Get your patient on Testosterone - Testosterone gel, Metered (Testosterone)

The recommended starting dose of testosterone gel 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 testosterone gel 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 testosterone gel are not substitutable with other topical testosterone products.

Testosterone gel should be applied directly to clean, dry, intact skin of the front and inner thighs. Do not apply testosterone gel to the genitals or other parts of the body. Patients should be instructed to use one finger to gently rub testosterone gel 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 testosterone gel, 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 testosterone gel-treated skin:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel.
• Testosterone gel 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 testosterone gel.
• Patients should cover the application site(s) with clothing (e.g., 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 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.

Risk Summary

Testosterone gel 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

Testosterone gel is not indicated for use in females.

Infertility

During treatment with large doses of exogenous androgens, including testosterone gel, 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 testosterone gel 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 testosterone gel 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 testosterone gel, 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.

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 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.

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 testosterone gel.

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 treatment with testosterone gel and initiate appropriate workup and management.

• 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 )] .

Testosterone can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, testosterone increased the mean systolic/diastolic blood pressure by 3.1/1.2 m m Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, testosterone increased the mean systolic/diastolic BP by 4.0/1.3 mm Hg from baseline. 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 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), includin g 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 blood pressure periodically in men using testosterone, especially men with hypertension. Testosterone is not recommended for use in patients with hypertension.

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, testosterone gel 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 testosterone gel, 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 (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 testosterone enanthate has produced multiple hepatic adenomas. Testosterone gel is not known to cause these adverse effects.

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 )] .

Gynecomastia may develop and persist in patients being treated with androgens, including testosterone gel, 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, such as testosterone. Monitor the lipid profile periodically, particularly after starting testosterone therapy.

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.

Androgens, including testosterone gel, 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 testosterone gel, are flammable; therefore, patients should be advised to avoid smoking, fire, or flame until the testosterone 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 testosterone gel [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 testosterone gel application), 1 with application site reaction (considered probably related to testosterone gel application), 1 with gastrointestinal hypomotility (considered possibly related to testosterone gel application), 1 with severe dyspnea (considered not related to testosterone gel application), and 1 with moderate contusion (considered not related to testosterone gel application).

Blood Pressure Increases

In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 223 patients. ABPM was conducted at baseline and at Week 16 of testosterone gel therapy. A total of 92 patients had acceptable ABPM recordings at both baseline and Week 16 and were at least 85% compliant with study drug. In that group, the mean change in 24-hour systolic blood pressure (BP) and diastolic BP from baseline to end-of-treatment at Week 16 (n=92) was 3.1 mm Hg (95% CI 0.9, 5.3) and 1.2 mm Hg (95% CI -0.1, 2.5), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 4.0 mm Hg [95% CI 0.3, 7.8] and 1.3 mm Hg [95% CI -0.9, 3.4], respectively [n=42]). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 1.5 mm Hg [95% CI -1.1, 4.1] and 0.6 mm Hg [95% CI -1.0, 2.1], respectively [n=45].

One patient (1.1 %) on testosterone gel, who was receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=1) or had their antihypertensive medication regimen adjusted (n=0) during the ABPM study.

Of the 223 patients in the ABPM study who used testosterone gel, 7 patients (3.1%) were reported to have either an adverse reaction of hypertension (5 patients, 2.2%) or increased blood pressure (2 patients, 0.9%).

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 5,198 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 2,452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2,357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35kg/m ² . 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=2,596). 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=1,683), 420.9 ng/dl (n=1,125), 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.

The following adverse reactions have been identified during post approval use of testosterone gel. 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 (5.1 )] .

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.

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 testosterone gel.

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

Testosterone gel 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 Testosterone Gel 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 testosterone gel 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 testosterone gel (30 mg testosterone) or placebo to 1 thigh only. At 2 hours after the application of testosterone gel 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 testosterone gel 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 testosterone gel 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 testosterone gel (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 testosterone gel 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 testosterone gel, 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 testosterone gel (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 (i.e., 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 testosterone gel 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 (i.e., 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.

Testosterone gel was evaluated in a multicenter, 90-day open-label, non-comparative trial of 149 hypogonadal males with body mass index (BMI) ≥22 kg/m ² and <35 kg/m ² 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%).

Testosterone gel 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 testosterone gel 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 1,140 ng/dL) on Day 90. In patients treated with testosterone gel, 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 1,500 ng/dL, and between 1,800 and 2,499 ng/dL on Day 90 were 5.4% and 1.6%, respectively. No patient had a C _max greater than or equal to 2,500 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.

Figure 2 summarizes the pharmacokinetic profiles of total testosterone in patients completing 90 days of testosterone gel 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)

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.