These Highlights Do Not Include All The Information Needed To Use Tlando®

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)]
• Increases in Prolactin [see Warnings and Precautions (5.15)]

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.

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.

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.

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident.

Treatment of overdosage consists of discontinuation of TLANDO and appropriate symptomatic and supportive care.

TLANDO (testosterone undecanoate) capsules contain 112.5 mg testosterone undecanoate, an ester of testosterone, for oral administration. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.

The chemical name of testosterone undecanoate is 17β-undecanoyloxy-4-androsten-3-one. It has an empirical formula of C₃₀H₄₈O₃ and a molecular weight of 456.7. The structural formula is:

Testosterone undecanoate is a white to off-white crystalline substance.

The inactive ingredients in TLANDO capsules are ascorbyl palmitate, glyceryl monolinoleate, polyethylene glycol 8000, and polyoxyl 40 hydrogenated castor oil. The capsule shell contains black iron oxide, gelatin, and titanium dioxide. The capsule is imprinted with black ink that contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

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 (5.2) ].

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.

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.

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 (5.3 and 5.4)].

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

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.

TLANDO is contraindicated in:

• Patients 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)].
• Known hypersensitivity to testosterone undecanoate or any of TLANDO’s ingredients [see Description ( 11)].

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.

Most common adverse reactions (incidence ≥ 2%): increased blood prolactin, hypertension, increased hematocrit, upper respiratory tract infection, weight increased, headache, and musculoskeletal pain (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Verity Pharma at 1-844-837-4891 or FDA at 1-800-FDA-1088 or  www.fda.gov/medwatch.

• Insulin: In patients with diabetes, concomitant use with TLANDO may decrease blood glucose and insulin requirements (7.1).
• Oral Anticoagulants: Concomitant use with TLANDO may cause changes in anticoagulant activity. Monitor International Normalized Ratio and prothrombin time frequently (7.2).
• Corticosteroids: Concomitant use with TLANDO 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 TLANDO may lead to additional increases in blood pressure (7.4).

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.

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

TLANDO 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's 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 [see Dosage and Administration (2.2 )].
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range [see Dosage and Administration (2.2 )].

Limitations of Use

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

• Safety and efficacy of TLANDO in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established [see Use in Specific Populations (8.5)].

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

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).

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) ].

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.

TLANDO contains testosterone undecanoate, a schedule III controlled substance.

• Polycythemia: Monitor hematocrit approximately every 3 months during the first year after beginning TLANDO and then every 6 months thereafter during treatment. Discontinue TLANDO if necessary (5.1).

• Venous thromboembolism (VTE): VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Discontinue TLANDO 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 with benign prostatic hyperplasia (BPH) 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: TLANDO 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: TLANDO may cause azoospermia (5.7, 8.3).

• Edema: Edema, with or without congestive heart failure (CHF) may occur in patients with preexisting cardiac, renal, or hepatic disease. Discontinue TLANDO and initiate appropriate workup (5.9).

• Sleep Apnea: TLANDO may potentiate sleep apnea  in those with risk factors (5.10).

• Lipid Changes: Testosterone may affect serum lipid profile.  Monitor patient lipid concentrations; if necessary, adjust dosage of lipid lowering drug(s) or discontinue TLANDO (5.12).

• Increases in Prolactin: Monitor serum prolactin levels prior to initiation of TLANDO and 3 to 4 months after starting TLANDO.  Discontinue TLANDO if serum prolactin levels remain elevated (5.15).

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.

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 TLANDO and initiate appropriate workup and management [see Adverse Reactions (6.2)].

• 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 (2.2).
• Recommended dosage is 225 mg orally twice daily with food (2.3).
• Monitor serum testosterone after initiating TLANDO to determine if TLANDO should be continued or discontinued (2.3).

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.

Capsules: 112.5 mg, white opaque body imprinted with “112” in black ink and grey opaque cap, banded with a colorless gelatin band.

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) ].

TLANDO can increase blood pressure. Based on ambulatory blood pressure monitoring in Study 18-001, TLANDO increased mean systolic/diastolic BP by 4.3/1.4 mmHg from baseline after 4 months of treatment.In patients with hypertension on antihypertensive therapy, TLANDO increased the mean systolic/diastolic BP by 4.8/1.6 mm Hg from baseline. [see Adverse Reactions (6.1)]. Blood pressure increases can increase cardiovascular (CV) risk over time.

