CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. Figure 2: Mean (+-SD) Serum Total Testosterone Concentrations on Day in Patients Following AndroGel 1.62% Once-Daily Application of 81 mg of Testosterone (N=33) for Days. 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 chord thickening; and alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism, clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelters 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 AndroGel 1.62%. 12.3 Pharmacokinetics. AbsorptionAndroGel 1.62% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (300 1000 ng/dL) seen in healthy men. AndroGel 1.62% provides continuous transdermal delivery of testosterone for 24 hours following once daily application to clean, dry, intact skin of the shoulders and upper arms. Average serum testosterone concentrations over 24 hours (Cavg) observed when AndroGel 1.62% was applied to the upper arms/shoulders were comparable to average serum testosterone concentrations (Cavg) when AndroGel 1.62% was applied using rotation method utilizing the abdomen and upper arms/shoulders. The rotation of abdomen and upper arms/shoulders was method used in the pivotal clinical trial [see Clinical Studies 14.1 )]. Figure 2: Mean (+-SD) Serum Total Testosterone Concentrations on Day in Patients Following AndroGel 1.62% Once-Daily Application of 81 mg of Testosterone (N=33) for DaysDistributionCirculating 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 loosely bound to albumin and other proteins. MetabolismTestosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT. ExcretionThere is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of dose of testosterone given intramuscularly is excreted in the urine as glucuronic acid and sulfuric acid conjugates of testosterone and its metabolites. About 6% of dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. When AndroGel 1.62% treatment is discontinued, serum testosterone concentrations return to approximately baseline concentrations within 48-72 hours after administration of the last dose. Potential for testosterone transferThe potential for testosterone transfer following administration of AndroGel 1.62% when it was applied only to upper arms/shoulders was evaluated in two clinical studies of males dosed with AndroGel 1.62% and their untreated female partners. In one study, male subjects applied single dose of AndroGel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes. Serum concentrations of testosterone were monitored in female subjects for 24 hours after contact occurred. After direct skin-to-skin contact with the site of application, mean testosterone Cavg and Cmax in female subjects increased by 280% and 267%, respectively, compared to mean baseline testosterone concentrations. In second study evaluating transfer of testosterone, 12 male subjects applied single dose of AndroGel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes while the site of application was covered by t-shirt. When t-shirt was used to cover the site of application, mean testosterone Cavg and Cmax in female subjects increased by 6% and 11%, respectively, compared to mean baseline testosterone concentrations. separate study was conducted to evaluate the potential for testosterone transfer from 16 males dosed with AndroGel 1.62% 81 mg when it was applied to abdomen only for days, site of application not approved for AndroGel 1.62%. Two (2) hours after application to the males on each day, the female subjects rubbed their abdomens for 15 minutes to the abdomen of the males. The males had covered the application area with T-shirt. The mean testosterone Cavg and Cmax in female subjects on day increased by 43% and 47%, respectively, compared to mean baseline testosterone concentrations. The mean testosterone Cavg and Cmax in female subjects on day increased by 60% and 58%, respectively, compared to mean baseline testosterone concentrations. Effect of showeringIn randomized, 3-way (3 treatment periods without washout period) crossover study in 24 hypogonadal men, the effect of showering on testosterone exposure was assessed after once daily application of AndroGel 1.62% 81 mg to upper arms/shoulders for days in each treatment period. On the 7th day of each treatment period, hypogonadal men took shower with soap and water at either 2, 6, or 10 hours after drug application. The effect of showering at or hours post-dose on Day resulted in 13% and 12% decreases in mean Cavg, respectively, compared to Day when no shower was taken after drug application. Showering at 10 hours after drug application had no effect on bioavailability. The amount of testosterone remaining in the outer layers of the skin at the application site on the 7th day was assessed using tape stripping procedure and was reduced by at least 80% after showering 2-10 hours post-dose compared to on the 6th day when no shower was taken after drug application. Effect of hand washingIn randomized, open-label, single-dose, 2-way crossover study in 16 healthy male subjects, the effect of hand washing on the amount of residual testosterone on the hands was evaluated. Subjects used their hands to apply the maximum dose (81 mg testosterone) of AndroGel 1.62% to their upper arms and shoulders. Within minute of applying the gel, subjects either washed or did not wash their hands prior to study personnel wiping the subjects hands with ethanol dampened gauze pads. The gauze pads were then analyzed for residual testosterone content. mean (SD) of 0.1 (0.04) mg of residual testosterone (0.12% of the actual applied dose of testosterone, and 96% reduction compared to when hands were not washed) was recovered after washing hands with water and soap. Effect of sunscreen or moisturizing lotion on absorption of testosteroneIn randomized, 3-way (3 treatment periods without washout period) crossover study in 18 hypogonadal males, the effect of applying moisturizing lotion or sunscreen on the absorption of testosterone was evaluated with the upper arms/shoulders as application sites. For days, moisturizing lotion or sunscreen (SPF 50) was applied daily to the AndroGel 1.62% application site hour after the application of AndroGel 1.62% 40.5 mg. Application of moisturizing lotion increased mean testosterone Cavg and Cmax by 14% and 17%, respectively, compared to AndroGel 1.62% administered alone. Application of sunscreen increased mean testosterone Cavg and Cmax by 8% and 13%, respectively, compared to AndroGel 1.62% applied alone.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Figure 3. Figure 4. 14.1 Clinical Trials in Hypogonadal Males. AndroGel 1.62% was evaluated in multi-center, randomized, double-blind, parallel-group, placebo-controlled study (182-day double-blind period) in 274 hypogonadal men with body mass index (BMI) 18-40 kg/m2 and 18-80 years of age (mean age 53.8 years). The patients had an average serum testosterone concentration of <300 ng/dL, as determined by two morning samples collected on the same visit. Patients were Caucasian 83%, Black 13%, Asian or Native American 4%. 7.5% of patients were Hispanic. Patients were randomized to receive active treatment or placebo using rotation method utilizing the abdomen and upper arms/shoulders for 182 days. All patients were started at daily dose of 40.5 mg (two pump actuations) AndroGel 1.62% or matching placebo on Day of the study. Patients returned to the clinic on Day 14, Day 28, and Day 42 for predose serum total testosterone assessments. The patients daily dose was titrated up or down in 20.25 mg increments if the predose serum testosterone value was outside the range of 350-750 ng/dL. The study included four active AndroGel 1.62% doses: 20.25 mg, 40.5 mg, 60.75 mg, and 81 mg daily. The primary endpoint was the percentage of patients with Cavg within the normal range of 300-1000 ng/dL on Day 112. In patients treated with AndroGel 1.62%, 81.6% (146/179) had Cavg within the normal range at Day 112. The secondary endpoint was the percentage of patients, with Cmax above three pre-determined limits. The percentages of patients with Cmax greater than 1500 ng/dL, and between 1800 and 2499 ng/dL on Day 112 were 11.2% and 5.5%, respectively. Two patients had Cmax >2500 ng/dL on Day 112 (2510 ng/dL and 2550 ng/dL, respectively); neither of these patients demonstrated an abnormal Cmax on prior or subsequent assessments at the same dose. Patients could agree to continue in an open-label, active treatment maintenance period of the study for an additional 182 days. Dose titrations on Days 14, 28, and 42 resulted in final doses of 20.25 mg 81 mg on Day 112 as shown in Table 6. Table 6: Mean (SD) Testosterone Concentrations (Cavg and Cmax) by final dose on Days 112 and 364 ParameterFinal Dose on Day 112 Placebo(n=27)20.25 mg(n=12)40.5 mg(n=34)60.75 mg(n=54)81 mg(n=79)All Active(n=179)Cavg (ng/dL)303 (135)457 (275)524 (228)643 (285)537 (240)561 (259)Cmax (ng/dL)450 (349)663 (473)798 (439)958 (497)813 (479)845 (480) Final Dose on Day 364 20.25 mg(n=7)40.5 mg(n=26)60.75 mg(n=29)81 mg(n=74)Continuing Active(n=136)Cavg (ng/dL) 386 (130)474 (176)513 (222)432 (186)455 (192)Cmax (ng/dL) 562 (187)715 (306)839 (568)649 (329)697 (389)Figure summarizes the pharmacokinetic profile of total testosterone in patients completing 112 days of AndroGel 1.62% treatment administered as starting dose of 40.5 mg of testosterone (2 pump actuations) for the initial 14 days followed by possible titration according to the follow-up testosterone measurements. Figure 3: Mean (+-SD) Steady-State Serum Total Testosterone Concentrations on Day 112 Efficacy was maintained in the group of men that received AndroGel 1.62% for one full year. In that group, 78% (106/136) had average serum testosterone concentrations in the normal range at Day 364. Figure summarizes the mean total testosterone profile for these patients on Day 364. Figure 4: Mean (+-SD) Steady-State Serum Total Testosterone Concentrations on Day 364 The mean estradiol and DHT concentration profiles paralleled the changes observed in testosterone. The levels of LH and FSH decreased with testosterone treatment. The decreases in levels of LH and FSH are consistent with reports published in the literature of long-term treatment with testosterone.

ADVERSE REACTIONS SECTION.

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 AbbVie Inc. at 1-800-633-9110 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 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 two-phase, 364-day, controlled clinical study. The first phase was 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 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 serum PSA value 4.0 ng/mL, two of whom had 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, of 28 (10.7%), had increased PSA as an adverse event in the open-label period. Table 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 PatientsAdverse ReactionAndroGel 1.62%N=234PlaceboN=40PSA increased 26 (11.1%) 0% Emotional lability (2.6%) 0% Hypertension (2.1%) 0% Hematocrit or hemoglobin increased (2.1%) 0% Contact dermatitis (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: 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 hypertrophy. During the 182-day, double-blind period of the clinical trial, 25 AndroGel 1.62%-treated patients (10.7%) discontinued treatment because of adverse reactions. These adverse reactions included 17 patients with PSA increased and report each of: hematocrit increased, blood pressure increased, frequent urination, diarrhea, fatigue, pituitary tumor, dizziness, skin erythema and skin nodule (same patient neither at application site), vasovagal syncope, and diabetes mellitus. During the 182-day, open-label period, patients discontinued treatment because of adverse reactions. These adverse reactions included reports of PSA increased, of hematocrit increased, and each of triglycerides increased and prostate cancer. Application Site ReactionsIn the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving AndroGel 1.62%, both of which resolved. Neither of these patients discontinued the study due to application site adverse reactions. In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with AndroGel 1.62%. None of these subjects were discontinued from the study due to application site reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of AndroGel 1.62%. Because the reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure (Table 5). Table 5: Adverse Reactions from Post Approval Experience of AndroGel 1.62% by System Organ Class System Organ ClassAdverse ReactionBlood and lymphatic system disorders:Elevated hemoglobin or hematocrit, polycythemia, anemia Cardiovascular disorders:Myocardial infarction, strokeEndocrine disorders:Hirsutism Gastrointestinal disorders:Nausea General disorders:Asthenia, edema, malaise Genitourinary disorders:Impaired urination Hepatobiliary disorders:Abnormal liver function tests Investigations:Lab test abnormal, elevated PSA, electrolyte changes (nitrogen, calcium, potassium [includes hypokalemia], phosphorus, sodium), impaired glucose tolerance, hyperlipidemia, HDL, fluctuating testosterone levels, weight increase Neoplasms:Prostate cancer Nervous system disorders:Dizziness, headache, insomnia, sleep apnea Psychiatric disorders:Amnesia, anxiety, depression, hostility, emotional lability, decreased libido, nervousness Reproductive system and breast disorders:Gynecomastia, mastodynia, oligospermia, priapism (frequent or prolonged erections), prostate enlargement, BPH, testis disorder Respiratory disorders:Dyspnea Skin and subcutaneous tissue disorders:Acne, alopecia, application site reaction (discolored hair, dry skin, erythema, paresthesia, pruritus, rash), skin dry, pruritus, sweating Vascular disorders:Hypertension, vasodilation (hot flushes), venous thromboembolism Impaired urination includes nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream Lab test abnormal includes elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, or elevated serum creatinine Testis disorder includes atrophy or non-palpable testis, varicocele, testis sensitivity or tenderness Secondary Exposure to Testosterone in ChildrenCases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In few cases, however, enlarged genitalia did not fully return to age appropriate normal size, and bone age remained modestly greater than chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary exposure from texts such as the testosterone gel users shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions 5.2 )].