Androderm

ANDRODERM is an androgen 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): idiopathic 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.

Important Limitations Of Use

Safety and efficacy of ANDRODERM in males < 18 years old have not been established .

Dosing Information

The recommended starting dose is one ANDRODERM 4 mg/day system (not two 2 mg/day systems) applied nightly for 24 hours, delivering approximately 4 mg of testosterone per day. To ensure proper dosing, approximately 2 weeks after starting therapy, the early morning serum testosterone concentration should be measured following system application the previous evening. Serum concentrations outside the range of 400 – 930 ng/dL require increasing the daily dose to 6 mg (i.e., one 4 mg/day and one 2 mg/day system) or decreasing the daily dose to 2 mg (i.e., one 2 mg/day system), maintaining nightly application.

Patients currently maintained on ANDRODERM 2.5 mg/day, 5 mg/day, and 7.5 mg/day may be switched to the 2 mg/day, 4 mg/day, and 6 mg/day dosage using the following schema:

• Patients using 2.5 mg daily may be switched to 2 mg/day systems at the next scheduled dose.
• Patients using 5 mg daily may be switched to 4 mg/day systems at the next scheduled dose.
• Patients using 7.5 mg daily may be switched to 6 mg (2 mg/day and 4 mg/day systems) at the next scheduled dose.

To ensure proper dosing, approximately 2 weeks after switching therapy, the early morning serum testosterone concentration should be measured following system application the previous evening.

The adhesive side of the ANDRODERM system should be applied to a clean, dry area of the skin on the back, abdomen, upper arms, or thighs. Avoid application over bony prominences or on a part of the body that may be subject to prolonged pressure during sleep or sitting (e.g., the deltoid region of the upper arm, the greater trochanter of the femur, and the ischial tuberosity). DO NOT APPLY TO THE SCROTUM. The sites of application should be rotated, with an interval of 7 days between applications to the same site. The area selected should not be oily, damaged, or irritated.

The system should be applied immediately after opening the pouch and removing the protective release liner. The system should be pressed firmly in place, making sure there is good contact with the skin, especially around the edges.

The patient should avoid swimming, showering, or washing the administration site for a minimum of 3 hours after application .

Mild skin irritation may be ameliorated by treatment of the affected skin with over-thecounter topical hydrocortisone cream applied after system removal. Applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the central drug reservoir of the ANDRODERM system has been shown to reduce the incidence and severity of skin irritation.

• ANDRODERM is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate .
• 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 .

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 .

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.

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 .

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.

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.

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 preexisting cardiac, renal, or hepatic disease .

Gynecomastia

Gynecomastia may develop and persist in patients being treated with androgens, including ANDRODERM, for hypogonadism.

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.

Lipids

Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.

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.

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.

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.

Patient Counseling Information

Use in Men with Known or Suspected Prostate or Breast Cancer

Men with known or suspected prostate or breast cancer should not use ANDRODERM .

Potential Adverse Reactions with Androgens

Patients should be informed that treatment with androgens may lead to adverse reactions that include:

• Changes in urinary habits such as increased urination at night, trouble starting your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having a urine accident, being unable to pass urine and having a weak urine flow
• Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness
• Too frequent or persistent erections of the penis
• Nausea, vomiting, changes in skin color, or ankle swelling

