The recommended starting dose of FORTESTA is 40 mg of testosterone (4 pump actuations) applied once daily to the thighs in the morning. The dose can be adjusted between a minimum of 10 mg of testosterone and a maximum of 70 mg of testosterone. To ensure proper dosing, the dose should be titrated based on the serum testosterone concentration from a single blood draw 2 hours after applying FORTESTA at approximately 14 days and 35 days after starting treatment or following dose adjustment. In addition, serum testosterone concentration should be assessed periodically thereafter. Table 1 describes the dose adjustments required at each titration step.

The application site and dose of FORTESTA are not interchangeable with other topical testosterone products.

FORTESTA should be applied directly to clean, dry, intact skin of the front and inner thighs. Do not apply FORTESTA to the genitals or other parts of the body. Patients should be instructed to use one finger to gently rub FORTESTA evenly onto the front and inner area of each thigh as directed in Table 2.

Once the application site is dry, the site should be covered with clothing [see Clinical Pharmacology (12.3)]. Wash hands thoroughly with soap and water. Avoid applying the gel to the thigh adjacent to the scrotum. Avoid fire, flames, or smoking until the gel has dried since alcohol based products, including FORTESTA, are flammable.

The patient should avoid swimming or showering or washing the administration site for a minimum of 2 hours after application [see Clinical Pharmacology (12.3)].

To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator eight times. The first 3 actuations may result in no discharge of gel. Safely discard the gel from the first 8 actuations. It is only necessary to prime the pump before the first dose.

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from FORTESTA-treated skin:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using FORTESTA.
• FORTESTA should only be applied to the front and inner thighs (area of application should be limited to the area that will be covered by the patient’s shorts or pants).
• Patients should wash their hands immediately with soap and water after applying FORTESTA.
• Patients should cover the application site(s) with clothing (eg, shorts of sufficient length or pants) after the gel has dried.
• Prior to any situation in which skin-to-skin contact with the application site is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue.
• In the event that unwashed or unclothed skin to which FORTESTA has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible.

• Patients with BPH treated with androgens are at an increased risk of 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. Evaluation of the patients for the presence of prostate cancer prior to initiating and during treatment with androgens is appropriate [see Contraindications (4)].

Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using FORTESTA [see Dosage and Administration (2.2), Use in Specific Populations (8.1), and Clinical Pharmacology (12.3)].

Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.

Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events.

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as FORTESTA. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with FORTESTA and initiate appropriate workup and management.

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. Patients should be informed of this possible risk when deciding whether to use or to continue to use FORTESTA.

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.

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

With large doses of exogenous androgens, including FORTESTA, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH which could possibly lead to adverse effects on semen parameters including sperm count.

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (eg, 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 testosterone enanthate has produced multiple hepatic adenomas. FORTESTA is not known to cause these adverse effects.

Androgens, including FORTESTA, 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 (6.2)].

Gynecomastia may develop and persist in patients being treated with androgens, including FORTESTA, for hypogonadism.

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 diseases.

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.

Androgens, including FORTESTA, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

Androgens, including FORTESTA, may decrease concentrations of thyroxin-binding globulins, 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.

Alcohol based products, including FORTESTA, are flammable; therefore, patients should be advised to avoid smoking, fire, or flame until the FORTESTA gel has dried.

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 clinical practice.

In a controlled multicenter, open-label, non-comparative 90-day clinical study, 149 hypogonadal patients were treated with FORTESTA [see Clinical Studies (14.1)]. Adverse reactions occurred in 22.8% (34/149) of patients. The most common adverse reaction reported in this study was skin reactions associated with the site of application (16.1%; 24/149) of which 79% (19/24) were mild and the remainder were moderate (21%; 5/24) (Table 3).

During the 90-day trial 5 patients (3.4%) discontinued treatment because of adverse reactions. These reactions were: 1 patient with contact dermatitis (considered probably related to FORTESTA application), 1 with application site reaction (considered probably related to FORTESTA application), 1 with gastrointestinal hypomotility (considered possibly related to FORTESTA application), 1 with severe dyspnea (considered not related to FORTESTA application), and 1 with moderate contusion (considered not related to FORTESTA application).

The following adverse reactions have been identified during post approval use of FORTESTA. 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 (Table 4).

Secondary Exposure to Testosterone in Children
Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In a few cases, however, enlarged genitalia did not fully return to age appropriate normal size, and bone age remained modestly greater than chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least 1 reported case, the reporter considered the possibility of secondary exposure from items such as the testosterone gel user’s shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions (5.2)].

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease insulin requirements.

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 anticoagulants, especially at the initiation and termination of androgen therapy.

The concurrent administration of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal, or hepatic disease.

Risk Summary
FORTESTA is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm based on data from animal studies and its mechanism of action [see Contraindications (4) and Clinical Pharmacology (12.1)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies.

Data
Animal Data
In developmental studies conducted in rats, rabbits, pigs, sheep, and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased anogenital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes.

Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

Risk Summary

FORTESTA is not indicated for use in females.

Infertility

During treatment with large doses of exogenous androgens, including FORTESTA, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions (5.8)], possibly leading to adverse effects on semen parameters including sperm count. Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence (9.2)]. With either type of use, the impact on fertility may be irreversible.

The safety and efficacy of FORTESTA in pediatric patients <18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing FORTESTA to determine whether efficacy in those over 65 years of age differs from younger subjects. Of the 149 patients enrolled in the pivotal clinical study utilizing FORTESTA, 20 were over 65 years of age. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer.

Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH.

No studies were conducted in patients with renal impairment.

No studies were conducted in patients with hepatic impairment.

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for the maintenance of secondary sex characteristics. These effects include the growth and maturation of the 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; and alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has 2 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).

No specific pharmacodynamic studies were conducted using FORTESTA.

Absorption
FORTESTA delivers physiologic amounts of testosterone, producing serum testosterone concentrations that approximate normal concentrations (> 300 ng/dL) seen in healthy men.

FORTESTA provides continuous transdermal delivery of testosterone for 24 hours following a single application to clean, dry, intact skin of the front and inner thighs (Figure 1).

Figure 1: Mean (±SD) Serum Total Testosterone Concentrations on Day 7 in Patients Following FORTESTA Once-Daily Application of 40 mg of Testosterone (N=12)

Figure 1: Mean (±SD) Serum Total Testosterone Concentrations on Day 7 in Patients Following FORTESTA Once-Daily Application of 40 mg of Testosterone (N=12)

Distribution
Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is loosely bound to albumin and other proteins.

Metabolism
Testosterone is metabolized to various 17-keto steroids through 2 different pathways. The major active metabolites of testosterone are estradiol and DHT.

Excretion
There is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic acid and sulfuric acid conjugates of testosterone and its metabolites. About 6% is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

Potential for Testosterone Transfer
The potential for testosterone transfer from healthy males dosed with FORTESTA to healthy females was evaluated in a placebo-controlled, 3-way crossover study. The washout period was approximately 29 days. Six (6) males were treated with either FORTESTA (30 mg testosterone) or placebo to 1 thigh only. At 2 hours after the application of FORTESTA to males, the females rubbed their forearms for 15 minutes on the thigh of the males. Serum concentrations of testosterone were monitored in females for 24 hours after the transfer procedure. When direct skin-to-skin transfer occurred with FORTESTA mean average concentration (C_avg) increased by 134% and mean maximum concentration (C_max) increased by 191%, compared to direct skin-to-skin transfer with placebo. When transfer occurred with FORTESTA while covering a thigh with boxer shorts, mean C_avg decreased by 3% and mean C_max increased by 2%, compared to direct skin-to-skin transfer with placebo [see Dosage and Administration (2.2)].

Effect of Showering
In a 2-way crossover study, the effects of showering on the pharmacokinetics of total testosterone following application of FORTESTA (30 mg testosterone to each thigh; total 60 mg testosterone) were assessed in 7 hypogonadal males. There were two 7-day treatment phases, with showering 2 hours post FORTESTA application, and without showering on Day 7 of each treatment phase. Showering decreased C_avg by 3% and it increased C_max by 13% [see Dosage and Administration (2.2)].

Effect of Hand Washing and Application Site (Inner Thigh) Washing
In an open-label, single-dose study, the amount of residual testosterone on the application finger and application site after washing was evaluated in 12 healthy male subjects. Prior to application of FORTESTA, each index finger and each intended application site (left and right front and inner thighs) was wiped using dry sponges to assess baseline skin testosterone. Subjects then used each index finger to rub FORTESTA (40 mg testosterone) onto each inner thigh. On one side, the index finger was immediately wiped using dry sponges to collect residual testosterone. On the other side, each subject washed their hands with liquid soap and warm tap water immediately after drug application, then wipe the index finger using dry sponges to collect residual testosterone. A mean (SD) of 0.002 (0.006) mg of residual testosterone (ie, 99.8% reduction compared to when hand was not washed) was recovered after washing hands with liquid soap and warm tap water.

Two (2) hours after the application of FORTESTA onto each inner thigh, one thigh was wiped using dry sponges.  On the other thigh, the application site was washed with liquid soap and warm tap water, dried, and then wiped using dry sponges. The sponges were assayed for testosterone. A mean (SD) of 0.24 (0.009) mg of residual testosterone (ie, 94.3% reduction compared to when application site was not washed) was recovered after application site washing.

