2.1 Important Dosage Information

TLANDO is not substitutable with other oral testosterone undecanoate products.

2.2 Confirmation of Hypogonadism Before Initiation of TLANDO

Prior to initiating TLANDO, 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 serum testosterone concentrations are below the normal range.

2.3 Recommended Dosage

The recommended dosage of TLANDO is 225 mg (taken as two 112.5 mg capsules), orally twice daily, once in the morning and once in the evening. Take with food.

Monitoring for Continued Use or Discontinuation

Monitor serum testosterone (8 to 9 hours after the morning dose) 3 to 4 weeks after initiating TLANDO, and periodically thereafter. Based on serum testosterone measurements, determine if TLANDO should be continued or discontinued: 

• Serum testosterone 300 - 1080 ng/dL: continue TLANDO
• Serum testosterone < 300 ng/dL: discontinue TLANDO
• Serum testosterone > 1080 ng/dL:  discontinue TLANDO

5.1 Increase in Blood Pressure

In Study 18-001, TLANDO increased systolic BP after 4 months of treatment by an average of 4.3 mmHg based on ambulatory blood pressure monitoring (ABPM) and 4.8 mmHg from baseline based on blood pressure cuff measurements [see Adverse Reactions (6.1)].

These 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 TLANDO may be too small to detect but can still increase the risk for MACE.

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

5.2 Polycythemia

Increases in hematocrit levels, reflective of increases in red blood cell mass, may require discontinuation of TLANDO. Check hematocrit prior to initiating TLANDO. Evaluate hematocrit approximately every 3 months during the first year of treatment, and then every 6 months thereafter while the patient is taking TLANDO. If hematocrit becomes elevated, stop TLANDO until hematocrit decreases to an acceptable concentration. If TLANDO is restarted and again causes hematocrit to become elevated, stop TLANDO 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 major adverse cardiovascular events (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.

TLANDO 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 TLANDO.

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, including measurement of prostate specific antigen (PSA), 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 TLANDO. 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 TLANDO and initiate appropriate workup and management [see Adverse Reactions (6.2)].

5.6 Abuse of Testosterone and Monitoring of Serum 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 serum testosterone concentrations to ensure they are within therapeutic range. 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 the potential for virilizing effects, TLANDO is not indicated for use in women [see Use in Specific Populations (8.1, 8.2)].

5.8 Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including TLANDO, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (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 TLANDO.

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. TLANDO is not a 17 alpha-alkyl androgen and is not known to produce hepatic adverse effects associated with 17-alpha-alkyl androgens.
Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue TLANDO while the cause is evaluated.

5.10 Edema

Androgens, including TLANDO, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse Reactions (6.1)]. In addition to discontinuation of the drug, appropriate work up and management of edema may be required.

5.11 Sleep Apnea

The treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.

5.12 Gynecomastia

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

5.13 Lipid Changes

Changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of testosterone therapy. Monitor the lipid profile periodically after starting testosterone therapy.

5.14 Hypercalcemia

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

5.15 Decreased Thyroxine-binding Globulin

Androgens, including TLANDO, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total T4 serum concentrations and increased resin uptake of triiodothyronine (T3) and thyroxine (T4). Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

5.16 Increases in Prolactin

Increases in serum prolactin have been reported in patients treated with TLANDO in clinical trials. Evaluate serum prolactin levels prior to initiating treatment with TLANDO. Re-evaluate serum prolactin levels 3 to 4 months after starting treatment. If serum prolactin remains elevated, discontinue TLANDO [see Adverse Reactions (6.1)].

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Increase in Blood Pressure [see Warnings and Precautions (5.1)]
• Polycythemia [see Warnings and Precautions (5.2)]
• Cardiovascular Risk [see Warnings and Precautions (5.3)]
• Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer [see Warnings and Precautions ((5.4)]
• Venous Thromboembolism [see Warnings and Precautions (5.5)]
• Hepatic Adverse Effects [see Warnings and Precautions (5.9)]
• Edema [see Warnings and Precautions (5.10)]
• Sleep Apnea [see Warnings and Precautions (5.11)]
• Gynecomastia [see Warnings and Precautions (5.12)]
• Lipid Changes [see Warnings and Precautions (5.13)]
• Hypercalcemia [see Warnings and Precautions (5.14)]
• Decreased Thyroxine-binding Globulin [see Warnings and Precautions (5.15)]
• Increases in Prolactin [see Warnings and Precautions (5.16)]

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 TLANDO 225 mg twice daily, without dose titration, was evaluated in 233 hypogonadal males during two clinical studies: Study LPCN 1021-18-001 (18-001) and Study LPCN 1021-16-002 (16-002) [see Clinical Studies (14)].

In Study 18-001, an uncontrolled ambulatory blood pressure monitoring (ABPM) study, 138 hypogonadal males were treated with TLANDO 225 mg twice daily with morning and evening meals for approximately four months. Patients had a median age of 54 years (range 26-75), 79% were White, 18% were Black, and 2% were Asian. In 138 hypogonadal male patients, 70% (n=96) were obese (BMI≥30 kg/m2), 24% (n=33) reported a history of type 2 diabetes, and 48% (n=66) reported a history of hypertension. 

Table 1 summarizes adverse reactions (>2%) reported in patients receiving TLANDO in Study 18-001.

