Testosterone Gel, 1% (Page 5 of 8)

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 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Testosterone gel, 1% 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 by 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.

10 OVERDOSAGE

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone concentrations of up to 11,400 ng/dL with a cerebrovascular accident.

Treatment of overdosage would consist of discontinuation of testosterone gel, 1%, washing the application site with soap and water, and appropriate symptomatic and supportive care.

11 DESCRIPTION

Testosterone Gel, 1% is a clear, colorless to yellowish hydroalcoholic gel containing testosterone.

The active pharmacologic ingredient in testosterone gel 1% is testosterone, an androgen. Testosterone, USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

http://medlibrary.org/lib/images-rx/testosterone-gel-1/structure.jpg

Pharmacologically inactive ingredients in testosterone gel, 1% are carbomer 980, ethyl alcohol 67.0%, isopropyl myristate, purified water, and sodium hydroxide. These ingredients are not pharmacologically active.

12 CLINICAL PHARMACOLOGY

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 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).

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted using testosterone gel, 1%.

12.3 Pharmacokinetics

Absorption

Testosterone gel, 1% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal concentrations (298 to 1043 ng/dL) seen in healthy men. Testosterone gel, 1% provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

Testosterone gel, 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from testosterone gel is absorbed into systemic circulation. In a study with testosterone gel, 1% 100 mg, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing.

With single daily applications of testosterone gel, 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (less than 300 ng/dL) maintained on testosterone gel, 1% 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration produced by testosterone gel, 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by testosterone gel, 1% 50 mg 566 (± 262) ng/dL.

Figure 1 : Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying Testosterone Gel, 1% Once Daily

//medlibrary.org/lib/images-rx/testosterone-gel-1/figure-01-300x162.jpg
(click image for full-size original)

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 concentrations increased in parallel with testosterone concentrations during testosterone gel, 1% treatment. The mean steady-state DHT/T ratio during 180 days of testosterone gel treatment ranged from 0.23 to 0.29 (50 mg of testosterone gel, 1%/day) and from 0.27 to 0.33 (100 mg of testosterone gel, 1%/day).

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 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.

When testosterone gel, 1% treatment is discontinued after achieving steady state, serum testosterone concentrations remain in the normal range for 24 to 48 hours but return to their pretreatment concentrations by the fifth day after the last application.

Testosterone Transfer from Male Patients to Female Partners

The potential for dermal testosterone transfer following testosterone gel, 1% use was evaluated in a clinical study between males dosed with testosterone gel, 1% and their untreated female partners. Two (2) to 12 hours after application of 100 mg of testosterone administered as testosterone gel, 1% by the male subjects, the couples (N = 38 couples) engaged in daily, 15-minute sessions of vigorous skin-to-skin contact so that the female partners gained maximum exposure to the testosterone gel, 1% application sites. Under these study conditions, all unprotected female partners had a serum testosterone concentration greater than 2 times the baseline value at some time during the study. When a shirt covered the application site(s), the transfer of testosterone from the males to the female partners was completely prevented.

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