Carcinogenesis

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, implant-induced cervical-uterine tumors metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenesis

Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog, and non-human primates, which was reversible on cessation of the treatment.

FORTESTA was evaluated in a multicenter, 90-day open-label, non-comparative trial of 149 hypogonadal males with body mass index (BMI) ≥ 22 kg/m² and < 35 kg/m² and 18 to 75 years of age (mean age 54.5 years). The patients were screened for a single serum total testosterone concentration < 250 ng/dL, or 2 consecutive serum total testosterone concentrations < 300 ng/dL. Patients were caucasian (80.5%), black (10.1%), Hispanic (7.4%), and other (2.0%).

FORTESTA was applied once each morning to the thighs at a starting dose of 40 mg of testosterone (4 pump actuations) per day. The dose was adjusted between a minimum of 10 mg and a maximum of 70 mg testosterone on the basis of total serum testosterone concentration obtained 2 hours post FORTESTA application on Days 14, 35, and 60 (± 3 days).

The primary endpoint was the percentage of patients with C_avg within the normal range (greater than or equal to 300 ng/dL and less than or equal to 1140 ng/dL) on Day 90. In patients treated with FORTESTA, 77.5% (100/129) had C_avg within the normal range on Day 90. The secondary endpoint was the percentage of patients with C_max above 3 pre-determined limits. The percentages of patients with C_max greater than 1500 ng/dL, and between 1800 and 2499 ng/dL on Day 90 were 5.4% and 1.6%, respectively. No patient had a C_max greater than or equal to 2500 ng/dL on Day 90.

Dose titrations on Days 14, 35, and 60 resulted in mean (SD) C_avg and C_max for final doses of 10 mg to 70 mg on Day 90 shown in Table 5.

 Table 5:     Mean (±SD) Steady-State Testosterone Concentrations (C_avg and C_max) by Final Dose on Day 90

Figure 2 summarizes the pharmacokinetic profiles of total testosterone in patients completing 90 days of FORTESTA treatment administered as 40 mg of testosterone once-daily for the initial 14 days followed by possible titration according to follow-up testosterone measurements.

Figure 2 Mean (±SD) Steady-State Serum Total Testosterone Concentrations on Day 90 (N=129)

Figure 2:     Mean (±SD) Steady-State Serum Total Testosterone Concentrations on Day 90 (N=129)

Additionally, there were no clinically significant changes from baseline for SHBG (slight decrease), estradiol (slight increase), and ratio of DHT to total testosterone (slight increase) at Day 90.

Men with known or suspected prostate or breast cancer should not use FORTESTA [see Contraindications (4) and Warnings and Precautions (5.1)].

Secondary exposure to testosterone in children and women can occur with the use of testosterone gel in men. Cases of secondary exposure to testosterone in children have been reported.

Physicians should advise patients of the reported signs and symptoms of secondary exposure which may include the following:

• In children; unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior.
• In women; changes in hair distribution, increase in acne, or other signs of testosterone effects.
• The possibility of secondary exposure to FORTESTA should be brought to the attention of a healthcare provider.
• FORTESTA should be promptly discontinued until the cause of virilization is identified.

Strict adherence to the following precautions is advised to minimize the potential for secondary exposure to testosterone from FORTESTA in men [see Medication Guide]:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using FORTESTA.
• Patients using FORTESTA should apply the product as directed and strictly adhere to the following:

  Wash hands with soap and water after application.

  Cover the application site(s) with clothing after the gel has dried.

  Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated.

• In the event that unwashed or unclothed skin to which FORTESTA has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration (2.2), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

• Changes in urinary habits such as increased urination at night, trouble starting your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having a urine accident, being unable to pass urine, and weak urine flow.
• Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness.
• Too frequent or persistent erections of the penis.
• Nausea, vomiting, changes in skin color, or ankle swelling.

• Read the Medication Guide before starting FORTESTA therapy and reread it each time the prescription is renewed.
• FORTESTA should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women.
• Keep FORTESTA out of the reach of children.
• FORTESTA is an alcohol based product and is flammable; therefore avoid fire, flame, or smoking until the gel has dried.
• It is important to adhere to all recommended monitoring.
• Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood.
• FORTESTA is prescribed to meet the patient’s specific needs, therefore, the patient should never share FORTESTA with anyone.
• Wait 2 hours before swimming or washing following application of FORTESTA. This will ensure that the greatest amount of FORTESTA is absorbed into their system.

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Manufactured for: Endo USA, Malvern, PA 19355

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