Natesto

. Dosing

The recommended dose of Natesto is 11 mg of testosterone (2 pump actuations; 1 actuation per nostril) administered intranasally three times daily for a total daily dose of 33 mg.

Serum total testosterone concentrations should be checked periodically, starting as soon as one month after initiating treatment with Natesto. When the total testosterone concentration consistently exceeds 1050 ng/dL, therapy with Natesto should be discontinued. If the total testosterone concentration is consistently below 300 ng/dL, an alternative treatment should be considered.

. Administration Instructions

Natesto is administered intranasally three times daily once in the morning, once in the afternoon and once in the evening (6 to 8 hours apart), preferably at the same time each day. Patients should be instructed to completely depress the pump 1 time in each nostril to receive the total dose. Do not administer Natesto to other parts of the body.

Administering the Dose

To administer the dose, patients should be instructed to perform the following steps:

• Blow the nose.
• Remove the cap from the dispenser.
• Place the right index finger on the pump of the actuator and while in front of a mirror, slowly advance the tip of the actuator into the left nostril upwards until their finger on the pump reaches the base of the nose.
  
• Tilt the actuator so that the opening on the tip of the actuator is in contact with the lateral wall of the nostril to ensure that the gel is applied to the nasal wall.
  
• Slowly and firmly depress the pump until it fully stops.
• Remove the actuator from the nose while wiping the tip along the inside of the lateral nostril wall to fully transfer the gel.
• Using your left index finger, repeat the steps outlined in bullets 3 through 6 for the right nostril.
• Use a clean, dry tissue to wipe the tip of the actuator.
• Replace the cap on the dispenser.
• Press on the nostrils at a point just below the bridge of the nose and lightly massage.
• Refrain from blowing the nose or sniffing for 1 hour after administration.

The dispenser should be replaced when the top of the piston inside the dispenser reaches the arrow at the top of the inside label. The inside label may be found by unwrapping the outer flap from around the container.

. Use with Nasally Administered Drugs Other Than Sympathomimetic Decongestants

The drug interaction potential between Natesto and nasally administered drugs other than sympathomimetic decongestants is unknown. Therefore, Natesto is not recommended for use with nasally administered drugs other than sympathomimetic decongestants

(e.g., oxymetazoline) [see Drug Interactions ( 7.4) and Clinical Pharmacology ( 12.3)].

. Temporary Discontinuation of Use for Severe Rhinitis

If the patient experiences an episode of severe rhinitis, temporarily discontinue Natesto therapy pending resolution of the severe rhinitis symptoms. If the severe rhinitis symptoms persist, an alternative testosterone replacement therapy is recommended.

. Pregnancy

Pregnancy Category X — Natesto is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

. Nursing Mothers

Although it is not known how much testosterone transfers into human milk, Natesto is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.

. Pediatric Use

Safety and efficacy of Natesto has not been established in pediatric patients less than 18 years of age. Improper use may result in acceleration of bone age and premature closure of epiphyses.

. Geriatric Use

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing Natesto to determine whether efficacy in those over 65 years of age differs from younger subjects.

Of the 306 patients enrolled in the Phase 3 clinical trial utilizing Natesto, 60 were 65 years of age or older, and 9 were 75 years of age or older. There are insufficient long-term safety data in geriatric patients to assess the potential for increased risks of cardiovascular disease and prostate cancer.

Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH [see Warnings and Precautions ( 5.5)].

. Renal Impairment

No studies were conducted in patients with renal impairment.

. Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

. Use in Men With Body Mass Index greater than 35 kg/m 2

Safety and efficacy of Natesto in males with body mass index greater than 35 kg/m 2has not been established.

. Allergic Rhinitis

Serum total testosterone concentrations were decreased by 21 to 24% in males with symptomatic allergic rhinitis, whether treated with nasal decongestants such as oxymetazoline, or left untreated [see Clinical Pharmacology ( 12.3)].

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.

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.

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.

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.

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, topical testosterone gel was associated with a higher risk of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE (0.9% vs 0.5%) [see Adverse Reactions (6.1)] .

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)].

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)].

Blood Pressure Increases

Testosterone products, such as Natesto, can increase blood pressure. Blood pressure increases can increase cardiovascular (CV) risk over time.

The CV risk associated with topical testosterone gel was evaluated in TRAVERSE, randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, topical testosterone gel increased mean systolic blood pressure by 1.8 mmHg from baseline. 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 topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions (6.1)] .

Monitor blood pressure periodically in men using Natesto, especially men with hypertension. Natesto is not recommended for use in patients with uncontrolled hypertension.

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.

Not for Use in Women

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

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.

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.

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.

Gynecomastia

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

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.

Lipid Changes

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.

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.

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.