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Testosterone: Drug information

Testosterone: Drug information
(For additional information see "Testosterone: Patient drug information" and see "Testosterone: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
REMS Drugs COVID-19 Safety Alert March 2020

Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.

Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.

ALERT: US Boxed Warning
Blood pressure increases (oral testosterone undecanoate; SUBQ testosterone enanthate)

Testosterone undecanoate and testosterone enanthate can cause blood pressure (BP) increases that can increase the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke and cardiovascular death, with greater risk for MACE in patients with cardiovascular risk factors or established cardiovascular disease. Before initiating, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled. Starting approximately 3 weeks (testosterone undecanoate) or 6 weeks (testosterone enanthate) after initiating therapy or changing the dose, periodically monitor for and treat new-onset hypertension or exacerbations of preexisting hypertension and reevaluate whether the benefits of testosterone undecanoate or testosterone enanthate outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease while on treatment. Due to this risk, use oral testosterone undecanoate or subcutaneous testosterone enanthate only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies.

Secondary exposure (transdermal gel, transdermal solution):

Virilization has been reported in children who were secondarily exposed to topical testosterone gel and solution. Children should avoid contact with unwashed or unclothed application sites in men using topical testosterone.

Advise patients to strictly adhere to recommended instructions for use.

Pulmonary oil microembolism (intramuscular testosterone undecanoate):

Serious pulmonary oil microembolism (POME) reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of testosterone undecanoate injection. These reactions can occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose.

Following each injection, observe patients in the health care setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis.

Because of the risks of serious POME reactions and anaphylaxis, testosterone undecanoate is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Aveed REMS Program.

Brand Names: US
  • Androderm;
  • AndroGel;
  • AndroGel Pump;
  • Aveed;
  • Depo-Testosterone;
  • Fortesta;
  • Jatenzo;
  • Kyzatrex;
  • Natesto;
  • Striant [DSC];
  • Testim;
  • Testopel;
  • Tlando;
  • Vogelxo;
  • Vogelxo Pump;
  • Xyosted
Brand Names: Canada
  • Androderm [DSC];
  • AndroGel;
  • Delatestryl;
  • Depo-Testosterone;
  • Natesto;
  • PMS-Testosterone Undecanoate;
  • TARO-Testosterone;
  • TARO-Testosterone Cypionate;
  • Testim
Pharmacologic Category
  • Androgen
Dosing: Adult

Note: Striant (buccal formulation) has been discontinued in the United States for >1 year.

Note: Testosterone enanthate IM formulation and testosterone enanthate SUBQ formulation are not interchangeable. Oral testosterone undecanoate products are not interchangeable.

Hormone therapy for transgender males

Hormone therapy for transgender males (assigned female at birth) (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]).

SUBQ (testosterone enanthate or testosterone cypionate): 50 to 100 mg every week (ES [Hembree 2017]; Spratt 2017).

Topical:

Gel (1% or 1.62%): 50 to 100 mg daily (ES [Hembree 2017]; Tangpricha 2022).

Transdermal system (Androderm): 2 to 8 mg/day (Safer 2019).

Dosage adjustment: May adjust dose after ≥3 months based on clinical response and serum testosterone levels (ES [Hembree 2017]).

Hypogonadism, male

Hypogonadism, male (primary or hypogonadotropic): Initial dosage and usual dosage range are based on dosage form as follows:

Testosterone Dosing Regimens for Male Hypogonadism

Administration route

Preparation

Initial dosage

Usual dosage range

a Striant (buccal formulation) has been discontinued in the United States for >1 year.

b Dosing for this formulation is from the following sources: AUA (Mulhall 2018), ES (Bhasin 2018).

c Canadian product.

dAndroGel 1% may also be applied to the abdomen.

e For the testosterone 1% gel and Vogelxo pump formulations, 1 pump actuation = 12.5 mg.

f Maximum dose according to manufacturers of Testim and Vogelxo.

g For the AndroGel 1.62% pump formulation, 1 pump actuation = 20.25 mg.

h Administer the 6 mg/day dosage as one 2 mg/day patch and one 4 mg/day patch.