The CV risk associated with topical testosterone gel was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors.  In TRAVERSE, topical testosterone gel increased mean systolic blood pressure by 1.0 mmHg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mmHg was observed in the placebo group at this timepoint, for a mean between group difference of 1.5 mmHg.  However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions (6.1)].

Monitor BP periodically in men using TLANDO, especially men with hypertension. TLANDO is not recommended for use in patients with uncontrolled hypertension.

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

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).  In patients with a history of hypertension at baseline, the mean ABPM systolic and diastolic blood pressure increased by 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 by 3.9 mmHg (95% CI 0.9, 6.8) and 1.2 mmHg (95% CI -0.1, 2.5), respectively (n =63).

2 patients (1.4 %) in the TLANDO safety set (n=138) either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=0) during Study 18-001.

Of the 138 patients in Study 18-001 who used TLANDO, 7 patients (5.1%) were reported to have either an adverse reaction of hypertension (7 patients, 5.1%) or increased blood pressure (0 patients, 0.0%).

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 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%), 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35 kg/m².  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.

The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596).  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: 0.78, 1.17]). 

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 (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.

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.

Geriatric Patients: Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH and hypertension (8.5).

Advise the patients to read the FDA-approved patient labeling (Medication Guide).

TLANDO is not substitutable with other oral testosterone undecanoate products.

TLANDO capsules for oral administration are available containing 112.5 mg of testosterone undecanoate. The capsules have a white opaque body imprinted with “112” in black ink and a grey opaque cap, banded with a colorless band.

TLANDO capsules are supplied in HDPE bottles with a foil liner and a child resistant cap.

Bottles of 120 capsules: NDC 74676-0112-2.

Store at 20ºC to 25°C (68ºF to 77°F); excursions permitted to 15ºC to 30°C (59ºF to 86°F). [See USP Controlled Room Temperature].

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

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.

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 (5.4) ] .

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.

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.

NDC 74676-0112-2    Rx Only

TLANDO^®

(testosterone undecanoate)

Capsules 112.5 mg CIII

Dispense accompanying

Medication Guide to each patient

Verity Pharmaceuticals, Inc.    120 capsules

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.

• 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)].

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)]
• Increases in Prolactin [see Warnings and Precautions (5.15)]

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.

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.

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.

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident.

Treatment of overdosage consists of discontinuation of TLANDO and appropriate symptomatic and supportive care.

TLANDO (testosterone undecanoate) capsules contain 112.5 mg testosterone undecanoate, an ester of testosterone, for oral administration. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.

The chemical name of testosterone undecanoate is 17β-undecanoyloxy-4-androsten-3-one. It has an empirical formula of C₃₀H₄₈O₃ and a molecular weight of 456.7. The structural formula is:

Testosterone undecanoate is a white to off-white crystalline substance.

The inactive ingredients in TLANDO capsules are ascorbyl palmitate, glyceryl monolinoleate, polyethylene glycol 8000, and polyoxyl 40 hydrogenated castor oil. The capsule shell contains black iron oxide, gelatin, and titanium dioxide. The capsule is imprinted with black ink that contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

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 (5.2) ].

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.

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.

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 (5.3 and 5.4)].

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

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.

TLANDO is contraindicated in:

• Patients 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)].
• Known hypersensitivity to testosterone undecanoate or any of TLANDO’s ingredients [see Description ( 11)].

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.

Most common adverse reactions (incidence ≥ 2%): increased blood prolactin, hypertension, increased hematocrit, upper respiratory tract infection, weight increased, headache, and musculoskeletal pain (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Verity Pharma at 1-844-837-4891 or FDA at 1-800-FDA-1088 or  www.fda.gov/medwatch.

• Insulin: In patients with diabetes, concomitant use with TLANDO may decrease blood glucose and insulin requirements (7.1).
• Oral Anticoagulants: Concomitant use with TLANDO may cause changes in anticoagulant activity. Monitor International Normalized Ratio and prothrombin time frequently (7.2).
• Corticosteroids: Concomitant use with TLANDO 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 TLANDO may lead to additional increases in blood pressure (7.4).

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.

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

TLANDO 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's 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 [see Dosage and Administration (2.2 )].
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range [see Dosage and Administration (2.2 )].

Limitations of Use

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

• Safety and efficacy of TLANDO in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established [see Use in Specific Populations (8.5)].

