Fortesta (Testosterone) - Description and Clinical Pharmacology

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DESCRIPTION

FORTESTA is a clear, colorless, odorless, gel containing testosterone. FORTESTA is available in a metered-dose pump. Each pump actuation provides 10 mg of testosterone and each container is capable of dispensing 120 pump actuations. One pump actuation dispenses 0.5 g of gel.

The active pharmacologic ingredient in FORTESTA is testosterone. Testosterone USP is a white to almost white powder described chemically as 17-beta hydroxyandrost-4-en-3-one.

Pharmacologically inactive ingredients in FORTESTA are: propylene glycol, purified water, ethanol, 2-propanol, oleic acid, carbomer 1382, triethanolamine and butylated hydroxytoluene.

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 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, 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 production of testosterone and is characterized by low serum testosterone concentrations. 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 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).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using FORTESTA.

Pharmacokinetics

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

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

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

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 two different pathways. The major active metabolites of testosterone are estradiol and DHT.

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

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

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

Effect of hand washing and application site (inner thigh) washing
In an open-label, single-dose study, the amount of residual testosterone on the application finger and application site after washing was evaluated in 12 healthy male subjects. Prior to application of FORTESTA, each index finger and each intended application site (left and right front and inner thighs) was wiped using dry sponges to assess baseline skin testosterone. Subjects then used each index finger to rub FORTESTA (40 mg testosterone) onto each inner thigh. On one side, the index finger was immediately wiped using dry sponges to collect residual testosterone. On the other side, each subject washed their hands with liquid soap and warm tap water immediately after drug application, then wiped 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 hours after the application of FORTESTA onto each inner thigh, one thigh was wiped using dry sponges.  On the other thigh, the application site was washed with liquid soap and warm tap water, dried, and then wiped using dry sponges. The sponges were assayed for testosterone. A mean (SD) of 0.24 (0.009) mg of residual testosterone (i.e., 94.3% reduction compared to when application site was not washed) was recovered after application site washing.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

CLINICAL STUDIES

Clinical Study in Hypogonadal Males

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

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

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

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

 Table 5 Mean (±SD) Steady-State Testosterone Concentrations (C_avg and C_max) by final dose on Day 90

		Final Dose
		10mg (n=1)	20mg (n=6)	30mg (n=16)	40mg (n=30)	50mg (n=26)	60mg (n=27)	70mg (n=23)
Cavg (ng/dL)	Mean	196	464	392	444	483	441	415
	SD		205	164	176	156	163	136
Cmax (ng/dL)	Mean	503	971	775	855	964	766	724
	SD		399	278	417	389	292	313

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

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

Additionally, there were no clinically significant changes from baseline for sex hormone binding globulin (SHBG) (slight decrease), E2 (slight increase) and ratio of DHT to total testosterone (slight increase) at Day 90.