Prescription Drugs

CLINICAL PHARMACOLOGY 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.

DESCRIPTION TESTODERM (testosterone transdermal) ®TTS, TESTODERM (testosterone transdermal) ® and TESTODERM (testosterone transdermal) ® WITH ADHESVIE Testosterone Transdermal Systems (referred to collectively as the TESTODERM (testosterone transdermal) ® 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 (testosterone transdermal) ®TTS) or scrotal skin (TESTODERM (testosterone transdermal) ® and TESTODERM (testosterone transdermal) ® WITH ADHESVIE). The TESTODERM (testosterone transdermal) ® products are described below. Product Dose (mg/day) Size (cm2) Application Site Testoderm (testosterone transdermal) ® TTS 5 60 Arm, Back, Upper Buttocks Testoderm®* 5 60 Scrotum Testoderm®* 4 40 Scrotum Testoderm (testosterone transdermal) ® with Adhesive 6 60 Scrotum * The composition of the two sizes per unit area is identical. 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. TESTODERM (testosterone transdermal) ® TTS is composed of the following layers: a flexible backing of 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 a 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. TESTODERM (testosterone transdermal) ® 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. TESTODERM (testosterone transdermal) ® WITH ADHESVIE 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 covers the adhesive stripes and the adhesive-free area of the drug film. The liner must be removed before application. The active component of the systems is testosterone. The remaining components of the systems are pharmacologically inactive.

OVERDOSE 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. CONTRAINDICATIONS Androgens are contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate. The TESTODERM (testosterone (transdermal)) 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 (testosterone (transdermal)) 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 (testosterone (transdermal)) TTS).

SIDE EFFECTS 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: 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. 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 (

WARNINGS 1. Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce these adverse effects. 2. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma. 3. 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 (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility and Laboratory Tests). 4. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required. 5. Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism. 6. There are literature reports that the treatment of hypogonadal men with testosterone esters may potentiate sleep apnea in some patients,1,2 especially those with risk factors such as obesity or chronic lung diseases.3,4,5 PRECAUTIONS General The physician should instruct patients to report any of the following: Too frequent or persistent erections of the penis. Any nausea, vomiting, changes in skin color, or ankle swelling. Breathing disturbances, including those associated with sleep. 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 (testosterone (transdermal)) system, the potential for transfer of testosterone to a sexual partner was 6 mc g, 1/45th the daily endogenous testosterone production by the female body. TESTODERM (testosterone (transdermal)) TTS, unlike TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE, has an occlusive backing that prevents the partner from coming in contact with the active material in the system. If a TESTODERM (testosterone (transdermal)) 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. Information for Patients 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. Laboratory Tests Hemoglobin and hematocrit levels should be checked periodically (to detect polycythemia) in patients on long-term androgen therapy. Liver function, prostatic specific antigen, cholesterol, and high-density lipoprotein should be checked periodically. To ensure proper dosing, serum testosterone concentrations may be measured (see DOSAGE AND ADMINISTRATION ). Drug Interactions 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 diabetic 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 T4 serum levels and increased resin uptake of T3 and T4. 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 (testosterone (transdermal)) products are not indicated for women and must not be used in women. Nursing Mothers The TESTODERM (testosterone (transdermal)) products are not indicated for women and must not be used in women. Pediatric Use Safety and efficacy of the TESTODERM (testosterone (transdermal)) products in pediatric patients has not been established.