Buccal

Buccal system (Striant)a

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

IM

Solution (testosterone enanthate, testosterone cypionate)

75 to 100 mg once weekly or 150 to 200 mg every 2 weeksb

50 to 100 mg once weekly or 100 to 200 mg every 2 weeksb

Solution (testosterone undecanoate)

750 mg; repeat 750 mg dose after 4 weeks, and then every 10 weeks thereafter

Intranasal

Gel (Natesto)

11 mg (2 pump actuations; 1 actuation per nostril) 3 times daily (6 to 8 hours apart)

Oral

Capsule (Jatenzo)

237 mg twice daily

158 to 396 mg twice daily

Capsule (Kyzatrex)

200 mg twice daily

100 mg once daily or 100 to 400 mg twice daily (maximum: 800 mg/day)

Capsule (Tlando)

225 mg twice daily

Capsule (testosterone undecanoate)c

120 to 160 mg/day in 2 divided doses for 2 to 3 weeks

40 to 120 mg/day

SUBQ (injection)

Solution (Xyosted)

75 mg once weekly

50 to 100 mg once weekly

SUBQ (implantation)

Pellet (Testopel)

150 to 450 mg every 3 to 6 months

Topical

1% Gel (eg, AndroGel 1%, Testim, Vogelxo)

50 mg applied once daily in the morning to the shoulders and/or upper armsd,e

50 to 100 mg/day (maximum: 100 mg/day)e,f

1.62% Gel (eg, AndroGel 1.62%)

40.5 mg applied once daily in the morning to the shoulders and upper armsg

20.25 to 81 mg/day (maximum: 81 mg/day)g

2% Gel (eg, Fortesta)

40 mg (4 pump actuations) applied once daily in the morning to the thighs

10 to 70 mg/day (1 to 7 pump actuations) (maximum: 70 mg/day)

Transdermal solution

60 mg (2 pump actuations) applied once daily in the morning to the axillae

30 to 120 mg/day (1 to 4 pump actuations)

Transdermal system (Androderm)

4 mg/day (as one 4 mg/day patch; do not use two 2 mg/day patches)

2 to 6 mg/dayh

Dosage adjustment: Adjust therapy within usual dosage range every 3 to 12 months if needed based on symptoms and testosterone levels; target total testosterone in the midnormal laboratory range (eg, 350 to 600 ng/dL) (AUA [Mulhall 2018]; ES [Bhasin 2018]). Dose adjustment is not necessary if symptoms resolve with testosterone levels below the target range (AUA [Mulhall 2018]).

Dosing conversion for transdermal system (Androderm): The 2.5 and 5 mg/day patches have been discontinued in the United States; 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 patch and one 5 mg/day patch) to 6 mg daily (one 2 mg/day patch 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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). May enhance edema formation. Testosterone cypionate is contraindicated in serious renal disease.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). May enhance edema formation. Testosterone cypionate is contraindicated in serious hepatic disease.

Dosing: Pediatric

(For additional information see "Testosterone: Pediatric drug information")

Note: Striant (buccal formulation) has been discontinued in the United States for >1 year. 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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

All patients: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution; may enhance edema formation. Testosterone cypionate is contraindicated in serious renal disease.

Dosing: Hepatic Impairment: Pediatric

All patients: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution; may enhance edema formation. Testosterone cypionate is contraindicated in serious hepatic disease.

Dosing: Older Adult

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]).

Dosage Forms: US

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)]

Kyzatrex: 100 mg, 150 mg, 200 mg [contains cremophor rh40]

Tlando: 112.5 mg [contains cremophor rh40]

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 [DSC]); 40.5 mg/2.5 g (1.62%) (2.5 g [DSC])

AndroGel: 50 mg/5 g (1%) (5 g [DSC]) [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 [DSC])

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:

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]

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

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

Capsule, Oral, as undecanoate:

Generic: 40 mg

Gel, Nasal:

Natesto: 5.5 mg/actuation (1 ea)

Gel, Transdermal:

