Androderm

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 Allergan at 1-800-678-1605 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) ]

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 pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman. 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 ) ] . Men with carcinoma of the breast or known or suspected carcinoma of the prostate. ( 4 , 5.1 ) Women who are pregnant. Testosterone may cause fetal harm. ( 4 , 5.6 , 8.1 )

11 DESCRIPTION ANDRODERM (testosterone transdermal system) is designed to deliver testosterone continuously for 24 hours following application to intact, non-scrotal skin (e.g., back, abdomen, thighs, upper arms). Two strengths of ANDRODERM are available that deliver approximately 2 mg or 4 mg of testosterone per day. ANDRODERM has a central drug delivery reservoir surrounded by a peripheral adhesive area. The ANDRODERM 2 mg/day system has a total contact surface area of 32 cm 2 with a 6.0 cm 2 central drug delivery reservoir containing 9.7 mg testosterone USP, dissolved in an alcohol-based gel. The ANDRODERM 4 mg/day system has a total contact surface area of 39 cm 2 with a 12.0 cm 2 central drug delivery reservoir containing 19.5 mg testosterone USP, dissolved in an alcohol-based gel. Testosterone USP is a white, or creamy white crystalline powder or crystals chemically described as 17ß-hydroxyandrost-4-en-3-one. The ANDRODERM systems have six components as shown in Figure 1. Proceeding from the top toward the surface attached to the skin, the system is composed of (1) metallized polyester/Surlyn ® (ethylene-methacrylic acid copolymer)/ethylene vinyl acetate backing film with alcohol resistant ink, (2) a drug reservoir of testosterone USP, alcohol USP, glycerin USP, glycerol monooleate, methyl laurate, sodium hydroxide NF, to adjust pH, and purified water USP, gelled with carbomer copolymer Type B NF, (3) a permeable polyethylene microporous membrane, and (4) a peripheral layer of acrylic adhesive surrounding the central, active drug delivery area of the system. Prior to opening of the system and application to the skin, the central delivery surface of the system is sealed with a peelable laminate disc (5) composed of a five-layer laminate containing polyester/polyesterurethane adhesive/aluminum foil/polyester-urethane adhesive/polyethylene. The disc is attached to and removed with the release liner (6), a silicone-coated polyester film, which is removed before the system can be used. The active ingredient in the system is testosterone. The remaining components of the system are pharmacologically inactive. Testosterone chemical formula. Figure 1: System Schematic

2 DOSAGE AND ADMINISTRATION Prior to initiating ANDRODERM confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range ( 2.1 ). 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. ( 2.1 ) To ensure proper dosing, approximately 2 weeks after starting therapy, the early morning serum testosterone concentration should be measured following system application in the previous evening. ( 2.1 , 12.3 ) Serum testosterone concentrations measured in the early morning 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. ( 2.1 ) Patients currently maintained on ANDRODERM 2.5 mg/day systems applied once daily may be switched to ANDRODERM 2 mg/day systems applied once daily in the evening at the next scheduled dose. ( 2.1 ) Patients currently maintained on ANDRODERM 5 mg/day systems applied once daily may be switched to ANDRODERM 4 mg/day systems applied once daily in the evening at the next scheduled dose. ( 2.1 ) Patients currently maintained on ANDRODERM 7.5 mg (2.5 mg/day and 5 mg/day systems) applied once daily may be switched to ANDRODERM 6 mg (2 mg/day and 4 mg/day systems) applied once daily in the evening at the next scheduled dose. ( 2.1 ) To ensure proper dosing, approximately 2 weeks after switching therapy an early morning serum testosterone concentration should be measured following system application the previous evening. ( 2.1 , 12.3 ) 2.1 Dosing Information Prior to initiating ANDRODERM, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. 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 [ see Clinical Pharmacology (12.3) ]. Mild skin irritation may be ameliorated by treatment of the affected skin with over-the-counter 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.

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 )

9.2 Abuse Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice. Abuse-Related Adverse Reactions Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression. The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. The following additional adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty. Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

9.1 Controlled Substance ANDRODERM contains testosterone, a Schedule III controlled substance in the Controlled Substance Act.

9.3 Dependence Behaviors Associated with Addiction Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors: Taking greater dosages than prescribed Continued drug use despite medical and social problems due to drug use Spending significant time to obtain the drug when the supplies of the drug are interrupted Giving a higher priority to drug use than other obligations Having difficulty in discontinuing the drug despite desires and attempts to do so Experiencing withdrawal symptoms upon abrupt discontinuation of use Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism. Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance ANDRODERM contains testosterone, a Schedule III controlled substance in the Controlled Substance Act. 9.2 Abuse Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice. Abuse-Related Adverse Reactions Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression. The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. The following additional adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty. Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 9.3 Dependence Behaviors Associated with Addiction Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors: Taking greater dosages than prescribed Continued drug use despite medical and social problems due to drug use Spending significant time to obtain the drug when the supplies of the drug are interrupted Giving a higher priority to drug use than other obligations Having difficulty in discontinuing the drug despite desires and attempts to do so Experiencing withdrawal symptoms upon abrupt discontinuation of use Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism. Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

10 OVERDOSAGE 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.

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.

