Testosterone Topical Solution

AXIRON is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone.

• Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above the normal range.
• Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.

Limitations Of Use

• Safety and efficacy of AXIRON in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
• Safety and efficacy of AXIRON in males <18 years old have not been established [see Use In Specific Populations].

Mechanism Of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature and fat distribution. 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 two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using AXIRON.

Pharmacokinetics

AXIRON delivers physiologic circulating testosterone that approximate normal concentration range (i.e., 300 -1050 ng/dL) seen in healthy men following application to the axilla.

On the skin, the ethanol and isopropyl alcohol evaporate leaving testosterone and octisalate. The skin acts as a reservoir from which testosterone is released into the systemic circulation over time (see Figure 1). In general, steady-state serum concentrations are achieved by approximately 14 days of daily dosing.

Figure 1: Mean (±SD) Serum Testosterone Concentrations on Day 7 in Patients Following AXIRON Once-Daily Application of 30 mg, 60 mg, or 90 mg of Testosterone

When AXIRON treatment is discontinued after achieving steady-state, serum testosterone concentrations returned to their pretreatment concentrations by 7 – 10 days after the last application.

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.

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT). DHT concentration increased in parallel with testosterone concentration during AXIRON treatment. The mean steady-state DHT/T ratio remained within normal limits and ranged from 0.17 to 0.26 across all doses on Days 15, 60, and 120.

There is considerable variation in the half-life of testosterone 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.

Potential for Testosterone Transfer

The potential for testosterone transfer from males dosed with AXIRON to healthy females was evaluated in a clinical study conducted with a 2% testosterone formulation. 10 males were treated with 60 mg of testosterone in each axilla (the maximum testosterone dose of 120 mg). At 2 hours after the application of AXIRON to the males, the females rubbed their outer forearms for 15 minutes on the axilla of the males. The males had covered the application area with a T-shirt. Serum concentrations of testosterone were monitored in the female subjects for 72 hours after the transfer procedure. Study results show a 13% and 17% increase in testosterone exposure (AUC[024]) and maximum testosterone concentration (Cmax), respectively, compared to baseline in these females. In a prior clinical study conducted with a 1% testosterone formulation under similar study conditions, direct skin-to-skin transfer showed a 131% and 297% increase in testosterone exposure (AUC[0-72]) and maximum testosterone concentration (Cmax), respectively, compared to when men had covered the application area with a T-shirt.

In a clinical study conducted with a 2% testosterone formulation to evaluate the effect of washing on the residual amount of testosterone at the axilla, 10 healthy male subjects received 60 mg of testosterone to each axilla (the maximum testosterone dose of 120 mg). Following 5 minutes of drying time, the left axilla was wiped with alcohol towelettes which were assayed for testosterone content. Subjects were required to shower with soap and water 30 minutes after application. The right axilla was then wiped with alcohol towelettes which were assayed for testosterone content. A mean (SD) of 3.1 (2.8) mg of residual testosterone (i.e., 92.6% reduction compared to when axilla was not washed) was recovered after washing this area with soap and water. [See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Use of deodorants and anti-perspirants: In a parallel designed clinical study evaluating the effect of deodorants and antiperspirants in healthy premenopausal females dosed with AXIRON, each subject applied either a combined deodorant/antiperspirant spray (6 subjects) or stick (6 subjects) or a deodorant spray (6 subjects) to a single axilla 2 minutes before the application of 30 mg of testosterone to the same axilla. A control group of 6 subjects only applied 30 mg of testosterone to a single axilla. Blood samples were collected for 72 hours from all subjects following AXIRON administration. Although a decrease of up to 33% of testosterone exposure (AUC[0-72]) was observed when antiperspirants or deodorants are used 2 minutes prior to AXIRON application, underarm deodorant or antiperspirant spray or stick products may be used 2 minutes prior to AXIRON application as part of normal, consistent, and daily routine. [See DOSAGE AND ADMINISTRATION , and PATIENT INFORMATION].

Effect of showering/washing: In a parallel designed clinical study to evaluate the effect of washing on the testosterone systemic exposure, two groups of 6 healthy premenopausal female subjects were each dosed with 30 mg of testosterone to a single axilla. The application sites of each group were washed with soap and water 2 hours or 6 hours after the application of AXIRON. A control group of 6 female subjects applied 30 mg of testosterone to a single axilla and did not wash the application site. Blood samples were collected for 72 hours from all subjects following dosing with AXIRON. A decrease of up to 35% of testosterone exposure (AUC[0-72]) was observed when applications sites were washed 2 hours and 6 hours after AXIRON application. Patients should be advised to avoid swimming or washing the application site until 2 hours following application of AXIRON. [See DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].