AndroGel: 25 mg/2.5 g (1%) (2.5 g); 50 mg/5 g (1%) (5 g); 12.5 mg/actuation (1%) (1.25 g, 2.5 g, 75 g) [contains alcohol, usp]

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

Generic: 25 mg/2.5 g (1%) (2.5 g); 50 mg/5 g (1%) (5 g)

Patch 24 Hour, Transdermal:

Androderm: 2.5 mg/24 hr ([DSC]); 5 mg/24 hr ([DSC]) [contains alcohol, usp]

Solution, Intramuscular, as cypionate:

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

Generic: 100 mg/mL (10 mL)

Solution, Intramuscular, as enanthate:

Delatestryl: 200 mg/mL (5 mL) [contains chlorobutanol (chlorobutol), sesame oil]

Product Availability

Striant (buccal formulation) has been discontinued in the United States for >1 year.

Kyzatrex capsules: FDA approved July 2022; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Kyzatrex is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Consult the prescribing information for additional information.

Controlled Substance

C-III

Administration: Adult

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 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 buccal 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, Kyzatrex, Tlando): Administer once in the morning and once in the evening with meals. In patients taking Kyzatrex once daily, administer in the morning with a meal.

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.

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

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

SUBQ injection (testosterone cypionate, testosterone enanthate) (off-label route):

Hormone therapy for transgender males (assigned female at birth) (off-label use): Administer dose using a 1 mL syringe with a 20- or 25-gauge needle. Administer in the abdomen or thigh (Spratt 2017).

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.

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.

Transdermal solution: 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 ≥2 minutes prior to testosterone. Once application site is dry, cover with clothing. After use, rinse applicator under running water and pat dry with a tissue.

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.

Administration: Pediatric

Parenteral:

IM:

Cypionate, enanthate: Warming injection to room temperature and shaking vial will help redissolve crystals that have formed after storage. Administer by deep IM injection into the gluteal muscle.

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.

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

Topical :

Buccal: Striant: One mucoadhesive for buccal application (buccal system) should be applied to a comfortable area above the incisor tooth. Apply flat side of system on fingertip. Gently push the curved side against upper gum. Rotate to alternate sides of mouth with each application. Hold buccal system firmly in place for 30 seconds to ensure adhesion. The buccal system should adhere to gum for 12 hours. If the buccal system falls out with the first 8 hours of dosing, replace with a new 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 placed and remain for 12 hours, then continue with the next regularly scheduled dose. System will soften and mold to shape of gum as it absorbs moisture from mouth. Do not chew or swallow the buccal system; check to ensure buccal system is in place following toothbrushing, use of mouthwash, and consumption of food or beverages. The buccal system will not dissolve; gently remove by sliding downwards from gum; avoid scratching gum.

Dermal:

Gels and solution: Apply to clean, dry, intact skin. Application sites should be allowed to dry for a few minutes prior to dressing. Hands should be washed with soap and water after application. Do not apply testosterone gel or solution to the genitals. Alcohol-based gels and solutions are flammable; avoid fire 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).

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 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 (eg, 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 ≥2 minutes prior to testosterone. Once application site is dry, cover with clothing. After use, rinse applicator under running water and pat dry with a tissue. The application site and dose of this product are not interchangeable with other topical testosterone products.

Fortesta: Apply to clean, dry, intact skin of front and inner thighs. Do not apply to 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 (eg, 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. The application site and dose of this product are not interchangeable with other topical testosterone products.

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.

Intranasal: 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.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

For IM preparation, double gloves, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator) are recommended. Double gloving and a protective gown are required during IM administration. NIOSH recommends double gloving, a protective gown, and (if liquid that could splash) eye/face protection for administration of a topical product; if there is potential for inhalation, respiratory protection is recommended (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use: Labeled Indications

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

Hypogonadism, male (primary or hypogonadotropic): Buccal; Capsule (oral); Gel (nasal, transdermal); IM injection (cypionate, enanthate, undecanoate); Patch (transdermal); Pellet; Solution (transdermal); SUBQ injection (Xyosted): 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; gonadotropin or luteinizing hormone-releasing hormone deficiency; or pituitary-hypothalamic injury from tumors, trauma, or radiation.

