JATENZO- testosterone undecanoate_capsule, liquid filled

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, a 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) to produce sufficient gonadotropins (FSH, LH). No specific pharmacodynamic studies were conducted using JATENZO. Absorption JATENZO delivers physiologic amounts of testosterone, producing testosterone concentrations that approximate normal concentrations seen in healthy men. JATENZO was taken orally at a starting dose of 237 mg twice per day with meals in a multicenter, open-label, randomized, 2-arm, active-controlled trial in hypogonadal males. The dose was adjusted, as needed, on Days 14 and 56 between a minimum of 158 mg twice per day and a maximum of 396 mg twice per day based on the average plasma testosterone concentration obtained over 24 hours after the morning dose. The average daily NaF-EDTA plasma testosterone concentration was 403 (+/- 128) ng/dL at the end of treatment, where the normal eugonadal range in NaF-EDTA plasma was 252-907 ng/dL in this study. Note that the titration scheme for use in clinical practice is based on serum total testosterone [ see Dosage and Administration ( 2. 2 Table 3 summarizes the pharmacokinetic (PK) parameters for plasma total testosterone in patients completing at least 105 days of JATENZO treatment administered twice daily. Table 3: NaF-EDTA Plasma Testosterone C avg max PK = pharmacokinetic; C avg max PK Parameter All Doses (N=151) C avg Mean 403 SD 128 C max Mean 1008 SD 581 Figure 2 summarizes the mean plasma total testosterone profile for the patients at the final PK visit. Figure 2: Mean (+/-SEM) Concentration-Time Profile for NaF-EDTA Plasma Total Testosterone in JATENZO Treated Subjects at Final PK Visit SEM = standard error of the mean; T = testosterone When JATENZO was dosed with different breakfasts containing various amounts of fat, the bioavailability with the 30 g fat, 45 g fat, and high-calorie high-fat breakfasts was comparable, but there was a food effect with the 15 g fat breakfast compared to the 30 g fat breakfast. The 15 g fat breakfast had a 25% decrease in testosterone exposure compared to the 30 g fat breakfast. Figure 2 Distribution Circulating 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. Metabolism The 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. Excretion About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

JATENZO (testosterone undecanoate) is an androgen 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 (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from causes such as tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use: Safety and efficacy of JATENZO in men with “age-related hypogonadism” have not been established. Safety and efficacy of JATENZO in males less than 18 years old have not been established [ see Use in Specific Populations ( 8. 4 JATENZO (testosterone undecanoate) 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 JATENZO in men with “age-related hypogonadism” have not been established ( 1 Safety and efficacy of JATENZO in males less than 18 years old have not been established ( 1 8.

Prior to initiating JATENZO, 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. 1 Take JATENZO with food ( 2. 2 Starting dose: 237 mg orally once in the morning and once in the evening. Adjust the dose to a minimum of 158 mg twice daily and a maximum of 396 mg twice daily based on serum testosterone drawn 6 hours after the morning dose at least 7 days after starting treatment or following dose adjustment and periodically thereafter ( 2. 2 Prior to initiating JATENZO, 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. Individualize the dosage of JATENZO based on the patient's serum testosterone concentration response to the drug. The recommended starting dose is 237 mg taken orally twice daily, once in the morning and once in the evening. Take JATENZO with food. Dose Adjustment To ensure proper dose adjustment, measure serum testosterone concentrations 6 hours after the morning dose in plain tubes, clotted at room temperature for 30 minutes prior to centrifugation. Adjust the JATENZO dose based on this serum testosterone measurement as shown in Table 1. Wait seven days after starting treatment or adjusting the dose before checking the serum testosterone concentration. Thereafter, periodically monitor serum testosterone concentrations 6 hours after the morning dose. Administer the same dose in the morning and evening. The minimum recommended dose is 158 mg twice daily. The maximum recommended dose is 396 mg (two 198 mg capsules) twice daily. Table 1: JATENZO Dose Adjustment Scheme Testosterone Concentration in Serum From Plain Tube Drawn 6 hours After Morning Dose Current JATENZO Dose New JATENZO Dose Less than 425 ng/dL 158 198 198 237 237 316 (two 158 mg capsules) 316 (two 158 mg capsules) 396 (two 198 mg capsules) 425 ng/dL en dash 970 ng/dL No Dose Change More than 970 ng/dL 396 (two 198 mg capsules) 316 (two 158 mg capsules) 316 (two 158 mg capsules) 237 237 198 198 158 158 Discontinue Treatment.

