FORTESTA (Page 4 of 7)

8.2 Lactation

Risk Summary

FORTESTA is not indicated for use in females.

8.3 Females and Males of Reproductive Potential


During treatment with large doses of exogenous androgens, including FORTESTA, 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.

8.4 Pediatric Use

The safety and efficacy of FORTESTA in pediatric patients <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 FORTESTA 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 FORTESTA, 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.

8.6 Renal Impairment

No studies were conducted in patients with renal impairment.

8.7 Hepatic Impairment

No studies were conducted in patients with hepatic impairment.


9.1 Controlled Substance

FORTESTA 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 in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse of men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids, and include 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.

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

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

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 include 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.


There is a single report of acute overdosage after parenteral administration of an approved testosterone product in the literature. This subject had serum testosterone concentrations of up to 11,400 ng/dL, which were implicated in a cerebrovascular accident. There were no reports of overdose in the FORTESTA clinical trial.

Treatment of overdosage would consist of discontinuation of FORTESTA, washing the application site with soap and water, and appropriate symptomatic and supportive care.


FORTESTA is a clear, colorless to slightly yellow, odorless, gel containing testosterone. The product may attain slightly yellow color during its shelf-life. 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 (1) 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.

Testosterone USP Chemical Structure
(click image for full-size original)

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


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 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).

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted using FORTESTA.

12.3 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)
(click image for full-size original)

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)

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.

Testosterone is metabolized to various 17-keto steroids through 2 different pathways. The major active metabolites of testosterone are estradiol and DHT.

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, 3-way crossover study. The washout period was approximately 29 days. Six (6) males were treated with either FORTESTA (30 mg testosterone) or placebo to 1 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 average concentration (Cavg ) increased by 134% and mean maximum concentration (Cmax ) 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 Cavg decreased by 3% and mean Cmax 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 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 Cavg by 3% and it increased Cmax 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 wipe the index finger using dry sponges to collect residual testosterone. A mean (SD) of 0.002 (0.006) mg of residual testosterone (ie, 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 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 (ie, 94.3% reduction compared to when application site was not washed) was recovered after application site washing.

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