Patients Should be Advised of these Application Instructions

• ANDRODERM should not be applied to the scrotum.
• ANDRODERM should not be applied over a bony prominence or on a part of the body that could be subject to prolonged pressure during sleep or sitting. Application to these sites has been associated with burn-like blister reactions.
• ANDRODERM does not have to be removed during sexual intercourse, nor while taking a shower or bath.
• ANDRODERM systems should be applied nightly. The site of application should be rotated, with an interval of 7 days between applications to the same site.
• If the ANDRODERM system becomes loose, smooth it down again by rubbing your finger firmly around the edges. If a patch falls off before noon, replace it with a fresh patch and wear it until you apply a fresh patch(es) that evening. If it falls off later in the day, do not replace it until you apply a fresh patch(es) that evening. If it falls off do not tape ANDRODERM to skin.
• If patients or caregivers experience difficulty separating the patch from the release liner or observe transfer of adhesive to the liner, tearing and/or other damage to the patch during removal from the liner, the patch should be discarded, and a new patch should be applied.
• ANDRODERM should be applied immediately after opening the individual pouch and removing the protective liner. Do not use if the individual pouch seal is broken or if the patch appears to be damaged. Do not cut patches. Only intact patches should be applied.
• Strenuous exercise or excessive perspiration may loosen a patch or cause it to fall off.
• 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.
• Avoid swimming or showering until 3 hours following application of ANDRODERM .

For all medical inquiries contact: WATSON Medical Communications Parsippany, NJ 07054 800-272-5525

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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. Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

Use In Specific Populations

Pregnancy

Pregnancy Category X — 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.

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 .

Pediatric Use

Safety and efficacy of ANDRODERM have not been established in males less than18 years of age. Improper use may result in acceleration of bone age and premature closure of epiphyses.

Geriatric 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.

Renal Impairment

No studies were conducted in patients with renal impairment.

Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

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.

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.

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.

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.

Drug Abuse And Dependence

Controlled Substance

ANDRODERM contains testosterone, a Schedule III controlled substance under the Anabolic Steroids Control Act.

Abuse

Anabolic steroids, such as testosterone, are abused. Abuse is often associated with adverse physical and psychological effects.

Dependence

Although drug dependence is not documented in individuals using therapeutic doses of anabolic steroids for approved indications, dependence is observed in some individuals abusing high doses of anabolic steroids. In general, anabolic steroid dependence is characterized by any three of the following:

• Taking more drug than intended
• Continued drug use despite medical and social problems
• Significant time spent in obtaining adequate amounts of drug
• Desire for anabolic steroids when supplies of the drug are interrupted
• Difficulty in discontinuing use of the drug despite desires and attempts to do so
• Experience of withdrawal syndrome upon discontinuation of anabolic steroid use

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%)

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%)

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.

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.

Vascular Disorders

Venous thromboembolism

No cases of overdose with ANDRODERM have been reported in clinical trials. There is one report of acute overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of ANDRODERM together with appropriate symptomatic and supportive care.

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; and alterations in body musculature and fat distribution. Testosterone and DHT are 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. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics, and osteoporosis.

Male hypogonadism has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter Syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

Pharmacodynamics

No specific pharmacodynamic studies were conducted using ANDRODERM.

Pharmacokinetics

Absorption

ANDRODERM delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate the normal concentration range (300 – 1030 ng/dL) seen in healthy men. ANDRODERM provides a continuous daily dose of testosterone in a self-contained transdermal system. Following ANDRODERM application, testosterone is continuously absorbed during the 24-hour dosing period with a median (range) Tmax of 8 (4-12) hours.

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).

During steady-state pharmacokinetic studies in hypogonadal men treated with ANDRODERM, the average DHT:T and E2:T ratios were approximately 1:10 and 1:200, respectively.

Excretion

There is considerable variation in the half-life of testosterone 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.

Upon removal of the ANDRODERM systems, serum testosterone concentrations decrease with an apparent half-life of approximately 70 minutes. Hypogonadal concentrations are reached within 24 hours following system removal. There is no accumulation of testosterone during continuous treatment.

Effect of Showering

In a two-way crossover study, the effects of showering on the pharmacokinetics of total testosterone following a single application of ANDRODERM 4 mg/day were assessed in 16 hypogonadal males. Showering 3 hours after application of ANDRODERM increased Cavg by 0.5% and decreased Cmax by 0.4% respectively, as compared to not showering. The systemic exposure to ANDRODERM was similar following applications with or without showering 3 hours after application.

