2.1 Dosing and Dose Adjustment

The recommended starting dose of testosterone gel is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day).

Dose Adjustment

To ensure proper dosing, serum testosterone levels should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily testosterone gel dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician (see Table 1, Dosing Information for testosterone gel). If the serum testosterone concentration exceeds the normal range, the daily testosterone gel dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 50 mg, testosterone gel therapy should be discontinued. In addition, serum testosterone concentration should be assessed periodically.

2.2 Administration Instructions

Testosterone gel should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient’s short sleeve T- shirt. Do not apply testosterone gel to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. Testosterone gel should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen.

The prescribed daily dose of testosterone gel should be applied to the right and left upper arms/shoulders and/or right/left abdomen as shown in the shaded areas in the figure below.

After applying the gel, the application site should be allowed to dry prior to dressing. Hands should be washed with soap and water after testosterone gel has been applied. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including testosterone gel, are flammable.

The patient should be advised to avoid swimming or showering for at least 5 hours after the application of testosterone gel.

Multi-Dose Pump

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 three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, patients should completely depress the pump one time (actuation) for every 12.5 mg of testosterone required to achieve the daily prescribed dosage. The product should be delivered directly into the palm of the hand and then applied to the desired application sites. Alternatively, testosterone gel can be applied directly to the application sites.

Table 1 provides dosing information for adult males.

Packets

The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.

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

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel.
• Patients should wash their hands immediately with soap and water after applying testosterone gel.
• Patients should cover the application site(s) with clothing (e.g., a T-shirt) 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 testosterone gel 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.

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

• Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.
• Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [ see Contraindications (4), Adverse reactions (6.1) and Nonclinical Toxicology (13.1)].

5.2 Potential for Secondary Exposure to Testosterone

Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. 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 testosterone gel. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone gel [ 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.

5.3 Polycythemia

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.

5.4 Venous Thromboembolism

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

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

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. This type of testosterone 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. Counsel patients concerning the serious adverse reactions associated with testosterone and anabolic androgenic steroid abuse. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in patients who present with serious cardiovascular or psychiatric adverse events.

5.7 Use in Women

Due to lack of controlled evaluations in women and potential virilizing effects, testosterone gel is not indicated for use in women [ see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].

5.8 Potential for Adverse Effects on Spermatogenesis

At large doses of exogenous androgens, including testosterone gel; spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

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. Testosterone gel is not known to produce these adverse effects.

5.10 Edema

Androgens, including testosterone gel, 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)].

5.11 Gynecomastia

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

5.12 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 [ see Adverse Reactions (6.2)].

5.13 Lipids

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

5.14 Hypercalcemia

Androgens, including testosterone gel, 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.

5.15 Decreased Thyroxine-binding Globulin

Androgens, including testosterone gel, may decrease levels of thyroxin-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

5.16 Flammability

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

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.

Clinical Trials in Hypogonadal Men

Table 2 shows the incidence of all adverse reactions with testosterone gel and reported by > 1% of patients in a 180 Day, Phase 3 study.

* Abnormal lab tests occurred in nine patients with one or more of the following events reported: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin.

** Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results.

*** Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis.

Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.

In this 180 day clinical trial, skin reactions at the site of application were reported with testosterone gel, but none was severe enough to require treatment or discontinuation of drug.

Six patients (4%) in this trial had adverse reactions that led to discontinuation of testosterone gel. These reactions included: cerebral hemorrhage, convulsion, depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No patients on testosterone gel discontinued due to skin reactions.

In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse reactions; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other.

In a 3 year, flexible dose, extension study, the incidence of all adverse reactions to testosterone gel and reported by > 1% of patients is shown in Table 3:

Table 3: Adverse Reactions to Testosterone gel in the 3 Year, Flexible Dose, Extension Study

+ Abnormal lab tests occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, elevated HDL, elevated serum creatinine.

* Urinary symptoms included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream.

** Testis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness.

Two patients reported serious adverse reactions considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP).

Discontinuation for adverse reactions in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient).

Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men

During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on testosterone gel in the 3 year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL.

Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as > 2X the baseline or any single serum PSA > 6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still < 2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%).

Four patients met this criterion by having a serum PSA > 6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient’s PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient’s PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of testosterone gel. Because the 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):

Table 4: Adverse Reactions from Postmarketing Experience of Testosterone Gel by MedDRA System Organ Class

Secondary Exposure to Testosterone in Children

Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarket surveillance. 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 one 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)].

7.1 Insulin

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

7.2 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of International Normalized Ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

7.3 Corticosteroids

The concurrent use 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.

