Testosterone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as undecanoate:

Jatenzo: 158 mg, 198 mg, 237 mg [contains cremophor rh40, fd&c yellow #6 (sunset yellow)]

Gel, Nasal:

Natesto: 5.5 mg/actuation (7.32 g)

Gel, Transdermal:

AndroGel: 25 mg/2.5 g (1%) (2.5 g) [contains alcohol, usp]

AndroGel: 20.25 mg/1.25 g (1.62%) (1.25 g); 40.5 mg/2.5 g (1.62%) (2.5 g)

AndroGel: 50 mg/5 g (1%) (5 g) [contains alcohol, usp]

AndroGel Pump: 20.25 mg/actuation (1.62%) (75 g)

Fortesta: 10 mg/actuation (2%) (60 g) [contains propylene glycol, trolamine (triethanolamine)]

Testim: 50 mg/5 g (1%) (5 g) [contains alcohol, usp, propylene glycol, tromethamine]

Vogelxo: 50 mg/5 g (1%) (5 g) [contains alcohol, usp, tromethamine]

Vogelxo Pump: 12.5 mg/actuation (1%) (75 g) [contains alcohol, usp, tromethamine]

Generic: 25 mg/2.5 g (1%) (2.5 g); 20.25 mg/1.25 g (1.62%) (1.25 g); 40.5 mg/2.5 g (1.62%) (2.5 g); 10 mg/actuation (2%) (60 g); 12.5 mg/actuation (1%) (75 g); 20.25 mg/actuation (1.62%) (75 g); 50 mg/5 g (1%) (5 g)

Miscellaneous, Buccal:

Striant: 30 mg (60 ea)

Patch 24 Hour, Transdermal:

Androderm: 2 mg/24 hr (1 ea, 60 ea); 4 mg/24 hr (1 ea, 30 ea)

Pellet, Implant:

Testopel: 75 mg (10 ea, 100 ea)

Solution, Transdermal:

Axiron: 30 mg/actuation (90 mL [DSC]) [contains isopropyl alcohol]

Generic: 30 mg/actuation (90 mL)

Solution, Intramuscular, as cypionate:

Depo-Testosterone: 100 mg/mL (10 mL); 200 mg/mL (1 mL, 10 mL) [contains benzyl alcohol, benzyl benzoate]

Generic: 100 mg/mL (10 mL); 200 mg/mL (1 mL, 10 mL)

Solution, Intramuscular, as enanthate:

Generic: 200 mg/mL (5 mL)

Solution, Intramuscular, as undecanoate:

Aveed: 750 mg/3 mL (3 mL) [contains benzyl benzoate, castor oil (ricine oil)]

Solution Auto-injector, Subcutaneous [preservative free]:

Xyosted: 50 mg/0.5 mL (0.5 mL); 75 mg/0.5 mL (0.5 mL); 100 mg/0.5 mL (0.5 mL) [contains sesame oil]

Pharmacology

Mechanism of Action

Principal endogenous androgen responsible for promoting the growth and development of the male sex organs and maintaining secondary sex characteristics in androgen-deficient males

Pharmacokinetics/Pharmacodynamics

Absorption

Transdermal gel: ~10% of applied dose

Metabolism

Hepatic; forms metabolites, including dihydrotestosterone (DHT) and estradiol (both active)

Excretion

Urine (90%; 40 mg oral capsule [Canadian product]: 45% to 48%); feces (6%)

Time to Peak

IM (undecanoate): 7 days (median; range: 4 to 42 days); Intranasal: ~40 minutes; Transdermal system: 8 hours (range: 4 to 12 hours); Buccal system: 10 to 12 hours; Oral capsule: Jatenzo: ~2 to 4 hours; 40 mg capsule [Canadian product]: 4 to 5 hours; SubQ (enanthate): 11.9 hours (median; range: 5.8 to 168.7 hours) following weekly administration for 12 weeks

Duration of Action

Route and ester dependent; IM: Cypionate and enanthate esters: 2 to 4 weeks; Undecanoate: 10 weeks; Transdermal gel: 24 hours

Half-Life Elimination

Variable: 10 to 100 minutes; Testosterone cypionate: ~8 days

Protein Binding

98% bound to sex hormone-binding globulin (40%) and albumin

Use: Labeled Indications

Breast cancer, metastatic: IM injection (enanthate): Secondary treatment in women with advancing inoperable metastatic (skeletal) mammary cancer who are 1 to 5 years postmenopausal. Use may be considered in premenopausal women with breast cancer who have benefited from oophorectomy and have a hormone-responsive tumor.

Delayed puberty: IM injection (enanthate); pellet: To stimulate puberty in carefully selected males with delayed puberty.

Hypogonadism, hypogonadotropic (congenital or acquired): Buccal; Capsule (oral); Gel (nasal, transdermal); IM injection (cypionate, enanthate, undecanoate); Patch (transdermal); Pellet; Solution (transdermal); SubQ injection (enanthate): Gonadotropin or luteinizing hormone-releasing hormone deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.

Hypogonadism, primary (congenital or acquired): Buccal; Capsule (oral); Gel (nasal, transdermal); IM injection (cypionate, enanthate, undecanoate); Patch (transdermal); Pellet; Solution (transdermal); SubQ injection (enanthate): Treatment of testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals.

Limitations of use: Safety and efficacy in men with age-related hypogonadism (or late-onset hypogonadism) has not been established (manufacturer's labeling). However, the Endocrine Society recommends offering testosterone therapy to patients with symptoms of testosterone deficiency and consistently and unequivocally low morning testosterone concentrations. In men >65 years of age, treatment should only be initiated on an individual basis and after consultation with the patient regarding risks and benefits (Endocrine Society [Bhasin 2018]).

Use: Off Label

Hormone therapy for transgender males (female-to-male)yes

Based on the Endocrine Society guidelines for the endocrine treatment of gender dysphoric/gender incongruent persons, testosterone as monotherapy is effective for elevating serum testosterone levels into the normal range for males, resulting in cessation of menses, clitoromegaly, decreased fat mass and fertility (temporary or permanent), deepening of the voice, increased acne, body and facial hair, muscle mass and sexual desire, and male pattern baldness (in those genetically predisposed) ES [Hembree 2017].

Contraindications

Breast cancer (males); prostate cancer (known or suspected); pregnancy

Androderm, Axiron, Fortesta, Natesto, Striant, Testim, Vogelxo: Additional contraindication: Breastfeeding women; women who may become pregnant

Aveed: Additional contraindications: Hypersensitivity to testosterone undecanoate, castor oil, benzyl benzoate; breastfeeding women; women who may become pregnant

Depo-Testosterone: Additional contraindications: Hypersensitivity to testosterone cypionate, serious cardiac, hepatic, or renal disease

Testosterone enanthate (IM injection): Additional contraindications: Hypersensitivity to any component of the formulation; women who may become pregnant

Testosterone enanthate (SubQ injection): Additional contraindications: Hypersensitivity to any component of the formulation; men with hypogonadal conditions that are not associated with structural or genetic etiologies (eg, age-related hypogonadism); women who may become pregnant

Testosterone undecanoate (oral): Additional contraindications: Hypersensitivity to any component of the formulation; men with hypogonadal conditions that are not associated with structural or genetic etiologies (eg, age-related hypogonadism)

Canadian labeling: Additional contraindication (not in the US labeling): Androderm: Hypersensitivity to any component of the formulation; skin contact in pregnant or breastfeeding women; not indicated for use in women

Documentation of allergenic cross-reactivity for androgens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Note: Testosterone enanthate IM formulation and testosterone enanthate SubQ formulation are not to be used interchangeably.

Breast cancer (females): IM (testosterone enanthate): 200 to 400 mg every 2 to 4 weeks.

Delayed puberty (males):

IM (testosterone enanthate): 50 to 200 mg every 2 to 4 weeks for a limited duration (eg, 4 to 6 months).

Pellet (for subcutaneous implantation): 150 to 450 mg every 3 to 6 months. Dosing is generally at the lower range for a limited duration (eg, 4 to 6 months).

Hormone therapy in transgender males(female-to-male), monotherapy(off-label use):

IM (testosterone enanthate or testosterone cypionate): 100 to 200 mg every 2 weeks or 50 to 100 mg every week (ES [Hembree 2017]).

IM (testosterone undecanoate): 1 g every 6 weeks for the first 2 doses, followed by 1 g every 12 weeks (ES [Hembree 2017]; Pelusi 2014; Wierckx 2014).

SubQ (testosterone enanthate): 50 to 100 mg every week (ES [Hembree 2017]).

Topical:Gel: Androgel 1.62%: 50 to 100 mg daily (ES [Hembree 2017]).

Hypogonadism (primary) or hypogonadism (hypogonadotropic) (males):

Note: Adjust therapy to achieve symptom improvement and normalization of testosterone levels. A total testosterone goal in the mid-normal therapeutic range (eg, 450 to 600 ng/dL for most laboratories) is reasonable for most patients to prevent over- or under-treatment (AUA [Mulhall 2018]). For injectable formulations (IM, SubQ), a range of 350 to 600 ng/dL may be reasonable (Endocrine Society [Bhasin 2018]; Xyosted manufacturer labeling). Dose titration is not necessary if complete symptom resolution occurs with testosterone levels below the suggested target range (AUA [Mulhall 2018]).

Buccal: 30 mg twice daily (every 12 hours) applied to the gum region above the incisor tooth.

IM (testosterone enanthate or testosterone cypionate):

Initial: 75 to 100 mg/week or 150 to 200 mg every 2 weeks; dosage range: 50 to 100 mg/week or 100 to 200 mg every 2 weeks (AUA [Mulhall 2018]; Endocrine Society [Bhasin 2018]).

Manufacturer labeling: Dosing in the prescribing information may not reflect current clinical practice. 50 to 400 mg IM every 2 to 4 weeks.

IM (testosterone undecanoate): Initial: 750 mg, followed by 750 mg administered 4 weeks later, then 750 mg administered every 10 weeks thereafter.

Intranasal: Testosterone gel: Natesto: 11 mg (2 pump actuations; 1 actuation per nostril) intranasally 3 times daily (6 to 8 hours apart). Total daily dose: 33 mg.

Oral capsule: Testosterone undecanoate:

Jatenzo: Initial: 237 mg twice daily. Dosage range: 158 to 396 mg twice daily.

40 mg capsule [Canadian product]): Initial: 120 to 160 mg/day in 2 divided doses for 2 to 3 weeks; usual maintenance dose: 40 to 120 mg/day (in divided doses).

Pellet (for subcutaneous implantation): 150 to 450 mg every 3 to 6 months.

SubQ (testosterone enanthate): Initial: 75 mg once weekly. Dosage range: 50 to 100 mg once weekly.

Topical:

Gel:

AndroGel 1%: Initial: 50 mg applied once daily in the morning to the shoulder and upper arms, or abdomen. Dosage range: 50 to 100 mg/day.

AndroGel 1.62%: Initial: 40.5 mg applied once daily in the morning to the shoulder and upper arms. Dosage range: 20.25 mg to 81 mg/day; maximum: 81 mg/day.

Fortesta: Initial: 40 mg once daily in the morning. Apply to the thighs. Dosing range: 10 to 70 mg/day; maximum: 70 mg/day.

Testim: Initial: 50 mg applied once daily (preferably in the morning) to the shoulder and upper arms. If testosterone concentrations are less than the normal range, dosage may be increased from 50 mg to 100 mg once daily; maximum: 100 mg/day.

Vogelxo: Initial: 50 mg applied once daily in the morning to the shoulder and/or upper arms. Dosage may be increased to a maximum of 100 mg/day.

Solution (Axiron): Initial: 60 mg once daily (dosage range: 30 to 120 mg/day). Apply to the axilla at the same time each morning.

Transdermal system (Androderm):

Initial: 4 mg/day (as one 4 mg/day patch; do not use two 2 mg/day patches). Dosage range: 2 to 6 mg/day.

Dosing conversion: The 2.5 mg/day and the 5 mg/day patches have been discontinued in the US; patients may be switched from the 2.5 mg/day patch, 5 mg/day patch, or the combination (ie, 7.5 mg/day) as follows:

From 2.5 mg/day patch to 2 mg/day patch.

From 5 mg/day patch to 4 mg/day patch.

From 7.5 mg daily (one 2.5 mg/day and one 5 mg/day patch) to 6 mg daily (one 2 mg/day and one 4 mg/day patch).

Note: Patch change should occur at the next scheduled dosing. Measure early morning testosterone concentrations ~2 weeks after switching therapy.

Dosing: Geriatric

Refer to adult dosing. Some data suggest a slightly lower testosterone target may be reasonable in older patients (eg, the lower end of the normal testosterone range) (AUA [Mulhall 2018]).

Dosing: Pediatric

Note: Dosage and duration of therapy depend upon age, sex, diagnosis, patient's response to therapy, and appearance of adverse effects; in general total doses >400 mg/month are not required due to the prolonged action of the drug.

Constitutional delay of growth and puberty (CDGP):

IM:

Children ≥12 years and Adolescents ≤17 years: Note: Typically not recommended for use before 14 years of age (Palmert 2012; Sperling 2014): Initial: Enanthate or cypionate: 50 mg/dose every 2 to 4 weeks for 3 to 6 months; may increase dose in 25 to 50 mg increments for another 3 to 6 months to effect; maximum dose: 100 mg; typical duration of therapy: 12 months; if no response or inadequate response after 1 year of treatment, diagnosis should be reconsidered and additional testing performed (Palmert 2012; Sperling 2014); Note: Other regimens have suggested high initial doses and taper downward as puberty progresses.

