NATESTO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NATESTO (NATESTO).
Testosterone replacement therapy; testosterone binds to androgen receptors, activating gene transcription for male sexual development and maintenance of secondary sexual characteristics.
| Metabolism | Metabolized in the liver via reduction, oxidation, and conjugation pathways, yielding inactive metabolites including androsterone and etiocholanolone, which are excreted in urine and feces. |
| Excretion | Following intramuscular administration of testosterone enanthate, approximately 90% of the dose is excreted in urine as glucuronide and sulfate conjugates of testosterone and its metabolites (e.g., androsterone, etiocholanolone). About 6% is excreted in feces via bile. Unchanged testosterone in urine is negligible (<1%). |
| Half-life | The terminal elimination half-life of testosterone after intramuscular injection of testosterone enanthate is approximately 8 days (range 4–12 days), reflecting slow absorption from the oily depot. This prolonged half-life supports a dosing interval of every 2–4 weeks. |
| Protein binding | Approximately 97–99% of circulating testosterone is bound to plasma proteins: 60–65% to sex hormone-binding globulin (SHBG) and 35–40% to albumin. Only about 1–3% is free (unbound) and biologically active. |
| Volume of Distribution | The apparent volume of distribution (Vd) of testosterone following intramuscular injection is approximately 1.0–1.3 L/kg. This large Vd indicates extensive distribution into tissues, including muscle, fat, and prostate. |
| Bioavailability | Testosterone enanthate is administered intramuscularly; oral bioavailability is negligible due to extensive first-pass hepatic metabolism. The absolute bioavailability of intramuscular testosterone enanthate is approximately 100% as the ester is hydrolyzed to active testosterone. |
| Onset of Action | Following intramuscular injection of testosterone enanthate, clinical effects (e.g., increase in serum testosterone levels) are detectable within 24–48 hours. Peak serum concentrations occur at 72–120 hours (3–5 days) post-dose. |
| Duration of Action | The duration of therapeutic effect (normalization of serum testosterone) after a single intramuscular dose of testosterone enanthate is approximately 2–4 weeks, depending on dose and individual metabolism. Serum testosterone levels remain within the normal range for 14–21 days, after which levels decline. |
| Molecular Weight | 288.42 |
One 10 mg buccal tablet applied twice daily to the gum region above the incisor tooth, approximately 12 hours apart; morning and evening.
| Dosage form | GEL, METERED |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment (eGFR <30 mL/min/1.73 m²); use with caution. |
| Liver impairment | Contraindicated in patients with severe hepatic dysfunction (Child-Pugh class C). Use with caution in moderate hepatic impairment (Child-Pugh class B); no specific dose adjustment established. Mild hepatic impairment (Child-Pugh class A): no adjustment needed. |
| Pediatric use | Safety and efficacy not established in pediatric patients younger than 18 years; not recommended. |
| Geriatric use | Limited data in geriatric patients >65 years; no specific dose adjustment recommended. Monitor for prostate hypertrophy and cardiovascular risk factors due to potential age-related comorbidities. |
| 1st trimester | Contraindicated in pregnancy due to risk of virilization of female fetus. Testosterone can cross placenta and cause clitoromegaly, labial fusion, and other masculinizing effects when administered during pregnancy. |
| 2nd trimester | Contraindicated in pregnancy. Continued risk of fetal harm, including potential effects on fetal development and virilization. |
| 3rd trimester | Contraindicated in pregnancy. Risk of adverse effects on fetus, including virilization and potential long-term developmental effects. |
Clinical note
Comprehensive clinical and safety monograph for NATESTO (NATESTO).
| Placental transfer | Testosterone crosses the placenta. Evidence demonstrates measurable concentrations in fetal circulation following maternal administration, with potential for virilization of female fetuses. |
| Breastfeeding | Testosterone is excreted in breast milk and may cause virilization and other adverse effects in nursing infants. Breastfeeding is not recommended during testosterone therapy. If use is clinically necessary, infant should be monitored for signs of masculinization and androgen excess. |
■ FDA Black Box Warning
WARNING: SECONDARY EXPOSURE TO TESTOSTERONE. Virilization has been reported in children following secondary exposure to topical testosterone gel. Children should avoid contact with treated skin sites. If a child develops signs of secondary exposure (e.g., enlarged penis or clitoris, early pubic hair, increased erections, aggressive behavior), discontinue use and contact healthcare provider.
| Serious Effects |
PregnancyKnown hypersensitivity to testosterone or any component of the productMen with breast cancerMen with known or suspected prostate cancerSignificant hepatic impairment
| Precautions | Secondary exposure to testosterone, Increased risk of cardiovascular events (e.g., MI, stroke) reported in some studies, Hepatic adverse effects (e.g., cholestatic hepatitis, jaundice), Polycythemia (increased hematocrit), Hypercalcemia in patients with metastatic prostate cancer, Edema (use with caution in patients with cardiac, renal, or hepatic disease), Sleep apnea, Gynecomastia, Bone growth effects in prepubertal males |
| Food/Dietary | No specific food interactions are reported. However, since NATESTO is administered nasally, absorption is not affected by food. Avoid grapefruit juice as it may increase testosterone levels via CYP3A4 inhibition, though clinical significance is unknown. |
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| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Testosterone, the active ingredient in NATESTO, is contraindicated in pregnancy. First trimester: Exposure may cause virilization of female fetus. Second and third trimesters: Associated with fetal harm, including clitoromegaly, labial fusion, and other ambiguous genitalia in females. Masculinization of male fetuses may occur at high doses. Risk for spontaneous abortion. |
| Fetal Monitoring | If exposure occurs during pregnancy, monitor fetal development with ultrasound for signs of virilization or other anomalies. Maternal serum testosterone levels may be checked, but no established therapeutic range in pregnancy. Assess for maternal adverse effects such as hirsutism or voice changes. |
| Fertility Effects | Testosterone can reduce spermatogenesis via suppression of gonadotropins, leading to impaired fertility in males. In females, high doses may disrupt ovulatory cycles. Reversible upon discontinuation. |
| Clinical Pearls | NATESTO (testosterone nasal gel) is a bioidentical testosterone replacement therapy for adult males with hypogonadism. Avoid nasal surgery or trauma within 6 months. Apply to both nostrils using the 11mg actuation. Do not administer to patients with prostate or breast cancer, severe lower urinary tract symptoms (AUA/IPSS >19), or hematocrit >54%. |
| Patient Advice | Apply NATESTO exactly as prescribed: one pump (11 mg) to each nostril once daily in the morning. · Alternate nostrils if irritation occurs, but do not skip doses. · Avoid blowing nose for 1 hour after application; if you do, reapply one additional pump to that nostril. · Keep the gel away from children and women, especially pregnant women, to prevent secondary exposure. · Report signs of virilization in female partners, such as acne or voice changes. · Monitor for increased blood pressure, sleep apnea, or prostate symptoms. · Do not use if you have nasal congestion, sinus infection, or epistaxis; consult your doctor. |