WARNING: SECONDARY EXPOSURE TO TESTOSTERONE Virilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. Healthcare providers should advise patients to strictly adhere to recommended instructions for use. (See WARNINGS, Potential for Secondary Exposure to Testosterone )
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warnings
WARNINGS Men with benign prostatic hyperplasia (BPH) are at an increased risk for worsening of BPH. In addition, men treated with androgens may be at an increased risk for prostate cancer. Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility and Laboratory Tests ). Potential for Secondary Exposure to Testosterone Secondary exposure to testosterone in children and women can occur with testosterone gel use in men. Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance of testosterone-containing 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. 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 testosterone gel product. 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. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from Testim ® -treated skin: Children and women should avoid contact with Testim ® application sites on the skin of men using Testim. Testim ® should only be applied to the shoulders or upper arms (area of application should be limited to the area that will be covered by the patient’s short sleeve t-shirt). Patients should wash their hands thoroughly and immediately with soap and water after application of Testim ® . Patients should cover the application site(s) with clothing (e.g., a shirt) after the gel has dried. Prior to any situation in which 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 Testim ® 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. Studies show that residual testosterone is removed from the skin surface by washing with soap and water. Testim ® should not be applied to the abdomen. 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 testosterone enanthate, which elevates blood levels for prolonged periods has produced multiple hepatic adenomas. Transdermal testosterone is not known to produce these adverse effects. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required. Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism. 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.
ADVERSE REACTIONS In a controlled clinical study, 304 patients were treated with Testim ® 50 mg or 100 mg or placebo gel for up to 90 days. Two hundred-five (205) patients received Testim ® 50 mg or 100 mg daily and 99 patients received placebo. Patients with adverse events that were possibly or probably related to study drug and reported by ≥1% of the Testim ® patients and greater than placebo are listed in Table 3. Table 3: Incidence of Adverse Events Judged Possibly, Probably or Definitely Related to Use of Testim ® in the Controlled Clinical Trial Event Testim ® 50 mg Testim ® 100 mg Placebo Application Site Reactions 2% 4% 3% Benign Prostatic Hyperplasia 0% 1% 1% Blood Pressure Diastolic Decreased 1% 0% 0% Blood Pressure Increased 1% 1% 0% Gynecomastia 1% 0% 0% Headache 1% 1% 0% Hematocrit/hemoglobin Increased 1% 2% 0% Hot Flushes 1% 0% 0% Insomnia 1% 0% 0% Lacrimation Increased 1% 0% 0% Mood Swings 1% 0% 0% Smell Disorder 1% 0% 0% Spontaneous Penile Erection 1% 0% 0% Taste Disorder 1% 1% 0% The following adverse events possibly or probably related to Testim ® occurred in fewer than 1% of patients but were greater in Testim ® groups compared to the placebo group: activated partial thromboplastin time prolonged, blood creatinine increased, prothrombin time prolonged, appetite increased, sensitive nipples, and acne. In this clinical trial of Testim ® , six patients had adverse events that led to their discontinuation. These events included: vertigo, coronary artery disease, depression with suicidal ideation, urinary tract infection/pneumonia (none of which were considered related to Testim ® administration), mood swings and hypertension. No Testim ® patients discontinued due to skin reaction. In one foreign Phase 3 trial, one subject discontinued due to a skin-related adverse event. In the pivotal U.S. and European Phase 3 trials combined, at the 50 mg dosage strength, the percentage of subjects reporting clinically notable increases in hematocrit or hemoglobin were similar to placebo. However, in the 100 mg dose group, 2.3% and 2.8% of patients had a clinically notable increase in hemoglobin (≥ 19 gm/dL) or hematocrit (≥ 58%), respectively. In the combined ongoing U.S. and European open label extension studies, approximately 140 patients received Testim ® for at least 6 months. The preliminary results from these studies are consistent with those reported for the U.S. controlled clinical trial. Postmarketing Experience The following adverse reactions have been identified during post-approval use of testosterone gel products. 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. Secondary Exposure to Testosterone in Children Cases 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 of 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 fabrics, such as towels and sheets (see WARNINGS ).