These Highlights Do Not Include All The Information Needed To Use Natesto Safely And Effectively. See Full Prescribing Information For Natesto.

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.

Instructions for Use



Natesto (Na-tes-to)



CIII (testosterone)



nasal gel

Supplies needed to give your Natesto dose:

• 1 Natesto dispenser
• 2 clean, dry tissues
• a clean and flat surface, like a table
• a mirror

Parts of your Natesto dispenser (See Figure A)

Information about your Natesto:

• Do notblow your nose or sniff for 1 hour after using Natesto.
• Before you use Natesto for the first time, you will need to prime your Natesto pump.

How to prime your Natesto pump:

• Hold your Natesto dispenser over a sink, turn it upside down (invert) and slowly press the pump and release 10 times (See Figure B).

• All the Natesto that comes out when you prime your pump should be rinsed down the sink with warm water.
• If there is any Natesto on the tip of your Natesto actuator after priming, wipe the tip with a clean, dry tissue.
• If any Natesto gel gets on your hands, it is recommended to wash your hands with warm water and soap.

Giving your Natesto dose:

Step 1:Blow your nose.

Step 2:Remove the Natesto cap.

Step 3:While looking in the mirror, put your right first (index) finger on the pump of your Natesto actuator and slowly slide the tip of the actuator up into your left nostril until your finger on the pump touches the bottom of your nose (See Figure C).

Step 4:Gently tilt the Natesto actuator so that the hole in the tip touches the lateral (side) wall of your nostril. This will make sure that Natesto is given in the correct place (See Figure D).

Step 5:With the actuator in place, slowly and firmly push the pump down until it fully stops and remove the actuator from your nose.

Step 6:While looking in the mirror, put your left first (index) finger on the pump of your Natesto actuator and slowly slide the tip of the actuator up into your right nostril until your finger on the pump touches the bottom of your nose (See Figure E).

Step 7:Gently tilt the tip of the Natesto actuator so that the hole in the tip touches the lateral (side) wall of your nostril. This will make sure that Natesto is given in the correct place (See Figure F).

Step 8:Slowly and firmly push down on the pump until it fully stops and remove the actuator from your nose.

Step 9:Wipe the tip of the actuator with a clean, dry tissue.

Step 10:Replace the cap.

Step 11:Press your nostrils together just below the middle of your nose (bridge) and lightly rub them together (See Figure G).

• Replace your Natesto dispenser when the top of the piston inside the dispenser reaches the arrow at the top of the inside label (See Figure H).

How to throw away your empty Natesto dispenser:

• Safely throw away your empty Natesto dispenser in your household trash.
• Keep Natesto and all medicines out of the reach of children and pets.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Marketed by: Acerus Pharmaceuticals Corporation, Toronto, ON M4W 3E2, Canada

Manufactured by: Haupt Pharma Amareg GmbH, Donaustaufer Str. 378, Regensburg, Bavaria D-93055, Germany

Revised: 12/2021

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.

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.

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.

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.

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.

No cases of overdose with Natesto have been reported in clinical trials. There is 1 report of acute overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident.

Treatment of overdosage would consist of discontinuation of Natesto together with appropriate symptomatic and supportive care.

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.

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.

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.

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.

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

A 2.6% decrease in mean AUC(0-24) and 3.6% decrease in mean C _maxof 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.

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.

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.

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.

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.

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 )].

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.

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)].

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.

• 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)

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.

No studies were conducted in patients with renal impairment.

No specific pharmacodynamic studies were conducted using Natesto.

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 )].

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.

No studies were conducted in patients with hepatic impairment.

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 )].

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

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).

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

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 numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (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 )].

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

• Nasal Adverse Reactions and Limited Long-Term Information on Nasal Safety: 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)
• 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. ( 5.4)
• Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.5)
• Blood Pressure Increases: Testosterone can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.6)
• Abuse of Testosterone: Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. ( 5.7)
• Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia ( 5.9)
• Edema: Edema with or without congestive heart failure (CHF) may be a complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.11)
• Sleep apnea: Sleep apnea may occur in those with risk factors. ( 5.13)
• Monitor prostate-specific antigen (PSA), hematocrit and lipid concentrations periodically. ( 5.5, 5.3, 5.14)

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.

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.

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 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. 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.

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 )]

Natesto is a slightly yellow gel for intranasal use and is available in a dispenser with a metered dose pump. One pump actuation delivers 5.5 mg of testosterone.

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.

There are insufficient long-term safety data in geriatric patients using Natesto to assess the potential risks of cardiovascular disease and prostate cancer. ( 8.5)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 (C _avg) 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 (C _max) 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 C _avgwithin the normal range (300 to 1050 ng/dL) on Day 90. The percentages of patients with C _avgbelow 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 3summarizes 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 C _maxgreater than 1500 ng/dL and between 1800 and 2500 ng/dL were 15.9% and 1.4%, respectively. No patient had a C _maxgreater than 2500 ng/dL.

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.

www.natesto.com

NDC 42667-5511-1

CIII

natesto ^®

(testosterone) nasal gel CIII

5.5mg of testosterone per actuation*

*Each actuation delivers 0.122 g of gel.

Multi-dose pump capable of

dispensing 60 metered pump

actuations.

For intranasal use only.

Warning: This package is not

child resistant. Keep out of

reach of children.

Total Contents: 11 g / dispenser.

Marketed by:

Acerus Pharmaceuticals Corporation

Toronto, Ontario, M4W 3E2, Canada

ACERUS

PHARMA

Manufactured by:

Haupt Pharma Amareg GmbH

Donaustaufer Str. 378

Regensburg, Bavaria D93055, Germany

Rx ONLY

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.

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.

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

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.

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.

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 )].

