Testoderm

Testosterone

The TESTODERM (testosterone (transdermal)) ® products deliver physiologic amounts of testosterone, the primary endogenous androgenic hormone. Endogenous testosterone serum concentrations in normal males follow a circadian pattern. Daily morning application of any of the TESTODERM (testosterone (transdermal)) ® products results in a serum testosterone profile that approximates the natural endogenous pattern of normal men.

General Androgen Effects

Endogenous androgens, including testosterone and dihydrotesterone (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 chord thickening, alterations in body musculature, and fat distribution. DHT is 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. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, and regression of secondary sexual characteristics.

Drugs in the androgen class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.

Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietin.

During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large does of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).

There is a lack of substantial evidence that androgens are effective in accelerating fracture healing or in shortening post-surgical convalescence.

Pharmacokinetics

Absorption

Daily morning application of any of the TESTODERM (testosterone (transdermal)) ® products approximates the natural endogenous pattern of serum testosterone of normal males. Following application, testosterone is continuously absorbed during the 24-hour dosing period. The serum testosterone concentration rises to a maximum at 2 to 4 hours and return toward baseline within approximately 2 hours after system removal. The testosterone levels achieved with TESTODERM (testosterone (transdermal)) ® products generally are within the range for normal men. Patients vary in their ability to absorb testosterone transdermally (see Clinical Studies).

TESTODERM (testosterone (transdermal)) ® TTS
For TESTODERM (testosterone (transdermal)) ® TTS three skin sites (arm, back, and upper buttocks), representing recommended application sites, are interchangeable based on equivalent testosterone AUC (0-27) (area under serum concentration curve) values.

In clinical trials, 94% of patients on TESTODERM (testosterone (transdermal)) TTS treatment achieved maximum and average serum testosterone concentrations (Cmax and Cavg, respectively) within the normal range; the average Cmax and Cavg serum testosterone concentrations were 531 ng/dL and 366 ng/dL, respectively. Within-subject coefficient of variation in testosterone Cavg for subjects on TESTODERM (testosterone (transdermal)) TTS therapy was 17%.

The typical steady state serum testosterone concentration pattern achieved with a nominal testosterone dose of 5 mg/day from TESTODERM (testosterone (transdermal)) TTS is shown in Figure 1.

Figure 1. Serum concentrations of testosterone (mean ± SD) during pretreatment baseline or while wearing a TESTODERM (testosterone (transdermal)) TTS system on the upper buttocks (n=32). Systems were applied at 0 hours (8 AM) and removed 24 hours later.
Normal range serum testosterone concentrations are reached during the first day of dosing.
There is no accumulation of testosterone following repeated application of TESTODERM (testosterone (transdermal)) TTS.
Two TESTODERM (testosterone (transdermal)) TTS systems deliver a testosterone dose which is twice that delivered by a single system.
There is no first-pass skin metabolism of testosterone to DHT when applied to arm, back or upper buttocks skin sites as recommended.

TESTODERM (testosterone (transdermal))
Scrotal skin is at least five times more permeable to testosterone than other skin sites. TESTODERM (testosterone (transdermal)) or TESTODERM (testosterone (transdermal)) WITH ADHESIVE will not produce adequate serum testosterone concentrations if applied to non-scrotal skin.

Hypogonadal men using TESTODERM (testosterone (transdermal)) therapy have trough serum testosterone concentrations that are about 15% of peak levels. Serum levels reach a plateau at 3 to 4 weeks.

TESTODERM (testosterone (transdermal)) WITH ADHESIVE
Data from a pharmacokinetic trial in 50 normal male subjects show that TESTODERM (testosterone (transdermal)) WITH ADHESIVE applied to scrotal skin is equivalent to TESTODERM (testosterone (transdermal)) with respect to rate (Cmax) and extent (AUC) of testosterone delivery.

Distribution

Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life.

Metabolism

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. Testosterone is a substrate for conversion to an active metabolite, dihydrotestosterone (DHT). Testosterone is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol and DHT. Concentrations of estradiol in normal men are 1.0 to 5.0 ng/dL. DHT concentrations in normal male serum are 30 to 85 ng/dL. DHT binds with greater affinity to SHBG than does testosterone. In many tissues the activity of testosterone appears to depend on reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-alpha and 3-beta androstanediol.