Limitations of use: Safety and efficacy in males with age-related hypogonadism (or late-onset hypogonadism) not associated with structural or genetic etiologies have not been established; some products are specifically contraindicated in this population (varies per manufacturer's labeling). However, the Endocrine Society suggests that testosterone therapy may be offered to patients with symptoms of testosterone deficiency and consistently and unequivocally low morning testosterone concentrations (regardless of etiology). In males >65 years of age, treatment should only be initiated on an individual basis and after consultation with the patient regarding risks and benefits (ES [Bhasin 2018]).

Use: Off-Label: Adult

Hormone therapy for transgender males (assigned female at birth)

Medication Safety Issues
Sound-alike/look-alike issues:

Testosterone may be confused with testolactone

AndroGel 1% may be confused with AndroGel 1.62%

Bio-T-Gel may be confused with T-Gel

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.

Older adult: High-Risk Medication:

Beers Criteria: Testosterone is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to its potential for cardiac problems; use is contraindicated in patients with prostate cancer. Avoid unless testosterone is used for confirmed hypogonadism with clinical symptoms (Beers Criteria [AGS 2019]).

Other safety concerns:

Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.

Adverse Reactions (Significant): Considerations
Breast cancer

Data to clearly establish or quantify a risk of breast cancer with testosterone therapy (TTh) remains elusive; however, it is plausible (Ref). Additionally, upregulation of over 200 genes associated with breast cancer–unique expression was found after 2 years of TTh (Ref). Further studies in the transgender population are needed, but a retrospective study looking at a median exposure duration of 13 years found the breast cancer risk increased toward cisgender female levels during feminizing treatment and the characteristics of breast cancer resembled a female pattern (Ref). Additionally, considerations of risk should be noted in transgender women (ie, BRCA +) (Ref). Medical evidence for reactivation of breast cancer is not found in the literature; however, mastectomy does not negate future risk of cancer development in residual breast tissue (Ref).

Mechanism: Proposed mechanisms include aromatization of testosterone to estrogens in peripheral tissues and the activation of androgen receptors which leads to cellular growth and proliferation, particularly in mammary tissues (Ref).

Onset: Delayed; onset in case reports range from 5 weeks to 15 years (Ref).

Risk factors:

• History of breast cancer (contraindication to initiation of testosterone) (Ref)

• Transmen secondary to inadequate population screening (Ref)

• Klinefelter syndrome (Ref)

Cardiovascular events

Testosterone undecanoate (TU) and testosterone enanthate (TE) may cause or exacerbate hypertension that can increase the risk of major adverse cardiovascular events (MACE). In a study comparing a new oral TU formulation to a testosterone topical product, a mean increase in systolic blood pressure (SBP) of 3 to 5 mmHg was observed with TU while diastolic blood pressure (DBP) was unchanged. No participants discontinued testosterone therapy (TTh) secondary to increase in blood pressure; antihypertensive therapy was initiated in 5.9% of TU participants (Ref). In a retrospective review of 5 years, no significant changes in either SBP or DBP was found with TU or TE (Ref). Available studies are inconclusive regarding the risk of developing MACE, such as nonfatal acute myocardial infarction (MI), ischemic stroke/transient ischemic attacks, or cardiovascular death following testosterone use (Ref). Some studies have suggested an increased risk of cardiovascular events among males prescribed testosterone therapy (Ref); although, the overall evidence does not demonstrate an increased or decreased cardiovascular risk (Ref).

Mechanism: Blood pressure increases: Not clearly established; potentially secondary to fluid retention and peripheral edema. Increase in edema may be associated with heart failure or other edematous states (Ref). Trends in SBP increases have not been linked to any specific mechanism (Ref).

Onset: Cardiovascular events: Delayed; one study demonstrated the highest risk in the first 6 months to 2 years of continuous use (Ref).