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

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).

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) ].

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.

TLANDO contains testosterone undecanoate, a schedule III controlled substance.

• Polycythemia: Monitor hematocrit approximately every 3 months during the first year after beginning TLANDO and then every 6 months thereafter during treatment. Discontinue TLANDO if necessary (5.1).

• Venous thromboembolism (VTE): VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Discontinue TLANDO 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 with benign prostatic hyperplasia (BPH) 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: TLANDO 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: TLANDO may cause azoospermia (5.7, 8.3).

• Edema: Edema, with or without congestive heart failure (CHF) may occur in patients with preexisting cardiac, renal, or hepatic disease. Discontinue TLANDO and initiate appropriate workup (5.9).

• Sleep Apnea: TLANDO may potentiate sleep apnea  in those with risk factors (5.10).

• Lipid Changes: Testosterone may affect serum lipid profile.  Monitor patient lipid concentrations; if necessary, adjust dosage of lipid lowering drug(s) or discontinue TLANDO (5.12).

• Increases in Prolactin: Monitor serum prolactin levels prior to initiation of TLANDO and 3 to 4 months after starting TLANDO.  Discontinue TLANDO if serum prolactin levels remain elevated (5.15).

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.

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 TLANDO and initiate appropriate workup and management [see Adverse Reactions (6.2)].

• 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 (2.2).
• Recommended dosage is 225 mg orally twice daily with food (2.3).
• Monitor serum testosterone after initiating TLANDO to determine if TLANDO should be continued or discontinued (2.3).

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.

Capsules: 112.5 mg, white opaque body imprinted with “112” in black ink and grey opaque cap, banded with a colorless gelatin band.

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) ].

TLANDO can increase blood pressure. Based on ambulatory blood pressure monitoring in Study 18-001, TLANDO increased mean systolic/diastolic BP by 4.3/1.4 mmHg from baseline after 4 months of treatment.In patients with hypertension on antihypertensive therapy, TLANDO increased the mean systolic/diastolic BP by 4.8/1.6 mm Hg from baseline. [see Adverse Reactions (6.1)]. Blood pressure increases can increase cardiovascular (CV) risk over time.

The CV risk associated with topical testosterone gel was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors.  In TRAVERSE, topical testosterone gel increased mean systolic blood pressure by 1.0 mmHg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mmHg was observed in the placebo group at this timepoint, for a mean between group difference of 1.5 mmHg.  However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions (6.1)].

Monitor BP periodically in men using TLANDO, especially men with hypertension. TLANDO is not recommended for use in patients with uncontrolled hypertension.

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

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).  In patients with a history of hypertension at baseline, the mean ABPM systolic and diastolic blood pressure increased by 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 by 3.9 mmHg (95% CI 0.9, 6.8) and 1.2 mmHg (95% CI -0.1, 2.5), respectively (n =63).

2 patients (1.4 %) in the TLANDO safety set (n=138) either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=0) during Study 18-001.

Of the 138 patients in Study 18-001 who used TLANDO, 7 patients (5.1%) were reported to have either an adverse reaction of hypertension (7 patients, 5.1%) or increased blood pressure (0 patients, 0.0%).

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 63.3 (7.9) years, with 2452 patients aged 65 years or more (47%), 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35 kg/m².  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.

The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596).  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: 0.78, 1.17]). 

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 (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.

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.

Geriatric Patients: Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH and hypertension (8.5).

Advise the patients to read the FDA-approved patient labeling (Medication Guide).

TLANDO is not substitutable with other oral testosterone undecanoate products.

TLANDO capsules for oral administration are available containing 112.5 mg of testosterone undecanoate. The capsules have a white opaque body imprinted with “112” in black ink and a grey opaque cap, banded with a colorless band.

TLANDO capsules are supplied in HDPE bottles with a foil liner and a child resistant cap.

Bottles of 120 capsules: NDC 74676-0112-2.

Store at 20ºC to 25°C (68ºF to 77°F); excursions permitted to 15ºC to 30°C (59ºF to 86°F). [See USP Controlled Room Temperature].

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

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.

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 (5.4) ] .

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.

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.

NDC 74676-0112-2    Rx Only

TLANDO^®

(testosterone undecanoate)

Capsules 112.5 mg CIII

Dispense accompanying

Medication Guide to each patient

Verity Pharmaceuticals, Inc.    120 capsules

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.

• 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)].