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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:
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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.
Among the 78 patients who received Natesto three times daily in the 90-day clinical study, the most common adverse reactions were: prostate specific antigen (PSA) increased, headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, upper respiratory tract infection (URI), sinusitis, bronchitis and nasal scab. PSA increased was considered an adverse reaction by meeting one of two pre-specified criteria: (1) increase from baseline serum PSA greater than 1.4 ug/L, or (2) serum PSA greater than 4.0 ug/L.
Table 1 shows adverse reactions reported by ≥3% of patients treated with 11 mg three times daily in the 90-day clinical study.
Table 1: Adverse Reactions Reported by ≥3% of Patients Treated with Natesto (11 mg of testosterone) Three Times Daily in the 90-Day Clinical Study
|
Adverse Reactions |
Natesto (11 mg of Testosterone) |
|
PSA increased |
4 (5.1) |
|
Headache |
3 (3.8) |
|
Rhinorrhea |
3 (3.8) |
|
Epistaxis |
3 (3.8) |
|
Nasal discomfort |
3 (3.8) |
|
Nasopharyngitis |
3 (3.8) |
|
Bronchitis |
3 (3.8) |
|
Upper respiratory tract infection |
3 (3.8) |
|
Sinusitis |
3 (3.8) |
|
Nasal scab |
3 (3.8) |
Adverse reactions reported by >2% but <3% of patients in the 90-day clinical study include: blood pressure increased, dysgeusia, nasal dryness, nasal congestion, and cough.
Among the 78 patients who received Natesto three times daily in the 90-day clinical study, a total of 69 patients received Natesto three times daily in the first 90-day extension period.
Among these 69 patients, the most common adverse reactions were: nasopharyngitis, PSA increased, parosmia, nasal discomfort, rhinorrhea and nasal scab.
Table 2 shows adverse reactions reported by ≥3% of patients who received Natesto three times daily in both the 90-day clinical study and in the 90-day extension period.
Table 2: Adverse Reactions Reported by ≥3% of Patients in Both the 90-Day Clinical Study and in the 90-Day Extension Period
|
Adverse Reactions |
Natesto 11 mg TID |
|
Nasopharyngitis |
6 (8.7) |
|
Rhinorrhea |
5 (7.2) |
|
PSA increased |
4 (5.8) |
|
Parosmia |
4 (5.8) |
|
Nasal discomfort |
4 (5.8) |
|
Nasal Scab |
4 (5.8) |
|
Upper respiratory tract infection |
3 (4.3) |
|
Bronchitis |
3 (4.3) |
|
Procedural pain |
3 (4.3) |
|
Pain in extremity |
3 (4.3) |
|
Headache |
3 (4.3) |
|
Epistaxis |
3 (4.3) |
A total of 18 patients received Natesto three times daily in all three treatment periods, including the 90-day clinical study, the first 90-day extension period, and the second 180-day extension period. Among these 18 patients, the following adverse reactions were reported in more than one patient each: nasopharyngitis, parosmia, PSA increased, nasal discomfort, nasal scab and hypertension. The following adverse reactions were reported in one patient each: nausea, nasal excoriation, thyroid stimulating hormone increased, decreased appetite, myalgia, anosmia, testicular atrophy, epistaxis, nasal septum disorder, nasal discomfort, and rhinorrhea.
In patients who received Natesto three times daily, mean serum PSA concentrations increased by 0.2 ng/mL, 0.1 ng/mL, and 0.2 ng/mL after 90, 180 and 360 days, respectively.
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%.
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%).
TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors. The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.
The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months. Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy.
The mean patient age (±SD) was 63.3 (7.9) years with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35 kg/m2.
Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively.
The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving topical testosterone gel were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively.
For patients treated with topical testosterone gel, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 [95% CI: 0.78, 1.17]).
Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in topical testosterone gel versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.
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)]
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 (12.3)]. Drug interaction potential with other nasally administered drugs other than oxymetazoline has not been studied.
Natesto contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.
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.
Behaviors Associated with Addiction
Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:
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.
Included as part of the PRECAUTIONS section.
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.
Due to lack of clinical data on the safety or efficacy, Natesto is not recommended for use in the following patients:
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.
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)].
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.
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.
Due to lack of controlled studies in women and potential virilizing effects, Natesto is not indicated for use in women.
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.
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.
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 (6.1)].
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.
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.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Men with known or suspected prostate or breast cancer should not use Natesto [see Contraindications (4) and Warnings and Precaution (5.5)].
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.
Patients should be informed that treatment with androgens may lead to adverse reactions which include:
Acerus Pharmaceuticals Corporation, Toronto, ON M4W 3E2, Canada
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 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)].
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).
No specific pharmacodynamic studies were conducted using Natesto.
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).
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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.
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.
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.
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.
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.
INSTRUCTIONS FOR USE
Natesto (Na-tes-to) CIII
(testosterone) nasal gel
Supplies needed to give your Natesto dose:
Parts of your Natesto dispenser (See Figure A)
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Figure A
Information about your Natesto:
How to prime your Natesto pump:
 |
Figure B
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).
 |
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).
 |
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).
 |
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).
 |
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).
 |
Figure G
 |
Figure H
How to throw away your empty Natesto dispenser:
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
