INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. KYZATREX(R) is indicated for testosterone replacement therapy in adult males for conditions associated with 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.. 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(R) is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with deficiency or absence of endogenous testosterone 1). Limitations of Use:Safety and efficacy of KYZATREX(R) in males less than 18 years old have not been established 1, 8.4). Safety and efficacy of KYZATREX(R) in men with age-related hypogonadism have not been established (1). Safety and efficacy of KYZATREX(R) in males less than 18 years old have not been established 1, 8.4). Safety and efficacy of KYZATREX(R) in men with age-related hypogonadism have not been established (1). Limitations of UseSafety and efficacy of KYZATREX(R) in males less than 18 years old have not been established [see Use in Specific Populations (8.4)] Safety and efficacy of KYZATREX(R) in men with age-related hypogonadism (also referred to as late-onset hypogonadism) have not been established.

RECENT MAJOR CHANGES SECTION.

Recent Major Changes. Boxed Warnings, Blood Pressure Increases Removed 07/2025Contraindications, Hypogonadal conditions not associated with structural or genetic etiologies (4), Removed 07/2025 Warnings and Precautions, Venous Thromboembolism 5.2) 07/2025 Warnings and Precautions, Blood Pressure Increases 5.4) 07/2025 Warnings and Precautions, Cardiovascular Risk (5.4) Removed 07/2025.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationIssued: 07/2025MEDICATION GUIDE KYZATREX (R) (ky-ZAH-treks) (testosterone undecanoate) capsules, for oral use, CIII What is KYZATREX(R) KYZATREX (R) is prescription medicine that contains testosterone. KYZATREX (R) is used to treat adult men who have low or no testosterone due to certain medical conditions. It is not known if KYZATREX (R) is safe or effective in children younger than 18 years old. Improper use of KYZATREX (R) may affect bone growth in children. KYZATREX (R) is controlled substance (CIII) because it contains testosterone that can be target for people who abuse prescription medicines. Keep your KYZATREX (R) in safe place to protect it. Never give your KYZATREX (R) to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and is against the law. KYZATREX (R) is not meant for use by women. Do not take KYZATREX (R) if you:have breast cancer.have or might have prostate cancer.are woman who is pregnant. KYZATREX (R) may harm your unborn baby. are allergic to KYZATREX (R) or any ingredients in KYZATREX (R). See the end of this Medication Guide for complete list of ingredients in KYZATREX (R). Before you take KYZATREX (R) 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.have history of diabetes.have heart problems.have high red blood cell count (hematocrit) or high hemoglobin laboratory value.have urinary problems due to an enlarged prostate.have liver or kidney problems.have problems breathing while you sleep (sleep apnea).Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking KYZATREX (R) with certain other medicines can affect each other. Especially, tell your healthcare provider if you take: insulinmedicines that decrease blood clotting (blood thinners)corticosteroidsmedicines that increase blood pressure such as some cold medicine and pain medicinesKnow the medicines you take. Ask your healthcare provider or pharmacist for list of these medicines, if you are not sure. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine. How should take KYZATREX (R) Take KYZATREX (R) exactly as your healthcare provider tells you take it. Take KYZATREX (R) by mouth times daily. Take time in the morning and take time in the evening. If your dose is 100 mg daily, take time in the morning. Take KYZATREX (R) with food. Your healthcare provider may change your KYZATREX (R) dose. Do not change your KYZATREX (R) dose without talking to your healthcare provider. What are the possible side effects of KYZATREX (R) KYZATREX (R) may cause serious side effects including:See What is the most important information should know about KYZATREX (R) Increase in red blood cell count (hematocrit) or hemoglobin.KYZATREX (R) increases red blood cell counts in some patients. High red blood cell counts increase the risk of blood clots, strokes, and heart attacks. You may need to stop KYZATREX (R) if your red blood cell count increases. Your healthcare provider should check your red blood cell count and hemoglobin while you take KYZATREX (R). If you already have an enlarged prostate, your signs and symptoms may worsen while taking KYZATREX (R) .These may include:increased urination at nighttrouble starting your urine streamurinating many times during the dayurge to go to the bathroom right awaya urine accidentinability to pass urine or weak urine flowIncreased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you take KYZATREX (R). Blood clots in the legs or lungs. Signs and symptoms of blood clot in your leg can include pain, swelling or redness. Signs and symptoms of blood clot in your lungs can include difficulty breathing or chest pain. Increase in blood pressure. KYZATREX (R) 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 (R), 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 (R) may need to be stopped. Your healthcare provider will monitor your blood pressure while you are being treated with KYZATREX (R) Abuse. Testosterone can be abused, when taken at higher than prescribed doses and when used with other anabolic androgenic steroids. Abuse can cause serious heart and psychological side effects. Your healthcare provider should check you for signs of abuse before and during treatment with KYZATREX (R). In large doses KYZATREX(R)may lower your sperm count.Liver problems.Symptoms of liver problems may include: nausea or vomitingyellowing of your skin or whites of your eyesdark urinepain on the right side of your stomach area (abdominal pain)Swelling of your ankles, feet, or body (edema), with or without heart failure.Enlarged or painful breasts.Breathing problems while you sleep (sleep apnea).Call your healthcare provider right away if you have any of the serious side effects listed above.The most common side effect of KYZATREX(R)is high blood pressure.Other side effects may include headache, joint or back pain, diarrhea, increased red blood cell count, anxiety, constipation, swelling of the legs, and increased prostate specific antigen (PSA) levels. