Testosterone

Warnings and Precautions ( 5.6 ) 03/2025

RECENT MAJOR CHANGES Warnings and Precautions ( 5.6 ) 03/2025

1 INDICATIONS AND USAGE Testosterone Topical Solution is indicated for replacement therapy in 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 (FSH, LH) above the normal range. • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use: • Safety and efficacy of Testosterone Topical Solution in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. • Safety and efficacy of Testosterone Topical Solution in males <18 years old have not been established [ see Use in Specific Populations ( 8.4 ) ]. Testosterone Topical Solution, 30 mg/1.5 mL 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 Testosterone Topical Solution, 30 mg/1.5 mL in men with “age-related hypogonadism” have not been established. ( 1 ) • Safety and efficacy of Testosterone Topical Solution, 30 mg/1.5 mL in males <18 years old have not been established. ( 8.4 )

2 DOSAGE AND ADMINISTRATION Prior to initiating Testosterone Topical Solution, 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. Prior to initiating Testosterone Topical Solution, 30 mg/1.5 mL, 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 Testosterone Topical Solution, 30 mg/1.5 mL dose is 60 mg of testosterone (1 pump actuation of 30 mg of testosterone to each axilla), applied once daily, at the same time each morning. ( 2.1 ) • Apply to clean, dry intact skin of the axilla, not to any other parts of the body including the abdomen or genitals. ( 2.2 ) • Dose adjustment: The dose of testosterone may be decreased from 60 mg (2 pump actuations) to 30 mg (1 pump actuation) or increased from 60 mg to 90 mg (3 pump actuations) or from 90 mg to 120 mg (4 pump actuations) based on the serum testosterone concentration from a single blood draw 2 to 8 hours after applying Testosterone Topical Solution, 30 mg/1.5 mL and at least 14 days after starting treatment or following dose adjustment. ( 2.2 ) • Patients should wash hands immediately with soap and water after applying Testosterone Topical Solution, 30 mg/1.5 mL and cover the application site with clothing after the solution 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 ) • The application site and dose of Testosterone Topical Solution, 30 mg/1.5 mL are not interchangeable with other topical testosterone products. ( 2.1 ) 2.1 Dosing and Dose Adjustment The recommended starting dose of Testosterone Topical Solution is 60 mg of testosterone (2 pump actuations) applied once daily. To ensure proper dosing, serum testosterone concentrations should be measured after initiation of therapy to ensure that the desired concentrations (300 ng/dL to 1050 ng/dL) are achieved. The Testosterone Topical Solution dose can be adjusted based on the serum testosterone concentration from a single blood draw 2 to 8 hours after applying Testosterone Topical Solution and at least 14 days after starting treatment or following dose adjustment. If the measured serum testosterone concentration is below 300 ng/dL, the daily testosterone dose may be increased from 60 mg (2 pump actuations) to 90 mg (3 pump actuations) or from 90 mg to 120 mg (4 pump actuations). If the serum testosterone concentration exceeds 1050 ng/dL, the daily testosterone dose should be decreased from 60 mg (2 pump actuations) to 30 mg (1 pump actuation) as instructed by a physician. If the serum testosterone concentration consistently exceeds 1050 ng/dL at the lowest daily dose of 30 mg (1 pump actuation), Testosterone Topical Solution therapy should be discontinued. The application site and dose of Testosterone Topical Solution are not interchangeable with other topical testosterone products. 2.2 Administration Instructions Testosterone Topical Solution is applied to the axilla, preferably at the same time each morning, to clean, dry, intact skin. Do not apply Testosterone Topical Solution to other parts of the body including to the scrotum, penis, abdomen, shoulders or upper arms. After applying the solution, the application site should be allowed to dry completely prior to dressing. Avoid fire, flames or smoking until the solution has dried since alcohol based products, including Testosterone Topical Solution, are flammable. Testosterone Topical Solution is applied to the axilla using an applicator. When using Testosterone Topical Solution for the first time, patients should be instructed to prime the pump by depressing the pump three (3) times, discard any produ …

3 DOSAGE FORMS AND STRENGTHS Testosterone Topical Solution USP is available as a metered-dose pump. One pump actuation delivers 30 mg of testosterone. Each metered-dose pump is supplied with an applicator. Testosterone Topical Solution, 30 mg/1.5 mL is available as a metered-dose pump. One pump actuation delivers 30 mg of testosterone. Each metered-dose pump is supplied with an applicator. ( 3 )

4 CONTRAINDICATIONS • Testosterone Topical Solution is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [ see Warnings and Precaution ( 5.1 ) ]. • Testosterone Topical Solution is contraindicated in women who are, or who may become pregnant, or who are breastfeeding. Testosterone Topical Solution may cause fetal harm when administered to a pregnant woman. Testosterone Topical Solution may cause serious adverse reactions in nursing infants. If a pregnant woman is exposed to Testosterone Topical Solution, she should be apprised of the potential hazard to the fetus. [ See Use in Specific Populations ( 8.1 , 8.3 ) ]. • Men with carcinoma of the breast or known or suspected carcinoma of the prostate ( 4 , 5.1 ) • Pregnant or breastfeeding women. Testosterone may cause fetal harm ( 4 , 8.1 , 8.3 )

