Limitations of Use

Safety and efficacy of Testosterone Undecanoate Capsules in males less than 18 years old have not been established [see Use in Specific Populations (8.4)].

2.1 Important Dosage Information

Testosterone Undecanoate Capsules is not substitutable with other oral testosterone undecanoate products.

2.2 Confirmation of Hypogonadism Before Initiation of Testosterone Undecanoate Capsules

Prior to initiating Testosterone Undecanoate Capsules, 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 Testosterone Undecanoate Capsules 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 Testosterone Undecanoate Capsules with food.

5.1 Increase in Blood Pressure

In Study MRS-TU-2019EXT, Testosterone Undecanoate Capsules increased 24-hour average systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) by 1.7 mmHg from baseline after 4 months of treatment and 1.8 mmHg from baseline after 6 months of treatment [see Adverse Reactions (6.1)] . Three percent of Testosterone Undecanoate Capsules treated patients were started on antihypertensive medications during the 6-month trial.

A history of antihypertensive treatment and diabetes mellitus at baseline were significant factors related to ambulatory SBP increases [see Adverse Reactions (6.1)].

Blood pressure (BP) increases can increase the risk of major adverse cardiovascular events (MACE), with greater risk in patients with established cardiovascular disease or risk factors for cardiovascular disease. In some patients, the increase in BP with Testosterone Undecanoate Capsules may be too small to detect but can still increase the risk for MACE.

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

5.2 Polycythemia

Androgens, including Testosterone Undecanoate Capsules, can cause increase in hemoglobin or hematocrit, reflective of increase in red blood cell mass. Check hematocrit prior to initiating Testosterone Undecanoate Capsules. An increase in red blood cell mass may increase the risk of thromboembolic events [see Warnings and Precautions (5.5)]. Evaluate hematocrit approximately every 3 months while the patient is on Testosterone Undecanoate Capsules. If hematocrit becomes elevated, stop Testosterone Undecanoate Capsules until the hematocrit decreases to an acceptable concentration. If Testosterone Undecanoate Capsules is restarted and again causes hematocrit to become elevated, permanently discontinue Testosterone Undecanoate Capsules.

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 testosterone use compared to non-use. Some studies have reported an increased risk of MACE in association with use of testosterone replacement therapy in men.

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

5.4 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)].

5.5 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 Testosterone Undecanoate Capsules. 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 Testosterone Undecanoate Capsules 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 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.

5.7 Not for Use in Women

Due to lack of controlled studies in women and potential virilizing effects,Testosterone Undecanoate Capsules 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 Testosterone Undecanoate Capsules, 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 Testosterone Undecanoate Capsules.

5.9 Hepatic Adverse Effects

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

5.10 Edema

Androgens, including Testosterone Undecanoate, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease [see Adverse Reactions (6.1)]. In addition to discontinuation of the drug, diuretic therapy may be required.

5.11 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.

5.12 Gynecomastia

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

5.13 Lipid Changes

In clinical trials, patients receiving Testosterone Undecanoate Capsules 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.

5.14 Hypercalcemia

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

5.15 Decreased Thyroxine-binding Globulin

Androgens, including Testosterone Undecanoate, 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.

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 Testosterone Undecanoate Capsules was evaluated in Study MRS-TU-2019EXT in 155 hypogonadal males [see Clinical Studies (14)]. All patients initially received Testosterone Undecanoate Capsules 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.

One (0.8%) patient who received of Testosterone Undecanoate Capsules 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 of Testosterone Undecanoate Capsules 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.

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
Vascular Disorders: Venous thromboembolism

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 Testosterone Undecanoate Capsules may lead to additional increases in blood pressure [see 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 Testosterone Undecanoate Capsules in pediatric patients less than 18 years old have not been established. Testosterone Undecanoate Capsules 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 Testosterone Undecanoate Capsules 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 Testosterone Undecanoate Capsules may be at risk for worsening of signs and symptoms of BPH [see Warnings and Precautions (5.4)].

9.1 Controlled Substance

Testosterone Undecanoate Capsules contains testosterone undecanoate, a Schedule III controlled substance

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, 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 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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

A 3-month repeat-dose oral toxicity study in male eugonadal dogs was conducted to evaluate whether phytosterol esters present in the Testosterone Undecanoate Capsules formulation influenced target organ toxicity due to their structural similarities to sex steroids like testosterone. Testosterone Undecanoate Capsules doses 2 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 a 4-week treatment-free period, findings in the testes, epididymides, and adrenal glands were not fully reversible at doses of 2 times the MRHDD of Testosterone Undecanoate Capsules as compared to treatment with the excipients alone, including phytosterol esters. Reversibility was not assessed in testosterone undecanoate groups without phytosterol esters.

Store at 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store the capsules in a dry place avoiding exposure to excessive moisture and humid conditions.

Dispose of unused Testosterone Undecanoate Capsules via a take-back option. If a take-back option is unavailable, follow FDA instructions at www.fda.gov/drugdisposal.

Increase in Blood Pressure and Cardiovascular Risk

• Inform patients that Testosterone Undecanoate Capsules can increase blood pressure (BP) which can result in an increase in the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. This risk is greater in patients with established cardiovascular disease or risk factors for cardiovascular disease [see Warnings and Precautions (5.1)].
• Instruct patients about the importance of monitoring BP periodically while on Testosterone Undecanoate Capsules. Instruct patients to report to their healthcare provider the use of concomitant prescription or nonprescription medication, including cough and cold medication which can also increase BP [see Warnings and Precautions (5.3)].

Polycythemia

Advise patients that Testosterone Undecanoate Capsules 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 Testosterone Undecanoate Capsules [see Warnings and Precautions (5.2)].

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

Advise patients that Testosterone Undecanoate Capsules can cause increased symptoms of BPH and can increase the risk for prostate cancer. Advise patients to contact their health care provider if they have any prostate-related symptoms [see Warnings and Precautions (5.4)].

Edema

Advise patients that Testosterone Undecanoate Capsules can cause edema in patients with preexisting cardiac, renal, or hepatic disease. Advice patients to notify their health care provider if edema develops or worsens [see Warnings and Precautions (5.10)].

Sleep Apnea

Advise patients that Testosterone Undecanoate Capsules can worsen sleep apnea especially in patients with risk factors such as obesity or chronic lung diseases [see Warnings and Precautions (5.11)].

Gynecomastia

Advise patients that Testosterone Undecanoate Capsules can cause gynecomastia [see Warnings and Precautions (5.12)].

Administration Instructions

Advise patients to take Testosterone Undecanoate Capsules with food [see Dosage and Administration (2.3)].