Natesto - Product Information
|Manufacture:||Endo Pharmaceuticals Inc.|
|Class:||Androgens and anabolic steroids|
|Form:||Cream, gel, liniment or balm, lotion, ointment, etc|
|Ingredients:||testosterone, castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide|
Indications and Usages
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 inSpecific Populations].
Dosage and Administration
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.
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.
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.
- 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);
- 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].
- Taking more drug than intended
- Continued drug use despite medical and social problems
- Significant time spent in obtaining adequate amounts of drug
- Desire for anabolic steroids when supplies of the drug are interrupted
- Difficulty in discontinuing use of the drug despite desires and attempts to do so
- Experience of withdrawal syndrome upon discontinuation of anabolic steroid use
- 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.
- 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.
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 and Clinical Pharmacology].
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.
Dosage Forms and Strengths
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.
Natesto is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precaution].
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 and Use in Specific Populations].
Warnings and Precautions
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 [seeAdverse Reactions (6.2)]. Patients should be instructed to report any nasal symptoms or signs to their health care professional. In that circumstance, health care professionals should determine whether further evaluation (e.g., otorhinolaryngology consultation) or discontinuation of Natesto is appropriate.
Use in Patients With Chronic Nasal Conditions and Alterations in Nasal Anatomy
Due to lack of clinical data on the safety or efficacy, Natesto is not recommended for use in the following patients:
Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer
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.
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].
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.
Use in Women
Due to lack of controlled studies in women and potential virilizing effects, Natesto is not indicated for use in women.
Potential for Adverse Effects on Spermatogenesis
With large doses of exogenous androgens, including Natesto, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH), which could possibly lead to adverse effects on semen parameters, including sperm count.
Hepatic Adverse Effects
Prolonged use of high doses of orally active 17 -alpha-alkyl androgens (methyltestosterone) has been associated with serious hepatic adverse effects (peliosis 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.
Androgens, including Natesto, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre -existing cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.
Gynecomastia may develop and may persist in patients being treated with androgens, including Natesto, for hypogonadism.[see Adverse Reactions].
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.
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.
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.
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.
(11 mg of Testosterone) Three Times Daily (N=78)
|PSA increased||4 (5.1)|
|Nasal discomfort||3 (3.8)|
|Upper respiratory tract infection||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.
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.
|Adverse Reactions||Natesto 11 mg TID (N=69)
|PSA increased||4 (5.8)|
|Nasal discomfort||4 (5.8)|
|Nasal Scab||4 (5.8)|
|Upper respiratory tract infection||3 (4.3)|
|Procedural pain||3 (4.3)|
|Pain in extremity||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.
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 Reaction
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%).
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].
Vascular Disorders: Venous thromboembolism [see Warnings and Precautions]
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.
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.
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.
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]. Drug interaction potential with other nasally administered drugs other than oxymetazoline has not been studied.
Use in Specific Populations
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.
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.
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].
No studies were conducted in patients with renal impairment.
No studies were conducted in patients with hepatic impairment.
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.
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].
Drug Abuse and Dependence
Natesto contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.
Anabolic steroids, such as testosterone, are abused. Abuse is often associated with adverse physical and psychological effects.
Although drug dependence is not documented in individuals using therapeutic doses of anabolic steroids for approved indications, dependence is observed in some individuals abusing high doses of anabolic steroids. In general, anabolic steroid dependence is characterized by any three of the following:
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.
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.
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.
Handling and Disposal
Used Natesto dispensers should be discarded in household trash in a manner that prevents accidental exposure of children or pets.
Patient Counseling Information
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 and Warnings and Precaution].
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: