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CONTROLLED DELIVERY
FOR ONCE-DAILY APPLICATION
TESTODERM® TTS, TESTODERM®, and TESTODERM® WITH ADHESIVE Testosterone Transdermal Systems (referred to collectively as the TESTODERM® products) are designed to release controlled amounts of testosterone, the primary circulating endogenous androgen, continuously upon application to the arm, back or upper buttocks (TESTODERM® TTS) or scrotal skin (TESTODERM® and TESTODERM® WITH ADHESIVE). The TESTODERM® products are described below.
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The active component of each of the systems is testosterone. Testosterone USP is a white or creamy-white crystalline powder or crystals chemically described as 17-beta hydroxyandrost-4-en-3-one. The remaining components of the systems are pharmacologically inactive.
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TESTODERM® TTS is composed of the following layers: a flexible backing of transparent polyester/ethylene-vinyl acetate copolymer film, a drug reservoir of testosterone USP and 1.2 mL alcohol USP gelled with hydroxypropyl cellulose, and an ethylene-vinyl acetate copolymer membrane coated with a layer of polyisobutylene adhesive formulation that controls the rate of release of testosterone from the system. A protective liner of silicone-coated polyester covers the adhesive surface. The liner must be removed before application.
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TESTODERM® is composed of two layers: a soft flexible backing of polyester and a testosterone-containing film of ethylene-vinyl acetate copolymer that contacts the skin surface and modulates the availability of the steroid. A protective liner of fluorocarbon diacrylate or silicone-coated polyester covers the drug film. The liner must be removed before application.
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TESTODERM® WITH ADHESIVE is composed of three layers: a soft flexible backing of polyester and a testosterone-containing film of ethylene-vinyl acetate copolymer. The surface of the drug film is partially covered by the third layer: thin and narrow adhesive stripes composed of polyisobutylene and colloidal silicon dioxide. A protective liner of fluorocarbon diacrylate-coated polyester covers the adhesive stripes and the adhesive-free area of the drug film. The liner must be removed before application.
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The TESTOSDERM® 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® products results in a serum testosterone profile that approximates the natural endogenous pattern of normal men.
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 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 doses 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.
Daily morning application of any of the TESTODERM® 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 concentrations rise to a maximum at 2 to 4 hours and return toward baseline within approximately 2 hours after system removal. The testosterone levels achieved with the TESTODERM® products generally are within the range for normal men. Patients vary in their ability to absorb testosterone transdermally (see Clinical Studies ).
TESTODERM® TTS
For TESTODERM® 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. The estimated mean pharmacokinetic parameters after Testoderm® TTS application to various skin sites are presented in Table 1.
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In clinical trials, 94% of patients on TESTODERM® TTS treatment achieved maximum and average serum testosterone concentrations (C max and C avg , respectively) within the normal range; the average C max and C avg serum testosterone concentrations were 531 ng/dL and 366 ng/dL, respectively. Within-subject coefficient of variation in testosterone C avg for subjects on TESTODERM® TTS therapy was 17%.
The typical steady state serum testosterone concentration pattern achieved with a nominal testosterone dose of 5 mg/day from TESTODERM® TTS is shown in Figure 1.
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Normal range serum testosterone concentrations are reached during the first day of dosing.
There is no accumulation of testosterone following repeated application of TESTODERM® TTS.
Two TESTODERM® 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®
Scrotal skin is at least five times more permeable to testosterone than other skin sites. TESTODERM® or TESTODERM® WITH ADHESIVE will not produce adequate serum testosterone concentrations if applied to non-scrotal skin.
Hypogonadal men using TESTODERM® therapy have trough serum testosterone concentrations that are about 15% of peak levels. Serum levels reach a plateau at 3 to 4 weeks.
TESTODERM® WITH ADHESIVE
Data from a pharmacokinetic trial in 50 normal male subjects show that TESTODERM® WITH ADHESIVE applied to scrotal skin is equivalent to TESTODERM® with respect to rate (C max ) and extent (AUC) of testosterone delivery.
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.
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® show elevated DHT concentrations and a change in the ratio of testosterone to DHT (T/DHT) during treatment. The range in this ratio ws 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® TTS treatment was not statistically significantly different from placebo treatment.
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.
Geriatric
In clinical trials with TESTODERM® TTS, C avg 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® products to compare testosterone pharmacokinetics in different racial groups.
There is no experience with the use of the TESTODERM® products in patients with renal insufficiency.
There is no experience with the use of the TESTODERM® products in patients with hepatic insufficiency.
See PRECAUTIONS : Drug Interactions .
TESTODERM® TTS
Of 32 hypogonadal men receiving daily application of a single TESTODERM® TTS system, 94% achieved normal serum concentrations of testosterone as determined by C max and C avg (200-1000 ng/dL). Mean free testosterone, estradiol, and dihydrotestosterone concentrations were also in the normal range after application of TESTODERM® TTS.
TESTODERM® and TESTODERM® WITH ADHESIVE
After at least 3 weeks of TESTODERM® therapy when steady-state is obtained, 30 hypogonadal men treated with 6 mg/day 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® 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® therapy produced positive effects on mood and sexual behavior. By five weeks, 45 patients not previously treated with TESTODERM® 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® 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.
The TESTODERM® products are indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone:
Androgens are contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate.
The TESTODERM® products are not indicated for use in women, have not been evaluated in women, and must not be used in women. Testosterone may cause fetal harm.
The TESTODERM® products should not be used in patients with known hypersensitivity to any components of the respective systems, e.g., ethanol (alcohol USP is a component of TESTODERM® TTS).
The physician should instruct patients to report any of the following:
Virilization of female partners has been reported with use of a topical testosterone solution. Percutaneous creams leave as much as 90 mg residual testosterone on the skin. The results from one study indicated that, after removal of a TESTODERM® system, the potential for transfer of testosterone to a sexual partner was 6 µg, 1/45th the daily endogenous testosterone production by the female body. TESTODERM® TTS, unlike TESTODERM® or TESTODERM® WITH ADHESIVE, has an occlusive backing that prevents the partner from coming in contact with the active material in the system. If a TESTODERM® TTS system is inadvertently transferred to a female partner, it should be removed immediately and the contacted skin washed. Changes in body hair distribution or significant increase in acne of the female partner should be brought to the attention of a physician.
An information brochure containing instructions for the use of TESTODERM® TTS is available. A separate instruction booklet is available for TESTODERM® and TESTODERM® WITH ADHESIVE. These booklets contain important information and instructions on how to properly use and dispose of the TESTODERM® products. Patients should be encouraged to ask questions of the physician and pharmacist.
Advise patients of the following:
Anticoagulants: C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped.
Oxyphenbutazone Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.
Insulin: In diebetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.
Propranolol: In a published pharmacokinetic study of an injectable testosterone product, administration of testosterone cypionate led to an increased clearance of propranolol in the majority of men tested. 6
Corticosteroids: The concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; thus these drugs should be administered cautiously, particularly in patients with cardiac or hepatic disease. 7
Drug/Laboratory Test Interactions
Androgens may decrease levels of thyroxin-binding globulin, resulting in decreased total T 4 serum levels and increased resin uptake of T 3 and T 4 . Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
Carcinogenesis, Mutagenesis, Impairment of Fertility Animal Data: Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which 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.
Human Data: There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.
Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma.
Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy.
In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men.
Pregnancy Category X (see Contraindications ). Teratogenic Effects: The TESTODERM® products are not indicated for women and must not be used in women.
Nursing Mothers: The TESTODERM® products are not indicated for women and must not be used in women.
Pediatric Use: Safety and efficacy of the TESTODERM® products in pediatric patients has not been established.
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® product.
In clinical studies of 457 participants (116 hypogonadal males and 341 healthy adult males) treated for up to 6 weeks with TESTODERM® TTS, the most commonly reported adverse events were application site reactions of transient itching (12%) and moderate or severe erythema (3%).
