Natesto Nasal Gel

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)].

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.

. Dosing

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

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

. Administration Instructions

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

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 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.

. Use with Nasally Administered Drugs Other Than Sympathomimetic Decongestants

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

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

. Temporary Discontinuation of Use for Severe Rhinitis

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

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.

. Controlled Substance

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

. 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.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

. Dependence

Behaviors Associated with Addiction

Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:

• Taking greater dosages than prescribed
• Continued drug use despite medical and social problems due to drug use
• Spending significant time to obtain the drug when supplies of the drug are interrupted
• Giving a higher priority to drug use than other obligations
• Having difficulty in discontinuing the drug despite desires and attempts to do so
• Experiencing withdrawal symptoms upon abrupt discontinuation of use

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.

Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

. 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).

. Pharmacodynamics

No specific pharmacodynamic studies were conducted using Natesto.

. Pharmacokinetics

Absorption

Natesto delivers physiologic amounts of testosterone, producing circulating concentrations that approximate normal testosterone concentrations (i.e., 300 to 1,050 ng/dL) seen in healthy men. The maximum concentration for Natesto is achieved within approximately 40 minutes of administration and has a half-life ranging from 10 to 100 minutes.

Figure 1 summarizes the pharmacokinetic profiles of total testosterone in patients completing 90 days of Natesto treatment administered as 33 mg of testosterone daily (11 mg three times daily).

Figure 1: Mean Serum Total Testosterone Concentrations on Day 90 Following Natesto Administered As 11 mg of Testosterone Three Times Daily (N=69)

The average daily testosterone concentration produced by Natesto administered as 11 mg of testosterone three times daily on Day 90 was 421 (± 116) ng/dL.

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.

Metabolism

Testosterone is metabolized to various 17-keto steroids through 2 different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT).

DHT concentrations increased in parallel with testosterone concentrations during Natesto treatment. After 90 days of treatment, the mean DHT/testosterone ratio was 0.09 which was within the normal range.

Excretion

About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

Drug Interactions

Use in patients with allergic rhinitis and oxymetazoline: The effects of allergic rhinitis and the use of oxymetazoline on the absorption of testosterone were investigated in a 3-way cross-over clinical study. Eighteen males with seasonal allergic rhinitis received 3 doses of 11 mg of testosterone intranasally (testosterone dose of 33 mg/day) while they were in the asymptomatic, symptomatic, and symptomatic but treated (with oxymetazoline) states using an environmental challenge chamber model.

Serum total testosterone concentrations were decreased by 21 to 24% in males with symptomatic allergic rhinitis. 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 nasally administered drugs other than oxymetazoline has not been studied.

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

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.

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 not blow 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 push the pump down until it 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 push down on the pump until it 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: Aytu BioScience, Inc., Englewood, CO 80112

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

Approved: 10/2016

Principal Display Panel - Natesto Nasal Gel Carton

www.natesto.com

NDC 69654-239-01

CIII

Natesto®
(testosterone) nasal gel

5.5 mg 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:

Aytu BioScience, Inc.

Englewood, CO 80112

Manufactured by:

Haupt Pharma Amareg GmbH

Donaustaufer Sir. 378

Regensburg, Bavaria D93055, Germany

AYTU
BioScience

Rx ONLY