Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE Testosterone gel is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: Primary Hypogonadism (congenital or acquired) - testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle stimulating hormone (FSH), luteinizing hormone (LH)) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired) - gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use: Safety and efficacy of testosterone gel in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established. Safety and efficacy of testosterone gel 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. (1, 12.3) Testosterone is an androgen 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 gel in men with age-related hypogonadism have not been established. (1) Safety and efficacy of testosterone gel in males less than 18 years old have not been established. (8.4) Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure. (1, 12.3)

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Advisory information

contraindications
4 CONTRAINDICATIONS Testosterone gel is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [ see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)]. Testosterone gel is contraindicated in women who are or may become pregnant, or who are breastfeeding. Testosterone gel may cause fetal harm when administered to a pregnant woman. Testosterone gel may cause serious adverse reactions in nursing infants. Exposure of a female fetus or nursing infant to androgens may result in varying degrees of virilization. Pregnant women or those who may become pregnant need to be aware of the potential for transfer of testosterone from men treated with testosterone gel. If a pregnant woman is exposed to testosterone gel, she should be apprised of the potential hazard to the fetus [ see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)]. Men with carcinoma of the breast or known or suspected prostate cancer. (4, 5.1) Pregnant or breast feeding women. Testosterone may cause fetal/neonatal harm. (4, 8.1, 8.3)
Adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5%) are acne, application site reactions, abnormal lab tests, and prostatic disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 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 incidence of all adverse reactions with testosterone gel and reported by > 1% of patients in a 180 Day, Phase 3 study. Dose of Testosterone Adverse Reaction 50 mg 75 mg 100 mg N = 77 N = 40 N = 78 Acne 1% 3% 8% Alopecia 1% 0% 1% Application Site Reaction 5% 3% 4% Asthenia 0% 3% 1% Depression 1% 0% 1% Emotional Lability 0% 3% 3% Gynecomastia 1% 0% 3% Headache 4% 3% 0% Hypertension 3% 0% 3% Abnormal Lab Tests* 6% 5% 3% Libido Decreased 0% 3% 1% Nervousness 0% 3% 1% Pain Breast 1% 3% 1% Prostate Disorder** 3% 3% 5% Testis Disorder*** 3% 0% 0% * Abnormal lab tests occurred in nine patients with one or more of the following events reported: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin. ** Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results. *** Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis. Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation. In this 180 day clinical trial, skin reactions at the site of application were reported with testosterone gel, but none was severe enough to require treatment or discontinuation of drug. Six patients (4%) in this trial had adverse reactions that led to discontinuation of testosterone gel. These reactions included: cerebral hemorrhage, convulsion, depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No patients on testosterone gel discontinued due to skin reactions. In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse reactions; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other. In a 3 year, flexible dose, extension study, the incidence of all adverse reactions to testosterone gel and reported by > 1% of patients is shown in Table 3: Table 3: Adverse Reactions to Testosterone gel in the 3 Year, Flexible Dose, Extension Study Adverse Reaction Percent of Subjects (N = 162) Abnormal Lab Tests+ 9.3 Skin dry 1.9 Application Site Reaction 5.6 Acne 3.1 Pruritus 1.9 Enlarged Prostate 11.7 Carcinoma of Prostate 1.2 Urinary Symptoms* 3.7 Testis Disorder** 1.9 Gynecomastia 2.5 Anemia 2.5 + Abnormal lab tests occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, elevated HDL, elevated serum creatinine. * Urinary symptoms included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream. ** Testis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness. Two patients reported serious adverse reactions considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP). Discontinuation for adverse reactions in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient). Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on testosterone gel in the 3 year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL. Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as > 2X the baseline or any single serum PSA > 6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still < 2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%). Four patients met this criterion by having a serum PSA > 6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient’s PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient’s PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of testosterone gel. Because the 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 (Table 4): Table 4: Adverse Reactions from Postmarketing Experience of Testosterone Gel by MedDRA System Organ Class Blood and lymphatic system disorders: Elevated Hgb, Hct (polycythemia) Cardiovascular disorders: Myocardial infarction, stroke Endocrine disorders: Hirsutism Gastrointestinal disorders: Nausea General disorders and administration site reactions: Asthenia, edema, malaise Genitourinary disorders: Impaired urination Hepatobiliary disorders: Abnormal liver function tests (e.g., transaminases, elevated GGTP, bilirubin) Investigations: Elevated PSA, electrolyte changes (nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (hyperlipidemia, elevated triglycerides, decreased HDL), impaired glucose tolerance, fluctuating testosterone levels, weight increase Neoplasms benign, malignant and unspecified (cysts and polyps): Prostate cancer Nervous system: Headache, dizziness, sleep apnea, insomnia Psychiatric disorders: Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety Reproductive system and breast disorders: Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, Oligospermia, priapism (frequent or prolonged erections) Respiratory disorders: Dyspnea Skin and subcutaneous tissue disorders: Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating Vascular disorders: Hypertension, vasodilation (hot flushes, venous thromboembolism) Secondary Exposure to Testosterone in Children Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarket surveillance. 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 a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In a few cases, however, enlarged genitalia did not fully return to age appropriate normal size, and bone age remained modestly greater than chronological age. 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 items such as the testosterone gel user’s shirts and/or other fabric, such as towels and sheets [ see Warnings and Precautions (5.2)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Prior to initiating testosterone gel, 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 gel, 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 testosterone gel is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied once daily in the morning. (2.1) Apply to clean, dry, intact skin of shoulders and upper arms and/or abdomen. Do NOT apply testosterone gel to any other parts of the body including the genitals, chest, armpits (axillae), knees, or back. (2.2) Dose adjustment: Testosterone gel can be dose adjusted using 50 mg, 75 mg, or 100 mg of testosterone on the basis of total serum testosterone concentration. Additionally, serum testosterone concentration should be assessed periodically. (2.1) Patients should wash hands immediately with soap and water after applying testosterone gel and cover the application site(s) with clothing after the gel has dried. Wash the application site thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. (2.2) 2.1 Dosing and Dose Adjustment The recommended starting dose of testosterone gel is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day). Dose Adjustment To ensure proper dosing, serum testosterone levels should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily testosterone gel dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician (see Table 1, Dosing Information for testosterone gel). If the serum testosterone concentration exceeds the normal range, the daily testosterone gel dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 50 mg, testosterone gel therapy should be discontinued. In addition, serum testosterone concentration should be assessed periodically. 2.2 Administration Instructions Testosterone gel should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient’s short sleeve T- shirt. Do not apply testosterone gel to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. Testosterone gel should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen. The prescribed daily dose of testosterone gel should be applied to the right and left upper arms/shoulders and/or right/left abdomen as shown in the shaded areas in the figure below. After applying the gel, the application site should be allowed to dry prior to dressing. Hands should be washed with soap and water after testosterone gel has been applied. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including testosterone gel, are flammable. The patient should be advised to avoid swimming or showering for at least 5 hours after the application of testosterone gel. Multi-Dose Pump To obtain a 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, patients should completely depress the pump one time (actuation) for every 12.5 mg of testosterone required to achieve the daily prescribed dosage. The product should be delivered directly into the palm of the hand and then applied to the desired application sites. Alternatively, testosterone gel can be applied directly to the application sites. Table 1 provides dosing information for adult males. Packets The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a 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. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from testosterone gel-treated skin: Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel. Patients should wash their hands immediately with soap and water after applying testosterone gel. Patients should cover the application site(s) with clothing (e.g., a T-shirt) after the gel has dried. Prior to any situation in which skin-to-skin contact with the application site 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 testosterone gel 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. Figure 1 Table 1
Use in special populations
8 USE IN SPECIFIC POPULATIONS There are insufficient long-term safety data in geriatric patients using testosterone gel to assess the potential risks of cardiovascular disease and prostate cancer. (8.5) 8.1 Pregnancy Pregnancy Category X [ see Contraindications (4)]: Testosterone gel 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, such as testosterone, 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 gel 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 gel in pediatric males 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 testosterone gel to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential 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.
Pregnancy and lactation
8.3 Nursing Mothers Although it is not known how much testosterone transfers into human milk, testosterone gel 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)].