Risk factors:

• Blood pressure increases:

- History of hypertension/taking antihypertensive medication (Ref)

- History or current treatment of edematous states (Ref)

- Preexisting diabetes mellitus

• Cardiovascular events:

- History of cardiovascular disease (avoid use in patients with a history of MI or stroke in the last 6 months) (Ref)

- Presence of cardiovascular disease risk factors (eg, edematous states, hypertension) (Ref)

Hepatotoxicity

Hepatic effects and hepatotoxicity, including abnormal hepatic function tests, cholestasis, jaundice, nodular regeneration, chronic vascular injury (peliosis hepatitis), hepatic adenoma, and hepatocellular neoplasm, have been limited to oral alkylated testosterone (eg, methyltestosterone) (Ref). Although the development of these events is ~1% (Ref), methyltestosterone should not be used in clinical practice secondary to the detrimental hepatic effects (Ref). Oral testosterone undecanoate has not been associated with clinically significant liver changes as it is predominately absorbed through the intestinal lymphatic system rather the liver. Furthermore, the small number of patients that experienced an increase in AST or ALT had transient changes <2 x ULN that returned to baseline with continued treatment (Ref).

Mechanism: Time-related; idiosyncratic. Androgens may stimulate genes that are important in cell growth and development, as well as decrease bile salt transporter proteins (Ref).

Onset: Delayed; most adenomas occur with long-term use (5 to 15 years), but changes may occur within 2 years of therapy initiation (Ref).

Risk factors:

• Long-term use (Ref)

• Risk factors for liver disease (ie, Fanconi syndrome, iron overload, chronic hepatitis C) (Ref)

• Oral products that do not bypass the liver (methyltestosterone) (Ref)

Polycythemia/erythrocytosis

Testosterone therapy (TTh) has been associated with polycythemia/erythrocytosis, especially during the first year of therapy. The resulting increased hematocrit or increased hemoglobin increases blood viscosity and platelet adhesiveness and decreases venous return which are potential risks for thromboembolic events and/or ischemic sequelae (Ref). Increases in hemoglobin of 5% to 7% have been observed (Ref). Baseline hematocrit value >50% is a contraindication to TTh, while values >54% are an indication to discontinue therapy (Ref).

Mechanism: Exact mechanism unknown; however, several hypotheses have been cited including the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors (Ref).

Onset: Delayed; dependent upon formulation and pharmacokinetics. Increases in hemoglobin/hematocrit have occurred as early as 1 month after TTh initiation and are most often observed within 1 year of initiation (Ref).

Risk factors:

• Males 60 to 75 years of age (Ref)

• Short-acting IM formulation (Ref)

Prostate cancer

Testosterone therapy (TTh) may increase the risk for benign prostatic hypertrophy (BPH) and/or prostate carcinoma; however, evidence is conflicting (Ref).

Risk factors:

• BPH:

- Severe (AUA/International Prostate Symptom Score >19) lower urinary tract symptoms (contraindicated) (Ref)

• Prostate cancer (withhold therapy pending urological evaluation):

- Palpable prostate nodule or induration (Ref)

- PSA >4 ng/mL (Ref)

- PSA >3 ng/mL in patients at high risk of prostate cancer (Ref)

Pulmonary oil microembolism

Intramuscular injection of testosterone undecanoate (TU) has been associated with pulmonary oil microembolism (POME) (Ref). The current US annual spontaneously reported adverse event rate for POME is <0.1%. Most events (95%) resolved; 76% resolved in ≤30 minutes. Furthermore, >60% had spontaneous resolution that required no medical intervention (Ref). Older observational data suggest the rate may be as high as 2.1% (Ref). Cough is the consistent symptom with increase blood pressure and heart rate, diaphoresis, red eyes, and “asthma-like symptoms” also reported (Ref). TU is only available under the Aveed Risk Evaluation and Mitigation Strategies Program (REMS). Subcutaneous injection with oil-based testosterone enanthate and cypionate in transgender patients did not report any POME events (Ref).

Mechanism: Non–dose-related; occurs due to oil vehicle delivery into venous circulation (Ref).

Onset: Rapid; within 1 hour (most reports observed coughing within minutes of injection). POME is independent of duration of therapy, as events have been association with the initial injection and subsequent injections (Ref).