Adolescents ≥18 years: Enanthate: 50 to 200 mg every 2 to 4 weeks for a limited duration (eg, 4 to 6 months)

Subcutaneous implant: Pellet: Children ≥12 years and Adolescents: Usual range: 150 to 450 mg every 3 to 6 months; usual duration: 4 to 6 months; dosing typically on the lower end of range; various regimens have been used

Male hypogonadism or hypogonadotropic hypogonadism:

IM: Enanthate or cypionate:

Children ≥12 years and Adolescents ≤17 years:

Initiation of pubertal growth: 25 to 75 mg every 3 to 4 weeks, gradually titrate dose every 6 to 9 months to 100 to 150 mg monthly; some experts suggest increasing the interval to every 2 weeks at this point; typical duration of initiation therapy 3 to 4 years (Han 2010; Sperling 2014; Wales 2012)

Maintenance therapy: 200 to 250 mg every 3 to 4 weeks; once expected adult height and adequate virilization achieved, may convert to other testosterone replacement dosage form (eg, patch, gel, etc) (Han 2010; Sperling 2014; Wales 2012)

Adolescents ≥18 years: 50 to 400 mg every 2 to 4 weeks (manufacturer's labeling); 75 to 100 mg/week or 150 to 200 mg every 2 weeks (Endocrine Society [Bhasin 2010])

IM: Undecanoate: Aveed: Adolescents ≥18 years: Initial dose: 750 mg, followed by 750 mg administered 4 weeks later, then 750 mg administered every 10 weeks thereafter.

Subcutaneous implant: Pellet:

Fixed dosing: Children ≥12 years and Adolescents: Usual range: 150 to 450 mg every 3 to 6 months; various regimens have been used

Weight-direct dosing: Limited data available: Children ≥12 years and Adolescents <17 years: 8 to 10 mg/kg/dose every 6 months (Zacharin 1997)

Topical: Adolescents ≥18 years:

Buccal: Striant: 30 mg twice daily (every 12 hours) applied to the gum region above the incisor tooth; discontinue if serum testosterone concentrations are consistently outside of the normal range.

Dermal:

Gel:

AndroGel 1%: 50 mg applied once daily in the morning to the shoulder and upper arms or abdomen. Dosage may be increased to a maximum of 100 mg. Dose adjustment based on serum testosterone levels:

Less than normal range: Increase dose from 50 mg to 75 mg or from 75 mg to 100 mg once daily

Greater than normal range: Decrease dose. Discontinue if consistently above normal at 50 mg daily.

AndroGel 1.62%: 40.5 mg applied once daily in the morning to the shoulder and upper arms; dose range: 20.25 to 81 mg. Maximum daily dose: 81 mg/day. Dose adjustment based on serum testosterone levels:

>750 ng/dL: Decrease dose by 20.25 mg/day

350 to 750 ng/dL: Maintain current dose

<350 ng/dL: Increase dose by 20.25 mg/day

Fortesta: 40 mg once daily in the morning. Apply to the thighs. Dosing range: 10 to 70 mg/day. Dose adjustment based on serum testosterone levels:

≥2,500 ng/dL: Decrease dose by 20 mg/day

≥1,250 to <2,500 ng/dL: Decrease dose by 10 mg/day

≥500 and <1,250 ng/dL: Maintain current dose

<500 ng/dL: Increase dose by 10 mg/day

Testim: 50 mg applied once daily (preferably in the morning) to the shoulder and upper arms. If serum testosterone concentrations are less than the normal range, dosage may be increased from 50 mg to 100 mg once daily; maximum daily dose: 100 mg/day.

Vogelxo: 50 mg applied once daily to the shoulder and/or upper arms. Dosage may be increased up to a maximum daily dose: 100 mg/day. Dose adjustment based on serum testosterone levels: If level less than normal range: Increase dose from 50 mg to 100 mg once daily.

Solution: Axiron: 60 mg once daily; dosage range: 30 to 120 mg/day. Apply to the axilla at the same time each morning; do not apply to other parts of the body. Dose adjustment based on serum testosterone levels:

>1,050 ng/dL: Decrease 60 mg/day dose to 30 mg/day; if levels >1,050 ng/dL persist after dose reduction discontinue therapy

<300 ng/dL: Increase 60 mg/day dose to 90 mg/day, or increase 90 mg/day dose to 120 mg/day

Transdermal system: Androderm:

Initial: 4 mg/day (as one 4 mg/day patch; do not use two 2 mg/day patches). Dose adjustment based on testosterone levels:

>930 ng/dL: Decrease dose to 2 mg/day

400 to 930 ng/dL: Continue 4 mg/day

<400 ng/dL: Increase dose to 6 mg/day (as one 4 mg/day and one 2 mg/day patch)

Dosing conversion of transdermal patches: If needed, patients may be switched from the 2.5 mg/day, 5 mg/day, and 7.5 mg/day patches as follows. Patch change should occur at their next scheduled dosing. Measure early morning testosterone concentrations ~2 weeks after switching therapy:

From 2.5 mg/day patch to 2 mg/day patch

From 5 mg/day patch to 4 mg/day patch

From 7.5 mg/day patch to 6 mg/day patch (one 2 mg/day and one 4 mg/day patch)

Intranasal: Testosterone gel: Natesto: 11 mg (2 pump actuations; 1 actuation per nostril) intranasally 3 times daily (6 to 8 hours apart). Total daily dose: 33 mg

Dose adjustment based on testosterone levels:

Less than normal range: Consider alternative treatment if consistently <300 ng/mL

Greater than normal range: Discontinue if consistently >1,050 ng/mL

Multiple pituitary hormone deficiency (with microphallus): Limited data available: Infants: IM: Enanthate or cypionate: 25 mg every 4 weeks for 3 months; may repeat for another second course if necessary (Kliegman 2016).

Reconstitution

Injection:

Testosterone enanthate (IM injection), testosterone cypionate: Warm and rotate vial between palms of hands to redissolve crystals that have formed after storage.

Testosterone undecanoate: Inject 3 mL of air through the gray rubber stopper into the vial to create positive pressure, and then withdraw 3 mL of solution (750 mg) from the vial. Expel any air bubbles from the syringe and change the syringe needle to a new IM needle. Discard unused portion.

Administration

IM: Administer by deep IM injection into the gluteal muscle.

Testosterone undecanoate: Inject into the gluteus medius; alternate injection between left and right buttock. Avoid intravascular injection, may lead to pulmonary oil microembolism; avoid the superior gluteal arteries and sciatic nerve.