Most common adverse reactions (incidence > 2%): polycythemia, diarrhea, dyspepsia, eructation, peripheral edema, nausea, increased hematocrit, headache, prostatomegaly, and hypertension ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Tolmar, Inc. at 1-844-4TO-LMAR or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 JATENZO was evaluated in a randomized, controlled clinical study with 166 patients treated with JATENZO twice daily with morning and evening meals for approximately 4 months. All patients were started on 237 mg twice daily, then the dose was titrated to 158 mg, 198 mg, 316 mg, or 396 mg twice daily to achieve testosterone concentrations in the eugonadal range. Table 2 summarizes adverse reactions (>=2%) reported in this 4-month study. Table 2: Number (%) of Patients with Adverse Reactions >= 2% in a 4-Month Study with JATENZO Among the 569 patients who received JATENZO in all Phase 2 and 3 trials combined, the following adverse reactions were reported in >2% of patients: polycythemia, diarrhea, dyspepsia, eructation, peripheral edema, nausea, increased hematocrit, headache, prostatomegaly, and hypertension. Three of the 166 patients (1. 8%) in the 4-month study experienced adverse reactions that led to premature discontinuation from the study, including rash (n=1) and headache (n=2). Preferred Term Overall (N = 166) n (%) Headache 8 (4. 8) Hematocrit increased 8 (4. 8) Hypertension 6 (3. 6) High-density lipoprotein decreased 5 (3. 0) Nausea 4 (2. 4) BP Increases In the 4-month clinical study, 24-hour ABPM was conducted on 166 patients. ABPM was conducted at baseline and at Day 139 of JATENZO therapy. A total of 135 patients had acceptable ABPM recordings at both time periods and were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic BP and diastolic BP from baseline to final on-treatment visit on Day 139 (n=135) was +4. 9 mmHg (95% CI 3. 5 mmHg (95% CI 1. 6), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 5. 4 mmHg [95% CI 3. 2 mmHg [95% CI 1. 7], respectively [n=67]. In patients with no history of hypertension, the mean ABPM systolic and diastolic blood pressure increased by 4. 4 mmHg [95% CI 2. 8 mmHg [95% CI 0. 3], respectively [n=63]. 2%) patients on JATENZO either started antihypertensive medications or had their antihypertensive regimen increased during the study. A total of 6 patients were reported to have an adverse reaction of hypertension (2 patients with hypertension and 4 patients with worsening hypertension), and 3 were reported to have an adverse reaction of increased blood pressure. HR Increases JATENZO increased mean heart rate by an average of 2. 2 beats per minute (bpm) [95% CI (1. 3), N=135] during the study. Patients without a history of hypertension had a greater average increase in mean heart rate (2. 7 bpm [95% CI (0. 6), N=63]) compared to patients with treated hypertension (1. 9 bpm [95% CI (0. 5), N=67)]). Increases in Hematocrit Increases in hematocrit were reported in 8 of the 166 (4. 8%) patients, which occurred in the second half of the study. None of these increases led to premature discontinuation of JATENZO. Headaches Headaches were reported in 8 of the 166 patients (4. 8%) of which three required treatment with analgesics or non-steroidal anti-inflammatory drugs and 2 led to premature discontinuation from the study. Five of these 8 patients had headache events that resolved within 1 to 2 days. Depression and suicidal ideation Two of the 166 patients (1. 2%) reported either worsening depression (n=1) or new-onset depression (n=1). One of the 569 patients (0. 2%) in clinical trials had suicidal ideation. Each patient completed the study. Increases in Serum PSA The mean increase from baseline in PSA was 0. 2 ng/mL (n=161). Increases in serum PSA concentrations, defined as an increase from baseline of at least 1. 4 ng/mL or PSA greater than 4 ng/mL, occurred in 3 (1. 9%) of the patients at the final visit. Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy. The mean patient age (+/-SD) was 63. 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. Approximately 55% had preexisting cardiovascular disease. The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220. 4 ng/dL (n=2129). 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. Additional Adverse Reactions Reported in TRAVERSE Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in topical testosterone gel versus placebo included: nonfatal arrythmias warranting intervention (5. 3%), atrial fibrillation (3. 4%), acute kidney injury (2. 5%) and bone fracture (3. For the adverse reaction of bone fracture, each event was adjudicated by clinical review. The following adverse reactions have been identified during post-approval use of testosterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Disorders see Warnings and Precautions ( 5. 4 Clinical Trial Experience ( 6. 1 Vascular Disorders see Warnings and Precautions ( 5.

JATENZO is contraindicated in: Men with carcinoma of the breast or known or suspected carcinoma of the prostate [ see Warnings and Precautions ( 5. 3 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 Men with known hypersensitivity to JATENZO or any of its ingredients [ see Description ( 11 Men with breast cancer or known or suspected prostate cancer ( 4 5. Testosterone may cause fetal harm ( 4 5. 2 Known hypersensitivity to JATENZO or any of its ingredients ( 4.

Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer ( 8. 5 Risk Summary JATENZO is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm based on data from animal studies and its mechanism of action [see Contraindications ( 4 12. 1 Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection 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. Risk Summary JATENZO is not indicated for use in women. Infertility During treatment with large doses of exogenous androgens, including JATENZO, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions ( 5. 7 [see Drug Abuse and Dependence ( 9. 2 The safety and efficacy of JATENZO in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses. There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing JATENZO to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. No patients over 65 years of age were enrolled in the 4-month efficacy and safety clinical study utilizing JATENZO. Additionally, there is insufficient long-term safety data in geriatric patients utilizing JATENZO to assess the potentially increased risk of cardiovascular disease and prostate cancer. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH [see Warnings and Precautions ( 5.

RECENT MAJOR CHANGES
Boxed Warning, Increases in Blood Pressure Removed 03/2025 Indications and Usage (1) 03/2025 Contraindications, Men with “age related hypogonadism” (4) Removed 03/2025 Warnings and Precautions , Venous Thromboembolism (5. 2) 03/2025 Warnings and Precautions, Blood Pressure Increases (5. 4) 03/2025 Warnings and Precautions, Cardiovascular Risk (5. 3) Removed 03/2025 Boxed Warning, Increases in Blood Pressure Removed 03/2025 Indications and Usage ( 1 Contraindications, Men with “age related hypogonadism” ( 4 Warnings and Precautions, Venous Thromboembolism ( 5. 2 Warnings and Precautions, Blood Pressure Increases ( 5. 4 Warnings and Precautions, Cardiovascular Risk ( 5.
DRUG INTERACTIONS
Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients ( 7. 1 Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended in patients taking warfarin ( 7. 2 Use of testosterone with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7. 3 Concomitant administration of medications that are known to increase blood pressure may lead to additional increases in blood pressure when used with JATENZO ( 7. 4 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, may necessitate a decrease in the dose of anti-diabetic medication. 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. 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. Some prescription medications and nonprescription analgesic and cold medications contain drugs known to increase blood pressure. Concomitant administration of these medications with JATENZO may lead to additional increases in blood pressure [see Warnings and Precautions ( 5.

OVERDOSAGE
There is a single report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone concentrations of up to 11,400 ng/dL which were implicated in a cerebrovascular accident. One case of overdose with JATENZO was reported in clinical trials. This patient inadvertently took a higher dose than prescribed (474 mg twice daily, which is 20% higher than the maximum recommended dose). He did not report any adverse reactions associated with the overdose. Treatment of overdosage consists of discontinuation of JATENZO and appropriate symptomatic and supportive care.
NONCLINICAL TOXICOLOGY
Carcinogenesis Testosterone 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. Mutagenesis Testosterone was negative in the in vitro in vivo Impairment of Fertility The administration of exogenous testosterone suppresses spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment. JATENZO has been evaluated in 3- and 9-month repeat-dose oral toxicity studies in male eugonadal dogs. JATENZO caused exaggerated pharmacological effects on androgen-responsive tissues including testes, epididymis, prostate and adrenals at exposures to testosterone or testosterone undecanoate, comparable to the maximum human exposure based on AUC comparisons. Following a 4-week drug-free period, a reduced severity of these findings was observed, suggesting partial reversibility. In adrenal glands, moderate to severe atrophy, characterized as thinning of the zona fasciculata, was observed with reduced adrenal weights and reduced circulating levels of cortisol in testosterone undecanoate-treated dogs after 3 months of treatment. Following 9-month treatment, there were dose-related decreases in adrenal weights in testosterone undecanoate-treated male dogs and moderate adrenal vacuolation in one testosterone undecanoate-treated male dog. The clinical significance of these adrenal and cortisol findings is unknown.
CLINICAL STUDIES
The efficacy and safety of JATENZO was evaluated in 166 adult hypogonadal males in an open-label study of approximately 4 months duration (NCT02722278). The study included a Screening Phase, a Treatment Titration Phase, and a Treatment Maintenance Phase. JATENZO was taken orally at a starting dose of 237 mg twice per day with meals. The dose was adjusted on Days 21 and 56 between a minimum of 158 mg twice per day and a maximum of 396 mg twice per day on the basis of the average testosterone concentration obtained over 24 hours post-morning dose. The primary endpoint was the percentage of patients with mean plasma total testosterone concentration (C avg Secondary endpoints were the percentage of patients with a maximum total testosterone concentration (C max One hundred and forty-five (87%) of the 166 hypogonadal men who received JATENZO had a mean total testosterone concentration (C avg The percentage of patients who received JATENZO and had C max [see Dosage and Administration ( 2.

TOLMAR Inc.

JATENZO- testosterone undecanoate_capsule, liquid filled Product manual source documgent