Risk factors:

• Oil-based formulations (Ref)

• IM route (Ref)

• Respiratory hypersensitivity (Ref)

• Incorrect injection technique (Ref)

Secondary exposure

When using topical preparations of testosterone, there is risk of transfer (secondary) exposure of testosterone (Ref). Secondary exposure has resulted in virilization of females, children (Ref), and fetuses (Ref). Degree of signs and symptoms are variable but may include acne vulgaris or irregular menses in females, precocious puberty in children (Ref), and clitoromegaly in fetuses (Ref). Of note, the fetal genitalia appear to be more susceptible to testosterone effects rather than the skeletal system (Patel 2010). Secondary exposure signs and symptoms regress when exposure is discontinued, but return to baseline is not absolute (Ref).

Mechanism: Non–dose-related; contact with site of topically applied testosterone to unintended recipient (Ref).

Risk factors:

• Topical testosterone formulations (Ref)

Venous thromboembolism

An established correlation between testosterone therapy and venous thromboembolism (VTE) including deep vein thrombosis and pulmonary embolism, are conflicting; data from randomized, placebo-controlled trials with VTE as a primary endpoint are lacking. A large case-crossover study showed increased risk of VTE with short-term therapy (<3 months) (Ref), while two other large observational studies (Ref) had conflicting conclusions. In a study with 67 females on testosterone therapy, there was an increased risk of VTE (Ref).

Mechanism: Non–dose-related; elevated hematocrit levels may increase viscosity, platelet accumulation, and thromboxane A2 concentration (Ref). However, there are case reports of VTE without elevated hematocrit levels (Ref).

Onset: Delayed; the highest risk for development of VTE appears to be within the first 3 months of therapy initiation (Ref). However, in another study, the median time to development of VTE was 6 months and was equated to the risk of VTE in females taking hormone replacement therapy, where the risk is highest in the first year of therapy (Ref).

Risk factors:

• Thrombophilia (contraindication) (Ref)

• Prior thrombotic event (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Hypertension (including exacerbation of hypertension: ≤13%) (table 1)

Testosterone: Adverse Reaction: Hypertension

Drug (Testosterone)

Placebo

Dose

Dosage Form

Number of Patients (Testosterone)

Number of Patients (Placebo)

13%

N/A

75 mg weekly, then titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/d

SUBQ injection

150

N/A

5%

N/A

225 mg daily

Oral capsule

138

N/A

4%

N/A

237 mg twice daily, then titrated to 158 mg, 198 mg, 316 mg, or 396 mg twice daily to achieve testosterone concentrations in the eugonadal range

Oral capsule

166

N/A

3%

N/A

50 mg

1% topical gel

77

N/A

3%

N/A

100 mg

1% topical gel

78

N/A

2%

0%

N/A

1.62% topical gel

234

40

2%

N/A

100 mg daily to 400 mg twice daily

Oral capsule

155

N/A

1%

N/A

N/A

Buccal

117

N/A

0%

N/A

75 mg

1% topical gel

40

N/A

Dermatologic: Skin blister (application site: 12%)

Genitourinary: Prostate specific antigen increase (1% to 18%) (table 2)

Testosterone: Adverse Reaction: Prostate Specific Antigen Increase

Drug (Testosterone)

Placebo

Dose

Dosage Form

Number of Patients (Testosterone)

Number of Patients (Placebo)

Comments

18%

N/A

N/A

1% topical gel

162

N/A

N/A

12%

N/A

75 mg weekly, then titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/d

SUBQ injection

150

N/A

N/A

11%

0%

N/A

1.62% topical gel

234

40

N/A

6%

N/A

11 mg three times daily

Nasal gel

69

N/A

N/A

5%

N/A

750 mg at initiation, at 4 weeks, and every 10 weeks thereafter

Intramuscular injection

153

N/A

N/A

3%

N/A

100 mg daily to 400 mg twice daily

Oral capsule

155

N/A

Prostate specific antigen increase >1.4 ng/mL

3%

N/A

75 mg weekly, then titrated to 50 mg or 100 mg weekly, as needed, to achieve pre-dose total testosterone concentrations of ≥350 ng/dL and <650 ng/d