Intranasal gel (Natesto): Administer intranasally 3 times daily, 6 to 8 hours apart, preferably at the same time each day. Prime pump prior to first use by inverting then depressing pump 10 times (discard this portion of product into sink). Blow nose prior to application. To administer the dose, insert actuator into nostril until pump reaches base of nose; tilt so the tip is in contact with the lateral wall of nostril. Depress slowly until pump stops, then remove from nose while wiping tip to transfer gel to lateral side of nostril. Following administration, press on the nostrils at a point just below the bridge of the nose and lightly massage. Refrain from blowing nose or sniffing for 1 hour after administration. If gel gets on hands, wash with warm soap and water. Temporarily discontinue with episodes of severe rhinitis; if severe rhinitis symptoms persist consider an alternative therapy.

Oral, buccal application (Striant): One mucoadhesive for buccal application (buccal system) should be applied to a comfortable area above the incisor tooth twice daily. Gently push the curved side against the upper gum. Hold buccal system firmly in place by pushing down on outside of the upper lip for 30 seconds to ensure adhesion. The buccal system should adhere to gum until it is removed. Rotate to alternate sides of mouth with each application. If the buccal system falls out, replace with a new system. If the system falls out within the first 8 hours of dosing, replace with a new buccal system and continue for a total of 12 hours from the placement of the first system. If the system falls out of position after 8 hours of dosing, a new buccal system should be applied and it may remain in place for 12 hours, then continue with the next regularly scheduled dosing. System will soften and mold to shape of gum as it absorbs moisture from mouth. Do not chew or swallow the buccal system. The buccal system will not dissolve; gently remove by sliding downwards from gum; avoid scratching gum. Remove prior to routine morning and evening oral care, prior to application of new system.

Oral, capsule (Jatenzo): Administer once in the morning and once in the evening with meals.

40 mg capsule [Canadian product]: Administer once in the morning and once in the evening with meals. Should be swallowed whole; do not crush or chew.

Subcutaneous implant (Testopel): Using strict sterile technique, must be surgically implanted.

Subcutaneous injection (Xyosted): Administer in the abdominal region only. Do not administer IM or IV.

Topical gel and solution: General information: Alcohol-based gels and solutions are flammable; avoid fire, flames, or smoking until dry. Testosterone may be transferred to another person following skin-to-skin contact with the application site. Strict adherence to application instructions is needed in order to decrease secondary exposure. Thoroughly wash hands after application and cover application site with clothing (ie, shirt) once gel or solution has dried, or clean application site thoroughly with soap and water prior to contact in order to minimize transfer. In addition to skin-to-skin contact, secondary exposure has also been reported following exposure to secondary items (eg, towel, shirt, sheets). If secondary exposure occurs, the other person should thoroughly wash the skin with soap and water as soon as possible. The application sites and doses of topical testosterone products are not interchangeable.

Product-specific administration instructions:

AndroGel 1%: Apply at the same time each morning to clean, dry, intact skin to an area of the shoulder, upper arms, and/or abdomen that will be covered by a short sleeve t-shirt. Do not apply to other parts of the body such as the genitals, chest, back, axillae, or knees. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Alternatively, a portion may be squeezed onto palm of hand and applied, repeating the process at the same or other site until entire packet has been applied. Avoid swimming, showering or washing the application site for ≥5 hours following application. Cover application site with clothing (eg t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times (and discard this portion of product) prior to initial use. Each actuation delivers 12.5 mg of testosterone (4 actuations = 50 mg; 6 actuations = 75 mg; 8 actuations = 100 mg). When using the pump, the gel may be delivered into the palm of the hand prior to application or applied directly to the application site.

AndroGel 1.62%: Apply at the same time each morning to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to other parts of the body such as the abdomen, genitals, chest, axillae, or knees. Upon opening the packet(s), the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Alternatively, a portion may be squeezed onto palm of hand and applied, repeating the process at the same or other site until entire packet has been applied. Avoid swimming, showering or washing the application site for ≥2 hours following application. Cover application site with clothing (eg t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times (and discard this portion of product) prior to initial use. Each actuation delivers 20.25 mg of testosterone (2 actuations = 40.5 mg; 3 actuations = 60.75 mg; 4 actuations = 81 mg). When using the pump, the gel may be delivered into the palm of the hand prior to application or applied directly to the application site.

Axiron: Apply using the applicator to clean, dry, intact skin on an area of the axilla at the same time each morning. Do not apply to other parts of the body (eg, abdomen, genitals, shoulders, upper arms). Avoid washing the site or swimming for 2 hours after application. Prior to first use, prime the applicator pump by depressing it 3 times (discard this portion of the product). After priming, position the nozzle over the applicator cup and depress pump fully one time; ensure liquid enters cup. Each pump actuation delivers testosterone 30 mg. No more than 30 mg (one pump) should be added to the cup at one time. The total dose should be divided between axilla (example, 30 mg/day: apply to one axilla only; 60 mg/day: apply 30 mg to each axilla; 90 mg/day: apply 30 mg to each axilla, allow to dry, then apply an additional 30 mg to one axilla; etc). To apply dose, keep applicator upright and wipe into the axilla; if solution runs or drips, use cup to wipe. Do not rub into skin with fingers or hand. If more than one 30 mg dose is needed, repeat process. Apply roll-on or stick antiperspirants or deodorants prior to testosterone. Once application site is dry, cover with clothing. After use, rinse applicator under running water and pat dry with a tissue.

Fortesta: Apply to clean dry intact skin once daily in the morning to skin of front and inner thighs. Do not apply to genitals or other parts of the body. Use one finger to rub gel evenly onto skin of each thigh. Avoid showering, washing the site, or swimming for ≥2 hours after application. Prior to first dose, prime the pump by holding canister upright and fully depressing the pump 8 times (discard this portion of the product). Each pump actuation delivers testosterone 10 mg. The total dose should be divided between thighs (example, 10 mg/day: apply 10 mg to one thigh only; 20 mg/day: apply 10 mg to each thigh; 30 mg/day: apply 20 mg to one thigh and 10 mg to the other thigh; etc). Once application site is dry, cover with clothing.

Testim: Apply once daily (preferably in the morning) to clean, dry, intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to the genitals or abdomen. Upon opening the tube, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). Avoid swimming, showering or washing the application site for ≥2 hours following application. Cover application site with clothing (eg t-shirt) once the gel has dried.

Vogelxo: Apply once daily at the same time each morning to clean dry intact skin to an area of the shoulder and upper arms that will be covered by a short sleeve t-shirt. Do not apply to the genitals or to the abdomen. Upon opening the tube or packet, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site(s). If two doses (testosterone 100 mg) are needed, apply one dose (50 mg) to upper arm and or/shoulder, then apply the second dose (50 mg) to the opposite upper arm and/or shoulder. Avoid showering, washing the site, or swimming for at least 2 hours following application. Cover application site with clothing (eg t-shirt) once the gel has dried. When using the multidose pump, prime pump 3 times by fully depressing the pump mechanism (actuation) and discard this portion of product. Each actuation delivers testosterone 12.5 mg (4 actuations = 50 mg; 8 actuations = 100 mg).

