AndroGel

1 INDICATIONS AND USAGE AndroGel 1.62% 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's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [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 AndroGel 1.62% in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. Safety and efficacy of AndroGel 1.62% in males less than 18 years old have not been established [see Use in Specific Populations ( 8.4 )] . Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure [see Indications and Usage ( 1 ), and Clinical Pharmacology ( 12.3 )] . AndroGel 1.62% is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired) ( 1 ) Hypogonadotropic hypogonadism (congenital or acquired) ( 1 ) Limitations of use: Safety and efficacy of AndroGel 1.62% in men with “age-related hypogonadism” have not been established. ( 1 ) Safety and efficacy of AndroGel 1.62% in males less than 18 years old have not been established. ( 1 , 8.4 ) Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure. ( 1 , 12.3 )

2 DOSAGE AND ADMINISTRATION Dosage and Administration for AndroGel 1.62% differs from AndroGel 1%. For dosage and administration of AndroGel 1% refer to its full prescribing information. ( 2 ) Prior to initiating AndroGel 1.62%, 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. Dosage and Administration for AndroGel 1.62% differs from AndroGel 1%. For dosage and administration of AndroGel 1% refer to its full prescribing information. ( 2 ) Prior to initiating AndroGel 1.62%, 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 ). Starting dose of AndroGel 1.62% is 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet), applied topically once daily in the morning. ( 2.1 ) Apply to clean, dry, intact skin of the shoulders and upper arms. Do not apply AndroGel 1.62% to any other parts of the body including the abdomen, genitals, chest, armpits (axillae), or knees. ( 2.2 , 12.3 ) Dose adjustment: AndroGel 1.62% can be dose adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20.25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets). The dose should be titrated based on the pre-dose morning serum testosterone concentration at approximately 14 days and 28 days after starting treatment or following dose adjustment. Additionally, serum testosterone concentration should be assessed periodically thereafter. ( 2.1 ) Patients should wash hands immediately with soap and water after applying AndroGel 1.62% and cover the application site(s) with clothing after the gel has dried. Wash the application site thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. ( 2.2 ) 2.1 Dosing and Dose Adjustment The recommended starting dose of AndroGel 1.62% is 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet) applied topically once daily in the morning to the shoulders and upper arms. The dose can be adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20.25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets). To ensure proper dosing, the dose should be titrated based on the pre-dose morning serum testosterone concentration from a single blood draw at approximately 14 days and 28 days after starting treatment or following dose adjustment. In addition, serum testosterone concentration should be assessed periodically thereafter. Table 1 describes the dose adjustments required at each titration step. Table 1: Dose Adjustment Criteria Pre-Dose Morning Total Serum Testosterone Concentration Dose Titration Greater than 750 ng/dL Decrease daily dose by 20.25 mg (1 pump actuation or the equivalent of one 20.25 mg packet) Equal to or greater than 350 and equal to or less than 750 ng/dL No change: continue on current dose Less than 350 ng/dL Increase daily dose by 20.25 mg (1 pump actuation or the equivalent of one 20.25 mg packet) The application site and dose of AndroGel 1.62% are not substitutable with other topical testosterone products. 2.2 Administration Instructions AndroGel 1.62% should be applied to clean, dry, intact skin of the upper arms and shoulders. Do not apply AndroGel 1.62% to any other parts of the body, including the abdomen, genitals, chest, armpits (axillae), or knees [see Clinical Pharmacology ( 12.3 )] . Area of application should be limited to the area that will be covered by the patient's short sleeve t-shirt. Patients should be instructed to use the palm of the hand to apply AndroGel 1.62% and spread across the maximum surface area as directed in Table 2 (…

5 WARNINGS AND PRECAUTIONS Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.4 ) Potential for Secondary Exposure to Testosterone: Avoid unintentional exposure of women or children to AndroGel 1.62%. Secondary exposure to testosterone can produce signs of virilization. AndroGel 1.62% should be discontinued until the cause of virilization is identified ( 5.1 ) Venous Thromboembolism (VTE): 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 ) Blood Pressure Increases: AndroGel 1.62% can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.5 ) Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia ( 5.8 ) Edema: Edema with or without congestive heart failure (CHF) may be a complication in patients with preexisting cardiac, renal, or hepatic disease ( 5.10 , 6.2 ) Sleep Apnea: Sleep apnea may occur in those with risk factors ( 5.12 ) Monitor serum testosterone, prostate specific antigen (PSA), hemoglobin, hematocrit, liver function tests and lipid concentrations periodically ( 5.1 , 5.2 , 5.9 , 5.13 ) Flammability: AndroGel 1.62% is flammable until dry ( 5.16 ) 5.1 Potential for Secondary Exposure to Testosterone Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using AndroGel 1.62% [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )]. Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified. 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 treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. 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 (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as AndroGel 1.62%. In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, AndroGel 1.62% …