Composite results of all studies with TESTODERM (testosterone (transdermal)) show elevated DHT concentrations and a change in the ratio of testosterone to DHT (T/DHT) during treatment. The range in this ratio was 0.7 - 12.5, as compared with a ratio of 3.6 - 15.2 in normal untreated men. The long-term effects of the change in this ratio are not known.

The T/DHT ratio during TESTODERM (testosterone (transdermal)) TTS treatment was not statistically significantly different from placebo treatment.

Excretion

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.

Special Populations

Geriatric

In clinical trials with TESTODERM (testosterone (transdermal)) TTS, Cavg testosterone concentrations were not different between men aged 65 and older and younger adult males.

Race

There is insufficient information available from trials with the TESTODERM (testosterone (transdermal)) products to compare testosterone pharmacokinetics in different racial groups.

Renal Insufficiency

There is no experience with the use of the TESTODERM (testosterone (transdermal)) products in patients with renal insufficiency.

Hepatic Insufficiency

There is no experience with the use of the TESTODERM (testosterone (transdermal)) products in patients with hepatic insufficiency.

Drug-Drug Interactions

See PRECAUTIONS: Drug Interactions.

Clinical Studies

TESTODERM (testosterone (transdermal)) TTS
Of 32 hypogonadal men receiving daily application of a single TESTODERM (testosterone (transdermal)) TTS system, 94% achieved normal serum concentrations of testosterone as determined by Cmax and Cavg (200-1000 ng/dL). Mean free testosterone, estradiol, and dihydrotestosterone concentrations were also in the normal range after application of TESTODERM (testosterone (transdermal)) TTS.

TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE
After at least 3 weeks of TESTODERM (testosterone (transdermal)) therapy when steady-state is obtained, 30 hypogonadal men treated with 6 mg/d systems for 22 hours daily achieved mean maximum serum testosterone concentrations of 593 ng/dL at 2 to 4 hours post application. Sixty percent of the patients achieved individual maximal testosterone concentrations >500 ng/dL. The mean 24 hour steady-state AUC (area under the curve) value was 9132 ng/dL. The mean DHT serum concentrations ranged from 134 to 162 ng/dL. Normal levels of testosterone have been maintained in patients who have worn the systems for up to six years. DHT levels also remain stable. The increase in serum testosterone concentration is proportional to the size of the system.

The variability of total testosterone concentrations among patients receiving TESTODERM (testosterone (transdermal)) treatment was 35% to 49%. The coefficient of variation of total testosterone concentrations within individual patients was 30% to 41%. This variability is comparable to the values reported in the literature for both normal and hypogonadal men.

In two 12-week clinical studies in 72 hypogonadal men, TESTODERM (testosterone (transdermal)) therapy produced positive effects on mood and sexual behavior. By five weeks, 45 patients not previously treated with TESTODERM (testosterone (transdermal)) showed statistically significant increases in sexual activity. Compared to baseline, mean sexual events per week increased for sexual intercourse (0.3 to 0.8), orgasm (0.4 to 1.2), waking erections (1.0 to 3.5), and spontaneous erections (0.4 to 2.8).

Changes in nonfasting serum lipid concentrations were observed during TESTODERM (testosterone (transdermal)) therapy. By three months total cholesterol and high-density lipoprotein cholesterol decreased an average of 8% and 13%, respectively. High-density lipoprotein cholesterol remained stable thereafter. Total cholesterol continued to decrease through two years. At the end of two years, the total cholesterol/high-density lipoprotein cholesterol ratio was not different from pretreatment values.

Estradiol levels increased to the normal range with treatment. Sporadic elevations of estradiol above the normal range for men were observed in 3 of 72 patients and these were not associated with feminizing side effects.