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of KYZATREX (R). For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store KYZATREX(R)Store KYZATREX (R) at room temperature between 68F to 77F (20C to 25C). Store KYZATREX (R) in dry place. Keep KYZATREX(R)and all medicines out of the reach of children.How should throw away (dispose of) KYZATREX(R)Throw away unused KYZATREX (R) via take-back option. If take-back option is unavailable, follow FDA instructions at www.fda.gov/drugdisposal for properly throwing away medicine. General information about the safe and effective use of KYZATREX(R)Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use KYZATREX (R) for condition for which it was not prescribed. Do not give KYZATREX (R) to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KYZATREX (R) that is written for health professionals. What are the ingredients in KYZATREX(R)Active ingredient: testosterone undecanoate Inactive ingredients: DL-alpha-tocopheryl acetate (Vitamin E), phytosterol esters, polyoxyl 40 hydrogenated castor oil and propylene glycol monolaurate. The ingredients of the gelatin capsule shells are gelatin, glycerin, purified water, sorbitol, and titanium dioxide. Marketed by: Marius Pharmaceuticals Raleigh, NC 27612 For more information, go to www.KYZATREX.com or call 1-833-949-5040 KYZATREX (R) is prescription medicine that contains testosterone. KYZATREX (R) is used to treat adult men who have low or no testosterone due to certain medical conditions. It is not known if KYZATREX (R) is safe or effective in children younger than 18 years old. Improper use of KYZATREX (R) may affect bone growth in children. KYZATREX (R) is controlled substance (CIII) because it contains testosterone that can be target for people who abuse prescription medicines. Keep your KYZATREX (R) in safe place to protect it. Never give your KYZATREX (R) to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and is against the law. KYZATREX (R) is not meant for use by women. have breast cancer.. have or might have prostate cancer.. are woman who is pregnant. KYZATREX (R) may harm your unborn baby. are allergic to KYZATREX (R) or any ingredients in KYZATREX (R). See the end of this Medication Guide for complete list of ingredients in KYZATREX (R). have high blood pressure or are being treated for high blood pressure.. have history of diabetes.. have heart problems.. have high red blood cell count (hematocrit) or high hemoglobin laboratory value.. have urinary problems due to an enlarged prostate.. have liver or kidney problems.. have problems breathing while you sleep (sleep apnea).. insulin. medicines that decrease blood clotting (blood thinners). corticosteroids. medicines that increase blood pressure such as some cold medicine and pain medicines. Take KYZATREX (R) exactly as your healthcare provider tells you take it. Take KYZATREX (R) by mouth times daily. Take time in the morning and take time in the evening. If your dose is 100 mg daily, take time in the morning. Take KYZATREX (R) with food. Your healthcare provider may change your KYZATREX (R) dose. Do not change your KYZATREX (R) dose without talking to your healthcare provider. See What is the most important information should know about KYZATREX (R) . Increase in red blood cell count (hematocrit) or hemoglobin.KYZATREX (R) increases red blood cell counts in some patients. High red blood cell counts increase the risk of blood clots, strokes, and heart attacks. You may need to stop KYZATREX (R) if your red blood cell count increases. Your healthcare provider should check your red blood cell count and hemoglobin while you take KYZATREX (R). KYZATREX (R) increases red blood cell counts in some patients. High red blood cell counts increase the risk of blood clots, strokes, and heart attacks. You may need to stop KYZATREX (R) if your red blood cell count increases. Your healthcare provider should check your red blood cell count and hemoglobin while you take KYZATREX (R). If you already have an enlarged prostate, your signs and symptoms may worsen while taking KYZATREX (R) .These may include:increased urination at nighttrouble starting your urine streamurinating many times during the dayurge to go to the bathroom right awaya urine accidentinability to pass urine or weak urine flow. These may include:. increased urination at night. trouble starting your urine stream. urinating many times during the day. urge to go to the bathroom right away. urine accident. inability to pass urine or weak urine flow. Increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you take KYZATREX (R). Blood clots in the legs or lungs. Signs and symptoms of blood clot in your leg can include pain, swelling or redness. Signs and symptoms of blood clot in your lungs can include difficulty breathing or chest pain. Increase in blood pressure. KYZATREX (R) 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 (R), 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 (R) may need to be stopped. Your healthcare provider will monitor your blood pressure while you are being treated with KYZATREX (R) Abuse. Testosterone can be abused, when taken at higher than prescribed doses and when used with other anabolic androgenic steroids. Abuse can cause serious heart and psychological side effects. Your healthcare provider should check you for signs of abuse before and during treatment with KYZATREX (R). In large doses KYZATREX(R)may lower your sperm count.. Liver problems.Symptoms of liver problems may include: nausea or vomitingyellowing of your skin or whites of your eyesdark urinepain on the right side of your stomach area (abdominal pain). nausea or vomiting. yellowing of your skin or whites of your eyes. dark urine. pain on the right side of your stomach area (abdominal pain). Swelling of your ankles, feet, or body (edema), with or without heart failure.. Enlarged or painful breasts.. Breathing problems while you sleep (sleep apnea).. Store KYZATREX (R) at room temperature between 68F to 77F (20C to 25C). Store KYZATREX (R) in dry place. Throw away unused KYZATREX (R) via take-back option. If take-back option is unavailable, follow FDA instructions at www.fda.gov/drugdisposal for properly throwing away medicine.

SPL UNCLASSIFIED SECTION.

Limitations of UseSafety and efficacy of KYZATREX(R) in males less than 18 years old have not been established [see Use in Specific Populations (8.4)] Safety and efficacy of KYZATREX(R) in men with age-related hypogonadism (also referred to as late-onset hypogonadism) have not been established.

STORAGE AND HANDLING SECTION.