Four of the 138 patients (2.9%) in Study 18-001 reported adverse reactions that led to premature discontinuation from the study, including dizziness (n=1), weight increased (n=1), insomnia (n=1), and hypertension (n=2).

In Study 16-002, 95 hypogonadal males were treated with TLANDO 225 mg twice daily with morning and evening meals for approximately 24 days. The dose of TLANDO was not titrated. Patients had a median age of 56 years (range 29-74), 81% were White, 16% were Black, 2% were mixed race, and 1% were Asian; 26% were Hispanic. In 95 hypogonadal male patients, 70% (n=66) were obese (BMI≥30 kg/m2), 23% (n=22) reported a history of type 2 diabetes, and 50% (n=47) reported a history of hypertension. 

Table 2 summarized adverse reactions (>2%) reported during Study 16-002 in patients receiving TLANDO.

One of the 95 patients (1.1%) in the 24-day study reported an adverse reaction (gastric ulcer hemorrhage) that led to premature discontinuation from the study.

Blood Pressure Increases

In Study 18-001 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 138 male patients, 126 of whom completed the study. ABPM was conducted at 2 distinct 24-hour time periods: at baseline and following approximately 16 weeks of treatment with TLANDO. A total of 123 patients had acceptable 24-hour ABPM recordings at both time periods. In that group, the mean change in systolic BP from Baseline to End of Study was + 4.3 mmHg (95% CI 2.1, 6.5) and the mean change in diastolic BP was 1.4 mmHg (95% CI 0.5, 2.3).  

The ABPM systolic and diastolic blood pressure increased in patients with a history of hypertension at baseline [4.8 mmHg (95% CI 1.0, 8.5) and 1.6 mmHg (95% CI 0.1, 3.0), respectively (n=60)]. In patients with no history of hypertension at baseline systolic and diastolic blood pressure increased [3.9 mmHg (95% CI 0.9, 6.8) and 1.2 mmHg (95% CI -0.1, 2.5), respectively (n =63)].

Increases in Hematocrit

Increases in hematocrit were reported in 6 of the 138 patients (4.3%) in Study 18-001. None of these increases led to premature discontinuation of TLANDO.

Increases in Prolactin

Increases in serum prolactin were reported in 6 (6.3%) of the 95 patients in the 24-day clinical study. The mean increase from baseline in serum prolactin was 7.0 ng/mL (n=93). The 4-month clinical study did not assess serum prolactin concentrations after the screening visit.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of testosterone replacement products. 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, insulin requirements.

7.2 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens. Frequent monitoring of INR and prothrombin time may be necessary in patients taking anticoagulants, 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 should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.

7.4 Drugs that May Also Increase Blood Pressure

Some prescription drugs and nonprescription analgesic and cold medications can increase blood pressure. Concomitant administration of these medications with TLANDO 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 effectiveness of TLANDO 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 in controlled clinical studies with TLANDO to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. Of the 95 patients enrolled in Study 16-002, the 24-day major safety and effectiveness study utilizing TLANDO, 16 (16.8%) were over 65 years of age.  Additionally, there is insufficient long-term safety data in geriatric patients utilizing TLANDO 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 and hypertension [see Warnings and Precautions (5.1)] and 5.4].

9.1 Controlled Substance

TLANDO 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 (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's Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The efficacy and safety of TLANDO was evaluated in Study 16-002 a multicenter, open-label, single-arm study in adult hypogonadal male patients (NCT03242590).  Patients received TLANDO 225 mg, orally twice daily with food for approximately 24 days; no titration was performed to adjust the dosage.

A total of 95 hypogonadal men received a dose of TLANDO and were included in the efficacy evaluation. Patients had a median age of 56 years (range 29-74 years), 81% were White, 16% were Black, 2% were mixed race, and 1% were Asian; 26% were Hispanic. 

The primary endpoint was the percentage of patients who achieved a 24-hour average serum testosterone concentration (Cavg0-24h) within the normal range of 300-1080 ng/dL on the final visit of the study. 

Table 3 shows the proportion of subjects, Study 16-002, with an average serum total testosterone concentration in the normal range (300-1080 ng/dL).

Secondary endpoints were the percentage of patients with maximum total testosterone concentration (Cmax) meeting three predetermined limits: less than or equal to 1.5 times the upper limit of the normal range (ULN) (1620 ng/dL), between 1.8 and 2.5 times ULN (1944 - 2700 ng/dL), and greater than 2.5 times ULN (2700 ng/dL).

The percentage of patients who received TLANDO and had T Cmax threshold less than or equal to 1620 ng/dL, between 1944 ng/dL and 2700 ng/dL, and greater than 2700 ng/dL at the PK visit were 82%, 5%, and 0%, respectively.   

Increase in Blood Pressure and Cardiovascular Risk
Advise patients that TLANDO 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. Advise patients about the importance of monitoring BP periodically while on TLANDO. Advise patients to report to their healthcare provider the use of concomitant prescription or nonprescription medication, including cough and cold medications which can also increase BP [see Warnings and Precautions (5.1 and 5.3)].

Polycythemia

Advise patients that TLANDO can cause an increase in 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 TLANDO. [see Warnings and Precautions (5.2)].

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

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

Sleep Apnea

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

Administration Instructions

• Advise patients to take TLANDO with food [see Dosage and Administration (2.3)].

Manufactured for:

Manufactured for Antares

Pharma, Inc.

Ewing, NJ 08628

Manufactured in the United Kingdom

LB-0190 V02