An information brochure containing instructions for the use of TESTODERM (testosterone (transdermal)) TTS is available. A separate instruction booklet is available for TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE. These booklets contain important information and instructions on how to properly use and dispose of the TESTODERM (testosterone (transdermal)) products. Patients should be encouraged to ask questions of the physician and pharmacist.

Advise patients of the following:

• TESTODERM (testosterone (transdermal)) TTS should not be applied to the scrotum.
• TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE are designed for application to scrotal skin only.
• The TESTODERM (testosterone (transdermal)) products should be applied once daily to dry, clean skin. If the TESTODERM (testosterone (transdermal)) product has come off after it has been worn for more than 12 hours and it cannot be reapplied, the patient may wait until the next routine application time to apply a new system.

Adverse events are reported in this section by product. Adverse events reported during use of a given product may occur in patients who are treated with any TESTODERM (testosterone (transdermal)) product.

Adverse Events with TESTODERM (testosterone (transdermal)) TTS
In clinical studies of 457 participants (116 hypogonadal males and 341 healthy adult males) treated for up to 6 weeks with TESTODERM (testosterone (transdermal)) TTS, the most commonly reported adverse events were application site reactions of transient itching (12%) and moderate or severe erythema (3%).

Adverse events reported by less than 1% of TESTODERM (testosterone (transdermal)) TTS users in clinical trials that were of probable or unknown relationship to drug were:

Topical Reactions
Of 457 study participants, 3 men (1%) discontinued prematurely because of application site reactions.

There were no clinically significant differences in skin tolerability in younger (

• Delatestryl
• Fortesta
• Natesto

• Striant
• Vogelxo

© Testoderm Patient Information is supplied by Cerner Multum, Inc. and Testoderm Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Testosterone is a prescription medication used to treat low testosterone levels (hypogonadism) in men who do not produce enough natural testosterone. It may also be used to treat delayed puberty in adolescent males. Testosterone may also be administered to women to treat certain types of cancer.

Testosterone is a hormone that is usually produced by the body. It controls the growth, development, and function of male sexual organs and characteristics.

This medication comes in several topical forms for the skin, nose, and mouth that are applied to the body one to three times daily, depending on the dosage form.

This medication is also available in an injectable form to be given directly into a muscle (IM) by a healthcare professional.

Common side effects of testosterone include irritation and redness at the site of application, headache, acne, stomach pain, nervousness, hair loss, changes in mood and behavior, and changes in the ability to taste or smell.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• Oral steroids such as dexamethasone (Decadron, Dexone), methylprednisone (Medrol), and prednisone (Deltasone)
• Inhaled steroids such as beclomethasone (QVAR), budesonide (Pulmicort, Rhinocort), flunisolide (AeroBid), fluticasone (Flovent, in Advair), and triamcinolone (Azmacort)
• Topical steroids such as alclometasone (Aclovate), betamethasone (Diprolene, Valisone), clobetasol (Temovate), desonide (DesOwen), Desoximetasone (Topicort), diflorasone (Psorcan, Florone), Fluocinolone (Derma-Smoother, Flurosyn, Synalar), fluocinonide (Lidex), flurandrenolide (Cordran), fluticasone (Cutivate), halcinonide (Halog), halobetasol (Ultravate), hydrocortisone (Cortizone, Westcort), mometasone (Elocon), and triamcinolone (Aristocort)
• Anticoagulants such as warfarin (Coumadin)
• Cosyntropin
• Propanolol (Inderal)
• Insulin

This is not a complete list of testosterone drug interactions. Ask your doctor or pharmacist for more information.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your age
• your gender

Topical:

The recommended dose of testosterone gel for the treatment of hypogonadism in males is 50 to 100 mg daily applied to the skin. The recommended dose of the nasal formulation of testosterone is 11 mg daily. The recommended dose of the buccal system of testosterone is 30 mg twice daily. The recommended dose of the testosterone transdermal patch is 4 to 6 mg daily.

Injectable:

The recommended dose of testosterone for the treatment of hypogonadism in males is 50 to 400 mg every 2 to 4 weeks.

The recommended dose of testosterone for the treatment of delayed puberty in adolescent males is 50 to 200 mg every 2 to 4 weeks for 4 to 6 months.