warnings and cautions
5 WARNINGS AND PRECAUTIONS Nasal adverse reactions: Instruct patients to report any nasal symptoms or signs ( 5.1 ) Not recommended for use in patients with chronic nasal conditions or alterations in nasal anatomy. ( 5.2 ) Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.3 ) 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. ( 5.5 ) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. ( 5.6 ) Women and children should not use Natesto. ( 5.7 ) Exogenous administration of androgens may lead to azoospermia ( 5.8 ) Edema with or without congestive heart failure (CHF) may be a 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. ( 5.3 , 5.4 , 5.13 ) 5.1. Nasal Adverse Reactions and Limited Long-Term Information on Nasal Safety Nasal adverse reactions, including nasopharyngitis, rhinorrhea, epistaxis, nasal discomfort and nasal scabbing, were reported in the clinical trial experience with Natesto. All nasal adverse reactions except one (a single case of upper respiratory infection) were reported as mild or moderate in severity; however, long-term clinical trial data on nasal safety is available in a limited number of subjects [ see Adverse Reactions ( 6.2 )] . Patients should be instructed to report any nasal symptoms or signs to their health care professional. In that circumstance, health care professionals should determine whether further evaluation (e.g., otorhinolaryngology consultation) or discontinuation of Natesto is appropriate. 5.2. Use in Patients with Chronic Nasal Conditions and Alterations in Nasal Anatomy Due to lack of clinical data on the safety or efficacy, Natesto is not recommended for use in the following patients: History of nasal disorders; History of nasal or sinus surgery; History of nasal fracture within the previous 6 months or nasal fracture that caused a deviated anterior nasal septum; Mucosal inflammatory disorders (e.g, Sjogren’s syndrome); and Sinus disease. 5.3. Worsening of Benign Prostatic Hyperplasia 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 treatment. It would be appropriate to re-evaluate patients 3 to 6 months after initiation of treatment and then in accordance with prostate cancer screening practices [ see Contraindications ( 4 )]. 5.4. Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require discontinuation of Natesto . Check hematocrit prior to initiating testosterone treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting testosterone treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.5. 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 Natesto. 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 Natesto and initiate appropriate workup and management [see Adverse Reactions ( 6.2 )]. 5.6 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 Natesto. 5.7. Use in Women Due to lack of controlled studies in women and potential virilizing effects, Natesto is not indicated for use in women. 5.8. Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including Natesto, 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 (methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatitis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatitis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. Natesto is not known to cause 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 Natesto while the cause is evaluated. 5.10. Edema Androgens, including Natesto, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required. 5.11. Gynecomastia Gynecomastia may develop and may persist in patients being treated with androgens, including Natesto, for hypogonadism .[see Adverse Reactions ( 6.1 )]. 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 and chronic lung disease. 5.13. Lipids Changes in the serum lipid profile may occur. Monitor the lipid profile periodically, particularly after starting testosterone therapy. Changes in serum lipid profile may require discontinuation of testosterone therapy. 5.14. Hypercalcemia Androgens, including Natesto, 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 Natesto, may decrease concentrations of thyroxine-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.