Clinical Studies

Clinical Studies In Hypogonadal Men

AXIRON was evaluated in a multicenter, open label, 120-day trial that enrolled 155 hypogonadal men at 26 clinical research centers. The median age of subjects was 53 years with a range of 19 – 78 years. Of the 144 subjects whose race was recorded, 122 (84.7%) were Caucasian, 13 (9.0%) were Hispanic, 6 (4.2%) were African Americans, 1 (0.7%) was Asian and 2 (1.4%) had race recorded as “Other”.

Patients were instructed to apply AXIRON to unclothed, clean, dry, and unbroken skin. The solution was applied to the axillary area. Patients were not instructed to alter their normal grooming routine, e.g., shave under the arm.

During the initial AXIRON treatment period (Days 1-15) 143 patients were treated with 60 mg of testosterone daily. On Day 45 of the trial, patients were maintained at the same dose, or were titrated up or down, based on their 24 hour average serum testosterone concentration measured on Day 15. On Day 90 of the trial, patients were maintained at the same dose, or were titrated up or down, based on their 24 hour average serum testosterone concentration measured on Day 60.

On day 120, 75% of responding patients finished the study on the starting dose of 60 mg of testosterone, while 2% had been titrated to 30 mg, 17% had been titrated to 90 mg and 6% had been titrated to the 120 mg dose.

On day 60, 84.8% of subjects had total testosterone concentrations in the normal range. Of those who had sufficient data for analysis on day 120, 84.1%, had their average serum testosterone concentration in the normal range of 300 – 1050 ng/dL.

Table 3 summarizes the proportion of subjects having average testosterone concentrations within the normal range on Days 60 and 120.

Table 3: Proportion of subjects who had an average Serum Total Testosterone in the range 300 to 1050 ng/dL and completed 120 days of treatment (N=138a)

Of the 135 patients who completed the 120 day treatment, 123 patients did so with no deviation from the protocol. By day 120, average serum testosterone concentration was within normal range for 67% of those who titrated down on the 30 mg dose, 89% of those on the 60 mg dose, 86% of those who titrated up to 90 mg and 70% of those who titrated up to the 120 mg dose. Table 4 below summarizes the testosterone concentration data in the patients who completed 120 days.

Table 4: Baseline-unadjusted Arithmetic Mean (±SD) Steady-State Serum Testosterone Concentrations on Days 15, 60 and 120 in Patients Who Completed 120 Days of Treatment

Figure 2 summarizes the pharmacokinetic profiles of total testosterone in patients completing 120 days of AXIRON treatment administered as 60 mg of testosterone for the initial 15 days followed by possible titration according to follow-up testosterone measurements.

Figure 2: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 120 (30, 60, 90 or 120 mg testosterone) in Patients Who Completed 120 Days (N=135) of AXIRON Once-Daily Treatment

8.1 Pregnancy

Pregnancy Category X [see Contraindications (4)] Testosterone Topical Solution 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 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 Topical Solution 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 Topical Solution has not been established in males less than 18 years of age. 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 Topical Solution to determine whether efficacy in those over 65 years of age differs from younger patients. Of the 155 patients enrolled in the pivotal clinical study utilizing Testosterone Topical Solution, 21 were over 65 years of age. Additionally, there were insufficient long-term safety data in these patients utilizing Testosterone Topical Solution to assess a potential incremental risk of cardiovascular disease and prostate cancer.

8.6 Renal Impairment

No formal studies were conducted involving patients with renal impairment.

8.7 Hepatic Impairment

No formal studies were conducted involving patients with hepatic impairment.

8.8 Use in Men with Body Mass Index (BMI) Greater Than 35 kg/m2

Safety and efficacy of Testosterone Topical Solution in males with BMI greater than 35 kg/m2 has not been established.

Testosterone Topical Solution is a clear, colorless, single phase solution containing 30 mg of testosterone in 1.5 mL of Testosterone Topical Solution for topical administration through the axilla. The active pharmacologic ingredient in Testosterone Topical Solution is testosterone. Testosterone, USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

The inactive ingredients are ethanol, isopropyl alcohol, octisalate, and povidone.