SUBQ injection

133

N/A

N/A

2%

N/A

237 mg twice daily, then titrated to 158 mg, 198 mg, 316 mg, or 396 mg twice daily to achieve testosterone concentrations in the eugonadal range

Oral capsule

161

N/A

N/A

2%

N/A

N/A

Buccal

117

N/A

N/A

1%

N/A

100 mg daily to 400 mg twice daily

Oral capsule

155

N/A

Prostate specific antigen increase >4 ng/mL

1%

N/A

N/A

Topical gel

149

N/A

N/A

Hematologic & oncologic: Increased hematocrit (1% to 14%)

Local: Application-site pruritus (37%)

1% to 10%:

Cardiovascular: Peripheral edema (3%), peripheral vascular disease

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

Endocrine & metabolic: Decreased HDL cholesterol (3%), decreased libido (1% to 3%), gynecomastia (1% to 3%), hot flash (1%), increased plasma estradiol concentration (3%), increased serum prolactin (6%), increased thyroid stimulating hormone level, weight gain (1% to 2%)

Gastrointestinal: Abdominal pain (2%), ageusia (buccal: 1%), bitter taste (buccal: 4%), decreased appetite, diarrhea (3% to 4%), dysgeusia (<3%), dyspepsia (>2%), eructation (>2%), gastric ulcer with hemorrhage (1%), gastroesophageal reflux disease, gastrointestinal hemorrhage, gingival pain (buccal: 3%; includes gingival tenderness), gingival swelling (buccal: 2%), gingivitis (buccal: ≤9%), increased appetite (≤3%), nausea (≤2%), oral irritation (buccal: ≤9%), oral mucosa changes (buccal; includes buccal mucosa roughening and gum blister: 1%), toothache (buccal: ≤1%), vomiting (3% to 4%)

Genitourinary: Benign prostatic hypertrophy (≤2%), breast hypertrophy (1%), difficulty in micturition (1%), dysuria, ejaculatory disorder (1%), hematuria (2%), impotence (<3%), mastalgia (1% to 3%), pelvic pain, prostate carcinoma (1%), prostate induration (1%), prostatic disease (3% to 5%), prostatitis (3%), spontaneous erections (1%), testicular atrophy, testicular disease (including testicular tenderness and non-palpable testes: 3%), urinary frequency (≤2%), urinary incontinence, urinary tract infection (3%)

Hematologic & oncologic: Anemia (3%), increased hemoglobin (1% to 5%), polycythemia (≤3%)

Hepatic: Abnormal hepatic function tests (1%), increased serum bilirubin (≤6%)

Local: Application-site burning (1% to 3%), application-site edema (1%), application-site erythema (5% to 7%), application-site induration (3%), application-site irritation (7% to 8%), application-site rash, application-site vesicles (6%), bleeding at injection site (3% to 6%), bruising at injection site (4% to 7%), erythema at injection site (1% to 3%), local skin exfoliation (application site), pain at injection site (5%)

Nervous system: Abnormal dreams (1%), abnormality in thinking, aggressive behavior (1%), altered sense of smell (1% to 6%), anosmia, anxiety (1%), asthenia (≤3%), body pain, chills, confusion, depression (≤3%), emotional lability (≤3%), fatigue (1% to 2%), headache (1% to 6%), insomnia (1% to 2%), irritability (2%), nervousness (1% to 3%), outbursts of anger (1%), paresthesia, stinging sensation (lips; buccal: 1%), vertigo

Neuromuscular & skeletal: Abnormal bone growth, arthralgia (≤2%), back pain (3%), hemarthrosis, increased creatine phosphokinase in blood specimen (3% to 4%), limb pain (4%), musculoskeletal pain (2%)

Renal: Polyuria

Respiratory: Bronchitis (intranasal: 4%), cough (2% to 3%), dry nose (intranasal: 2% to 4%), epistaxis (intranasal: 4% to 7%), nasal congestion (intranasal: 2% to 4%), nasal discomfort (intranasal: 4% to 6%), nasal mucosa swelling (buccal: 1%), nasopharyngitis (1% to 9%), rhinorrhea (intranasal: 4% to 8%), sinusitis (4%), sleep apnea (2%), upper respiratory tract infection (4%)