Store at 20C to 25C (68F to 77F), with excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store the capsules in dry place avoiding exposure to excessive moisture and humid conditions.Dispose of unused KYZATREX(R) via take-back option. If take-back option is unavailable, follow FDA instructions at www.fda.gov/drugdisposal.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. -. Geriatric Patients: Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH and hypertension 8.5). 8.1 Pregnancy. -. Risk SummaryKYZATREX(R) 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 pregnant woman based on data from animal studies (see Data) and its mechanism of action [see Clinical Pharmacology (12.1) ]. Exposure of 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 DataIn 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.. 8.2 Lactation. -. Risk SummaryKYZATREX(R) is not indicated for use in females.. 8.3 Females and Males of Reproductive Potential. -. Infertility. MalesDuring treatment with large doses of exogenous androgens, including KYZATREX(R), spermatogenesis may be suppressed through feedback inhibition of the hypothalamicpituitary-testicular axis [see [See Warnings and Precautions (5.7) and Impairment of Fertility (13.1)] possibly leading to adverse effects on semen parameters including sperm count. Reduced fertility has been 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. 8.4 Pediatric Use. The safety and efficacy of KYZATREX(R) in pediatric patients less than 18 years old have not been established. KYZATREX(R) is not recommended for use in patients less than 18 years of age because of the potential for acceleration of bone age and premature closure of epiphyses.. 8.5 Geriatric Use. Clinical studies of KYZATREX(R) did not include any patients 65 years of age and older. Therefore, it cannot be determined whether these patients respond differently from younger adult patients. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potentially increased risk of cardiovascular disease and prostate cancer.Geriatric patients treated with androgens including KYZATREX(R) may be at risk for worsening of signs and symptoms of BPH [see (see Warnings and Precautions (5.3)].

ABUSE SECTION.

9.2 Abuse. Drug abuse is intentional non-therapeutic use of drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids, and not obtained by prescription through pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.. Abuse-Related Adverse ReactionsSerious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility, and aggression.The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities. The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.Because these reactions are reported voluntarily from population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

ADVERSE REACTIONS SECTION.