Transdermal patch (Androderm): Apply to skin immediately upon removal from the protective pouch. Apply at the same time each night to clean, dry area of skin on the back, abdomen, upper arms, or thigh. Do not apply to bony areas or parts of the body that are subject to prolonged pressure while sleeping or sitting. Do not apply to oily, damaged, or irritated skin. Do not apply to the scrotum. Rotate administration sites, allowing 7 days between applying to the same site. Avoid showering, washing the site, or swimming for ≥3 hours after application. Following patch removal, mild skin irritation may be treated with OTC hydrocortisone cream. A small amount of triamcinolone acetonide 0.1% cream may be applied under the system to decrease irritation; do not use ointment (triamcinolone ointment decreases testosterone absorption). Dispose of any used or unused patches by folding adhesive ends together, replace in pouch or sealed container, and discard properly in trash away from children and pets.

Storage

Androderm: Store at 20°C to 25°C (68°F to 77°F). Do not store outside of pouch. Excessive heat may cause system to burst.

AndroGel 1%, Axiron, Aveed: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Store Aveed in original container.

AndroGel 1.62%, Fortesta, Natesto, Testim, Vogelxo: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze.

Depo-Testosterone: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Oral capsule:

Jatenzo: 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). Avoid exposing the capsules to moisture (store in a dry place).

40 mg capsule [Canadian product]: Store between 15°C and 30°C (59°F to 86°F); protect from light and moisture; keep blister in outer carton.

Striant: Store at 20°C to 25°C (68°F to 77°F). Protect from heat and moisture.

Testopel: Store in a cool location.

Testosterone enanthate injection:

IM injection: Store at room temperature.

SubQ injection: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not refrigerate or freeze. Protect from light; keep in original carton.

Drug Interactions

Ajmaline: Androgens may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Blood Glucose Lowering Agents: Androgens may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

C1 inhibitors: Androgens may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

Corticosteroids (Systemic): May enhance the fluid-retaining effect of Androgens. Monitor therapy

CycloSPORINE (Systemic): Androgens may enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

Dehydroepiandrosterone: May enhance the adverse/toxic effect of Testosterone. Avoid combination

Vitamin K Antagonists (eg, warfarin): Androgens may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Test Interactions

May decrease thyroxine-binding globulin, resulting in decreased total T₄ and increased resin uptake of T₃ and T₄; free thyroid hormone levels are not changed.

Adverse Reactions

>10%:

Cardiovascular: Hypertension (≤13%; intranasal: >6%)

Dermatologic: Skin blister (application site; transdermal: 12%)

Genitourinary: Prostate specific antigen increase (≤18%; buccal, oral: 2%), benign prostatic hypertrophy (12%)

Hematologic & oncologic: Increased hematocrit (subcutaneous: 8% to 14%; topical, oral: ≤6%; buccal, intramuscular: 1%)

Local: Application-site pruritus (transdermal: 17% to 37%)

1% to 10%:

Cardiovascular: Peripheral edema (<1%; subcutaneous: 3%), peripheral vascular disease (transdermal: <3%)

Central nervous system: Emotional lability (buccal: ≤8%; intramuscular, topical: ≤3%), altered sense of smell (intranasal: 5% to >6%; topical: 1%), anosmia (intranasal: 6%; buccal: 1%), headache (≤5%), procedural pain (intramuscular, intranasal: 4%), depression (≤3%), nervousness (≤3%), abnormality in thinking (transdermal: <3%), anxiety (<3%), body pain (transdermal: <3%), chills (transdermal: <3%), confusion (transdermal: <3%), fatigue (<3%), paresthesia (<3%), vertigo (transdermal: <3%), irritability (intramuscular: 2%), sleep apnea (2%), insomnia (intramuscular, subcutaneous, topical: 1% to 2%), aggressive behavior (buccal, intramuscular: 1%), stinging sensation (lips; buccal: 1%)

Dermatologic: Acne vulgaris (≤8%), crusted skin (nasal scab; intranasal: 4% to 6%), excoriation of skin (nasal; intranasal: ≤6%), contact dermatitis (topical, transdermal: 2% to 4%), bulla (application site; transdermal: <3%), skin rash (<3%), pruritus (≤2%), xeroderma (topical: ≤2%), erythema (topical: ≥1%), hyperhidrosis (intramuscular: 1%), alopecia (topical: ≤1%)

Endocrine & metabolic: Decreased HDL cholesterol (topical, oral: ≤6%), hyperlipidemia (≤6%), hypokalemia (topical: ≤6%), increased serum triglycerides (≤6%), increased thyroid stimulating hormone level (intranasal: ≤6%), increased plasma estradiol concentration (intramuscular: 3%), decreased libido (≤3%), gynecomastia (≤3%), hot flash (intramuscular, topical: 1%), weight gain (intramuscular: 1%)

Gastrointestinal: Gingivitis (buccal: ≤9%), oral irritation (buccal: ≤9%), decreased appetite (intranasal: ≤6%), nausea (≤6%; oral, subcutaneous: 2%), diarrhea (≤4%), gingival pain (buccal: 3%; includes gingival tenderness), dysgeusia (<3%), gastroesophageal reflux disease (transdermal: <3%), gastrointestinal hemorrhage (transdermal: <3%), increased appetite (topical, transdermal: <3%), abdominal pain (buccal, subcutaneous: 2%), gingival swelling (buccal: 2%), toothache (buccal: ≤1%), oral mucosa changes (buccal; includes buccal mucosa roughening and gum blister)

Genitourinary: Testicular atrophy (intranasal, topical: ≤6%), prostatic disease (topical, transdermal: 3% to 5%), hypogonadism (intramuscular: 3%), mastalgia (topical: ≤3%; buccal: 1%), prostatitis (intramuscular, subcutaneous, transdermal: ≤3%), urinary tract infection (subcutaneous, transdermal: ≤3%), dysuria (intramuscular, transdermal: <3%), hematuria (subcutaneous, transdermal: <3%), impotence (transdermal: <3%), pelvic pain (transdermal: <3%), urinary incontinence (transdermal: <3%), testicular disease (including testicular tenderness and non-palpable testes: topical: 2%), urinary frequency (topical: ≤2%), breast hypertrophy (buccal: 1%), difficulty in micturition (buccal, topical: 1%), ejaculatory disorder (intramuscular: 1%), prostate induration (intramuscular: 1%), spontaneous erections (topical: 1%)

Hematologic & oncologic: Anemia (topical: 3%), polycythemia (≤3%), prostate carcinoma (topical, transdermal: <3%), increased hemoglobin (intramuscular, topical: ≤2%)

Hepatic: Increased serum bilirubin (topical: ≤6%), abnormal hepatic function tests (1%)

