2.1. 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.

2.2. 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 depress the pump until it 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.

2.3. 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)].

2.4. 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.

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 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 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.

5.11 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.

6.1 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of testosterone. 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.

Cardiovascular Disorders: myocardial infarction, stroke [see Warnings and Precautions (5.6)]

Vascular Disorders: Venous thromboembolism [see Warnings and Precautions (5.5)]

7.1 Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may necessitate a decrease in the dose of anti-diabetic medication.

7.2 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ration (INR) and prothrombin time is recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy.

7.3 Corticosteroids

The concurrent use of testosterone with corticosteroids may result in increased fluid retention and requires monitoring particularly in patients with cardiac, renal, or hepatic disease.

7.4 Oxymetazoline

A 2.6% decrease in mean AUC(0-24) and 3.6% decrease in mean Cmax of total testosterone was observed in males with symptomatic seasonal rhinitis when treated with oxymetazoline 30 minutes prior to Natesto compared to when left untreated. Oxymetazoline does not impact the absorption of testosterone when concomitantly administered with Natesto [see Clinical Pharmacology (12.3)]. Drug interaction potential with other nasally administered drugs other than oxymetazoline has not been studied.

8.1. 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.

8.3. 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.

8.4. 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.

8.5. 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 (5.3)].

8.6. Renal Impairment

No studies were conducted in patients with renal impairment.

8.7. Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

8.8. Use in Men With Body Mass Index greater than 35 kg/m2

Safety and efficacy of Natesto in males with body mass index greater than 35 kg/m2 has not been established.

8.9. 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)].

9.1. Controlled Substance

Natesto contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

9.2. Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.

9.3. Dependence

12.1. Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.2. Pharmacodynamics

No specific pharmacodynamic studies were conducted using Natesto.

12.3. Pharmacokinetics

13.1. Carcinogenesis, Mutagenesis, and Impairment of Fertility

14.1. Testosterone Replacement Therapy

Natesto was evaluated for efficacy in a 90-day, open-label, multicenter study of 306 hypogonadal men. Eligible patients were 18 years of age and older (mean age 54 years) and had morning serum total testosterone concentrations less than 300 ng/dL. Patients were Caucasian (89%), African-American (6%), Asian (5%), or of other ethnicities (less than 1%).

Patients were instructed to self-administer Natesto (11 mg of testosterone) intranasally either two or three times daily.

The primary endpoint was the percentage of patients with an average serum total testosterone concentration (Cavg) within the normal range (300 to 1050 ng/dL) on Day 90.

The secondary endpoint was the percentage of patients with a maximum total testosterone concentration (Cmax) above three predetermined limits: greater than 1500 ng/dL, between 1800 and 2500 ng/dL, and greater than 2500 ng/dL.

A total of 78 hypogonadal men received Natesto (11 mg of testosterone) three times daily (33 mg of testosterone daily). Of these, a total of 73 hypogonadal men were included in the statistical evaluation of efficacy (total testosterone pharmacokinetics) on Day 90 based on the intent-to-treat (ITT) population with last observation carried forward (LOCF). Ninety percent (90%) of these 73 patients had a Cavg within the normal range (300 to 1050 ng/dL) on Day 90. The percentages of patients with Cavg below the normal range (less than 300 ng/dL) and above the normal range (greater than 1050 ng/dL) on Day 90 were 10% and 0%, respectively.

Table 3 summarizes the mean (SD) serum total testosterone concentrations on Day 90 in 69 patients who had a full pharmacokinetic sampling profile and were treated with Natesto (11 mg of testosterone) three times daily for 90 days.

The percentages of patients with Cmax greater than 1500 ng/dL and between 1800 and 2500 ng/dL were 15.9% and 1.4%, respectively. No patient had a Cmax greater than 2500 ng/dL.

16.1. How Supplied

Natesto (testosterone) nasal gel is available as a metered dose pump containing 11 grams of gel dispensed as 60 metered pump actuations. One pump actuation delivers 5.5 mg of testosterone in 0.122 grams of gel.

16.2. Storage

Keep Natesto out of reach of children.

Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.

16.3. Handling and Disposal

Used Natesto dispensers should be discarded in household trash in a manner that prevents accidental exposure of children or pets.

Use in Men With Known or Suspected Prostate or Breast Cancer

Men with known or suspected prostate or breast cancer should not use Natesto [see Contraindications (4) and Warnings and Precaution (5.3)].

Nasal Adverse Reactions

Nasal adverse reactions, including nasopharyngitis, rhinorrhea, epistaxis, nasal discomfort and nasal scabbing, were reported in clinical trials of Natesto. Advise patients to report any nasal symptoms or signs to their health care professional.

Potential Adverse Reactions With Androgens

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

• Changes in urinary habits such as increased urination at night, trouble starting your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having urine accident, being unable to pass urine, and having a weak urine flow.
• Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness.
• Too frequent or persistent erections of the penis.
• Nausea, vomiting, changes in skin color, or ankle swelling.

Patients Should be Advised of the Following Instructions For Use

• Read the Patient Information accompanying each Natesto metered dose pump.
• Prime the pump by depressing it 10 times prior to its first use. No priming is needed with subsequent uses of that pump.
• Administer Natesto intranasally and NOT to other parts of the body. Administer Natesto 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.
• Keep Natesto out of the reach of children.
• Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, mood, nasal irritation or rhinitis.
• Never share Natesto with anyone.