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)] 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 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(R) was evaluated in Study MRS-TU-2019EXT in 155 hypogonadal males [see Clinical Studies (14)]. All patients initially received KYZATREX(R) 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: 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 summarizes adverse reactions reported in >=2% of patients in this 6-month study.Table 2: Adverse Reactions in >= 2% of Patients Receiving KYZATREX(R) in STUDY MRS-TU-2019EXTAdverse ReactionN 155 (%) Hypertension Based upon blood pressure cuff measurements (2.6)One (0.8%) patient who received KYZATREX(R) experienced an adverse reaction (acne) that lead to premature discontinuation from the study.In 12-month, open-label study in hypogonadal adult males (N=212) who received KYZATREX(R) 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 IncreasesIn 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 distinct 24-hour time periods: at baseline and following approximately months and months of treatment with KYZATREX(R). 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 months and 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 months and 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 history of hypertension on antihypertensive therapy at baseline, the mean ABPM systolic blood pressure increased from Baseline to months and 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 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 with 95% confidence intervals. No significant difference was observed between the 4-month and 6-month Changes from Baseline Table 3: Blood Pressure IncreasesBlood PressureChange from Baseline (95% CI) mm HgSystolicDiastolic24-Hour Ambulatory4 Month1.7 (0.3 to 3.1)0.6 (-0.3 to 1.6)6 Month1.8 (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 presents the Least Squares Mean estimates of Change from Baseline, with 95% CIs, for sub-populations of subjects at study start either with or without hypertensive treatment or with or without diabetes mellitus. total of of 155 patients (3.2%) on KYZATREX(R) in Study MRS-TU-2019EXT began taking new antihypertensive medications after study start. No patient had dose increase in their antihypertensive medication by the end of treatment.Of the 155 patients in Study MRS-TU-2019EXT who used KYZATREX(R), patients (2.6%) were reported to have an adverse reaction of hypertension.Cardiovascular OutcomesTRAVERSE was 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 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 TRAVERSEAdditional 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 IncreasesKYZATREX(R) 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 months and 1.9 (0.6 to 3.1) bpm at 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 HemoglobinIncreases in hemoglobin were reported in out of 155 patients (4.5%) in Study MRS-TU2019EXT. None of these increases led to premature discontinuation of KYZATREX(R).Hematocrit was not assessed in this study.. HeadachesHeadaches were reported in of 155 patients (1.9%) receiving KYZATREX(R) in Study MRSTU-2019EXT.. Increases in Serum PSAFour out of 155 patients (2.6%) receiving KYZATREX(R) 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 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 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular Disorders: myocardial infarction, stroke Vascular Disorders: Venous thromboembolism.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. 3-month repeat-dose oral toxicity study in male eugonadal dogs was conducted to evaluate whether phytosterol esters present in the KYZATREX(R) formulation influenced target organ toxicity due to their structural similarities to sex steroids like testosterone. KYZATREX(R) doses times the MRHDD (based on mean AUC exposure to testosterone) produced similar effects on androgen-responsive tissues as testosterone undecanoate without phytosterol esters. These included mild to marked effects on the testes (decreased size, germ cell depletion, Leydig cell atrophy), epididymides (aspermia), adrenal glands (vacuolation in the zona fasciculata) and prostate (increased size and glandular hypertrophy/hyperplasia). Following 4-week treatment-free period, findings in the testes, epididymides, and adrenal glands were not fully reversible at doses of times the MRHDD of KYZATREX(R) as compared to treatment with the excipients alone, including phytosterol esters. Reversibility was not assessed in testosterone undecanoate groups without phytosterol esters.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. -. Polycythemia: Monitor hemoglobin or hematocrit approximately every months to detect increased red blood cell mass and polycythemia. Discontinue KYZATREX(R) 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(R) 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(R) 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(R) 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(R) and initiate appropriate workup 5.9). Sleep Apnea: KYZATREX(R) may potentiate sleep apnea in those with risk factors 5.10) Lipid Changes: KYZATREX(R) may affect serum lipid profile. Monitor patient lipid concentrations periodically; if necessary, adjust dosage of lipid lowering drug(s) or discontinue KYZATREX(R) 5.12). Polycythemia: Monitor hemoglobin or hematocrit approximately every months to detect increased red blood cell mass and polycythemia. Discontinue KYZATREX(R) 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(R) 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(R) 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(R) 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(R) and initiate appropriate workup 5.9). Sleep Apnea: KYZATREX(R) may potentiate sleep apnea in those with risk factors 5.10) Lipid Changes: KYZATREX(R) may affect serum lipid profile. Monitor patient lipid concentrations periodically; if necessary, adjust dosage of lipid lowering drug(s) or discontinue KYZATREX(R) 5.12). 5.1 Polycythemia. Androgens, including KYZATREX(R), can cause increase in hemoglobin or hematocrit, reflective of increase in red blood cell mass. Check hematocrit prior to initiating KYZATREX(R). An increase in red blood cell mass may increase the risk of thromboembolic events [see Warnings and Precautions 5.2)]. Evaluate hematocrit approximately every months while the patient is on KYZATREX(R). If hematocrit becomes elevated, stop KYZATREX(R) until the hematocrit decreases to an acceptable concentration. If KYZATREX(R) is restarted and again causes hematocrit to become elevated, permanently discontinue KYZATREX(R). 5.2 Venous 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(R).In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy Response in hypogonadal men (TRAVERSE) Study, randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, topical testosterone gel was associated with 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 venous thromboembolic event is suspected, discontinue KYZATREX(R) 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)]. 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. KYZATREX(R) can increase blood pressure. Based on ambulatory blood monitoring in Study MRS-TU-2019EXT, KYZATREX(R) increased mean systolic/diastolic blood pressure by 1.7/0.6 mm Hg from baseline after months of treatment and 1.8/0.6 mm Hg from baseline after months of treatment [see Adverse Reactions (6.1) ]. In patients with hypertension on antihypertensive therapy, KYZATREX(R) increased the mean systolic/diastolic BP by 3.4/0.7 mm Hg from baseline after months of treatment and 3.1/1.0 mm Hg from baseline after 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, randomized, double-blind, placebo controlled, CV outcomes study in men with 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 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(R), especially men with hypertension. KYZATREX(R) is not recommended for use in patients with uncontrolled hypertension.. 5.5 Abuse 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. 5.6 Not for Use In Women. Due to lack of controlled studies in women and potential virilizing effects, KYZATREX(R) is not indicated for use in women [see Contraindications (4) and Use in Specific Populations 8.1 8.2 )]. 5.7 Potential for Adverse Effects on Spermatogenesis. With large doses of exogenous androgens, including KYZATREX(R), 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(R). 5.8 Hepatic Adverse Effects. KYZATREX(R) is not 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 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(R) while the cause is evaluated.. 5.9 Edema. Androgens, including KYZATREX(R), may promote retention of sodium and water. Edema, with or without congestive heart failure, may be serious complication in patients with pre-existing cardiac, renal, or hepatic disease [see Adverse Reactions (6.1)]. In addition to discontinuation of the drug, diuretic therapy may be required. 5.10 Sleep Apnea. The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung disease.. 5.11 Gynecomastia. Gynecomastia may develop and persist in patients being treated for hypogonadism.. 5.12 Lipid Changes. In clinical trials, patients receiving KYZATREX(R) experienced reductions in lipid parameters, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides [see Adverse Reactions (6.1)]. Changes in the serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of testosterone therapy. Monitor the lipid profile periodically, particularly after starting testosterone therapy. 5.13 Hypercalcemia. Androgens, including KYZATREX(R), should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Monitor serum calcium concentrations periodically during treatment with KYZATREX(R) in these patients.. 