Local: Bruising at injection site (subcutaneous: 4% to 7%), application-site erythema (topical, transdermal: ≤7%), application-site vesicles (transdermal: 6%), bleeding at injection site (subcutaneous: 3% to 6%), application-site reaction (topical: ≤6%), pain at injection site (intramuscular: 5%), application-site induration (transdermal: 3%), erythema at injection site (subcutaneous: 3%; intramuscular: 1%), application-site irritation (transdermal: <3%), application-site rash (transdermal: <3%), local skin exfoliation (transdermal; application site: <3%), application-site burning (topical, transdermal: 1% to 3%), application-site edema (topical: ≥1%)

Neuromuscular & skeletal: Back pain (subcutaneous, transdermal: 3% to 6%), myalgia (intramuscular, intranasal: ≤6%), limb pain (intranasal, topical: ≤4%), increased creatine phosphokinase in blood specimen (subcutaneous: 3% to 4%), asthenia (topical: ≤3%), abnormal bone growth (accelerated; transdermal: <3%), hemarthrosis (transdermal: <3%), arthralgia (subcutaneous: 2%)

Renal: Increased serum creatinine (topical: ≤6%), polyuria (transdermal: <3%)

Respiratory: Nasopharyngitis (intranasal: 4% to 9%; topical: ≥1%), rhinorrhea (intranasal: 4% to 8%), epistaxis (intranasal: 4% to 7%), nasal discomfort (intranasal: 4% to 6%), bronchitis (intranasal: 4%), upper respiratory tract infection (intranasal: 4%), dry nose (intranasal: ≤4%), nasal congestion (intranasal: ≤4%), sinusitis (intramuscular, intranasal: ≤4%), cough (intramuscular, intranasal, subcutaneous: ≤3%), nasal mucosa swelling (buccal: 1%)

Frequency not defined:

Cardiovascular: Exacerbation of hypertension (buccal)

Central nervous system: Hostility (topical)

Gastrointestinal: Gingival recession (buccal)

Hepatic: Hepatic adenoma (intramuscular; long-term testosterone enanthate therapy)

Local: Induration at injection site (subcutaneous)

<1%, postmarketing, and/or case reports: Abscess at injection site, acute myocardial infarction, allergic dermatitis, altered hormone level (fluctuating testosterone levels), amnesia, anaphylactic shock, anaphylaxis, androgenetic alopecia, angina pectoris, angioedema, asthma, azoospermia, bitter taste, breast induration, calcium retention, cardiac failure, cerebral infarction, cerebrovascular accident, cerebrovascular insufficiency, change in HDL, chest pain, cholestatic jaundice, chronic obstructive pulmonary disease, circulatory shock, clotting factors suppression (factors II, V, VII, X), coronary artery disease, coronary occlusion, decreased plasma testosterone, decreased thyroxine binding globulin, deep vein thrombosis, diabetes mellitus, diaphoresis, discomfort at injection site, dizziness, drug abuse, dyspnea, edema, electrolyte disorder (calcium, nitrogen, phosphorus, potassium, sodium), erectile dysfunction, fluid retention, flu-like symptoms, frequent erections, genitourinary infection (prostate), gingival erythema, hair discoloration, hearing loss (sudden), hematoma at injection site, hepatic neoplasm, hepatocellular neoplasm, hepatotoxicity (idiosyncratic; Chalasani 2014), hirsutism, hyperchloremia, hypernatremia, hyperparathyroidism, hypersensitivity angiitis, hypersensitivity reaction, hyperventilation, increased gamma-glutamyl transferase, increased intraocular pressure, increased libido, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, increased serum prolactin, increased serum transaminases, increased testosterone level, infection, injection site reaction, inorganic phosphate retention, irritation at injection site, Korsakoff syndrome (nonalcoholic), lip edema, localized infection (abscess, cellulitis), malaise, malignant neoplasm of prostate, migraine, musculoskeletal chest pain, musculoskeletal pain, nephrolithiasis, nipple tenderness (sensitivity), nonimmune anaphylaxis, oligospermia (may occur at high dosages), oral inflammation, oral mucosa ulcer, orgasm disturbance (male), osteoporosis, papular rash, peliosis hepatitis, peripheral venous insufficiency, pharyngeal edema, pharyngolaryngeal pain, pollakiuria, potassium retention, priapism, prolonged partial thromboplastin time, prolonged prothrombin time, prostatic intraepithelial neoplasia, pulmonary embolism (including pulmonary oil microembolism), renal colic, renal function abnormality, renal pain, respiratory distress, restlessness, reversible ischemic neurological deficit, rhinitis, sleep disorder, snoring, sodium retention, spermatocele, stomatitis, suicidal ideation, syncope, systemic lupus erythematosus, tachycardia, testicular pain, thrombocytopenia, thromboembolism, thrombosis, tinnitus, transient ischemic attacks, upper abdominal pain, urination disorder, vasodilation, venous thromboembolism, vitreous detachment, voice disorder, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Blood pressure increases: [US Boxed Warning]: Increase in blood pressure has been observed with oral testosterone undecanoate and subcutaneous testosterone enanthate. These effects have been reported with other testosterone products as well. Check BP prior to initiation of therapy, at approximately 3 to 6 weeks and periodically thereafter. Some patients may require initiation or adjustment of antihypertensive therapy.
• Breast cancer: Long term use (>10 years) of parenteral testosterone for male hypogonadism may increase the risk of breast cancer (Medras 2006).
• Cardiovascular events: Available studies are inconclusive regarding the risk of developing major adverse cardiovascular events (MACE) such as nonfatal MI, stroke, or cardiovascular death following testosterone use. Some studies have suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy (Basaria 2010; Finkle 2014; Vigen 2013), although the overall evidence does not demonstrate an increased or decreased cardiovascular risk (Endocrine Society [Bhasin 2018]; Corona 2014; Morgentaler 2015). According to the FDA, prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions (eg, disorders of the testicles, pituitary gland, brain) and confirmed by laboratory tests (FDA Drug Safety Communication 2015). However, in a position statement issued by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE), they recommend that after a thorough diagnostic work-up, testosterone replacement should be guided by signs and symptoms and testosterone concentrations rather than the underlying cause (AACE/ACE [Goodman 2015]). The Endocrine Society recommends avoiding testosterone therapy in men who have experienced an MI or stroke within the past six months (Endocrine Society [Bhasin 2018]). Evaluate patients for cardiovascular risk factors prior to initiating therapy and monitor closely during therapy for cardiovascular events.
• Dyslipidemia: May alter serum lipid profile; use caution with history of MI or coronary artery disease.
• Gynecomastia: May cause gynecomastia, which may persist in patients treated for hypogonadism.
• Hepatic effects: Prolonged use of high doses of androgens has been associated with serious hepatic effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, jaundice). Prolonged use of intramuscular testosterone enanthate has been associated with multiple hepatic adenomas. Discontinue therapy if signs or symptoms of hepatic dysfunction (such as jaundice) develop.
• Hypercalcemia: May cause hypercalcemia in patients with prolonged immobilization or cancer.
• Oligospermia: Large doses may suppress spermatogenesis; oligospermia may occur. Discontinue therapy if this occurs, if restarted, a lower dose should be used.
• Polycythemia: May increase hematocrit requiring dose adjustment or discontinuation. Withhold initial treatment in patients with hematocrit >48% or >50% if living at higher altitudes. Discontinue therapy if hematocrit exceeds 54%; may reinitiate at lower dose (Endocrine Society [Bhasin 2018]).
• Priapism: Priapism or excessive sexual stimulation may occur; discontinue therapy if this occurs, if restarted, a lower dose should be used.
• Prostate cancer: May increase the risk of prostate cancer. Withhold therapy pending urological evaluation in patients with palpable prostate nodule or induration, PSA >4 ng/mL, or PSA >3 ng/mL in men at high risk of prostate cancer (Endocrine Society [Bhasin 2018]).
• Venous thromboembolism: Venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported with testosterone products. Evaluate patients with symptoms of pain, edema, warmth, and erythema in the lower extremity for DVT and those with acute shortness of breath for PE. Discontinue therapy if a venous thromboembolism is suspected. Use in hypogonadal men with thrombophilia is not recommended (Endocrine Society [Bhasin 2018]).