8.1 Pregnancy

Pregnancy Category X [ see Contraindications (4)]:

Testosterone gel is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens, such as testosterone, may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8.3 Nursing Mothers

Although it is not known how much testosterone transfers into human milk, testosterone gel is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation. [ see Contraindications (4)].

8.4 Pediatric Use

Safety and efficacy of testosterone gel in pediatric males less than 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing testosterone gel to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is 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.

8.6 Renal Impairment

No studies were conducted involving patients with renal impairment.

8.7 Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

9.1 Controlled Substance

Testosterone gel contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

9.2 Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often not obtained by prescription and not obtained through a pharmacy and typically in combination with other anabolic androgenic steroids (AAS), is 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.

Behaviors Associated with Addiction

• Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:
• Taking greater dosages than prescribed
• Continued drug use despite medical and social problems due to drug use
• Spending significant time to obtain the drug when supplies of the drug are interrupted
• Giving a higher priority to drug use than other obligations
• Having difficulty in discontinuing the drug despite desires and attempts to do so
• Experiencing withdrawal symptoms upon abrupt discontinuation of use

Abuse-Related Adverse Reactions

Serious adverse reactions, including cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression, have been reported in individuals who abuse anabolic androgenic steroids.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

9.3 Dependence

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking Supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which included depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism. Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

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 chord thickening, 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, can present as primary hypogonadism caused by defects of the gonads, such as Klinefelter’s Syndrome or Leydig cell aplasia, while secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted using testosterone gel.

12.3 Pharmacokinetics

Absorption

In a single-dose, crossover clinical study conducted in 24 hypogonadal males under fasting conditions, the serum testosterone exposure (AUC 0-72) and maximum testosterone concentration (C max) following a topical administration of 100 mg testosterone administered as 2 x 5 g testosterone gel packets (2 packets applied to the shoulder/upper arm) were bioequivalent to those following a topical administration of an approved testosterone gel product.

Testosterone gel delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (298 to 1043 ng/dL) seen in healthy men.

Testosterone gel provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

Testosterone gel is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from testosterone gel is absorbed into systemic circulation. In a study with testosterone gel 100 mg, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24 hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing.

With single daily applications of testosterone gel, follow-up measurements 30, 90, and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (< 300 ng/dL) maintained on testosterone gel 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by 100 mg on Day 30 was 792 (± 294) ng/dL and by testosterone gel 50 mg was 566 (± 262) ng/dL.

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 bound to albumin and other proteins.

Metabolism

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

DHT concentrations increased in parallel with testosterone concentrations during testosterone gel treatment. The mean steady-state DHT/T ratio during 180 days of testosterone gel treatment remained within normal limits and ranged from 0.23 to 0.29 (5 g/day) and from 0.27 to 0.33 (10 g/day).

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 and sulfuric acid conjugates of testosterone and its metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

When testosterone gel treatment is discontinued after achieving steady state, serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application.

Testosterone Transfer from Male Patients to Female Partners

The potential for dermal testosterone transfer following testosterone gel use was evaluated in a clinical study between males dosed with testosterone gel and their untreated female partners. Two (2) hours after application of 100 mg of testosterone from 10 g (2 x 5 g packets) of testosterone gel to upper arm and shoulder of one side by the male subjects, the couples (N = 20 couples) engaged in a 15 minute session of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the testosterone gel application sites. Serum concentrations of testosterone were monitored in the female subjects for 24 hours after the transfer procedure. Under these study conditions, unprotected female partners had a mean testosterone AUC 0-24 and C max that were more than 2 times greater than their mean baseline values. When a shirt covered the application site, study results showed a 16% and 48% increase in testosterone AUC 0-24 and C max, respectively, compared to baseline in these females. The potential for dermal testosterone transfer following testosterone gel application on the abdomen has not been evaluated.

Effect of Hand Washing and Showering

In a separate clinical study conducted to evaluate the effect of hand washing on the residual amount of testosterone, 33 healthy male subjects received 100 mg of testosterone from 10 g (2 x 5 g packets) of testosterone gel on a hand and applied testosterone gel to the upper arm and shoulder of one side. Subjects washed their hands with liquid soap and warm tap water immediately after drug application. Then the hand was wiped with 3 ethanol dampened gauzes which were then combined together and analyzed for testosterone content. A mean (SD) of 0.40 (0.20) mg of residual testosterone (i.e., approximately 0.4% of the theoretical dose of 100 mg testosterone administered) was recovered after washing hands with liquid soap and warm tap water.