5.14 Descreased Thyroxine-binding Globulin. Androgens, including KYZATREX(R), may decrease concentrations of thyroxin-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. -. CarcinogenesisTestosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.. MutagenesisTestosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.. Impairment of FertilityThe administration of exogenous testosterone suppressed spermatogenesis and impaired fertility in the rat, dog, and non-human primate, which was reversible on cessation of treatment.A reproductive toxicology study was conducted in rats to evaluate functional effects of KYZATREX(R) on male fertility. In untreated female rats mated with males receiving times the maximum recommended human daily dose (MRHDD) of KYZATREX(R) (based on mean AUC exposure to testosterone), the number of impregnated females was reduced, fertility was significantly lower, and pre-implantation loss was significantly higher compared to the control group. There was no impairment of fertility in males receiving an equivalent dose of KYZATREX(R) to the MRHDD.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. -. 12.1 Mechanism of Action. Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.Male hypogonadism, clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter syndrome or Leydig cell aplasia, whereas secondary hypogonadism (also known as hypogonadotropic hypogonadism) is the failure of the hypothalamus (or pituitary gland) to produce sufficient gonadotropins (FSH, LH).. 12.2 Pharmacodynamics. There is insufficient data to characterize an exposure-response relationship or time course of pharmacodynamics.. 12.3 Pharmacokinetics. -. AbsorptionKYZATREX(R) was taken orally at starting dose of 200 mg twice per day with meals in multicenter, open-label trial in hypogonadal males. The dose was adjusted, as needed, on Days 28 and 56 from minimum dose of 100 mg (morning-only) to maximum dose of 400 mg twice per day based on the plasma testosterone concentration obtained by single blood draw collected to hours after the morning dose. The average daily NaF/EDTA plasma testosterone concentration was 393.3 (+-113.6) ng/dL after 90 days of treatment (normal eugonadal range in NaF/EDTA plasma: 222-800 ng/dL. Note that the titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)] KYZATREX(R) is expected to produce testosterone concentrations that approximate normal concentrations seen in healthy men.Table summarizes the pharmacokinetic (PK) parameters for plasma total testosterone in patients completing at least 90 days of KYZATREX(R) treatment administered daily.Table 5: NaF-EDTA Plasma Testosterone avg and max at Day 90 Visit PK ParameterPlasma (N=130)PK pharmacokinetic; avg 24-hour average concentration; max maximum concentration avg (ng/dL) n127Mean393.3SD113.6C max (ng/dL) n130Mean852.4SD311.3Figure summarizes the mean plasma total testosterone profile at the final PK visit.Figure 2: Mean (+-SEM) Concentration-Time Profile for NaF-EDTA Plasma Total Testosterone in KYZATREX(R)-Treated Patients at Day 90 VisitSEM standard error of the mean Testosterone normal ranges: plasma 222-800 ng/dL When KYZATREX(R) was given with breakfast containing 16%, 33%, and 45% fat, the exposure (AUC 0-24 hr) of testosterone was increased by 37%, 87%, and 94%, respectively, compared to when given under fasted conditions. The primary efficacy and safety study was conducted under fed conditions regardless of the type of meals and the primary efficacy endpoint of achieving testosterone avg in normal testosterone range was met. There was no effect on testosterone PK when KYZATREX(R) was administered with 20% alcohol along with high-fat meal versus high-fat meal alone.. Figure 2. DistributionCirculating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.. MetabolismThe androgenic activity of testosterone undecanoate occurs after the ester bond linking the testosterone to the undecanoic acid is cleaved by endogenous non-specific esterases.Undecanoic acid is metabolized like all fatty acids via the beta-oxidation pathway.Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are dihydrotestosterone (DHT) and estradiol.. ExcretionAbout 90% of dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. About 6% of dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy and safety of KYZATREX(R) were evaluated in Study MRS-TU-2019EXT (NCT04467697) multi-center, open-label study of approximately months of duration in 155 hypogonadal males.Patients received KYZATREX(R) at starting dose of 200 mg twice daily with meals. The dosage was adjusted on Days 28 and 56 between minimum dose of 100 mg (single morning dose) and maximum dose of 800 mg (400 mg twice daily) based on plasma testosterone concentration from single blood draw between to hours after the morning dose.The primary efficacy endpoint was the percentage of KYZATREX(R)-treated patients with mean plasma total testosterone concentration (C avg) over 24-hours within the normal range of 222-800 ng/dL on the final PK visit of the study at Day 90. The efficacy population consisted of 139 hypogonadal, males with median age of 50 years (range 22 to 66 years), 79% were White, 16% were Black, 3% were Asian, and 2% were American Indian, Alaskan Native or Other.Primary efficacy results are summarized in Table 6.Table 6: Proportion of Patients in Study MRS-TU-2019EXT with Average Plasma Total Testosterone in the Normal Range (222-800 ng/dL) on Day 90ParameterN=139C avg 24-hour average concentration Patients (%) with Testosterone, avg (ng/dL), 222-800 ng/dL 122 (88%)95% Confidence Interval(82%, 93%)Secondary endpoints were the percentage of patients with maximum total testosterone concentration (C max) meeting three predetermined limits: less than or equal to 1.5 times the upper limit of normal range (ULN) (1200 ng/dL), between 1.8 and 2.5 times ULN (1440-2000 ng/dL), and greater than 2.5 times ULN (2000 ng/dL). The percentage of patients who received KYZATREX(R) and had testosterone Cmax threshold less than or equal to 1200 ng/dL, between 1440 and 2000 ng/dL, and greater than 2000 ng/dL at the final PK visit were 88%, 4%, and 0%, respectively.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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(R) was evaluated in Study MRS-TU-2019EXT in 155 hypogonadal males [see Clinical Studies (14)]. All patients initially received KYZATREX(R) 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: 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 summarizes adverse reactions reported in >=2% of patients in this 6-month study.Table 2: Adverse Reactions in >= 2% of Patients Receiving KYZATREX(R) in STUDY MRS-TU-2019EXTAdverse ReactionN 155 (%) Hypertension Based upon blood pressure cuff measurements (2.6)One (0.8%) patient who received KYZATREX(R) experienced an adverse reaction (acne) that lead to premature discontinuation from the study.In 12-month, open-label study in hypogonadal adult males (N=212) who received KYZATREX(R) 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 IncreasesIn 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 distinct 24-hour time periods: at baseline and following approximately months and months of treatment with KYZATREX(R). 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 months and 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 months and 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 history of hypertension on antihypertensive therapy at baseline, the mean ABPM systolic blood pressure increased from Baseline to months and 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 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 with 95% confidence intervals. No significant difference was observed between the 4-month and 6-month Changes from Baseline Table 3: Blood Pressure IncreasesBlood PressureChange from Baseline (95% CI) mm HgSystolicDiastolic24-Hour Ambulatory4 Month1.7 (0.3 to 3.1)0.6 (-0.3 to 1.6)6 Month1.8 (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 presents the Least Squares Mean estimates of Change from Baseline, with 95% CIs, for sub-populations of subjects at study start either with or without hypertensive treatment or with or without diabetes mellitus. total of of 155 patients (3.2%) on KYZATREX(R) in Study MRS-TU-2019EXT began taking new antihypertensive medications after study start. No patient had dose increase in their antihypertensive medication by the end of treatment.Of the 155 patients in Study MRS-TU-2019EXT who used KYZATREX(R), patients (2.6%) were reported to have an adverse reaction of hypertension.Cardiovascular OutcomesTRAVERSE was 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 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 TRAVERSEAdditional 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 IncreasesKYZATREX(R) 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 months and 1.9 (0.6 to 3.1) bpm at 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 HemoglobinIncreases in hemoglobin were reported in out of 155 patients (4.5%) in Study MRS-TU2019EXT. None of these increases led to premature discontinuation of KYZATREX(R).Hematocrit was not assessed in this study.. HeadachesHeadaches were reported in of 155 patients (1.9%) receiving KYZATREX(R) in Study MRSTU-2019EXT.. Increases in Serum PSAFour out of 155 patients (2.6%) receiving KYZATREX(R) 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 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 months (n=135).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. KYZATREX(R) 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 pregnant woman see Use in Specific Populations (8.1) ]. Patients with known hypersensitivity to KYZATREX(R) or any of its ingredients [see Description (11)] . 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 pregnant woman see Use in Specific Populations (8.1) ]. Patients with known hypersensitivity to KYZATREX(R) 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(R) or any of its ingredients 4) Hypogonadal conditions not associated with structural or genetic etiologies 4) 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(R) or any of its ingredients 4) Hypogonadal conditions not associated with structural or genetic etiologies 4).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance. KYZATREX(R) contains testosterone undecanoate, Schedule III controlled substance.

