FDA label e7fcb379-2173-46f5-860b-fa461e16e211

5 WARNINGS AND PRECAUTIONS Gum-related adverse reactions: Instruct patients to regularly inspect their gum region where Striant is applied. ( 5.1 ) Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 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 ) Women and children should not use Striant ( 5.7 ) Exogenous administration of androgens may lead to azoospermia. ( 5.8 ) Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.10 ) Sleep apnea may occur in those with risk factors. ( 5.12 ) Monitor prostate specific antigen (PSA), hematocrit, and lipid concentrations periodically. ( 5.2 , 5.3 , 5.9 , 5.13 ) 5.1 Gum-Related Adverse Reactions and Limited Long-Term Information on Oral Safety Gum-related adverse reactions, including severe gum irritation, were reported in clinical trials of Striant. Long-term clinical trial data on gum safety is available in only a limited number of patients (117 patients, 51 patients and 48 patients with at least 6 months, 1 year, and 2 years of exposure, respectively). It is recommended that patients regularly inspect their own gum region where Striant is applied. Any abnormal finding should be brought promptly to the attention of the patient’s physician. In such circumstances, dental consultation may be appropriate. 5.2 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 [ see Contraindications ( 4 ) and Adverse Reactions ( 6.1 ) ]. 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 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. 5.4 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 Striant. 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 Striant 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 Striant. 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 lack of controlled evaluations in women and potential virilizing effects, Striant is not indicated for use in women. 5.8 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including Striant, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead 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 testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue Striant while the cause is evaluated. 5.10 Edema Androgens, including Striant, 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. In addition to discontinuation of the drug, diuretic therapy may be required [ see Adverse Reactions ( 6.1 ) ]. 5.11 Gynecomastia Gynecomastia may develop and persist in patients being treated with androgens, including Striant, 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 the serum lipid profile may occur. Monitor the lipid profile periodically, particularly after starting therapy. 5.14 Hypercalcemia Androgens, including Striant, 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 Striant, may decrease concentrations of thyroxine-binding globulins, resulting in decreased total T4 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.

6 ADVERSE REACTIONS Most common adverse reactions, occurring in > 1% of patients, are gum or mouth irritation, bitter taste, gum pain, gum tenderness, headache, gum edema and taste perversion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals, Inc. at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Twelve Week Clinical Trials in Hypogonadal Men In the Phase 3, open-label study, 98 patients received Striant for up to 12 weeks. Adverse reactions to Striant reported by ≥1% of patients are listed in Table 1. Table 1. Adverse Reactions Observed With the Use of Striant in ≥1% of Patients Adverse Reaction Striant (n=98) Gum or Mouth Irritation 9.2% Taste Bitter 4.1% Gum Pain 3.1% Gum Tenderness 3.1% Headache 3.1% Gum Edema 2.0% Taste Perversion 2.0% Gum irritation generally resolved in 1 to 8 days. Gum tenderness resolved in 1 to 14 days [ see Gum-related adverse events and gum examinations in Adverse Reactions ( 6.1 ) ]. The following adverse reactions to Striant occurred in 1 patient each: acne, anxiety, breast enlargement, breast pain, buccal mucosal roughening, difficulty in micturition, fatigue, gingivitis, gum blister, gustatory sense diminished, hematocrit increased, lipids serum increased, liver function tests abnormal, nose edema, stinging of lips, and toothache. There was one additional 12-week study in 12 patients. In this study, additional adverse reactions to Striant and reported by 1 patient each included emotional lability and hypertension. Long-Term Extension Clinical Trials in Hypogonadal Men In two extension trials, a total of 117 and 51 patients received Striant for at least 6 months and 1 year, respectively. Of 117 patients treated for at least 6 months, adverse reactions reported by 1 patient each included: anxiety, buccal inflammation, depression, dry mouth, gum redness, hypertension, infection, medication error, nausea, pruritus, renal function abnormal, stomatitis, taste bitter, taste perversion and toothache. Polycythemia and increased serum prostate specific antigen (PSA) were reported in three and two patients, respectively. In these two extension studies, a total of 48 patients received Striant for at least 2 years. In these patients, adverse reactions included: gingival recession, lip ulceration, stomatitis, rash, prostate cancer, increased PSA, abdominal pain, diarrhea, hypertension aggravated, headache, nervousness, polycythemia, taste perversion, aggressiveness, hyperlipidemia, peripheral edema, and anxiety. Gum-related adverse events and gum examinations In the open-label study, all reported gum-related adverse events were collected and gum examinations were conducted at Baseline and every month thereafter. A total of 16 patients reported 19 gum-related adverse reactions. Of these, ten patients (10.2%) reported 12 reactions of mild intensity, four patients (4.1%) reported 5 reactions of moderate intensity, and two patients (2.0%) reported 2 reactions of severe intensity. Four patients (4.1%) discontinued treatment with Striant due to gum or mouth-related adverse reactions including two with severe gum irritation, one with mouth irritation, and one with “bad taste in mouth.” Gum irritation generally resolved in 1 to 8 days. Gum tenderness resolved in 1 to 14 days. Monthly gum examinations were conducted to assess for gingivitis, gum edema, oral lesions, ulcerations or leukoplakia. No cases of ulceration or leukoplakia were observed. No new oral lesions were observed. The incidence of gingivitis and gum edema was not increased during treatment. In the two extension trials, gum examinations were conducted every 3 months while on treatment. In one of these trials, no patient had a gum abnormality, and in the other trial, moderate gingivitis and mild gum edema were reported by 1 patient each. In these two extension studies, patient-reported information on Striant gum adherence was collected every 3 months for 1 year. At each visit, 37% to 52% of patients reported problems with Striant adhering to the gum. Circumstances surrounding Striant detachment included eating, drinking and oral care. Hot foods and hot beverages were more likely to be associated with detachment than cold food and cold beverages. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Striant. 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: dry mouth, gingival swelling, lip swelling, mouth ulceration, stomatitis, red blood cell increased, dysgeusia, venous thromboembolism, myocardial infarction, and stroke.

<table> <caption>Table 1. Adverse Reactions Observed With the Use of Striant in &#x2265;1% of Patients</caption> <col/> <col/> <tbody> <tr> <td styleCode=" Botrule Toprule Lrule Rrule "> Adverse Reaction</td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> Striant (n=98)</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Gum or Mouth Irritation</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 9.2%</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Taste Bitter</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 4.1%</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Gum Pain</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 3.1%</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Gum Tenderness</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 3.1%</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Headache</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 3.1%</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Gum Edema</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 2.0%</td> </tr> <tr> <td styleCode=" Botrule Lrule Rrule "> Taste Perversion</td> <td align="center" styleCode=" Botrule Lrule Rrule "> 2.0%</td> </tr> </tbody> </table>