INTERACTIONS Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients ( 7.1 ) Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended ( 7.2 ) Use of testosterone with adrenocorticotrophic hormone (ACTH) or corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 )
7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease insulin requirements.
7.2 Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.
7.3 Corticosteroids The concurrent use of testosterone with adrenocorticotropic hormone (ACTH) or corticosteroids may result in increased fluid retention and requires careful monitoring particularly in patients with cardiac, renal or hepatic disease.
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.
Testosterone gel, 1% 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, 1% is contraindicated in women who are pregnant. Testosterone gel, 1% can cause virilization of the female fetus when administered to a pregnant woman. Pregnant women need to be aware of the potential for transfer of testosterone from men treated with testosterone gel, 1%. If a pregnant woman is exposed to testosterone gel, 1%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 )] . Men with carcinoma of the breast or known or suspected prostate cancer. ( 4 , 5.1 ) Women who are pregnant. Testosterone may cause fetal harm. ( 4 , 8.1 )
AND PRECAUTIONS Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.1 ) Potential for Secondary Exposure to Testosterone: Avoid unintentional exposure of women or children to testosterone gel, 1.62%. Secondary exposure to testosterone can produce signs of virilization. Testosterone gel, 1.62% should be discontinued until the cause of virilization is identified. ( 5.2 )
Venous
Thromboembolism (VTE): VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. ( 5.4 )
Blood Pressure
Increases: Testosterone gel, 1.62% can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.5 ) Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia. ( 5.8 ) Edema: Edema, with or without congestive heart failure (CHF), may be a complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.10 , 6.2 ) Sleep apnea: Sleep apnea may occur in those with risk factors. ( 5.12 ) Monitor serum testosterone, prostate specific antigen (PSA), hemoglobin, hematocrit, liver function tests, and lipid concentrations periodically. ( 5.1 , 5.3 , 5.9 , 5.13 ) Flammability: Testosterone gel, 1.62% is flammable until dry. ( 5.16 )
5.1 Potential for Secondary Exposure to Testosterone Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone gel, 1.62% <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )]</span>. Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.
5.2 Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events.
5.3 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as testosterone gel, 1.62%. In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, Testosterone gel, 1.62% was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 a venous thromboembolic event is suspected, discontinue treatment with testosterone gel, 1.62% and initiate appropriate workup and management <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .
5.4 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. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Adverse Reactions ( 6.1 ) and Nonclinical Toxicology ( 13.1 )]</span> .
5.5 Blood Pressure Increases Testosterone gel, 1.62% can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, testosterone gel, 1.62% increased the mean systolic/diastolic blood pressure by 1.9/1.3 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, testosterone gel, 1.62% increased the mean systolic/diastolic BP by 3.0/2.2 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time. The CV risk associated with testosterone gel, 1.62% was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, mean systolic blood pressure in the group treated with testosterone gel, 1.62% increased by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for testosterone gel, 1.62% vs 7.3% for placebo) [See Adverse Reactions ( 6.1 )]. Monitor blood pressure periodically in men using testosterone gel, 1.62%, especially men with hypertension. Testosterone gel, 1.62% is not recommended for use in patients with uncontrolled hypertension.
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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9 )]</span> . 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 Not for Use in Women Due to the lack of controlled evaluations in women and potential virilizing effects, testosterone gel, 1.62% is not indicated for use in women <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 , 8.2 )]</span>.
5.8 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including testosterone gel, 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 a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. Testosterone gel, 1.62% is not known to cause these adverse effects.
5.10 Edema Androgens, including testosterone gel, 1.62%, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .
5.11 Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including testosterone gel, 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 Lipid Changes Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as testosterone gel, 1.62%. Monitor the lipid profile periodically, particularly after starting testosterone therapy.
5.14 Hypercalcemia Androgens, including testosterone gel, 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 testosterone gel, 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 testosterone gel, 1.62%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the testosterone gel, 1.62% has dried.
5.1 Potential for Secondary Exposure to Testosterone Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone gel, 1.62% <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )]</span>. Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.
5.2 Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating treatment. It would also be appropriate to re-evaluate the hematocrit 3 to 6 months after starting treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable concentration. An increase in red blood cell mass may increase the risk of thromboembolic events.
5.3 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products such as testosterone gel, 1.62%. In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, Testosterone gel, 1.62% was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 a venous thromboembolic event is suspected, discontinue treatment with testosterone gel, 1.62% and initiate appropriate workup and management <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .
5.4 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. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Adverse Reactions ( 6.1 ) and Nonclinical Toxicology ( 13.1 )]</span> .
5.5 Blood Pressure Increases Testosterone gel, 1.62% can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, testosterone gel, 1.62% increased the mean systolic/diastolic blood pressure by 1.9/1.3 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, testosterone gel, 1.62% increased the mean systolic/diastolic BP by 3.0/2.2 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time. The CV risk associated with testosterone gel, 1.62% was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, mean systolic blood pressure in the group treated with testosterone gel, 1.62% increased by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for testosterone gel, 1.62% vs 7.3% for placebo) [See Adverse Reactions ( 6.1 )]. Monitor blood pressure periodically in men using testosterone gel, 1.62%, especially men with hypertension. Testosterone gel, 1.62% is not recommended for use in patients with uncontrolled hypertension.
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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9 )]</span> . 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 Not for Use in Women Due to the lack of controlled evaluations in women and potential virilizing effects, testosterone gel, 1.62% is not indicated for use in women <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 , 8.2 )]</span>.
5.8 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including testosterone gel, 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 a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. Testosterone gel, 1.62% is not known to cause these adverse effects.
5.10 Edema Androgens, including testosterone gel, 1.62%, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .
5.11 Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including testosterone gel, 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 Lipid Changes Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy, such as testosterone gel, 1.62%. Monitor the lipid profile periodically, particularly after starting testosterone therapy.
5.14 Hypercalcemia Androgens, including testosterone gel, 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 testosterone gel, 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 testosterone gel, 1.62%, are flammable; therefore, patients should be advised to avoid fire, flame or smoking until the testosterone gel, 1.62% has dried.