12 CLINICAL PHARMACOLOGY 12.1 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, a clinical syndrome resulting from insufficient secretion of testosterone, 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). 12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted using ANDRODERM. 12.3 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) T max 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 C avg by 0.5% and decreased C max 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.

12.1 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, a clinical syndrome resulting from insufficient secretion of testosterone, 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).

12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted using ANDRODERM.

12.3 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) T max 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 C avg by 0.5% and decreased C max 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.

20200518

11

3 DOSAGE FORMS AND STRENGTHS Transdermal system: 2 mg/day and 4 mg/day. Transdermal system: 2 mg/day and 4 mg/day. ( 3 )

Androderm Testosterone TESTOSTERONE TESTOSTERONE ALCOHOL GLYCERIN GLYCERYL OLEATE METHYL LAURATE WATER CARBOMER 1342 SODIUM HYDROXIDE Androderm Testosterone TESTOSTERONE TESTOSTERONE ALCOHOL GLYCERIN GLYCERYL OLEATE METHYL LAURATE WATER CARBOMER 1342 SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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. Mutagenesis Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. Impairment of Fertility 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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. Mutagenesis Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. Impairment of Fertility 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.

NDA020489

Androderm

Testosterone

0023-5992

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

PRINCIPAL DISPLAY PANEL Androderm (testos terone transdermal system) CIII NDC 0023-5990-60 Carton x 60 systems, 2 mg/day Androderm (testosterone transdermal system) CIII NDC 0023-5990-60 Carton x 60 systems, 2 mg/day

Contraindications ( 4 ) 05/2020

17 PATIENT COUNSELING INFORMATION See "FDA-approved patient labeling ( Patient Information )." Patients should be informed of the following information: Use in Men with Known or Suspected Prostate or Breast Cancer Potential Adverse Reactions with Androgens Men with known or suspected prostate or breast cancer should not use ANDRODERM [see Contraindications (4) and Warnings and Precautions (5.1) ] . 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 [see Dosage and Administration (2) and Clinical Pharmacology (12.3) ]. For all medical inquiries contact: Allergan Medical Communications 1-800-678-1605 ANDRODERM ® is a registered trademark of Allergan Sales, LLC. Distributed by: Allergan USA, Inc. Madison, NJ 07940 © 2020 Allergan. All rights reserved. v1.0USPI5990

14 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 grams, 5 grams, 7.5 grams or 10 grams; or Testim ® 2.5 grams or 5 grams 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 C avg 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 C avg below 300 ng/dL and none had C avg concentrations above 1030 ng/dL. The mean (SD) serum testosterone C max 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 C avg categories by treatment. Table 3. Testosterone C avg Categories on Day 28 after One Titration on Day 15 C avg Category Current Testosterone User N = 35 300 - 1030 ng/dL (n (%) (95% CI)) 34/35 (97%) (85%, 100%) < 300 ng/dL (n (%)) 1/35 (3%) 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. 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. Figure 2. Mean (SD) Steady-State Serum Total Testosterone Concentration (ng/dL) on Day 28

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.

8.4 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.

8.1 Pregnancy Risk Summary ANDRODERM is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action [ see Contraindications ( 4 ) and Clinical Pharmacology ( 12.1 ) ]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies. Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased ano-genital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes. Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

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 Risk Summary ANDRODERM is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action [ see Contraindications ( 4 ) and Clinical Pharmacology ( 12.1 ) ]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies. Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased ano-genital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes. Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy. 8.2 Lactation Risk Summary ANDRODERM is not indicated for use in women. 8.3 Females and Males of Reproductive Potential Infertility Testicular abnormalities have been identified during use of ANDRODERM [see Adverse Reactions ( 6.1 ]. During treatment with large doses of exogenous androgens, including ANDRODERM, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions ( 5.7 )]. Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence ( 9.2 )]. With either type of use, the impact on fertility may be irreversible. 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.

16 HOW SUPPLIED/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 [ see Description (11) ] . Cartons of 60 systems NDC 0023-5990-60 ANDRODERM (testosterone transdermal system) 4 mg/day. Each system contains 19.5 mg testosterone USP for delivery of 4 mg of testosterone per day [ see Description (11) ] . Cartons of 30 systems NDC 0023-5992-30 Store at 20-25°C (68-77°F). [See USP controlled room temperature.] 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.