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 two-phase, 364-day, controlled clinical study. The first phase was 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 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 serum PSA value 4.0 ng/mL, two of whom had 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, of 28 (10.7%), had increased PSA as an adverse event in the open-label period. Table 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 PatientsAdverse ReactionAndroGel 1.62%N=234PlaceboN=40PSA increased 26 (11.1%) 0% Emotional lability (2.6%) 0% Hypertension (2.1%) 0% Hematocrit or hemoglobin increased (2.1%) 0% Contact dermatitis (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: 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 hypertrophy. During the 182-day, double-blind period of the clinical trial, 25 AndroGel 1.62%-treated patients (10.7%) discontinued treatment because of adverse reactions. These adverse reactions included 17 patients with PSA increased and report each of: hematocrit increased, blood pressure increased, frequent urination, diarrhea, fatigue, pituitary tumor, dizziness, skin erythema and skin nodule (same patient neither at application site), vasovagal syncope, and diabetes mellitus. During the 182-day, open-label period, patients discontinued treatment because of adverse reactions. These adverse reactions included reports of PSA increased, of hematocrit increased, and each of triglycerides increased and prostate cancer. Application Site ReactionsIn the 182-day double-blind period of the study, application site reactions were reported in two (2/234; 0.9%) patients receiving AndroGel 1.62%, both of which resolved. Neither of these patients discontinued the study due to application site adverse reactions. In the open-label period of the study, application site reactions were reported in three (3/219; 1.4%) additional patients that were treated with AndroGel 1.62%. None of these subjects were discontinued from the study due to application site reactions.

DOSAGE & ADMINISTRATION SECTION.

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 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 minimum of 20.25 mg of testosterone (1 pump actuation or single 20.25 mg packet) and 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) 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 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 minimum of 20.25 mg of testosterone (1 pump actuation or single 20.25 mg packet) and 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) Andro shoulders ben 05092014. Andro shoulders side view. 2.1 Dosing and Dose Adjustment. The recommended starting dose of AndroGel 1.62% is 40.5 mg of testosterone (2 pump actuations or single 40.5 mg packet) applied topically once daily in the morning to the shoulders and upper arms. The dose can be adjusted between minimum of 20.25 mg of testosterone (1 pump actuation or single 20.25 mg packet) and 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 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 describes the dose adjustments required at each titration step. Table 1: Dose Adjustment Criteria Pre-Dose Morning Total Serum Testosterone ConcentrationDose TitrationGreater 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 interchangeable 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 patients 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 (for pump) and Table (for packets) and in Figure 1. Table 2: Application Sites for AndroGel 1.62%, PumpTotal Dose of TestosteroneTotal Pump Actuations Pump Actuations Per Upper Arm and Shoulder Upper Arm and Shoulder 1Upper Arm and Shoulder 220.25 mg 1 40.5 mg 1 60.75 mg 2 81 mg 2 Table 3: Application Sites for AndroGel 1.62%, PacketsTotal Doseof TestosteroneTotal packetsGel Applications Per Upper Arm and Shoulder Upper Arm andShoulder 1Upper Arm andShoulder 220.25 mgOne 20.25 mgpacket One 20.25 mg packet040.5 mgOne 40.5 mgpacket Half of contents of One 40.5 mg packet Half of contents of One 40.5 mg packet 60.75 mgOne 20.25 mgpacket AND One 40.5 mgpacket One 40.5 mg packetOne 20.25 mg packet81 mgTwo 40.5 mgpackets One 40.5 mg packetOne 40.5 mg packetThe prescribed daily dose of AndroGel 1.62% should be applied to the right and left upper arms and shoulders as shown in the shaded areas in Figure 1. Figure 1. Application Sites for AndroGel 1.62%Once the application site is dry, the site should be covered with clothing [see Clinical Pharmacology 12.3 )]. Wash hands thoroughly with soap and water. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel 1.62%, are flammable. The patient should avoid swimming or showering or washing the administration site for minimum of hours after application [see Clinical Pharmacology 12.3 )]. To obtain full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, fully depress the actuator once for every 20.25 mg of AndroGel 1.62%. AndroGel 1.62% should be delivered directly into the palm of the hand and then applied to the application sites. When using packets, the entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. When 40.5 mg packets need to be split between the left and right shoulder, patients may squeeze portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied. Alternatively, AndroGel 1.62% can be applied directly to the application sites from the pump or packets. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AndroGel 1.62%-treated skin:Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%. AndroGel 1.62% should only be applied to the upper arms and shoulders. The area of application should be limited to the area that will be covered by short sleeve t-shirt. Patients should wash their hands with soap and water immediately after applying AndroGel 1.62%. Patients should cover the application site(s) with clothing (e.g., t-shirt) after the gel has dried. Prior to situations in which direct skin-to-skin contact is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible. Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%. AndroGel 1.62% should only be applied to the upper arms and shoulders. The area of application should be limited to the area that will be covered by short sleeve t-shirt. Patients should wash their hands with soap and water immediately after applying AndroGel 1.62%. Patients should cover the application site(s) with clothing (e.g., t-shirt) after the gel has dried. Prior to situations in which direct skin-to-skin contact is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible.