6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than 4%) are skin application site reactions, increased hematocrit, headache, diarrhea, vomiting, and increased serum PSA ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. Clinical Trials in Hypogonadal Men Table 2 shows the treatment emergent adverse reactions that were reported by either greater than 4% of 155 patients in a 120 day, Phase 3 study or by greater than 4% of 71 patients who continued to use testosterone topical solution for up to 180 days. These data reflect the experience primarily with a testosterone dose of 60 mg, which was taken by all patients at the start of the study, and was the maintenance dose for 97 patients. However, the doses used varied from 30 mg to 120 mg. Table 2: Adverse Reactions Seen With the Use of Testosterone Topical Solution in either the 120 Day Clinical Trial or in the Extension to 180 Days (greater than 4%) Event 120 Days (155 Patients) 180 Days (71 Patients) Application Site Irritation 11 (7%) 6 (8%) Application Site Erythema 8 (5%) 5 (7%) Headache 8 (5%) 4 (6%) Hematocrit Increased 6 (4%) 5 (7%) Diarrhea 4 (3%) 3 (4%) Vomiting 4 (3%) 3 (4%) PSA Increased 2 (1%) 3 (4%) Other less common adverse reactions reported by at least 2 patients in the 120 day trial included: application site edema, application site warmth, increased hemoglobin, hypertension, erythema (general), increased blood glucose, acne, nasopharyngitis, anger and anxiety. Other less common adverse reactions reported in fewer than 1% of patients in the 120 day trial included: asthenia, affect lability, folliculitis, increased lacrimation, breast tenderness, increased blood pressure, increased blood testosterone, neoplasm prostate and elevated red blood cell count. During the 120 day trial one patient discontinued treatment because of affect lability/anger which was considered possibly related to testosterone topical solution administration. During the 120 day clinical trial there was an increase in mean PSA values of 0.13 ± 0.68 ng/mL from baseline. At the end of the 180 day extension clinical trial, there was an overall increase in mean PSA values of 0.1 ± 0.54 ng/mL. Following the 120 day study, seventy-one (71) patients entered a two-month extension study with testosterone topical solution. Two patients (3%) had adverse reactions that led to discontinuation of treatment during the period from Day 120 to Day 180. These reactions were: one patient with application site irritation (considered possibly related to testosterone topical solution application) and one patient with dry skin and erythema, but not at the application site (considered not related to testosterone topical solution administration) and application site erythema (considered possibly related to testosterone topical solution administration). No serious adverse reactions to testosterone topical solution were reported during either the 120 day trial, or the extension to 180 days. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of testosterone topical solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Disorders: myocardial infarction, stroke [see Warnings and Precautions ( 5.5 )] . Vascular Disorders: Venous thromboembolism [see Warnings and Precautions ( 5.4 )] .

7 DRUG INTERACTIONS • Androgens may decrease blood glucose and insulin requirement in diabetic patients ( 7.1 ). • Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended ( 7.2 ). • Use of testosterone with Adrenocorticotropic Hormone (ACTH) or corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 ). 7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirement. 7.2 Oral anticoagulants Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.

8 USE IN SPECIFIC POPULATIONS There are insufficient long-term safety data in geriatric patients using testosterone topical solution to assess the potential risks of cardiovascular disease and prostate cancer ( 8.5 ). 8.1 Pregnancy Pregnancy Category X [see Contraindications ( 4 )] — Testosterone topical solution is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers Although it is not known how much testosterone transfers into human milk, testosterone topical solution is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other androgens may adversely affect lactation. [See Contraindications ( 4 )] . 8.4 Pediatric Use Safety and efficacy of testosterone topical solution has not been established in males less than 18 years of age. 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 testosterone topical solution to determine whether efficacy in those over 65 years of age differs from younger patients. Of the 155 patients enrolled in the pivotal clinical study utilizing testosterone topical solution, 21 were over 65 years of age. Additionally, there were insufficient long-term safety data in these patients utilizing testosterone topical solution to assess a potential incremental risk of cardiovascular disease and prostate cancer. 8.6 Renal Impairment No formal studies were conducted involving patients with renal impairment. 8.7 Hepatic Impairment No formal studies were conducted involving patients with hepatic impairment. 8.8 Use in Men with Body Mass Index (BMI) Greater Than 35 kg/m 2 Safety and efficacy of testosterone topical solution in males with BMI greater than 35 kg/m 2 has not been established.

12.1 Mechanism of Action Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

11 DESCRIPTION Testosterone Topical Solution USP, 30 mg/1.5 mL is a clear, colorless, single phase solution containing 30 mg of testosterone in 1.5 mL of Testosterone Topical Solution for topical administration through the axilla. The active pharmacologic ingredient in Testosterone Topical Solution is testosterone. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is: The inactive ingredients are ethanol, isopropyl alcohol, octisalate, and povidone. chemical-structure

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

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Testosterone topical solution USP is available as a metered-dose pump containing 110 mL of solution. The pump is capable of dispensing 90 mL of solution in 60 metered pump actuations. One actuation delivers 30 mg of testosterone in 1.5 mL of solution. Each metered-dose pump is supplied with an applicator. The bottle and the applicator cup are not made with natural rubber latex. NDC Pump Type 62332-488-11 Pump Actuated 16.2 Storage and Handling Keep testosterone topical solution out of reach of children. Store upright at 25°C (77°F). Excursions are permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Used testosterone topical solution bottles and applicators should be discarded in household trash in a manner that prevents accidental exposure of children or pets.

16.1 How Supplied Testosterone topical solution USP is available as a metered-dose pump containing 110 mL of solution. The pump is capable of dispensing 90 mL of solution in 60 metered pump actuations. One actuation delivers 30 mg of testosterone in 1.5 mL of solution. Each metered-dose pump is supplied with an applicator. The bottle and the applicator cup are not made with natural rubber latex. NDC Pump Type 62332-488-11 Pump Actuated