Natesto Nasal Gel (Page 2 of 6)

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 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.

5.8 Use in Women

Due to lack of controlled studies in women and potential virilizing effects, Natesto is not indicated for use in women.

5.9 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.

5.10 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 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. 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.

5.11 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.

5.12 Gynecomastia

Gynecomastia may develop and may persist in patients being treated with androgens, including Natesto, for hypogonadism .[see Adverse Reactions ( 6.1)].

5.13 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.

5.14 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.

5.15 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.

5.16 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.

6. ADVERSE REACTIONS

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Natesto was evaluated in a multicenter, open-label, 90-day clinical study. Patients could continue treatment with Natesto in two, open-label extension periods for an additional 90 and 180 days, respectively. A total of 306 hypogonadal men with morning testosterone concentrations ≤ 300 ng/dL received Natesto. Of these, 78 received Natesto at a dose of 11 mg three times daily.

90-Day Clinical Study

Among the 78 patients who received Natesto three times daily in the 90-day clinical study, the most common adverse reactions were: prostate specific antigen (PSA) increased, headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, upper respiratory tract infection (URI), sinusitis, bronchitis and nasal scab. PSA increased was considered an adverse reaction by meeting one of two pre-specified criteria: (1) increase from baseline serum PSA greater than 1.4 ug/L, or (2) serum PSA greater than 4.0 ug/L.

Table 1 shows adverse reactions reported by ≥3% of patients treated with 11 mg three times daily in the 90-day clinical study.

Table 1: Adverse Reactions Reported by ≥3% of Patients Treated with Natesto (11 mg of testosterone) Three Times Daily in the 90-Day Clinical Study
Adverse Reactions Natesto (11 mg of Testosterone) Three Times Daily (N=78) n (%)
PSA increased 4 (5.1)
Headache 3 (3.8)
Rhinorrhea 3 (3.8)
Epistaxis 3 (3.8)
Nasal discomfort 3 (3.8)
Nasopharyngitis 3 (3.8)
Bronchitis 3 (3.8)
Upper respiratory tract infection 3 (3.8)
Sinusitis 3 (3.8)
Nasal scab 3 (3.8)

Adverse reactions reported by >2% but <3% of patients in the 90-day clinical study include: blood pressure increased, dysgeusia, nasal dryness, nasal congestion, and cough.

Extension Periods

Among the 78 patients who received Natesto three times daily in the 90-day clinical study, a total of 69 patients received Natesto three times daily in the first 90-day extension period.

Among these 69 patients, the most common adverse reactions were: nasopharyngitis, PSA increased, parosmia, nasal discomfort, rhinorrhea and nasal scab.

Table 2 shows adverse reactions reported by ≥3% of patients who received Natesto three times daily in both the 90-day clinical study and in the 90-day extension period.

Table 2: Adverse Reactions Reported by ≥3% of Patients in Both the 90-Day Clinical Study and in the 90-Day Extension Period
Adverse Reactions Natesto 11 mg TID (N=69) n (%)
Nasopharyngitis 6 (8.7)
Rhinorrhea 5 (7.2)
PSA increased 4 (5.8)
Parosmia 4 (5.8)
Nasal discomfort 4 (5.8)
Nasal Scab 4 (5.8)
Upper respiratory tract infection 3 (4.3)
Bronchitis 3 (4.3)
Procedural pain 3 (4.3)
Pain in extremity 3 (4.3)
Headache 3 (4.3)
Epistaxis 3 (4.3)

A total of 18 patients received Natesto three times daily in all three treatment periods, including the 90-day clinical study, the first 90-day extension period, and the second 180-day extension period. Among these 18 patients, the following adverse reactions were reported in more than one patient each: nasopharyngitis, parosmia, PSA increased, nasal discomfort, nasal scab and hypertension. The following adverse reactions were reported in one patient each: nausea, nasal excoriation, thyroid stimulating hormone increased, decreased appetite, myalgia, anosmia, testicular atrophy, epistaxis, nasal septum disorder, nasal discomfort, and rhinorrhea.

In patients who received Natesto three times daily, mean serum PSA concentrations increased by 0.2 ng/mL, 0.1 ng/mL, and 0.2 ng/mL after 90, 180 and 360 days, respectively.

Discontinuations due to Adverse Reactions

Among all subjects (n=306) who received Natesto at any dose in the 90-day clinical study and its 90- and 180-day extension periods, a total of 6 subjects withdrew from treatment for the following adverse reactions, reported by 1 subject each: nasal discomfort, headache, dysgeusia, PSA increased, allergic reaction (hives, swollen lips and tongue), and 1 patient with myalgia, arthralgia, fever, chills and petechiae.

Increased Hematocrit

Among all subjects (n=306) who received Natesto at any dose in the 90-day clinical study and its 90- and 180-day extension periods, a total of 4 subjects had a hematocrit level > 55%. These 4 patients had baseline hematocrits of 48% and 51%. In no case did hematocrit exceed 58%.

Nasal Adverse Reactions

Among all subjects (n=306) who received Natesto at any dose in the 90-day clinical study and its 90- and 180-day extension periods, the following nasal adverse reactions were reported: nasopharyngitis (8.2%), rhinorrhea (7.8%), epistaxis (6.5%), nasal discomfort (5.9%), parosmia (5.2%), nasal scab (5.2%), upper respiratory infection (4.2%), nasal dryness (4.2%), and nasal congestion (3.9%).

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