Disease-related concerns:

• Benign prostatic hyperplasia (BPH): Androgens may worsen BPH; use in patients with severe lower urinary tract symptoms ([AUA]/International Prostate Symptom Score [IPSS] >19) is not recommended (Endocrine Society [Bhasin 2018]). Discontinue therapy if urethral obstruction develops in patients with BPH (use lower dose if restarted).
• Depression: Use with caution in patients with depression; testosterone may increase risk of depression and suicidal ideation. Evaluate patients with new onset or worsening depression, anxiety, mood changes, or suicidal ideation or behavior.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including cardiac impairment; testosterone may cause fluid retention. Treatment of androgen deficiency syndromes is not recommended for men with uncontrolled or poorly controlled heart failure (Endocrine Society [Bhasin 2018]).
• Hepatic impairment: Use with caution in patients with hepatic impairment; testosterone may cause fluid retention; testosterone cypionate is contraindicated in serious hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment; testosterone may cause fluid retention; testosterone cypionate is contraindicated in serious renal impairment.
• Sleep apnea: May potentiate sleep apnea in some male patients, especially those with risk factors (eg, obesity or chronic lung disease). Withhold initial treatment in patients with untreated obstructive sleep apnea (Endocrine Society [Bhasin 2018]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Geriatric patients may be at greater risk for prostatic hyperplasia, prostate cancer, fluid retention, and transaminase elevations. Testosterone replacement in patients >65 years of age is not routinely recommended and should only be considered on a case by case basis if conditions or symptoms suggestive of low testosterone are present along with consistently and unequivocally low morning testosterone concentrations (Endocrine Society [Bhasin 2018]).
• Pediatric: May accelerate bone maturation (without producing compensatory gain in linear growth) and premature closure of the epiphyses in children; in prepubertal children perform radiographic examination of the hand and wrist every 6 months to determine the rate of bone maturation and to assess the effect of treatment on the epiphyseal centers. Use with caution in males with delayed puberty. Some formulations/products are not approved for use in patients <18 years of age.
• Women: During treatment for metastatic breast cancer, women should be monitored for signs of virilization; discontinue if mild virilization is present to prevent irreversible symptoms.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Castor oil: Some products may contain castor oil.
• Gel, intranasal: Use of the intranasal gel is not recommended in patients with sinus disease, mucosal inflammatory disorders (eg, Sjogren syndrome), or with a history of nasal disorders, nasal or sinus surgery, nasal fracture within the previous 6 months, or nasal fracture that caused a deviated anterior nasal septum. Safety and efficacy have not been established in males with a BMI >35 kg/m².
• Gel, topical: Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure; these products are not interchangeable.
• Injection: Testosterone cypionate should not be used interchangeably with testosterone propionate due to differences in duration of action.
• Pellet: Pellet insertion has been associated with infection and/or pellet extrusion at or around the implantation site, occurring concurrently or separately. Most reported cases occurred <1 month after implantation. Symptoms may include induration, inflammation, fibrosis, bleeding, bruising, drainage, pain, itching, and pellet extrusion; further treatment may be warranted if infection or extrusion occurs.
• Pulmonary oil microembolism: Testosterone undecanoate injection: [US Boxed Warning]: Serious pulmonary oil microembolism (POME) reactions and anaphylaxis have been reported with testosterone undecanoate injection. Reactions include anaphylaxis, chest pain, urge to cough, dizziness, dyspnea, throat tightening, and syncope; may be life threatening. Reactions may occur after any injection during the course of therapy, including the first dose. Patients must be monitored for 30 minutes after injection. Due to the risk of serious POME reactions, Aveed is only available through the Aveed REMS program. To minimize risk of adverse reactions, inject deeply into gluteal muscle. Rare reports of reactions involving urge to cough, coughing fits, and respiratory distress immediately after the intramuscular injection of testosterone enanthate (an oil-based depot preparation) have also been reported.
• Sesame oil: Some products may contain sesame oil.
• Solution: Axiron is not interchangeable with other topical testosterone products. Use in males with BMI >35 kg/m² has not been established.
• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI.

Other warnings/precautions:

• Abuse/misuse/diversion: Anabolic steroids may be abused, typically at doses higher than recommended and in combination with other anabolic androgenic steroids; abuse may be associated with serious cardiovascular and psychiatric adverse reactions. Inform patients of the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids; if abuse is suspected, check serum testosterone levels (testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives). Consider the possibility of abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.
• Dependence: Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented; however dependence may occur when used outside of approved dosage/indications.
• Secondary exposure: Testosterone may be transferred to another person following skin-to-skin contact with the application site. [US Boxed Warning]: Virilization in children has been reported following contact with unwashed or unclothed application sites of men using topical testosterone. Patients should strictly adhere to instructions for use in order to prevent secondary exposure. Children and women should avoid contact with application sites of men using topical products. Symptoms of virilization generally regress following removal of exposure; however, in some children, enlarged genitalia and bone age did not fully return to age appropriate normal. Signs of inappropriate virilization in women or children following secondary exposure to topical testosterone should be brought to the attention of a healthcare provider.

Monitoring Parameters

Prior to treatment initiation: Confirm hypogonadism by measuring serum total testosterone on at least 2 separate mornings following overnight fasting. Liver function tests, lipid panel, hemoglobin and hematocrit (withhold initial treatment with hematocrit >48% or >50% in males living at higher altitudes) (Endocrine Society [Bhasin 2018]). PSA and prostate exam in men 55 to 69 years of age or ≥40 years of age and at increased risk for prostate cancer (withhold treatment pending urological evaluation in patients with palpable prostate nodule or induration or PSA >4 ng/mL or if PSA >3 ng/mL in men at high risk of prostate cancer (Endocrine Society [Bhasin 2018]); blood pressure.

