1 INDICATIONS AND USAGE ANDRODERM is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. • Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter Syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above the normal range. • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use • Safety and efficacy of ANDRODERM in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. • Safety and efficacy of ANDRODERM in males less than 18 years old have not been established [see Use in Specific Populations (8.4) ]. ANDRODERM is an androgen indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone (1): Primary hypogonadism (congenital or acquired) Hypogonadotropic hypogonadism (congenital or acquired) Limitations of use: Safety and efficacy of ANDRODERM in men with “age-related hypogonadism” have not been established. (1) Safety and efficacy of ANDRODERM in males less than 18 years old have not been established. (1, 8.4)
3 DOSAGE FORMS AND STRENGTHS Transdermal system: 2 mg/day and 4 mg/day. Transdermal system: 2 mg/day and 4 mg/day. (3)
4 CONTRAINDICATIONS ANDRODERM is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.1) ]. ANDRODERM is contraindicated in women who are, or who may become pregnant, or who are breastfeeding. ANDRODERM may cause fetal harm when administered to a pregnant woman. ANDRODERM may cause serious adverse reactions in nursing infants. If a pregnant woman is exposed to ANDRODERM, she should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 , 8.3 ) ]. Men with carcinoma of the breast or known or suspected carcinoma of the prostate. (4, 5.1) Pregnant or breastfeeding women. Testosterone may cause fetal harm. (4, 8.1, 8.3)
5 WARNINGS AND PRECAUTIONS Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. (5.1) Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. (5.3) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with the use of testosterone replacement therapy. (5.4) Avoid exposure of women or children to ANDRODERM. (5.5) Exogenous administration of testosterone may lead to azoospermia. (5.6) Edema with or without congestive heart failure, may be a complication in patients with pre-existing cardiac, renal, or hepatic disease. (5.8) Sleep apnea may occur in those with risk factors. (5.10) Monitor serum testosterone, prostate specific antigen (PSA), liver function, lipid concentrations, hematocrit and hemoglobin periodically. (5.1, 5.2, 5.7, 5.11) Skin burns have been reported at the application site in patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because ANDRODERM contains aluminum, it is recommended to remove the system before undergoing an MRI. (5.14) 5.1 Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating treatment. It is appropriate to re-evaluate patients 3 to 6 months after initiation of treatment, and then in accordance with prostate cancer screening practices [see Contraindications (4) ]. 5.2 Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating testosterone treatment. It is appropriate to re-evaluate the hematocrit 3 to 6 months after starting testosterone treatment, and then monitor annually. Discontinue testosterone therapy if the hematocrit becomes elevated. Testosterone therapy may be restarted when the hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.3 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as ANDRODERM. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with ANDRODERM and initiate appropriate workup and management [see Adverse Reactions (6.2) ]. 5.4 Cardiovascular Risk Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE) such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use ANDRODERM. 5.5 Use in Women and Children Women and children should not use ANDRODERM. Use in women and children has not been studied with ANDRODERM. Due to lack of controlled studies in women and potential virilizing effects, ANDRODERM is not indicated for use in women and children [see Contraindications (4) and Use in Specific Populations ( 8.1 , 8.3 , 8.4 )]. 5.6 Potential for Adverse Effects on Spermatogenesis At large doses of exogenous androgens, including ANDRODERM, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) that could lead to adverse effects on semen parameters including reduction of sperm count. 5.7 Hepatic Adverse Effects Prolonged use of high doses of orally active 17-alpha-alkyl androgens (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 intramuscular testosterone enanthate has produced multiple hepatic adenomas. ANDRODERM is not known to cause these adverse effects. 5.8 Edema Androgens, including ANDRODERM, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease [see Adverse Reactions (6) ]. 5.9 Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including ANDRODERM, for hypogonadism. 5.10 Sleep Apnea The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity and chronic lung disease. 5.11 Lipids Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy. 5.12 Hypercalcemia Androgens, including ANDRODERM, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients. 5.13 Decreased Thyroxine-Binding Globulin Androgens, including ANDRODERM, may decrease concentrations of thyroxine-binding globulins, resulting in decreased total T4 serum concentration and increased resin uptake of T3 and T4. Free thyroid hormone concentration remains unchanged and there is no clinical evidence of thyroid dysfunction. 5.14 Magnetic Resonance Imaging (MRI) Skin burns have been reported at the application site in patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because ANDRODERM contains aluminum, it is recommended to remove the system before undergoing an MRI.