Clinical Studies

ANDRODERM 2 mg/day and 4 mg/day were studied in a trial designed to evaluate the use and titration of 2 mg/day and 4 mg/day systems in a clinic setting of 40 men with hypogonadism. Thirty-eight of the 40 subjects (95%) who were enrolled into the study were white and 2 subjects were African American. Ten (25%) subjects were Hispanic and 30 (75%) were Non-Hispanic. Men were between 34 and 76 years of age (mean: 55 years). Patients had previously been on stable therapy of ANDRODERM 5 mg; Androgel® 2.5 g, 5 g, 7.5 g or 10 g; or Testim® 2.5 g or 5 g daily before switching to ANDRODERM 4 mg/day.

Patients applied an ANDRODERM 4 mg/day system around 10 p.m. once daily for 14 days, and then were titrated up to 6 mg/day or down to 2 mg/day according to a morning serum testosterone concentration obtained at 6 a.m. on Day 8. Out of 36 patients who entered the study, 31 (86%) patients remained on the 4 mg/day dose, 4 (11%) were titrated downward to 2 mg/day, and 1 (3%) was titrated upward to 6 mg/day based on the Day 8 testosterone concentrations. The one patient that was titrated to 6 mg/day discontinued from the study for a non-safety related reason. Of the patients who were receiving ANDRODERM 5 mg/day prior to study entry (n = 11), 10 remained at 4 mg/day after titration, and 1 was titrated down to the 2 mg/day dose.

After a total of 28 days of therapy, 34 of the 35 subjects (97%) had serum testosterone Cavg within the normal range during the dosing period, with the lower bound of the 95% confidence interval for this estimate being 85% (Table 3). One subject who received ANDRODERM 4 mg/day treatment had serum testosterone Cavg below 300 ng/dL and none had Cavg concentrations above 1030 ng/dL. The mean (SD) serum testosterone Cmax following treatment with the 2 mg/day (N = 4) and 4 mg/day (N = 31) systems was 648 (145) ng/dL and 696 (158) ng/dL, respectively. Table 3 summarizes testosterone Cavg categories by treatment.

Table 3: Testosterone Cavg Categories on Day 28 after One Titration on Day 15

Figure 2 summarizes the pharmacokinetic profiles of total testosterone in 35 patients completing 28 days of ANDRODERM treatment applied as a starting dose of 4 mg/day for the initial 14 days followed by a possible dose titration.

Figure 2: Mean (SD) Steady-State Serum Total Testosterone Concentration (ng/dL) on Day 28

In separate clinical studies using the ANDRODERM 2.5 mg/day system, 1% used 2.5 mg daily, 93% of patients used 5 mg daily, and 6% used 7.5 mg daily. The hormonal effects of ANDRODERM 2.5 mg/day system as a treatment for male hypogonadism was demonstrated in four open-label trials that included 94 hypogonadal men, ages 15 to 65 years. In these trials, ANDRODERM produced average morning serum testosterone concentrations within the normal reference range in 92% of patients.

Dosage Forms And Strengths

Transdermal system: 2 mg/day and 4 mg/day.

Storage And Handling

ANDRODERM (testosterone transdermal system) 2 mg/day

Each system contains 9.7 mg testosterone USP for delivery of 2 mg of testosterone per day .

Cartons of 60 systems NDC 52544-076-60

ANDRODERM (testosterone transdermal system) 4 mg/day

Each system contains 19.5 mg testosterone USP for delivery of 4 mg of testosterone per day .

Cartons of 30 systems NDC 52544-077-30

Store at 20-25°C (68-77°F). Apply to skin immediately upon removal from the protective pouch. Do not store outside the pouch provided. Damaged systems should not be used. The drug reservoir may be burst by excessive pressure or heat. Discard systems in household trash in a manner that prevents accidental application or ingestion by children, pets or others.

Manufactured By: Watson Laboratories, Inc. Salt Lake City, UT 84108 USA. Distributed By: Watson Pharma, Inc. Parsippany, NJ 07054 USA. Revised: June 2014