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance AndroGel 1.62% contains testosterone, Schedule III controlled substance in the Controlled Substances Act. 9.2 Abuse Drug abuse is intentional non-therapeutic use of 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 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 ReactionsSerious 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 women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities. The following 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 population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. 9.3 Dependence Behaviors Associated with AddictionContinued 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 supplies of the drug are interrupted Giving 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 usePhysical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or significant dose reduction of 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. 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 supplies of the drug are interrupted Giving 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE AndroGel 1.62% is indicated for replacement therapy in adult males for conditions associated with 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, Klinefelters 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 )]. Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelters 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. 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 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) Primary hypogonadism (congenital or acquired) (1) Hypogonadotropic hypogonadism (congenital or acquired) (1) 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide Patients should be informed of the following: 17.1 Use in Men with Known or Suspected Prostate or Breast Cancer Men with known or suspected prostate or breast cancer should not use AndroGel 1.62% [see Contraindications 4 and Warnings and Precautions 5.1 )]. 17.2 Potential for Secondary Exposure to Testosterone and Steps to Prevent Secondary Exposure Secondary exposure to testosterone in children and women can occur with the use of testosterone gel in men [see Warnings and Precautions 5.2 )]. Cases of secondary exposure to testosterone have been reported in children. Physicians should advise patients of the reported signs and symptoms of secondary exposure, which may include the following: In children: unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior. In women: changes in hair distribution, increase in acne, or other signs of testosterone effects. The possibility of secondary exposure to testosterone gel should be brought to the attention of healthcare provider. AndroGel 1.62% should be promptly discontinued until the cause of virilization is identified. Strict adherence to the following precautions is advised to minimize the potential for secondary exposure to testosterone from AndroGel 1.62% in men [see Medication Guide ]: Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%. Patients using AndroGel 1.62% should apply the product as directed and strictly adhere to the following: Wash hands with soap and water immediately after application. Cover the application site(s) with clothing after the gel has dried. Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration 2.2 ), Warnings and Precautions 5.2 and Clinical Pharmacology 12.3 )]. In children: unexpected sexual development including inappropriate enlargement of the penis or clitoris, premature development of pubic hair, increased erections, and aggressive behavior. In women: changes in hair distribution, increase in acne, or other signs of testosterone effects. The possibility of secondary exposure to testosterone gel should be brought to the attention of healthcare provider. AndroGel 1.62% should be promptly discontinued until the cause of virilization is identified. Children and women should avoid contact with unwashed or unclothed application site(s) of men using AndroGel 1.62%. Patients using AndroGel 1.62% should apply the product as directed and strictly adhere to the following: Wash hands with soap and water immediately after application. Cover the application site(s) with clothing after the gel has dried. Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. In the event that unwashed or unclothed skin to which AndroGel 1.62% has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible [see Dosage and Administration 2.2 ), Warnings and Precautions 5.2 and Clinical Pharmacology 12.3 )]. 17.3 Potential Adverse Reactions with Androgens Patients should be informed that treatment with androgens may lead to adverse reactions which include: Changes in urinary habits such as increased urination at night, trouble starting the urine stream, passing urine many times during the day, having an urge to go to the bathroom right away, having urine accident, being unable to pass urine and 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. Changes in urinary habits such as increased urination at night, trouble starting the urine stream, passing urine many times during the day, having an urge to go to the bathroom right away, having urine accident, being unable to pass urine and 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. 17.4 Patients Should Be Advised of the Following Instructions for Use Read the Medication Guide before starting AndroGel 1.62% therapy and to reread it each time the prescription is renewed.AndroGel 1.62% should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women.Keep AndroGel 1.62% out of the reach of children. AndroGel 1.62% is an alcohol based product and is flammable; therefore avoid fire, flame or smoking until the gel has dried.It is important to adhere to all recommended monitoring. Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood. AndroGel 1.62% is prescribed to meet the patients specific needs; therefore, the patient should never share AndroGel 1.62% with anyone. Wait hours before swimming or washing following application of AndroGel 1.62%. This will ensure that the greatest amount of AndroGel 1.62% is absorbed into their system. Marketed by: AbbVie Inc.North Chicago, IL 60064, USA (C) 2011-2020 AbbVie Inc. 5005035 Revised November, 2020 Read the Medication Guide before starting AndroGel 1.62% therapy and to reread it each time the prescription is renewed.. AndroGel 1.62% should be applied and used appropriately to maximize the benefits and to minimize the risk of secondary exposure in children and women.. Keep AndroGel 1.62% out of the reach of children. AndroGel 1.62% is an alcohol based product and is flammable; therefore avoid fire, flame or smoking until the gel has dried.. It is important to adhere to all recommended monitoring. Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood. AndroGel 1.62% is prescribed to meet the patients specific needs; therefore, the patient should never share AndroGel 1.62% with anyone. Wait hours before swimming or washing following application of AndroGel 1.62%. This will ensure that the greatest amount of AndroGel 1.62% is absorbed into their system.