DEPENDENCE SECTION.

9.3 Dependence. Behaviors Associated with AddictionContinued abuse of testosterone and other anabolic steroids leading to addiction is characterized by the following behaviors:Taking greater dosages than prescribedContinued drug use despite medical and social problems due to drug useSpending significant time to obtain the drug when supplies of the drug are interruptedGiving higher priority to drug use than other obligationsHaving difficulty in discontinuing the drug despite desires and attempts to do soExperiencing withdrawal symptoms upon abrupt discontinuation of usePhysical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or significant dose reduction of drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months, which may include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism.Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.. Taking greater dosages than prescribed. Continued drug use despite medical and social problems due to drug use. Spending significant time to obtain the drug when supplies of the drug are interrupted. Giving higher priority to drug use than other obligations. Having difficulty in discontinuing the drug despite desires and attempts to do so. Experiencing withdrawal symptoms upon abrupt discontinuation of use.

DESCRIPTION SECTION.

11 DESCRIPTION. KYZATREX(R) is provided as gelatin capsule containing testosterone undecanoate, fatty-acid ester of testosterone. Testosterone undecanoate is white to off-white yellow crystalline powder. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.Testosterone undecanoate is chemically described as 17-hydroxyandrost-4-en-3-one undecanoate. It has the empirical formula of 30H 48O and molecular weight of 456.7 g/mol. The structural formula for testosterone undecanoate is presented in Figure 1. Figure 1: Testosterone UndecanoateKYZATREX(R) (testosterone undecanoate) capsules for oral use are available in three dosage strengths- 100 mg, 150 mg, and 200 mg. The 100 mg strength is an opaque, white capsule imprinted with MP100 in red ink. The 150 mg strength is an opaque white capsule imprinted with MP150 in red ink. The 200 mg strength is an opaque white capsule imprinted with MP200 in red ink. All capsule strengths also contain DL-alpha-tocopheryl acetate (Vitamin E), phytosterol esters, polyoxyl 40 hydrogenated castor oil, and propylene glycol monolaurate as inactive ingredients.Gelatin capsule shells are composed of the following inactive ingredients: gelatin, glycerin, purified water, sorbitol, and titanium dioxide.. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. -. KYZATREX(R) is not substitutable with other oral testosterone undecanoate products 2.1). Prior to initiating KYZATREX(R), confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these concentrations are below the normal range 2.2). Take KYZATREX(R) with food 2.3). Starting dosage: 200 mg orally once in the morning and once in the evening 2.3). Adjust the dosage to minimum of 100 mg once in the morning and maximum of 400 mg twice daily based on serum testosterone drawn to hours after the morning dose at least days after starting treatment or following dose adjustment and periodically thereafter 2.3). KYZATREX(R) is not substitutable with other oral testosterone undecanoate products 2.1). Prior to initiating KYZATREX(R), confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these concentrations are below the normal range 2.2). Take KYZATREX(R) with food 2.3). Starting dosage: 200 mg orally once in the morning and once in the evening 2.3). Adjust the dosage to minimum of 100 mg once in the morning and maximum of 400 mg twice daily based on serum testosterone drawn to hours after the morning dose at least days after starting treatment or following dose adjustment and periodically thereafter 2.3). 2.1 Important Dosage Information. KYZATREX(R) is not substitutable with other oral testosterone undecanoate products.. 2.2 Confirmation of Hypogonadism Before Initiation of KYZATREX(R). Prior to initiating KYZATRE(R), confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these testosterone concentrations are below the normal range.. 2.3 Recommended Dosage and Administration. Individualize the dosage of KYZATREX(R) based on the patients serum testosterone concentration response to the drug.The recommended starting dose is 200 mg orally twice daily, once in the morning and once in the evening. Take KYZATREX(R) with food.. Dosage AdjustmentCheck serum testosterone concentrations days after starting treatment or after dosage adjustment, to hours after the morning dose. Adjust the KYZATREX(R) dose as necessary as shown in Table 1. Thereafter, periodically monitor serum testosterone concentrations.The minimum recommended dose is 100 mg once daily in the morning. The maximum recommended dose is 400 mg twice daily. For total daily doses greater than 100 mg, administer the same dose in the morning and evening.Table 1: KYZATREX(R) Dosage Adjustment SchemeSerum Testosterone ConcentrationCurrent KYZATREX(R) DosageNew KYZATREX(R) DosageLess than 460 ng/dL100 mg with breakfast only100 mg twice daily with meals100 mg twice daily with meals200 mg twice daily with meals200 mg twice daily with meals300 mg twice daily with meals300 mg twice daily with meals400 mg twice daily with meals460 to 971 ng/dLNo Dosage ChangeMore than 971 ng/dL400 mg twice daily with meals300 mg twice daily with meals300 mg twice daily with meals200 mg twice daily with meals200 mg twice daily with meals100 mg twice daily with meals100 mg twice daily with meals100 mg with breakfast only100 mg with breakfast onlyDiscontinue treatment.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules:100 mg, oval, opaque, white, imprinted with MP100 in red ink150 mg, oblong, opaque, white, imprinted with MP150 in red ink200 mg, oblong, opaque, white, imprinted with MP200 in red ink. 100 mg, oval, opaque, white, imprinted with MP100 in red ink. 150 mg, oblong, opaque, white, imprinted with MP150 in red ink. 200 mg, oblong, opaque, white, imprinted with MP200 in red ink. Capsules: 100 mg, 150 mg, 200 mg 3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. -. 9.1 Controlled Substance. KYZATREX(R) contains testosterone undecanoate, Schedule III controlled substance. 9.2 Abuse. Drug abuse is intentional non-therapeutic use of drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids, and not obtained by prescription through pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.. Abuse-Related Adverse ReactionsSerious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility, and aggression.The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities. The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.Because these reactions are reported voluntarily from population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. 