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Adverse events reported by less than 1% of TESTODERM® TTS users in clinical trials that were of probable or unknown relationship to drug were: Body as a Whole: abdominal pain, back pain, infection; Cardiovascular System: congestive heart failure, hypertension, tachycardia; Digestive System: diarrhea, nausea; Metabolic and Nutritional System: hyperglycemia, hyperlipemia, hyponatremia; Musculoskeletal System: arthralgia; Nervous System: nervousness, depression, dizziness, dry mouth, insomnia, decreased libido, personality disorder, CNS stimulation; Respiratory System: bronchitis; Skin System: application site reactions - papules/pustules, edema, vesicles, pain, other--, acne, alopecia, hirsutism; Urogenital System: abnormal ejaculation, breast pain, dysuria, urinary tract infection, and impaired urination.
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 (<65 years old) and older (>/= 65 years old) subjects.
A contact sensitization rate of 0.5% for TESTODERM® TTS was observed in a 6-week study of 233 normal male volunteers.
In one study with 14 days of daily use, 42% of patients reported 3 or more detachments of their TESTODERM® TTS; of these detachments, 33% occurred during exercise.
In clinical studies of 104 patients treated with TESTODERM®, the most common adverse effects reported were local effects. In US clinical trials, most of the 72 patients filling out a daily questionnaire reported scrotal itching, discomfort, or irritation at some time during therapy. Of all the daily questionnaire responses, 7% reported itching, 4% discomfort, and 2% irritation. All topical reactions decreased with duration of use.
The following adverse effects (greater than 1%) were reported in association with TESTODERM® therapy in 104 patients using the product for up to three years. These effects are listed in decreasing frequency of occurrence with the percentages of patients reporting the effect in parentheses: Gynecomastia (5%), acne (4%), prostatitis/urinary tract infection (4%), breast tenderness (3%), stroke (2%). For this same patient population, the following adverse effects were reported by 1% of users: memory loss, pupillary dilation, abnormal liver enzymes, scrotal cellulitis, deep vein phlebitis, benign prostatic hyperplasia, rectal mucosal lesion over prostate, hematuria/bladder cancer, papilloma on scrotum, and congestive heart failure.
See CLINICAL PHARMACOLOCY , Clinical Studies , regarding effects on serum lipids.
In a pharmacokinetic study in 50 normal men, skin assessment scores following a single 24-hour application of TESTODERM® WITH ADHESIVE to scrotal skin were similar to those for TESTODERM®. Other adverse events reported during the study were headache (6%), dizziness (6%), back pain, pain, nausea, and pustular rash (1% each).
Skin and Appendages: Hirsutism, male pattern baldness, seborrhea, and acne.
Endocrine and Urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high doses (see CLINICAL PHARMACOLOGY ).
Fluid and Electrolyte Disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
Gastrointestinal Nausea, cholestatic jaundice, alterations in liver function tests. Rare instances of hepatocellular neoplasms and peliosis hepatis have occurred (see ).
Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.
Nervous System: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
Metabolic: Increased serum cholesterol.
Miscellaneous: Rarely, anaphylactoid reactions.
The TESTODERM® products contain a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.
TESTODERM® TTS is designed for application to arm, back or upper buttocks skin.
TESTODERM® and TESTODERM® WITH ADHESIVE are designed for application to scrotal skin only. Because scrotal skin is at least five times more permeable to testosterone than other skin sites, TESTODERM® or TESTODERM® WITH ADHESIVE will not produce adequate serum testosterone concentrations if applied to non-scrotal skin.
Ingestion of testosterone, or the contents of any of the TESTODERM® products will not result in clinically significant serum testosterone concentrations due to extensive first-pass metabolism. In addition, an intramuscular injection of testosterone from any of the TESTODERM® products will not produce adequate serum testosterone levels due to its short half-life (about 10 minutes).