Interactions

7 DRUG INTERACTIONS Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients. (7.1) Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (“INR”) and prothrombin time is recommended. (7.2) Use of testosterone with 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, may decrease insulin requirements. 7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of International Normalized Ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.

More information

Category Value
Authorisation number NDA203098
Agency product number 3XMK78S47O
Orphan designation No
Product NDC 70518-1171
Date Last Revised 14-05-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1596780
Marketing authorisation holder REMEDYREPACK INC.
Warnings WARNING: SECONDARY EXPOSURE TO TESTOSTERONE Virilization has been reported in children who were secondarily exposed to testosterone gel [ see Warnings and Precautions (5.2) and Adverse Reactions (6.2)] . Children should avoid contact with any unwashed or unclothed application sites in men using testosterone gel [ see Dosage and Administration (2.2), Warnings and Precautions (5.2)] . Healthcare providers should advise patients to strictly adhere to recommended instructions for use [ see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Patient Counseling Information (17)] . WARNING: SECONDARY EXPOSURE TO TESTOSTERONE See full prescribing information for complete boxed warning. Virilization has been reported in children who were secondarily exposed to testosterone gel. (5.2, 6.2) Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. (2.2, 5.2) Healthcare providers should advise patients to strictly adhere to recommended instructions for use. (2.2, 5.2, 17)