6 ADVERSE REACTIONS The most common adverse reactions (incidence > 3%) are application site reactions, and back pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 shows the adverse reactions that were reported by > 3% of 36 hypogonadal men who were treated with ANDRODERM 2 mg/day, 4 mg/day, or 6 mg/day for 28 days. Of note, all hypogonadal men studied had been stable users of topical testosterone replacement products prior to the study and there was no washout period between therapies. Furthermore, there was only one subject titrated to 6 mg/day and he withdrew from the study prematurely. Table 1. Adverse Reactions Seen With the Use of ANDRODERM 2 mg/day, 4 mg/day, or 6 mg/day (> 3%) Adverse Reaction Overall N = 36 % Application site pruritus 17 Application site vesicles 6 Back pain 6 Other less common adverse reactions reported by < 3% of patients included: application site erythema, application site exfoliation, chills, diarrhea, fatigue, gastroesophageal reflux disease, hemarthrosis, hematuria, headache, polyuria, and prostatitis. The overall incidence of application site reactions of any kind was 28% (10 subjects with 13 adverse reactions). No serious adverse reactions to ANDRODERM 2 mg/day and 4 mg/day were reported during the clinical trial. Table 2 shows the adverse reactions that were reported in > 3% of 122 patients in clinical studies with ANDRODERM dosage strengths of 2.5 mg/day, 5 mg/day, and 7.5 mg/day. The most common adverse reactions reported were application site reactions. Transient mild to moderate erythema was observed at the site of application in the majority of patients at some time during treatment. The overall incidence of application site reactions of any kind was 48% (59 subjects with 107 adverse reactions). Table 2. Adverse Reactions Seen With the Use of ANDRODERM 2.5 mg/day, 5 mg/day, or 7.5 mg/day (> 3%) Adverse Reaction Overall N = 122 % Application site pruritus 37 Application site blistering 12 Application site erythema 7 Application site vesicles 6 Prostate abnormalities 5 Headache 4 Contact dermatitis to system 4 Application site burning 3 Application site induration 3 Depression 3 The following reactions occurred in less than 3% of patients: rash, gastrointestinal bleeding, fatigue, body pain, pelvic pain, hypertension, peripheral vascular disease, increased appetite, accelerated growth, anxiety, confusion, decreased libido, paresthesia, thinking abnormalities, vertigo, acne, bullae at application site, mechanical irritation at application site, rash at application site, contamination of application site, prostate carcinoma, dysuria, hematuria, impotence, urinary incontinence, urinary tract infection, and testicular abnormalities. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ANDRODERM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Disorders: Myocardial infarction, stroke [see Warnings and Precautions (5.4) ] Vascular Disorders: Venous thromboembolism [see Warnings and Precautions (5.3) ]
7 DRUG INTERACTIONS Androgens may decrease blood glucose and insulin requirement in diabetic patients. (7.1) Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended. ( 7.2) Use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease. (7.3) 7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirement. 7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored, particularly in patients with cardiac, renal or hepatic disease. 7.4 Triamcinolone The topical administration of 0.1% triamcinolone cream to the skin under the central drug reservoir prior to the application of the ANDRODERM system did not significantly alter transdermal absorption of testosterone; however, the rate of complete adherence was lower. Pretreatment with triamcinolone ointment formulation significantly reduced testosterone absorption from the ANDRODERM system.
8 USE IN SPECIFIC POPULATIONS There are insufficient long-term safety data in geriatric patients using ANDRODERM to assess the potential risks of cardiovascular disease and prostate cancer. (8.5) 8.1 Pregnancy Pregnancy Category X [see Contraindications (4) ] — ANDRODERM is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers Although it is not known how much testosterone transfers into human milk, ANDRODERM is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation [see Contraindications (4) ]. 8.4 Pediatric Use Safety and efficacy of ANDRODERM have not been established in males <18 years of age. Improper use may result in acceleration of bone age and premature closure of epiphyses. 8.5 G eriatric Use There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing ANDRODERM to determine whether efficacy in those over 65 years of age differs from younger patients. Additionally, there are insufficient long-term safety data in geriatric patients utilizing ANDRODERM to assess a potential incremental risk of cardiovascular disease and prostate cancer. 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.