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAndroGel 1.62% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (300 1000 ng/dL) seen in healthy men. AndroGel 1.62% provides continuous transdermal delivery of testosterone for 24 hours following once daily application to clean, dry, intact skin of the shoulders and upper arms. Average serum testosterone concentrations over 24 hours (Cavg) observed when AndroGel 1.62% was applied to the upper arms/shoulders were comparable to average serum testosterone concentrations (Cavg) when AndroGel 1.62% was applied using rotation method utilizing the abdomen and upper arms/shoulders. The rotation of abdomen and upper arms/shoulders was method used in the pivotal clinical trial [see Clinical Studies 14.1 )]. Figure 2: Mean (+-SD) Serum Total Testosterone Concentrations on Day in Patients Following AndroGel 1.62% Once-Daily Application of 81 mg of Testosterone (N=33) for DaysDistributionCirculating 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 loosely bound to albumin and other proteins. MetabolismTestosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT. ExcretionThere is considerable variation in the half-life of testosterone concentration as reported in the literature, ranging from 10 to 100 minutes. About 90% of dose of testosterone given intramuscularly is excreted in the urine as glucuronic acid and sulfuric acid conjugates of testosterone and its metabolites. About 6% of dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. When AndroGel 1.62% treatment is discontinued, serum testosterone concentrations return to approximately baseline concentrations within 48-72 hours after administration of the last dose. Potential for testosterone transferThe potential for testosterone transfer following administration of AndroGel 1.62% when it was applied only to upper arms/shoulders was evaluated in two clinical studies of males dosed with AndroGel 1.62% and their untreated female partners. In one study, male subjects applied single dose of AndroGel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes. Serum concentrations of testosterone were monitored in female subjects for 24 hours after contact occurred. After direct skin-to-skin contact with the site of application, mean testosterone Cavg and Cmax in female subjects increased by 280% and 267%, respectively, compared to mean baseline testosterone concentrations. In second study evaluating transfer of testosterone, 12 male subjects applied single dose of AndroGel 1.62% 81 mg to their shoulders and upper arms. Two (2) hours after application, female subjects rubbed their hands, wrists, arms, and shoulders to the application site of the male subjects for 15 minutes while the site of application was covered by t-shirt. When t-shirt was used to cover the site of application, mean testosterone Cavg and Cmax in female subjects increased by 6% and 11%, respectively, compared to mean baseline testosterone concentrations. separate study was conducted to evaluate the potential for testosterone transfer from 16 males dosed with AndroGel 1.62% 81 mg when it was applied to abdomen only for days, site of application not approved for AndroGel 1.62%. Two (2) hours after application to the males on each day, the female subjects rubbed their abdomens for 15 minutes to the abdomen of the males. The males had covered the application area with T-shirt. The mean testosterone Cavg and Cmax in female subjects on day increased by 43% and 47%, respectively, compared to mean baseline testosterone concentrations. The mean testosterone Cavg and Cmax in female subjects on day increased by 60% and 58%, respectively, compared to mean baseline testosterone concentrations. Effect of showeringIn randomized, 3-way (3 treatment periods without washout period) crossover study in 24 hypogonadal men, the effect of showering on testosterone exposure was assessed after once daily application of AndroGel 1.62% 81 mg to upper arms/shoulders for days in each treatment period. On the 7th day of each treatment period, hypogonadal men took shower with soap and water at either 2, 6, or 10 hours after drug application. The effect of showering at or hours post-dose on Day resulted in 13% and 12% decreases in mean Cavg, respectively, compared to Day when no shower was taken after drug application. Showering at 10 hours after drug application had no effect on bioavailability. The amount of testosterone remaining in the outer layers of the skin at the application site on the 7th day was assessed using tape stripping procedure and was reduced by at least 80% after showering 2-10 hours post-dose compared to on the 6th day when no shower was taken after drug application. Effect of hand washingIn randomized, open-label, single-dose, 2-way crossover study in 16 healthy male subjects, the effect of hand washing on the amount of residual testosterone on the hands was evaluated. Subjects used their hands to apply the maximum dose (81 mg testosterone) of AndroGel 1.62% to their upper arms and shoulders. Within minute of applying the gel, subjects either washed or did not wash their hands prior to study personnel wiping the subjects hands with ethanol dampened gauze pads. The gauze pads were then analyzed for residual testosterone content. mean (SD) of 0.1 (0.04) mg of residual testosterone (0.12% of the actual applied dose of testosterone, and 96% reduction compared to when hands were not washed) was recovered after washing hands with water and soap. Effect of sunscreen or moisturizing lotion on absorption of testosteroneIn randomized, 3-way (3 treatment periods without washout period) crossover study in 18 hypogonadal males, the effect of applying moisturizing lotion or sunscreen on the absorption of testosterone was evaluated with the upper arms/shoulders as application sites. For days, moisturizing lotion or sunscreen (SPF 50) was applied daily to the AndroGel 1.62% application site hour after the application of AndroGel 1.62% 40.5 mg. Application of moisturizing lotion increased mean testosterone Cavg and Cmax by 14% and 17%, respectively, compared to AndroGel 1.62% administered alone. Application of sunscreen increased mean testosterone Cavg and Cmax by 8% and 13%, respectively, compared to AndroGel 1.62% applied alone.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of AndroGel 1.62%. Because the reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure (Table 5). Table 5: Adverse Reactions from Post Approval Experience of AndroGel 1.62% by System Organ Class System Organ ClassAdverse ReactionBlood and lymphatic system disorders:Elevated hemoglobin or hematocrit, polycythemia, anemia Cardiovascular disorders:Myocardial infarction, strokeEndocrine disorders:Hirsutism Gastrointestinal disorders:Nausea General disorders:Asthenia, edema, malaise Genitourinary disorders:Impaired urination Hepatobiliary disorders:Abnormal liver function tests Investigations:Lab test abnormal, elevated PSA, electrolyte changes (nitrogen, calcium, potassium [includes hypokalemia], phosphorus, sodium), impaired glucose tolerance, hyperlipidemia, HDL, fluctuating testosterone levels, weight increase Neoplasms:Prostate cancer Nervous system disorders:Dizziness, headache, insomnia, sleep apnea Psychiatric disorders:Amnesia, anxiety, depression, hostility, emotional lability, decreased libido, nervousness Reproductive system and breast disorders:Gynecomastia, mastodynia, oligospermia, priapism (frequent or prolonged erections), prostate enlargement, BPH, testis disorder Respiratory disorders:Dyspnea Skin and subcutaneous tissue disorders:Acne, alopecia, application site reaction (discolored hair, dry skin, erythema, paresthesia, pruritus, rash), skin dry, pruritus, sweating Vascular disorders:Hypertension, vasodilation (hot flushes), venous thromboembolism Impaired urination includes nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream Lab test abnormal includes elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, or elevated serum creatinine Testis disorder includes atrophy or non-palpable testis, varicocele, testis sensitivity or tenderness Secondary Exposure to Testosterone in ChildrenCases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In few cases, however, enlarged genitalia did not fully return to age appropriate normal size, and bone age remained modestly greater than chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary exposure from texts such as the testosterone gel users shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions 5.2 )].

SPL MEDGUIDE SECTION.

