnings and Precautions ( 5.2 )]. Evaluate hematocrit approximately every 3 months while the patient is on KYZATREX®. If hematocrit becomes elevated, stop KYZATREX® until the hematocrit decreases to an acceptable concentration.
If KYZATREX® is restarted and again causes hematocrit to become elevated, permanently discontinue KYZATREX®.
5.2Venous Thromboembolism
There have been post-marketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone replacement products such as KYZATREX®. 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 )].
Evaluate patients who report symptoms of pain, edema, warmth, and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue KYZATREX® and initiate appropriate workup and management [see Adverse Reactions ( 6.2 )].
5.3 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer 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)].
5.4Blood Pressure Increases
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.
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.
5.5Abuse of Testosterone and Monitoring of Testosterone Centrations.
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 [see Drug Abuse and Dependence (9) ]. If testosterone abuse is suspected, check testosterone concentrations to ensure they are within therapeutic range [see Dosage and Administration ( 2.2 )].
Testosterone levels may remain 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. Also consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.
5.6Not for Use In Women Due
to lack of controlled studies in women and potential virilizing effects, KYZATREX® is not indicated for use in women [see Contraindications (4) and Use in Specific Populations ( 8.1 , 8.2 )].
5.7Potential for Adverse Effects on Spermatogenesis
With large doses of exogenous androgens, including KYZATREX®, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH, possibly leading to adverse effects on semen parameters including sperm count [see Use in Specific Populations (8.3) ]. Inform patients of this possible risk when deciding whether to use or to continue to use KYZATREX®.
5.8Hepatic Adverse Effects
KYZATREX® is not a 17-alpha-alkyl androgen and is not known to cause hepatic adverse effects. However, prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas.
Patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue KYZATREX® while the cause is evaluated.
5.9Edema
Androgens, including KYZATREX®, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease [see Adverse Reactions (6.1)]. In addition to discontinuatio
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Interactions
- Insulin: In patients with diabetes, concomitant use with KYZATREX® may decrease blood glucose and insulin requirements ( 7.1 ). Oral Anticoagulants: Concomitant use with KYZATREX® may cause changes in anticoagulant activity. Monitor International Normalized Ratio (INR) and prothrombin time (PT) frequently ( 7.2 ). Corticosteroids: Concomitant use with KYZATREX® may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 ).
Drugs that May Also Increase Blood Pressure: Concomitant use with KYZATREX® may lead to additional increases in blood pressure ( 7.4 ).
7.1Insulin Changes
in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and therefore necessitate a decrease in the dose of anti-diabetic medication.
7.2Oral Vitamin K Antagonist Anticoagulants Changes
in anticoagulant activity may be seen with androgens; therefore, more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy.
7.3Corticosteroids
The concurrent use of testosterone with corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal, or hepatic disease.
7.4 Medications that May Also Increase Blood Pressure Some prescription medications and nonprescription analgesic and cold medications contain drugs known to increase blood pressure. Concomitant administration of these medications with KYZATREX® may lead to additional increases in blood pressure [see Warnings and Precautions (5.4)] .
Pregnancy and breastfeeding
8.1 Pregnancy - Risk Summary KYZATREX® is contraindicated in pregnant women and not indicated for use in females [see Contraindications (4) ]. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies (see Data ) and its mechanism of action [see 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 do 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 injections 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.
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 .
6.1Clinical 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 hemog
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Composition
Active ingredients
TESTOSTERONE UNDECANOATE 200MG
Strengths and forms
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