The same study also evaluated the effect of showering on the residual amount of testosterone on the application site. Subjects washed the application site by showering two hours after drug application. The application site was then wiped with 3 ethanol dampened gauzes which were then combined together and analyzed for testosterone content. A mean (SD) of 5.80 (2.77) mg of residual testosterone (i.e., approximately 5.8% of the theoretical dose of 100 mg testosterone administered) was recovered after showering.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which 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.

14.1 Clinical Trials in Adult Hypogonadal Males

Testosterone gel was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180 day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1 to 90), 73 patients were randomized to testosterone gel 50 mg daily, 78 patients to testosterone gel 100 mg daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of testosterone gel but open-label for active control. Patients who were originally randomized to testosterone gel and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to 75 mg daily on Day 91. During the Extended Treatment Period (Days 91 to 180), 51 patients continued on testosterone gel 50 mg daily, 52 patients continued on testosterone gel 100 mg daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received testosterone gel 75 mg daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of testosterone gel for an additional period of up to 3 years.

Mean peak, trough and average serum testosterone concentrations within the normal range (298 to 1043 ng/dL) were achieved on the first day of treatment with doses of 50 mg and 100 mg of testosterone gel. In patients continuing on testosterone gel 50 mg and 100 mg, these mean testosterone levels were maintained within the normal range for the 180-day duration of the original study.

Figure 3 summarizes the 24 hour pharmacokinetic profiles of testosterone administered as testosterone gel for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed testosterone gel treatment.

Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 50 mg, 75 mg, or 100 mg, of testosterone. The 75 mg dose produced mean concentrations intermediate to those produced by 50 mg and 100 mg of testosterone.

Table 5: Mean (± SD) Steady-State Serum Testosterone Concentrations During Therapy (Day 180)

Of 129 hypogonadal men who were appropriately titrated with testosterone gel and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the normal range on Treatment Day 180.

In patients treated with testosterone gel, there were no observed differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypogonadism, or body mass index.

14.2 Skin Irritation Study

Testosterone gel was evaluated in a randomized, five-treatment, single-center, controlled, within-subject comparison study with healthy subjects using a cumulative irritation patch test design. Thirty-three (33) subjects completed the study involving testosterone gel, a comparator control product, vehicle, and positive and negative controls. All five treatments were applied to the skin separately with an occlusive patch. Each subject received a set of 5 patches, once daily for 21 consecutive days. Evaluation of dermal reactions at the application sites were assessed every day at the time of removal of each patch using an established ordinal (6-point) scoring system. Testosterone gel showed no evidence of significant irritation and was statistically significantly less irritating than the positive control (P<0.001).

14.3 Skin Sensitization Study

Testosterone gel was evaluated in a randomized, five-treatment, single-center, controlled, within-subject study to evaluate the sensitizing potential on healthy volunteers, using a Repeat Insult Patch Test design. Two hundred three (203) subjects completed the study involving Testosterone Gel, a comparator control product, vehicle, and positive and negative controls. All five treatments were applied to the skin separately with an occlusive patch. Each subject received a set of 5 patches, every 48-72 hours for 21 consecutive days. Evaluation of dermal reactions at the application sites were assessed clinically every day at the time of removal of each patch using an established ordinal (6-point) scoring system. Observations at the naïve site during challenge and the pattern of reactivity during induction provided bases for an interpretation of contact sensitizations. Under these conditions there was no evidence of sensitization to testosterone gel, In the cumulative irritancy analysis, testosterone gel was statistically significantly less irritating than the positive control (P<0.001).

17.1 Use in Men with Known or Suspected Prostate or Breast Cancer

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

17.2 Potential for Secondary Exposure to Testosterone and Steps to Prevent Secondary Exposure

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

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 testosterone gel should be brought to the attention of a healthcare provider
• Testosterone gel 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 testosterone gel in men.
• Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel
• Patients using testosterone gel 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 testosterone gel 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)].

17.3 Potential Adverse Reactions with Androgens

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.

17.4 Patients Should Be Advised of the Following Instructions for Use:

• Read the Medication Guide before starting testosterone gel therapy and reread it each time the prescription is renewed
• Testosterone gel should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women
• Keep testosterone gel out of the reach of children
• Testosterone gel 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
• Testosterone gel is prescribed to meet the patient’s specific needs; therefore, the patient should never share testosterone gel with anyone.
• Wait 5 hours before showering or swimming. This will ensure that the greatest amount of testosterone gel is absorbed into their system.