MEDICATION GUIDEANDROGEL(R) (AN DROW JEL) CIII(testosterone gel) 1.62% for topical use What is the most important information should know about ANDROGEL 1.62%1. ANDROGEL 1.62% can transfer from your body to others including, children and women. Children and women should avoid contact with the unwashed or not covered (unclothed) areas where ANDROGEL 1.62% has been applied to your skin. Early signs and symptoms of puberty have occurred in young children who have come in direct contact with testosterone by touching areas where men have used ANDROGEL 1.62%. Children Signs and symptoms of early puberty in child when they come in direct contact with ANDROGEL 1.62% may include: Abnormal sexual changes: enlarged penis or clitoris. early growth of hair near the vagina or around the penis (pubic hair). erections or acting out sexual urges (sex drive). Behavior problems: acting aggressively, behaving in an angry or violent way. Women Signs and symptoms in women when they come in direct contact with ANDROGEL 1.62% may include: changes in body hair. an abnormal increase in pimples (acne). Stop using ANDROGEL 1.62% and call your healthcare provider right away if you see any signs and symptoms in child or woman that may have happened through accidental touching of the area where you have applied ANDROGEL 1.62%. 2. To lower the risk of transfer of ANDROGEL 1.62% from your body to others, follow these important instructions: Apply ANDROGEL 1.62% only to your shoulders and upper arms that will be covered by short sleeve t-shirt. Wash your hands right away with soap and water after applying ANDROGEL 1.62%. After the gel has dried, cover the application area with clothing. Keep the area covered until you have washed the application area well or have showered. If you expect to have skin-to-skin contact with another person, first wash the application area well with soap and water. If child or woman touches the area where you have applied ANDROGEL 1.62%, that area on the child or woman should be washed well with soap and water right away. What is ANDROGEL 1.62%ANDROGEL 1.62% is prescription medicine that contains testosterone. ANDROGEL 1.62% is used to treat adult males who have low or no testosterone due to certain medical conditions.Your healthcare provider will test your blood before you start and while you are using ANDROGEL 1.62%. It is not known if ANDROGEL 1.62% is safe or effective to treat men who have low testosterone due to aging. It is not known if ANDROGEL 1.62% is safe or effective in children younger than 18 years old. Improper use of ANDROGEL 1.62% may affect bone growth in children. ANDROGEL 1.62% is controlled substance (CIII) because it contains testosterone that can be target for people who abuse prescription medicines. Keep your ANDROGEL 1.62% in safe place to protect it. Never give your ANDROGEL 1.62% to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and is against the law. ANDROGEL 1.62% is not meant for use in women. Do not use ANDROGEL 1.62% if you:have breast cancer. have or might have prostate cancer. are pregnant. ANDROGEL 1.62% may harm your unborn baby. Women who are pregnant should avoid contact with the area of skin where ANDROGEL 1.62% has been applied.Before using ANDROGEL 1.62%, tell your healthcare provider about all of your medical conditions, including if you:have breast cancer. have or might have prostate cancer. have urinary problems due to an enlarged prostate. have heart problems. have kidney or liver problems. have problems breathing while you sleep (sleep apnea).Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using ANDROGEL 1.62% with certain other medicines can affect each other.Especially, tell your healthcare provider if you take:insulin medicines that decrease blood clotting (blood thinners) corticosteroids How should use ANDROGEL 1.62%See the detailed Instructions for Use about how to use ANDROGEL 1.62% at the end of this Medication Guide. It is important that you apply ANDROGEL 1.62% exactly as your healthcare provider tells you to. Your healthcare provider may change your ANDROGEL 1.62% dose. Do not change your ANDROGEL 1.62% dose without talking to your healthcare provider. Apply ANDROGEL 1.62% at the same time each morning. ANDROGEL 1.62% should be applied after showering or bathing. What are the possible side effects of ANDROGEL 1.62%ANDROGEL 1.62% can cause serious side effects including:See What is the most important information should know about ANDROGEL 1.62%If you already have enlargement of your prostate gland your signs and symptoms can get worse while using ANDROGEL 1.62%. This can include: increased urination at night. trouble starting your urine stream. having to pass urine many times during the day. having an urge to go to the bathroom right away. having urine accident. being unable to pass urine or weak urine flow. Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you use ANDROGEL 1.62%. Blood clots in the legs or lungs. Signs and symptoms of blood clot in your leg can include leg pain, swelling, or redness. Signs and symptoms of blood clot in your lungs can include difficulty breathing or chest pain. Possible increased risk of heart attack or stroke.In large doses ANDROGEL 1.62% may lower your sperm count.Swelling of your ankles, feet, or body, with or without heart failure.Enlarged or painful breasts.Have problems breathing while you sleep (sleep apnea).Call your healthcare provider right away if you have any of the serious side effects listed above.The most common side effects of ANDROGEL 1.62% include: increased prostate specific antigen (a test used to screen for prostate cancer) mood swings hypertension increased red blood cell count skin irritation where ANDROGEL 1.62% is applied Other side effects include more erections than are normal for you or erections that last long time. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ANDROGEL 1.62%. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of ANDROGEL 1.62%Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ANDROGEL 1.62% for condition for which it was not prescribed. Do not give ANDROGEL 1.62% to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ANDROGEL 1.62% that is written for health professionals. What are the ingredients in ANDROGEL 1.62%Active ingredient: testosterone Inactive ingredients: carbopol 980, ethyl alcohol, isopropyl myristate, purified water and sodium hydroxide. Marketed by: AbbVie Inc., North Chicago, IL 60064, USA (C) 2011-2020 AbbVie Inc. For more information about ANDROGEL 1.62%, call 1-800-633-9110 or go to www.androgel.com. This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: 11/2020 5005035 enlarged penis or clitoris. early growth of hair near the vagina or around the penis (pubic hair). erections or acting out sexual urges (sex drive).. acting aggressively, behaving in an angry or violent way.. changes in body hair. an abnormal increase in pimples (acne).. Apply ANDROGEL 1.62% only to your shoulders and upper arms that will be covered by short sleeve t-shirt. Wash your hands right away with soap and water after applying ANDROGEL 1.62%. After the gel has dried, cover the application area with clothing. Keep