Axiron

CLINICAL PHARMACOLOGY

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 results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis.

Male hypogonadism 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

Absorption

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

Mean (±SD) Serum Testosterone Concentrations - Illustration

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.

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 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.

Excretion

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 (2 pump actuations) 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[0-24]) 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 (2 pump actuations) 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 (1 pump actuation) of testosterone to the same axilla. A control group of 6 subjects only applied 30 mg (1 pump actuation) 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 (1 pump actuation) 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 (1 pump actuation) 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)

Evaluation Time Statistics Value
Baseline Testosterone Mean (SD) 194.6 ng/dL (92.9 ng/dL)
Day 15 Normalb 76.1%c
95% CI (69.0%, 83.2%)
Day 60 Normalb 84.8%
95% CI (78.8%, 90.8%)
Day 120 Normalb 84.1%
95% CI (77.9%, 90.2%)
a Three patients who withdrew from the study due to adverse reactions are included as treatment failures.
b Normal represents the percentage of patients with average testosterone concentration in the range of 300 – 1050 ng/dL.
c On Day 15, 72.2% of the 90 subjects in the US study population had an average serum testosterone in the range of 300 ng/dL – 1050 ng/dL.

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

  Dose of AXIRON
30 mg 60 mg 90 mg 120 mg Overall
Day 15 [N=0] [N=135] [N=0] [N=0] [N=135]
  Cavg (ng/dL) -- 456 (±226) -- -- 456 (±226)
  Cmax (ng/dL) -- 744 (±502) -- -- 744 (±502)
Day 60 [N=1] [N=105] [N=29] [N=0] [N=135]
  Cavg (ng/dL) 343 (--) 523 (±207) 368 (±138) -- 488 (±204)
  Cmax (ng/dL) 491 (--) 898 (±664) 646 (±382) -- 840 (±620)
Day 120 [N=3] [N=97] [N=25] [N=10] [N=135]
  Cavg (ng/dL) 493 (±239) 506 (±175) 415 (±165) 390 (±160) 480 (±177)
  Cmax (ng/dL) 779 (±416) 839 (±436) 664 (±336) 658 (±353) 792 (±417)

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

AXIRON (testosterone) Figure 2 Illustration

Last reviewed on RxList: 1/9/2012
This monograph has been modified to include the generic and brand name in many instances.

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