Kyzatrex

1 INDICATIONS AND USAGE KYZATREX® is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (folliclestimulating hormone (FSH), luteinizing hormone (LH)) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low serum testosterone concentrations but have gonadotropins in the normal or low range. KYZATREX® is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone ( 1 ). Limitations of Use: Safety and efficacy of KYZATREX® in males less than 18 years old have not been established ( 1 , 8.4 ). Safety and efficacy of KYZATREX® in men with “age-related hypogonadism” have not been established (1) . Limitations of Use Safety and efficacy of KYZATREX® in males less than 18 years old have not been established [see Use in Specific Populations (8.4) ] . Safety and efficacy of KYZATREX® in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.

2 DOSAGE AND ADMINISTRATION - KYZATREX® is not substitutable with other oral testosterone undecanoate products ( 2.1 ). Prior to initiating KYZATREX®, 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® with food ( 2.3 ). Starting dosage: 200 mg orally once in the morning and once in the evening ( 2.3 ). Adjust the dosage to a minimum of 100 mg once in the morning and a maximum of 400 mg twice daily based on serum testosterone drawn 3 to 5 hours after the morning dose at least 7 days after starting treatment or following dose adjustment and periodically thereafter ( 2.3 ). 2.1 Important Dosage Information KYZATREX® is not substitutable with other oral testosterone undecanoate products. 2.2 Confirmation of Hypogonadism Before Initiation of KYZATREX® Prior to initiating KYZATRE®, 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® based on the patient's 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® with food. Dosage Adjustment Check serum testosterone concentrations 7 days after starting treatment or after dosage adjustment, 3 to 5 hours after the morning dose. Adjust the KYZATREX® 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® Dosage Adjustment Scheme Serum Testosterone Concentration Current KYZATREX® Dosage New KYZATREX® Dosage Less than 460 ng/dL 100 mg with breakfast only 100 mg twice daily with meals 100 mg twice daily with meals 200 mg twice daily with meals 200 mg twice daily with meals 300 mg twice daily with meals 300 mg twice daily with meals 400 mg twice daily with meals 460 to 971 ng/dL No Dosage Change More than 971 ng/dL 400 mg twice daily with meals 300 mg twice daily with meals 300 mg twice daily with meals 200 mg twice daily with meals 200 mg twice daily with meals 100 mg twice daily with meals 100 mg twice daily with meals 100 mg with breakfast only 100 mg with breakfast only Discontinue treatment

5 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 ). 5.1 Polycythemia 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®. 5.2 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®. 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)]. 5.4 Blood Pressure Increases KYZATREX® can increase blood pressure. Based on ambulatory blood mon…

4 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 )

7 DRUG 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 ). 7.1 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 a decrease in the dose of anti-diabetic medication. 7.2 Oral 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. 7.3 Corticosteroids 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)] .

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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Polycythemia [see Warnings and Precautions (5.1) ] Venous Thromboembolism [see Warnings and Precautions (5.2) ] Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer [ see Warnings and Precautions (5.3) ] Blood Pressure Increases [see Warnings and Precautions (5.4) ] Hepatic Adverse Effects [see Warnings and Precautions (5.8) ] Edema [see Warnings and Precautions (5.9) ] Sleep Apnea [see Warnings and Precautions (5.10) ] Gynecomastia [see Warnings and Precautions (5.11) ] Lipid Changes [see Warnings and Precautions (5.12) ] Hypercalcemia [see Warnings and Precautions (5.13) ] Decreased Thyroxine-binding Globulin [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence ≥ 2%): hypertension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Marius Pharmaceuticals at 1-833-949-5040 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of KYZATREX® was evaluated in Study MRS-TU-2019EXT in 155 hypogonadal males [see Clinical Studies (14) ]. All patients initially received KYZATREX® 200 mg orally twice daily. If needed, the dosage was titrated to 100 mg once daily in the morning or 100 mg, 300 mg, or 400 mg twice daily to achieve testosterone concentrations in the normal range . After the dosage titration period, patients continued their optimized dose for the remainder of the duration of the 6-month study. The mean duration of exposure was 168 days (range: 1 to 180 days). The median age was 52 years (range: 22 to 66 years); 77% were White, 19% were Black, 3% were Asian, and 2% were American Indian, Alaskan Native or Other. Table 2 summarizes adverse reactions reported in ≥2% of patients in this 6-month study. Table 2: Adverse Reactions in ≥ 2% of Patients Receiving KYZATREX® in STUDY MRS-TU-2019EXT Adverse Reaction N = 155 n (%) Hypertensión Based upon blood pressure cuff measurements 4 (2.6) One (0.8%) patient who received KYZATREX® experienced an adverse reaction (acne) that lead to premature discontinuation from the study. In a 12-month, open-label study in hypogonadal adult males (N=212) who received KYZATREX® 200 mg once daily to 400 mg twice daily (n=202) the following additional adverse reactions were reported: headache, arthralgia, diarrhea, hemoglobin increased, anxiety, constipation, peripheral edema, and PSA increased. Blood Pressure Increases In Study MRS-TU-2019EXT, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 155 male patients, 135 of whom completed the study. ABPM was conducted at 3 distinct 24-hour time periods: at baseline and following approximately 4 months and 6 months of treatment with KYZATREX®. A total of 151 patients had acceptable 24-hour ABPM recordings at both time periods. In that group, the mean change in systolic BP from Baseline to 4 months and 6 months was + 1.7 mm Hg (95% CI 0.3, 3.1) and 1.8 mm Hg (95% CI 0.3, 3.2), respectively. In that group, the mean change in diastolic BP from Baseline to 4 months and 6 months was 0.6 mm Hg (95% CI -0.3, 1.6) and 0.6 mm Hg (95% CI -0.4, 1.6), respectively. In patients with a history of hypertension on antihypertensive therapy at baseline, the mean ABPM systolic blood pressure increased from Baseline to 4 months and 6 months by 3.4 mm Hg (95% CI 1.0, 5.9) and 3.1 mm Hg (95% CI 0.6, 5.6), respectively (n=49). In patients with no history of hypertension at baseline, the mean systolic blood pressure from Baseline increased by 0.7 mm Hg (95% CI -1.0, 2.4) at 4 months and 1.0 mm Hg (95% CI -0.7, 2.8), at six months respectively (n =90). Ambulatory (24-hour) blood pressure Cha…