the area covered until you have washed the application area well or have showered. If you expect to have skin-to-skin contact with another person, first wash the application area well with soap and water. If child or woman touches the area where you have applied ANDROGEL 1.62%, that area on the child or woman should be washed well with soap and water right away. Your healthcare provider will test your blood before you start and while you are using ANDROGEL 1.62%. It is not known if ANDROGEL 1.62% is safe or effective to treat men who have low testosterone due to aging. It is not known if ANDROGEL 1.62% is safe or effective in children younger than 18 years old. Improper use of ANDROGEL 1.62% may affect bone growth in children. have breast cancer. have or might have prostate cancer. are pregnant. ANDROGEL 1.62% may harm your unborn baby. Women who are pregnant should avoid contact with the area of skin where ANDROGEL 1.62% has been applied.. have breast cancer. have or might have prostate cancer. have urinary problems due to an enlarged prostate. have heart problems. have kidney or liver problems. have problems breathing while you sleep (sleep apnea).. insulin medicines that decrease blood clotting (blood thinners) corticosteroids See the detailed Instructions for Use about how to use ANDROGEL 1.62% at the end of this Medication Guide. It is important that you apply ANDROGEL 1.62% exactly as your healthcare provider tells you to. Your healthcare provider may change your ANDROGEL 1.62% dose. Do not change your ANDROGEL 1.62% dose without talking to your healthcare provider. Apply ANDROGEL 1.62% at the same time each morning. ANDROGEL 1.62% should be applied after showering or bathing. If you already have enlargement of your prostate gland your signs and symptoms can get worse while using ANDROGEL 1.62%. This can include: increased urination at night. trouble starting your urine stream. having to pass urine many times during the day. having an urge to go to the bathroom right away. having urine accident. being unable to pass urine or weak urine flow. Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you use ANDROGEL 1.62%. Blood clots in the legs or lungs. Signs and symptoms of blood clot in your leg can include leg pain, swelling, or redness. Signs and symptoms of blood clot in your lungs can include difficulty breathing or chest pain. Possible increased risk of heart attack or stroke.. In large doses ANDROGEL 1.62% may lower your sperm count.. Swelling of your ankles, feet, or body, with or without heart failure.. Enlarged or painful breasts.. Have problems breathing while you sleep (sleep apnea).. increased prostate specific antigen (a test used to screen for prostate cancer) mood swings hypertension increased red blood cell count skin irritation where ANDROGEL 1.62% is applied.

SPL PATIENT PACKAGE INSERT SECTION.

INSTRUCTIONS FOR USEANDROGEL(R) (AN DROW JEL) CIII(testosterone gel) 1.62%for topical use Read this Instructions for Use for ANDROGEL1.62% before you start using it and each time you get refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Applying ANDROGEL 1.62%:ANDROGEL 1.62% comes in pump or in packets.Before applying ANDROGEL 1.62% make sure that your shoulders and upper arms are clean, dry, and that there is no broken skin. ANDROGEL 1.62% is to be applied to the area of your shoulders and upper arms that will be covered by short sleeve t-shirt (See Figure A). Do not apply ANDROGEL 1.62% to any other parts of your body such as your stomach area (abdomen), penis, scrotum, chest, armpits (axillae), or knees. (Figure A)If you are using ANDROGEL 1.62% pump:Before using new bottle of ANDROGEL 1.62 for the first time, you will need to remove the cap and then prime the pump. To prime the ANDROGEL 1.62% pump, slowly push the pump all the way down times, over the sink drain. Do not use any ANDROGEL 1.62% that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your ANDROGEL 1.62% pump is now ready to use. Remove the cap from the pump. Then, put the spout opening at the top of the pump where the medicine comes out over the palm of your hand and slowly push the pump all the way down. Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site. Your healthcare provider will tell you the number of times to press the pump for each dose. Wash your hands with soap and water right away. Find Your Dose as Prescribed by Your Healthcare ProviderApplication Method1 pump20.25 mg Apply pump of ANDROGEL 1.62% to upper arm and shoulder. pumps40.5 mg Apply pump of ANDROGEL 1.62% to upper arm and shoulder and then apply pump of ANDROGEL 1.62% to the opposite upper arm and shoulder. pumps60.75 mg Apply pumps of ANDROGEL 1.62% to upper arm and shoulder and then apply pump of ANDROGEL 1.62% to the opposite upper arm and shoulder. pumps81 mg Apply pumps of ANDROGEL 1.62% to upper arm and shoulder and then apply pumps of ANDROGEL 1.62% to the opposite upper arm and shoulder. If you are using ANDROGEL 1.62% packets:Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top. Squeeze all of the ANDROGEL 1.62% out of the packet into the palm of your hand. Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site. Let the application site dry completely before putting on t-shirt. ANDROGEL 1.62% is flammable until dry. Let ANDROGEL 1.62% dry before smoking or going near an open flame. Avoid showering, swimming or bathing for at least hours after you apply ANDROGEL 1.62%. Wash your hands right away with soap and water after applying ANDROGEL 1.62%. Find Your Dose asPrescribed by YourHealthcare ProviderApplication MethodOne 20.25 mg packet20.25 mgApply packet of ANDROGEL 1.62% to upper arm and shoulder.One 40.5 mg packet40.5 mgApply half of the 40.5 mg packet of ANDROGEL 1.62% to upper arm and shoulder and then apply the remaining packet contents to the opposite upper arm and shoulder. One 40.5 mg packetand one 20.25 mgpacket 60.75 mgApply one 40.5 mg packet of ANDROGEL 1.62% to upper arm and shoulder and then apply one 20.25 mg packet of ANDROGEL 1.62% to the opposite upper arm and shoulder. Two 40.5 mg packets81 mgApply one 40.5 mg packet of ANDROGEL 1.62% to upper arm and shoulder and then apply one 40.5 mg packet of ANDROGEL 1.62% to the opposite upper arm and shoulder. How should store ANDROGEL 1.62%Store ANDROGEL 1.62% at room temperature between 68oF to 77oF (20oC to 25oC). When it is time to throw away the pump or packets, safely throw away used ANDROGEL 1.62% in the household trash. Be careful to prevent accidental exposure of children or pets. Keep ANDROGEL 1.62% away from fire. Keep ANDROGEL 1.62% and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: 11/2020 5005035 ANDROGEL 1.62% comes in pump or in packets.. Before applying ANDROGEL 1.62% make sure that your shoulders and upper arms are clean, dry, and that there is no broken skin. ANDROGEL 1.62% is to be applied to the area of your shoulders and upper arms that will be covered by short sleeve t-shirt (See Figure A). Do not apply ANDROGEL 1.62% to any other parts of your body such as your stomach area (abdomen), penis, scrotum, chest, armpits (axillae), or knees. Before using new bottle of ANDROGEL 1.62 for the first time, you will need to remove the cap and then prime the pump. To prime the ANDROGEL 1.62% pump, slowly push the pump all the way down times, over the sink drain. Do not use any ANDROGEL 1.62% that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your ANDROGEL 1.62% pump is now ready to use. Remove the cap from the pump. Then, put the spout opening at the top of the pump where the medicine comes out over the palm of your hand and slowly push the pump all the way down. Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site. Your healthcare provider will tell you the number of times to press the pump for each dose. Wash your hands with soap and water right away. Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top. Squeeze all of the ANDROGEL 1.62% out of the packet into the palm of your hand. Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site. Let the application site dry completely before putting on t-shirt. ANDROGEL 1.62% is flammable until dry. Let ANDROGEL 1.62% dry before smoking or going near an open flame. Avoid showering, swimming or bathing for at least hours after you apply ANDROGEL 1.62%. Wash your hands right away with soap and water after applying ANDROGEL 1.62%. Store ANDROGEL 1.62% at room temperature between 68oF to 77oF (20oC to 25oC). When it is time to throw away the pump or packets, safely throw away used ANDROGEL 1.62% in the household trash. Be careful to prevent accidental exposure of children or pets. Keep ANDROGEL 1.62% away from fire.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS There are insufficient long-term safety data in geriatric patients using AndroGel 1.62% to assess the potential risks of cardiovascular disease and prostate cancer. (8.5) 8.1 Pregnancy Risk SummaryAndroGel 1.62% is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to pregnant woman based on data from animal studies and its mechanism of action [see Contraindications 4 and Clinical Pharmacology 12.1 )]. Exposure of 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. DataAnimal DataIn 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 SummaryAndroGel 1.62% is not indicated for use in women. 8.3 Females and Males of Reproductive Potential. InfertilityTestis disorder, testicular atrophy, and oligospermia have been identified during use of AndroGel 1.62% [see Adverse Reactions 6.1 6.2 )]. During treatment with large doses of exogenous androgens, including AndroGel 1.62%, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions 5.8 )]. 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 The safety and effectiveness of AndroGel 1.62% in pediatric patients less than 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AndroGel 1.62% to determine whether efficacy in those over 65 years of age differs from younger subjects. Of the 234 patients enrolled in the clinical trial utilizing AndroGel 1.62%, 21 were over 65 years of age. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potentially increased risks of cardiovascular disease and prostate cancer. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH. 8.6 Renal Impairment No studies were conducted involving patients with renal impairment. 8.7 Hepatic Impairment No studies were conducted in patients with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH (5.1) 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 (5.2) 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. (5.4) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. (5.5) Exogenous administration of androgens may lead to azoospermia (5.8) Edema with or without congestive heart failure (CHF) may be complication in patients with preexisting cardiac, renal, or hepatic disease (5.10) 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, 5.3, 5.9, 5.13) AndroGel 1.62% is flammable until dry (5.16) Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH (5.1) 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 (5.2) 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. (5.4) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. (5.5) Exogenous administration of androgens may lead to azoospermia (5.8) Edema with or without congestive heart failure (CHF) may be complication in patients with preexisting cardiac, renal, or hepatic disease (5.10) 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, 5.3, 5.9, 5.13) AndroGel 1.62% is flammable until dry (5.16) 5.1 Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at increased risk for prostate cancer. Evaluation of patients for prostate cancer prior to initiating and during treatment with androgens is appropriate [see Contraindications 4 )]. Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at increased risk for prostate cancer. Evaluation of patients for prostate cancer prior to initiating and during treatment with androgens is appropriate [see Contraindications 4 )]. 5.2 Potential for Secondary Exposure to Testosterone Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance of testosterone gel products. 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 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 physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified. 5.3 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 to 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. 5.4 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 AndroGel 1.62%. 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 venous thromboembolic event is suspected, discontinue treatment with AndroGel 1.62% and initiate appropriate workup and management [see Adverse Reactions 6.2 )]. 5.5 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 AndroGel 1.62%. 5.6 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations. Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions [see Drug Abuse and Dependence 9 )]. If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events. 5.7 Use in Women Due to the lack of controlled evaluations in women and potential virilizing effects, AndroGel 1.62% is not indicated for use in women [see Contraindications 4 and Use in Specific Populations 8.1 8.2 )]. 5.8 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including AndroGel 1.62%, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH possibly leading to adverse effects on semen parameters including sperm count. 5.9 Hepatic Adverse Effects Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. AndroGel 1.62% is not known to cause these adverse effects. 5.10 Edema Androgens, including AndroGel 1.62%, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse Reactions 6.2 )]. 5.11 Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including AndroGel 1.62%, for hypogonadism. 5.12 Sleep Apnea The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases. 5.13 Lipids Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy. 5.14 Hypercalcemia Androgens, including AndroGel 1.62 %, 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. 5.15 Decreased Thyroxine-binding Globulin Androgens, including AndroGel 1.62%, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. 5.16 Flammability Alcohol based products, including AndroGel 1.62%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the AndroGel 1.62% has dried.