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.

• 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)].

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.

Instructions for Use



Natesto (Na-tes-to)



CIII (testosterone)



nasal gel

Supplies needed to give your Natesto dose:

• 1 Natesto dispenser
• 2 clean, dry tissues
• a clean and flat surface, like a table
• a mirror

Parts of your Natesto dispenser (See Figure A)

Information about your Natesto:

• Do notblow your nose or sniff for 1 hour after using Natesto.
• Before you use Natesto for the first time, you will need to prime your Natesto pump.

How to prime your Natesto pump:

• Hold your Natesto dispenser over a sink, turn it upside down (invert) and slowly press the pump and release 10 times (See Figure B).

• All the Natesto that comes out when you prime your pump should be rinsed down the sink with warm water.
• If there is any Natesto on the tip of your Natesto actuator after priming, wipe the tip with a clean, dry tissue.
• If any Natesto gel gets on your hands, it is recommended to wash your hands with warm water and soap.

Giving your Natesto dose:

Step 1:Blow your nose.

Step 2:Remove the Natesto cap.

Step 3:While looking in the mirror, put your right first (index) finger on the pump of your Natesto actuator and slowly slide the tip of the actuator up into your left nostril until your finger on the pump touches the bottom of your nose (See Figure C).

Step 4:Gently tilt the Natesto actuator so that the hole in the tip touches the lateral (side) wall of your nostril. This will make sure that Natesto is given in the correct place (See Figure D).

Step 5:With the actuator in place, slowly and firmly push the pump down until it fully stops and remove the actuator from your nose.

Step 6:While looking in the mirror, put your left first (index) finger on the pump of your Natesto actuator and slowly slide the tip of the actuator up into your right nostril until your finger on the pump touches the bottom of your nose (See Figure E).

Step 7:Gently tilt the tip of the Natesto actuator so that the hole in the tip touches the lateral (side) wall of your nostril. This will make sure that Natesto is given in the correct place (See Figure F).

Step 8:Slowly and firmly push down on the pump until it fully stops and remove the actuator from your nose.

Step 9:Wipe the tip of the actuator with a clean, dry tissue.

Step 10:Replace the cap.

Step 11:Press your nostrils together just below the middle of your nose (bridge) and lightly rub them together (See Figure G).

• Replace your Natesto dispenser when the top of the piston inside the dispenser reaches the arrow at the top of the inside label (See Figure H).

How to throw away your empty Natesto dispenser:

• Safely throw away your empty Natesto dispenser in your household trash.
• Keep Natesto and all medicines out of the reach of children and pets.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Marketed by: Acerus Pharmaceuticals Corporation, Toronto, ON M4W 3E2, Canada

Manufactured by: Haupt Pharma Amareg GmbH, Donaustaufer Str. 378, Regensburg, Bavaria D-93055, Germany

Revised: 12/2021

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.

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.

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.

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.

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.

No cases of overdose with Natesto have been reported in clinical trials. There is 1 report of acute overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident.

Treatment of overdosage would consist of discontinuation of Natesto together with appropriate symptomatic and supportive care.

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.

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.

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.

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.

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

A 2.6% decrease in mean AUC(0-24) and 3.6% decrease in mean C _maxof 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.

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.

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.

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.

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.

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 )].

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.

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)].

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.

• 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)

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.

No studies were conducted in patients with renal impairment.

No specific pharmacodynamic studies were conducted using Natesto.

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 )].

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.

No studies were conducted in patients with hepatic impairment.

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 )].

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

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).

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

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 numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (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 )].

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

• Nasal Adverse Reactions and Limited Long-Term Information on Nasal Safety: 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)
• 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. ( 5.4)
• Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. ( 5.5)
• Blood Pressure Increases: Testosterone can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.6)
• Abuse of Testosterone: Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. ( 5.7)
• Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia ( 5.9)
• Edema: Edema with or without congestive heart failure (CHF) may be a complication in patients with preexisting cardiac, renal, or hepatic disease. ( 5.11)
• Sleep apnea: Sleep apnea may occur in those with risk factors. ( 5.13)
• Monitor prostate-specific antigen (PSA), hematocrit and lipid concentrations periodically. ( 5.5, 5.3, 5.14)

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.

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.

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 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. 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.

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 )]

Natesto is a slightly yellow gel for intranasal use and is available in a dispenser with a metered dose pump. One pump actuation delivers 5.5 mg of testosterone.

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.

There are insufficient long-term safety data in geriatric patients using Natesto to assess the potential risks of cardiovascular disease and prostate cancer. ( 8.5)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 (C _avg) 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 (C _max) 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 C _avgwithin the normal range (300 to 1050 ng/dL) on Day 90. The percentages of patients with C _avgbelow 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 3summarizes 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 C _maxgreater than 1500 ng/dL and between 1800 and 2500 ng/dL were 15.9% and 1.4%, respectively. No patient had a C _maxgreater than 2500 ng/dL.

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.

www.natesto.com

NDC 42667-5511-1

CIII

natesto ^®

(testosterone) nasal gel CIII

5.5mg of testosterone per actuation*

*Each actuation delivers 0.122 g of gel.

Multi-dose pump capable of

dispensing 60 metered pump

actuations.

For intranasal use only.

Warning: This package is not

child resistant. Keep out of

reach of children.

Total Contents: 11 g / dispenser.

Marketed by:

Acerus Pharmaceuticals Corporation

Toronto, Ontario, M4W 3E2, Canada

ACERUS

PHARMA

Manufactured by:

Haupt Pharma Amareg GmbH

Donaustaufer Str. 378

Regensburg, Bavaria D93055, Germany

Rx ONLY

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.

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.

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

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.

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.

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 )].

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.

• 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)].