NATESTO NASAL GEL

Natesto (testosterone) nasal gel is a slightly yellow gel containing 5.5 mg of testosterone in 122.5 mg of Natesto gel for nasal administration. The active pharmacologic ingredient in Natesto is testosterone, an androgen. Testosterone is a white to practically white crystalline powder chemically described as 17β-Hydroxyandrost-4-en-3-one. The structural formula is: The inactive ingredients are castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide. Figure

Natesto is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use: Safety and efficacy of Natesto in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established. Safety and efficacy of Natesto in males less than 18 years old have not been established [see Use in Specific Populations ( 8.4 )] . Natesto is an androgen indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired) ( 1 ) Hypogonadotropic hypogonadism (congenital or acquired) ( 1 ) Limitations of use: Safety and efficacy of Natesto in men with "age-related hypogonadism" have not been established ( 1 ). Safety and efficacy of Natesto in males less than 18 years old have not been established. ( 1 , 8.4 )

Prior to initiating Natesto, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. Prior to initiating Natesto, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range ( 2 ). The recommended dose of Natesto is 11 mg of testosterone (2 pump actuations, one per nostril), applied intranasally three times daily. ( 2.1 ) Serum total testosterone concentrations should be checked periodically, starting as soon as one month after initiating treatment with Natesto. If total testosterone concentrations consistently exceed 1050 ng/dL, therapy with Natesto should be discontinued. If total testosterone concentrations are consistently below 300 ng/dL, an alternative treatment should be considered. ( 2.1 ) Not recommended for use with nasally administered drugs other than sympathomimetic decongestants (e.g., oxymetazoline). ( 2.3 , 7.4 , 12.3 ). 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. Preparing the Pump When using Natesto for the first time, patients should be instructed to prime the pump by inverting the pump, depressing the pump 10 times, and discarding any small amount of product dispensed directly into a sink and then washing the gel away thoroughly with warm water. The tip should be wiped with a clean, dry tissue. If the patient gets Natesto gel on their hands, it is recommended that they wash their hands with warm water and soap. This priming should be done only prior to the first use of each dispenser. 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. Figure Figure Figure 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.

Natesto is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [ see Warnings and Precaution ( 5.5 )]. Natesto is contraindicated in women who are or who may become pregnant, or who are breast- feeding. Natesto may cause fetal harm when administered to a pregnant woman. Natesto may cause serious adverse reactions in nursing infants. Exposure of a fetus or nursing infant to androgens may result in varying degrees of virilization. If a pregnant woman is exposed to Natesto, she should be apprised of the potential hazard to the fetus [ see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 , 8.3 )]. Men with carcinoma of the breast or known or suspected prostate cancer ( 4 , 5.5 ) Pregnant or breast-feeding women. Testosterone may cause fetal harm ( 4 , 8.1 )

Most common adverse reactions (incidence ≥3%) are: PSA increased, headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, bronchitis, upper respiratory tract infection, sinusitis, and nasal scab. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Acerus Pharmaceuticals Corporation at 1-833-698-3786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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%). Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy. The mean patient age (±SD) was 63.3 (7.9) years with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35 kg/m 2 . Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively. The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving topical testosterone gel were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively. For patients treated with topical testosterone gel, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]). Additional Adverse Reactions Reported in TRAVERSE Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in topical testosterone gel versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review. 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 ( 5.4 )]

Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients. ( 7.1 ) Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended in patients taking warfarin. ( 7.2 ) Use of testosterone with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease. ( 7.3 ) 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 C max 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.

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.