During treatment:

Blood pressure (3 to 6 weeks after initiation or dosage adjustments, and periodically thereafter), liver function tests, lipid panel, hemoglobin and hematocrit (at 3 to 6 months, at 12 months, then annually); discontinue therapy if hematocrit exceeds 54% (Endocrine Society [Bhasin 2018]). Monitor urine and serum calcium and signs of virilization in women treated for breast cancer. Serum glucose (may be decreased by testosterone, monitor patients with diabetes). Evaluate males for response to treatment and adverse events 3 to 12 months after initiation and then annually; monitor for cardiovascular events closely during therapy.

Bone mineral density:

Prepubertal children: Radiologic examination of wrist and hand every 6 months.

Hypogonadal men with osteoporosis or low trauma fracture: Monitor after 1 to 2 years of therapy (Endocrine Society [Bhasin 2018]).

Prostate-specific antigen (PSA): In men 55 to 69 years of age or ≥40 years of age and at increased risk for prostate cancer, PSA and prostate exam at 3 to 12 months, then as recommended based on current prostate cancer screening guidelines. Withhold treatment pending urological evaluation if there is a confirmed increase in PSA of >1.4 ng/mL from baseline, a confirmed PSA >4.0 ng/mL, or prostatic abnormality or substantial worsening of LUTS (Endocrine Society [Bhasin 2018]).

Testosterone (free): Free testosterone should be measured in patients with conditions associated with increased or decreased SHBG, or in patients with total testosterone concentrations in the borderline zone around the lower limit of the normal range (eg 200 to 400 ng/dL) (Endocrine Society [Bhasin 2018]).

Testosterone (total):

General recommendations: 3 to 6 months after initiation (formulation-dependent), at 12 months, then every 6 to 12 months (AUA [Mulhall 2018]; Endocrine Society [Bhasin 2018]).

Formulation-specific monitoring:

Buccal: Striant: Examine application area of gums; total serum testosterone 4 to 12 weeks after initiating treatment, prior to morning dose. Discontinue therapy if the total serum testosterone is consistently outside of the normal range.

Injection:

Testosterone cypionate injection: Measure testosterone level midway between injections (Endocrine Society [Bhasin 2018]).

Testosterone enanthate IM injection: Measure testosterone level midway between injections (Endocrine Society [Bhasin 2018]).

Testosterone enanthate SubQ injection: Measure total testosterone trough levels after 6 weeks of dosing, after 6 weeks following a dose adjustment, and periodically during therapy. Trough concentrations should be measured 7 days after the most recent dose.

Testosterone undecanoate (Aveed): Monitor for 30 minutes after injection; appropriate treatment should be available in the event of a serious POME reaction or anaphylaxis. Measure testosterone level just prior to each subsequent injection and adjust dosing interval to maintain nadir levels in low-mid range (Endocrine Society [Bhasin 2018]). Alternatively, may measure halfway between each 10-week injection (AUA [Mulhall 2018]).

Intranasal: Natesto: Measure testosterone periodically, beginning 1 month after initiating therapy. Discontinue therapy if the total serum testosterone is consistently outside of the normal range.

Oral capsule: Jatenzo: Measure testosterone 6 hours after the morning dose beginning 7 days after initiation of therapy or after dosage adjustments and then periodically thereafter; 40 mg capsule [Canadian product]: Measure testosterone 5 hours after a dose.

Pellet (for subcutaneous implant): Testopel: Measure testosterone at the end of the dosing interval (Endocrine Society [Bhasin 2018]).

Topical: Note: Serum concentrations may vary substantially with topical gel or solution; single measurements may not consistently correspond to average testosterone levels, and may not adequately guide dosage adjustments (Muram 2016; Swerdloff 2015).

AndroGel 1%: Morning (pre-dose) serum testosterone levels ~14 days after start of therapy or dose adjustments.

AndroGel 1.62%: Morning (pre-dose) serum testosterone levels after 14 and 28 days of starting therapy or dose adjustments and periodically thereafter.

Androderm: Morning serum testosterone levels (following application the previous evening) ~14 days after start of therapy or dose adjustments.

Axiron: Serum testosterone levels can be measured 2 to 8 hours after application and after 14 days of starting therapy or dose adjustments.

Fortesta: Serum testosterone levels can be measured 2 hours after application and after 14 and 35 days of starting therapy or dose adjustments.

Testim: Morning (pre-dose) serum testosterone levels ~14 days after start of therapy or dose adjustments.

Vogelxo: Morning (pre-dose) serum testosterone ~14 days after initiation of therapy.

Hormone therapy in transgender males (female-to-male): Routine cancer and laboratory screening as in non-transgender individuals for all tissues present; serum testosterone levels every 3 months during the first year and then annually or biannually. Ensure testosterone levels remain within normal range for males throughout treatment (320 to 1,000 ng/dL).

Pregnancy

Pregnancy Considerations

Use is contraindicated during pregnancy.

Exposure to a fetus may cause virilization of varying degrees. Because of the potential for secondary exposure, all children and women should avoid skin-to-skin contact to areas where testosterone has been applied topically on another person.

Some products contain benzyl alcohol, which can cross the placenta.

Use may be contraindicated in persons who may become pregnant. Large doses of testosterone may suppress spermatogenesis; the impact on fertility may be irreversible. Treatment of hypogonadotropic hypogonadism is not recommended for men desiring fertility (Endocrine Society [Bhasin 2018]).

Patient Education

What is this drug used for?

• It is used to treat low testosterone levels.
• It is used in certain children when puberty is delayed.
• It is used to treat breast cancer in women.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Acne
• Diarrhea
• Heartburn
• Burping
• Emotional instability
• Loss of strength and energy
• Trouble sleeping
• Sore throat
• Change in taste
• Bad taste
• Back pain
• Application site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High calcium like weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Chest pain
• Cough
• Sweating a lot
• Throat tightness
• Severe headache
• Dizziness
• Passing out
• Vision changes
• Erection that lasts more than 4 hours
• Passing a lot of urine
• Unable to pass urine
• Change in amount of urine passed
• Leaking of urine
• Depression
• Mood changes
• Behavioral changes
• Thoughts of suicide
• Enlarged breasts
• Breast pain
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Nausea
• Vomiting
• Difficulty breathing during sleep
• Day fatigue
• Skin discoloration
• Testicle irregularities
• Nosebleed
• Nasal dryness
• Stuffy nose
• Runny nose
• Nasal scabs
• Sneezing
• Gingival changes
• Virilization like in females a deep voice, facial hair, acne, or menstrual changes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.