NATESTO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for NATESTO (NATESTO).

How it works

Testosterone replacement therapy; testosterone binds to androgen receptors, activating gene transcription for male sexual development and maintenance of secondary sexual characteristics.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for NATESTO (NATESTO).

Breastfeeding	Testosterone is excreted in human milk; M/P ratio not established. Breastfeeding is contraindicated due to potential adverse effects on the nursing infant, including virilization and suppression of lactation.
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.

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Breast cancer (male)","Known or suspected prostate cancer","Pregnancy (testosterone can cause fetal harm)","Hypersensitivity to testosterone or any product components","Women who may become pregnant (risk of virilization of fetus)"]

Clinical Precautions

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"]

Clinical Tips & Counseling

Drug interactions

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NATESTO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for NATESTO (NATESTO).

How it works

Testosterone replacement therapy; testosterone binds to androgen receptors, activating gene transcription for male sexual development and maintenance of secondary sexual characteristics.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for NATESTO (NATESTO).

Breastfeeding	Testosterone is excreted in human milk; M/P ratio not established. Breastfeeding is contraindicated due to potential adverse effects on the nursing infant, including virilization and suppression of lactation.
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.