9.3 Dependence. Behaviors Associated with AddictionContinued abuse of testosterone and other anabolic steroids leading to addiction is characterized by the following behaviors:Taking greater dosages than prescribedContinued drug use despite medical and social problems due to drug useSpending significant time to obtain the drug when supplies of the drug are interruptedGiving higher priority to drug use than other obligationsHaving difficulty in discontinuing the drug despite desires and attempts to do soExperiencing withdrawal symptoms upon abrupt discontinuation of usePhysical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or significant dose reduction of drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months, which may include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism.Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.. Taking greater dosages than prescribed. Continued drug use despite medical and social problems due to drug use. Spending significant time to obtain the drug when supplies of the drug are interrupted. Giving higher priority to drug use than other obligations. Having difficulty in discontinuing the drug despite desires and attempts to do so. Experiencing withdrawal symptoms upon abrupt discontinuation of use.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. -. Insulin: In patients with diabetes, concomitant use with KYZATREX(R) may decrease blood glucose and insulin requirements 7.1). Oral Anticoagulants: Concomitant use with KYZATREX(R) may cause changes in anticoagulant activity. Monitor International Normalized Ratio (INR) and prothrombin time (PT) frequently 7.2). Corticosteroids: Concomitant use with KYZATREX(R) 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(R) may lead to additional increases in blood pressure 7.4). Insulin: In patients with diabetes, concomitant use with KYZATREX(R) may decrease blood glucose and insulin requirements 7.1). Oral Anticoagulants: Concomitant use with KYZATREX(R) may cause changes in anticoagulant activity. Monitor International Normalized Ratio (INR) and prothrombin time (PT) frequently 7.2). Corticosteroids: Concomitant use with KYZATREX(R) 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(R) may lead to additional increases in blood pressure 7.4). 7.1 Insulin. 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 decrease in the dose of anti-diabetic medication.. 7.2 Oral Vitamin 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(R) may lead to additional increases in blood pressure [see Warnings and Precautions (5.4)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. -. Infertility. MalesDuring treatment with large doses of exogenous androgens, including KYZATREX(R), spermatogenesis may be suppressed through feedback inhibition of the hypothalamicpituitary-testicular axis [see [See Warnings and Precautions (5.7) and Impairment of Fertility (13.1)] possibly leading to adverse effects on semen parameters including sperm count. Reduced fertility has been 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of KYZATREX(R) did not include any patients 65 years of age and older. Therefore, it cannot be determined whether these patients respond differently from younger adult patients. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potentially increased risk of cardiovascular disease and prostate cancer.Geriatric patients treated with androgens including KYZATREX(R) may be at risk for worsening of signs and symptoms of BPH [see (see Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. KYZATREX(R) capsules are available in three strengths of 100 mg, 150 mg, and 200 mg packaged as 60, 90 and 120 units in wide-mouth, round, white HDPE bottles with white, polypropylene, child resistant caps and induction-sealed liner 100 mg: Oval, opaque, white capsules imprinted with MP100 in red ink supplied in bottles; NDC 80603-101-11 for 90 capsules and NDC 80603-101-22 for 120 capsules.150 mg: Oblong, opaque, white capsules imprinted with MP150 in red ink supplied in bottles; NDC 80603-103-11 for 90 capsules and NDC 80603-103-22 for 120 capsules.200 mg: Oblong, opaque, white capsules imprinted with MP200 in red ink supplied in bottles; NDC 80603-105-33 for 60 capsules NDC 80603-105-11 for 90 capsules and NDC 80603-105-22 for 120 capsules .. Store at 20C to 25C (68F to 77F), with excursions permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store the capsules in dry place avoiding exposure to excessive moisture and humid conditions.Dispose of unused KYZATREX(R) via take-back option. If take-back option is unavailable, follow FDA instructions at www.fda.gov/drugdisposal.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. PolycythemiaAdvise patients that KYZATREX(R) can cause an increase in hemoglobin/hematocrit levels that may increase the risk of thromboembolic events. Advise patients about the importance of completing laboratory testing as instructed by their health care provider while on KYZATREX(R) [see Warnings and Precautions (5.1)] . Venous ThromboebolisnAdvise patients that KYZATREX(R) 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(R) and seek urgent medical care.. Worsening of Benign Prostatic Hyperplasia (BPH)Advise patients that KYZATREX(R) can cause increased symptoms of BPH. Advise patients to contact their health care provider if they have any prostate-related symptoms [see Warnings and Precautions (5.3)] . Blood Pressure IncreasesInform patients that KYZATREX(R) can increase blood pressure (BP) which can increase cardiovascular risk over time Instruct patients about the importance of monitoring BP periodically while on KYZATREX(R). If BP increases while on KYZATREX(R), antihypertensive medications may need to be started, added, or adjusted to control BP, or KYZATREX(R) may need to be discontinued [see Warnings and Precautions (5.4)] EdemaAdvise patients that KYZATREX(R) can cause edema in patients with preexisting cardiac, renal, or hepatic disease. Advise patients to notify their health care provider if edema develops or worsens [see Warnings and Precautions (5.9)]. Sleep ApneaAdvise patients that KYZATREX(R) can worsen sleep apnea especially in patients with risk factors such as obesity or chronic lung diseases (TM) [see Warnings and Precautions (5.10)]. GynecomastiaAdvise patients that KYZATREX(R) can cause gynecomastia [see Warnings and Precautions (5.11)]. Administration InstructionsAdvise patients to take KYZATREX(R) with food [see Dosage and Administration (2.3)].

LACTATION SECTION.

8.2 Lactation. -. Risk SummaryKYZATREX(R) is not indicated for use in females.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.Male hypogonadism, clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter syndrome or Leydig cell aplasia, whereas secondary hypogonadism (also known as hypogonadotropic hypogonadism) is the failure of the hypothalamus (or pituitary gland) to produce sufficient gonadotropins (FSH, LH).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. -. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. -. CarcinogenesisTestosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.. MutagenesisTestosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.. Impairment of FertilityThe administration of exogenous testosterone suppressed spermatogenesis and impaired fertility in the rat, dog, and non-human primate, which was reversible on cessation of treatment.A reproductive toxicology study was conducted in rats to evaluate functional effects of KYZATREX(R) on male fertility. In untreated female rats mated with males receiving times the maximum recommended human daily dose (MRHDD) of KYZATREX(R) (based on mean AUC exposure to testosterone), the number of impregnated females was reduced, fertility was significantly lower, and pre-implantation loss was significantly higher compared to the control group. There was no impairment of fertility in males receiving an equivalent dose of KYZATREX(R) to the MRHDD.. 13.2 Animal Toxicology and/or Pharmacology. 3-month repeat-dose oral toxicity study in male eugonadal dogs was conducted to evaluate whether phytosterol esters present in the KYZATREX(R) formulation influenced target organ toxicity due to their structural similarities to sex steroids like testosterone. KYZATREX(R) doses times the MRHDD (based on mean AUC exposure to testosterone) produced similar effects on androgen-responsive tissues as testosterone undecanoate without phytosterol esters. These included mild to marked effects on the testes (decreased size, germ cell depletion, Leydig cell atrophy), epididymides (aspermia), adrenal glands (vacuolation in the zona fasciculata) and prostate (increased size and glandular hypertrophy/hyperplasia). Following 4-week treatment-free period, findings in the testes, epididymides, and adrenal glands were not fully reversible at doses of times the MRHDD of KYZATREX(R) as compared to treatment with the excipients alone, including phytosterol esters. Reversibility was not assessed in testosterone undecanoate groups without phytosterol esters.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with cerebrovascular accident.Treatment of overdosage consists of discontinuation of KYZATREX(R) and appropriate symptomatic and supportive care.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

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PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of KYZATREX(R) in pediatric patients less than 18 years old have not been established. KYZATREX(R) is not recommended for use in patients less than 18 years of age because of the potential for acceleration of bone age and premature closure of epiphyses.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. There is insufficient data to characterize an exposure-response relationship or time course of pharmacodynamics.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. -. AbsorptionKYZATREX(R) was taken orally at starting dose of 200 mg twice per day with meals in multicenter, open-label trial in hypogonadal males. The dose was adjusted, as needed, on Days 28 and 56 from minimum dose of 100 mg (morning-only) to maximum dose of 400 mg twice per day based on the plasma testosterone concentration obtained by single blood draw collected to hours after the morning dose. The average daily NaF/EDTA plasma testosterone concentration was 393.3 (+-113.6) ng/dL after 90 days of treatment (normal eugonadal range in NaF/EDTA plasma: 222-800 ng/dL. Note that the titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)] KYZATREX(R) is expected to produce testosterone concentrations that approximate normal concentrations seen in healthy men.Table summarizes the pharmacokinetic (PK) parameters for plasma total testosterone in patients completing at least 90 days of KYZATREX(R) treatment administered daily.Table 5: NaF-EDTA Plasma Testosterone avg and max at Day 90 Visit PK ParameterPlasma (N=130)PK pharmacokinetic; avg 24-hour average concentration; max maximum concentration avg (ng/dL) n127Mean393.3SD113.6C max (ng/dL) n130Mean852.4SD311.3Figure summarizes the mean plasma total testosterone profile at the final PK visit.Figure 2: Mean (+-SEM) Concentration-Time Profile for NaF-EDTA Plasma Total Testosterone in KYZATREX(R)-Treated Patients at Day 90 VisitSEM standard error of the mean Testosterone normal ranges: plasma 222-800 ng/dL When KYZATREX(R) was given with breakfast containing 16%, 33%, and 45% fat, the exposure (AUC 0-24 hr) of testosterone was increased by 37%, 87%, and 94%, respectively, compared to when given under fasted conditions. The primary efficacy and safety study was conducted under fed conditions regardless of the type of meals and the primary efficacy endpoint of achieving testosterone avg in normal testosterone range was met. There was no effect on testosterone PK when KYZATREX(R) was administered with 20% alcohol along with high-fat meal versus high-fat meal alone.. Figure 2. DistributionCirculating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.. MetabolismThe androgenic activity of testosterone undecanoate occurs after the ester bond linking the testosterone to the undecanoic acid is cleaved by endogenous non-specific esterases.Undecanoic acid is metabolized like all fatty acids via the beta-oxidation pathway.Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are dihydrotestosterone (DHT) and estradiol.. ExcretionAbout 90% of dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. About 6% of dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of testosterone. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular Disorders: myocardial infarction, stroke Vascular Disorders: Venous thromboembolism.

PREGNANCY SECTION.

8.1 Pregnancy. -. Risk SummaryKYZATREX(R) 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 pregnant woman based on data from animal studies (see Data) and its mechanism of action [see Clinical Pharmacology (12.1) ]. Exposure of 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 DataIn 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.