2.1 Confirmation of Hypogonadism Before Initiation of JATENZO

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.

2.2 Dosing and Dose Adjustment Information

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.

5.1 Increase in Blood Pressure

In a clinical trial, JATENZO increased systolic BP during 4 months of treatment by an average of 4.9 mmHg based on ambulatory blood pressure monitoring (ABPM) and by an average of 2.8 mmHg from baseline based on blood pressure cuff measurements [see Adverse Reactions (6.1)]. Average blood pressures had not plateaued at the end of the trial. Seven percent of JATENZO-treated patients were started on antihypertensive medications or required intensification of their antihypertensive medication regimen during the 4-month trial.

These BP increases can increase the risk of MACE, with greater risk in patients with established cardiovascular disease or risk factors for cardiovascular disease [see Boxed Warning].

In some patients, the increase in BP with JATENZO may be too small to detect, but can still increase the risk for MACE.

Before initiating JATENZO, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled. Check BP approximately 3 weeks after initiating JATENZO or increasing the dose and periodically thereafter. Treat new-onset hypertension or exacerbations of pre-existing hypertension. Re-evaluate whether the benefits of continued treatment with JATENZO outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease.

JATENZO is contraindicated in men with hypogonadal conditions such as “age-related hypogonadism,” because the efficacy of JATENZO has not been established for these conditions and the increases in BP can increase the risk of MACE [see Contraindications (4)].

5.2 Polycythemia

Increases in hematocrit reflective of increases in red blood cell mass, may require lowering the dose or discontinuation of JATENZO. Check that hematocrit is not elevated prior to initiating JATENZO. Evaluate hematocrit approximately every 3 months while the patient is on JATENZO. If hematocrit becomes elevated, stop JATENZO until the hematocrit decreases to an acceptable concentration. If JATENZO is restarted and again causes hematocrit to become elevated, stop JATENZO permanently. An increase in red blood cell mass may increase the risk of thromboembolic events [see Warnings and Precautions (5.5)].

5.3 Cardiovascular Risk

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of MACE, such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men.

JATENZO can cause BP increases that can increase the risk of MACE [see Boxed Warning and Warnings and Precautions (5.1)]. Patients should be informed of this possible risk when deciding whether to use or to continue to use JATENZO.

5.4 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer

Patients with BPH 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)].

5.5 Venous Thromboembolism

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone replacement products such as JATENZO. 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 treatment with JATENZO and initiate appropriate workup and management [see Adverse Reactions (6.2)].

5.6 Abuse of Testosterone and Monitoring of Testosterone Concentrations

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 Dose and Administration (2)]. However, testosterone levels may be 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. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

5.7 Not for Use in Women

Due to lack of controlled studies in women and potential virilizing effects, JATENZO is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.2)].

5.8 Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including JATENZO, 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)]. Patients should be informed of this possible risk when deciding whether to use or to continue to use JATENZO.

5.9 Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. JATENZO is not known to cause these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g. jaundice). If these occur, promptly discontinue JATENZO while the cause is evaluated.

5.10 Edema

Androgens, including JATENZO, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

5.11 Gynecomastia

Gynecomastia may develop and persist in patients being treated for hypogonadism.

5.12 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.

5.13 Lipids

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.

5.14 Hypercalcemia

Androgens, including JATENZO, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Monitor serum calcium concentrations regularly during treatment with JATENZO in these patients.

5.15 Decreased Thyroxine-binding Globulin

Androgens, including JATENZO, 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.

5.16 Risk of Depression and Suicide

Depression and suicidal ideation has been reported in patients treated with JATENZO in clinical trials. Advise patients and caregivers to seek medical attention for manifestations of new onset or worsening depression, suicidal ideation or behavior, anxiety, or other mood changes [see Adverse Events (6.1)].

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 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of testosterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular Disorders: myocardial infarction, stroke [see Warnings and Precautions (5.3)]

Vascular Disorders: Venous thromboembolism [see Warnings and Precautions (5.5)]

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, may 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 JATENZO may lead to additional increases in blood pressure [see Boxed Warning and Warnings and Precautions (5.1)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

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.

8.5 Geriatric Use

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 (5.4)].

9.1 Controlled Substance

JATENZO contains testosterone undecanoate, which is a Schedule III controlled substance as defined under the Controlled Substances Act.

9.2 Abuse

Drug abuse is intentional non-therapeutic use of a 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 (AAS), and not obtained by prescription through a 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.

9.3 Dependence

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, 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).

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted using JATENZO.

12.3 Pharmacokinetics

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 Cavg and Cmax at Final PK Visit

PK = pharmacokinetic; Cavg = 24-hour average concentration; Cmax = maximum concentration
PK Parameter		All Doses (N=151)
Cavg (ng/dL)	Mean	403
	SD	128
Cmax (ng/dL)	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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

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.

14.1 Clinical Trials in Hypogonadal Males

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 (Cavg) over 24-hours within the normal eugonadal range on the final PK visit of the study.

Secondary endpoints were the percentage of patients with a maximum total testosterone concentration (Cmax) above three predetermined limits: less than or equal to 1500 ng/dL, between 1800 and 2500 ng/dL, and greater than 2500 ng/dL.

One hundred and forty-five (87%) of the 166 hypogonadal men who received JATENZO had a mean total testosterone concentration (Cavg) within the normal eugonadal range at the end of treatment.

The percentage of patients who received JATENZO and had Cmax less than or equal to 1500 ng/dL, between 1800 and 2500 ng/dL, and greater than 2500 ng/dL at the final PK visit were 83%, 3%, and 3%, respectively. Note that the testosterone concentrations were not measured in serum but the effects of different sample preparation conditions were accounted for in data analysis of the results shown here. The titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)].

• Inform patients that JATENZO can increase BP that can increase the risk for MACE, including myocardial infarction, stroke, and cardiovascular death.
• Instruct patients about the importance of monitoring BP periodically while on JATENZO. If BP increases while on JATENZO, antihypertensive medications may need to be started, added, or adjusted to control BP, or JATENZO may need to be discontinued.

Other Adverse Reactions

Inform patients that treatment with androgens may lead to adverse reactions which include:

• Changes in urinary habits related to effects on prostate size, such as increased urination at night, hesitancy, frequency, urinary urgency, having a urine accident, being unable to pass urine and weak urine flow
• Breathing disturbances that may reflect obstructive sleep apnea, including those associated with sleep, or excessive daytime sleepiness
• Too frequent or persistent erections of the penis
• Ankle swelling that may reflect peripheral edema
• Red blood cell count increase
• PSA increase
• Nausea and vomiting

Instruct patients to report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood including new onset or worsening of depression, or suicidal ideation.

Keep JATENZO out of the reach of children.

Distributed by:
Tolmar, Inc. Fort Collins, CO 80526

Issued: 01/2023
708707 Rev. 1 01/23