There is one report of acute overdosage by injection of testosterone enanthate: testosterone levels of up to 11,400 ng/dL were implicated in a cerebrovascular accident.
One system is applied at about the same time each day. The adhesive side of the TESTODERM® TTS system should be placed on a clean, dry area of skin on the arm, back or upper buttocks immediately upon removal from the protective pouch. DO NOT APPLY TO THE SCROTUM. The area selected should not be oily, damaged, or irritated. The system should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. In the event that a system should fall off, the same system may be reapplied. If the system comes off after it has been worn for more than 12 hours and it cannot be reapplied, a new system may be applied at the next routine application time. In either case, the daily treatment schedule should be continued. The TESTODERM® TTS system should be worn approximately 24 hours and then replaced. To ensure proper dosing, serum testosterone concentration may be measured 2-4 hours after an application of TESTODERM® TTS. If the serum testosterone concentrations are low, the dosing regimen may be increased to 2 systems. Because of variability in analytical values among diagnostic laboratories, all testosterone measurements should be performed at the same laboratory.
Patients should start therapy with a 6 mg/day system of either TESTODERM® or TESTODERM® WITH ADHESIVE applied daily; if the scrotal area cannot accommodate a 6 mg/day system, a 4 mg/day TESTODERM® system should be used. One TESTODERM® or TESTODERM® WITH ADHESIVE system should be placed on clean, dry, scrotal skin. Scrotal hair should be dry-shaved for optimal skin contact. Chemical depilatories should not be used (see Patient Information ). TESTODERM® or TESTODERM® WITH ADHESIVE should be worn 22-24 hours.
After 3-4 weeks of daily system use, blood should be drawn 2-4 hours after system application for determination of serum total testosterone. Because of variability in analytical values among diagnostic laboratories, this laboratory work and later analyses for assessing the effect of the TESTODERM® and TESTODERM® WITH ADHESIVE therapy should be performed at the same laboratory.
If patients have not achieved desired results by the end of 6-8 weeks of treatment with any of the TESTODERM® products, another form of testosterone replacement therapy should be considered.
TESTODERM® TTS, TESTODERM®, and TESTODERM® WITH ADHESIVE testosterone transdermal systems contain a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.
TESTODERM® TTS
TESTODERM® TTS systems are supplied as individually pouched systems, 30 per carton. TESTODERM® TTS 5 mg/day (Testosterone Transdermal System) - each 60 cm 2 system contains 328 mg testosterone USP for nominal dose of 5 mg/day
Carton of 30 TESTODERM® TTS 5 mg/day systems
............................................... NDC 17314-4717-3
TESTODERM® and TESTODERM® WITH ADHESIVE
TESTODERM® and TESTODERM® WITH ADHESIVE systems are supplied as individually pouched systems, 30 per carton.
TESTODERM® 4 mg/day (Testosterone Transdermal System) - each 40 cm 2 system contains 10 mg testosterone USP for nominal delivery of 4 mg for one day.
Carton of 30 TESTODERM® 4 mg/day systems
............................................... NDC 17314-4608-3
TESTODERM® and TESTODERM® WITH ADHESIVE
6 mg/day (Testosterone Transdermal System) - each 60 cm 2 system contains 15 mg testosterone USP for nominal delivery of 6 mg for one day.
Carton of 30 TESTODERM® 6 mg/day systems
............................................... NDC 17314-4609-3
Carton of 30 TESTODERM® WITH ADHESIVE 6 mg/day systems
............................................... NDC 17314-2836-3
TESTODERM® TTS
Store at controlled room temperature below 25°C (77°F).
TESTODERM® and TESTODERM® WITH ADHESIVE
Store at room temperature 15°-30°C (59°-86°F).
TESTODERM® products should be discarded in household trash in a manner that prevents accidental application or ingestion by children or pets.
Rx only
Manufactured by ALZA Corporation, Palo Alto, CA 94304, USA.
ALZA PHARMACEUTICALS
A DIVISION OF ALZA CORPORATION
Edition: 01/98
00071212
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