4 CONTRAINDICATIONS AndroGel 1.62% is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )]. AndroGel 1.62% is contraindicated in women who are pregnant. AndroGel 1.62% can cause virilization of the female fetus when administered to a pregnant woman. Pregnant women need to be aware of the potential for transfer of testosterone from men treated with AndroGel 1.62%. If a pregnant woman is exposed to AndroGel 1.62%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . Men with carcinoma of the breast or known or suspected prostate cancer ( 4 , 5.4 ) Women who are pregnant. Testosterone may cause fetal harm ( 4 , 8.1 )

7 DRUG INTERACTIONS Androgens may decrease blood glucose and therefore may decrease insulin requirements 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 adrenocorticotrophic 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, may decrease insulin requirements. 7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.

8.1 Pregnancy Risk Summary AndroGel 1.62% 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.

6 ADVERSE REACTIONS The most common adverse reaction (incidence ≥ 5%) is an increase in prostate specific antigen (PSA). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ASCEND Therapeutics US, LLC at 1-877-204-1013 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. AndroGel 1.62% was evaluated in a two-phase, 364-day, controlled clinical study. The first phase was a multi-center, randomized, double-blind, parallel-group, placebo-controlled period of 182 days, in which 234 hypogonadal men were treated with AndroGel 1.62% and 40 received placebo. Patients could continue in an open-label, non-comparative, maintenance period for an additional 182 days [see Clinical Studies ( 14.1 )]. The most common adverse reaction reported in the double-blind period was increased prostate specific antigen (PSA) reported in 26 AndroGel 1.62%-treated patients (11.1%). In 17 patients, increased PSA was considered an adverse event by meeting one of the two pre-specified criteria for abnormal PSA values, defined as (1) average serum PSA >4 ng/mL based on two separate determinations, or (2) an average change from baseline in serum PSA of greater than 0.75 ng/mL on two determinations. During the 182-day, double-blind period of the clinical trial, the mean change in serum PSA value was 0.14 ng/mL for patients receiving AndroGel 1.62% and -0.12 ng/mL for the patients in the placebo group. During the double-blind period, seven patients had a PSA value >4.0 ng/mL, four of these seven patients had PSA less than or equal to 4.0 ng/mL upon repeat testing. The other three patients did not undergo repeat PSA testing. During the 182-day, open-label period of the study, the mean change in serum PSA values was 0.10 ng/mL for both patients continuing on active therapy and patients transitioning onto active from placebo. During the open-label period, three patients had a serum PSA value > 4.0 ng/mL, two of whom had a serum PSA less than or equal to 4.0 ng/mL upon repeated testing. The other patient did not undergo repeat PSA testing. Among previous placebo patients, 3 of 28 (10.7%), had increased PSA as an adverse event in the open-label period. Table 4 shows adverse reactions reported by >2% of patients in the 182-day, double-blind period of the AndroGel 1.62% clinical trial and more frequent in the AndroGel 1.62% treated group versus placebo. Table 4: Adverse Reactions Reported in >2% of Patients in the 182-Day, Double-Blind Period of AndroGel 1.62% Clinical Trial Number (%) of Patients Adverse Reaction AndroGel 1.62% N=234 Placebo N=40 PSA increased* 26 (11.1%) 0% Emotional lability** 6 (2.6%) 0% Hypertension 5 (2.1%) 0% Hematocrit or hemoglobin increased 5 (2.1%) 0% Contact dermatitis*** 5 (2.1%) 0% * PSA increased includes: PSA values that met pre-specified criteria for abnormal PSA values (an average change from baseline > 0.75 ng/mL and/or an average PSA value >4.0 ng/mL based on two measurements) as well as those reported as adverse events. ** Emotional lability includes: mood swings, affective disorder, impatience, anger, and aggression. *** Contact dermatitis includes: 4 patients with dermatitis at non-application sites. Other adverse reactions occurring in less than or equal to 2% of AndroGel 1.62%-treated patients and more frequently than placebo included: frequent urination, and hyperlipidemia. In the open-label period of the study (N=191), the most commonly reported adverse reaction (experienced by greater than 2% of patients) was increased PSA (n=13; 6.2%) and sinusitis. Other adverse reactions reported by less than or equal to 2% of patients included increased hemoglobin or hematocrit, hypertension, acne, libido decreased, insomnia, and benign prostatic hy…