<1%:

Dermatologic: Folliculitis

Gastrointestinal: Gingival erythema, oral inflammation, stomatitis, xerostomia

Genitourinary: Breast tenderness, nipple tenderness (sensitivity)

Hematologic & oncologic: Prolonged partial thromboplastin time, prolonged prothrombin time

Hypersensitivity: Anaphylaxis

Infection: Infection

Nervous system: Suicidal ideation, suicidal tendencies

Neuromuscular & skeletal: Myalgia

Ophthalmic: Increased lacrimation

Renal: Increased serum creatinine

Frequency not defined:

Dermatologic: Lip blister (ulceration)

Endocrine: Hyperlipidemia

Gastrointestinal: Constipation, decreased gastrointestinal motility, gingival recession

Hematologic & oncologic: Petechia

Hepatic: Hepatic adenoma

Local: Induration at injection site

Nervous system: Dizziness, hostility

Miscellaneous: Fever

Postmarketing:

Cardiovascular: Acute myocardial infarction (Loo 2019), angina pectoris, chest pain, circulatory shock, coronary artery disease, coronary occlusion, deep vein thrombosis, edema, heart failure, peripheral venous insufficiency, pulmonary embolism (including pulmonary oil microembolism [POME]) (Pastuszak 2020), syncope, tachycardia, thromboembolism, thrombosis, vasodilation, venous thromboembolism

Dermatologic: Allergic dermatitis, androgenetic alopecia (Griggs 2018), diaphoresis, hair discoloration, papular rash, wound secretion

Endocrine & metabolic: Calcium retention, change in HDL, diabetes mellitus, electrolyte disorder (calcium, chloride, nitrogen, phosphorus, potassium, sodium), fluid retention, hirsutism, hyperparathyroidism, hypertriglyceridemia, hypoglycemia, increased libido, increased serum glucose, inorganic phosphate retention, potassium retention, sodium retention

Gastrointestinal: Cholestasis (LiverTox 2012), mesenteric ischemia (portal vein thrombosis, mesenteric venous occlusion) (Poirier-Blanchette 2021), oral mucosa ulcer, upper abdominal pain

Genitourinary: Azoospermia (Jan 2012), breast induration, erectile dysfunction, frequent erections, genitourinary infection (prostate), malignant neoplasm of prostate, oligospermia, orgasm disturbance (male), pollakiuria, priapism (Ichioka 2006), prostatic intraepithelial neoplasia, spermatocele, testicular pain, virilization (in children secondarily exposed to topical testosterone)

Hematologic & oncologic: Clotting factors suppression (factors II, V, VII, X), thrombocytopenia

Hepatic: Cholestatic jaundice, hepatocellular neoplasm (LiverTox 2012), hepatotoxicity (idiosyncratic; Chalasani 2021), increased gamma-glutamyl transferase, jaundice (LiverTox 2012), peliosis hepatitis (LiverTox 2012)

Hypersensitivity: Anaphylactic shock, angioedema, hypersensitivity angiitis, lip edema, nonimmune anaphylaxis

Local: Abscess at injection site, discomfort at injection site, fibrosis at injection site, hematoma at injection site, inflammation at injection site, injection-site infection (cellulitis), irritation at injection site

Nervous system: Amnesia, cerebral infarction, cerebrovascular accident, cerebrovascular insufficiency, drug abuse, ischemic stroke (Loo 2019), Korsakoff syndrome (nonalcoholic), malaise, migraine, restlessness, reversible ischemic neurological deficit, sleep disorder, transient ischemic attacks (Loo 2019), voice disorder

Neuromuscular & skeletal: Musculoskeletal chest pain, osteoporosis, systemic lupus erythematosus

Ophthalmic: Increased intraocular pressure, retinopathy (central serous chorioretinopathy) (Grieshaber 2007), vitreous detachment

Otic: Hearing loss (sudden) (Tikka 2016), tinnitus

Renal: Nephrolithiasis, renal colic, renal pain

Respiratory: Asthma, chronic obstructive pulmonary disease, dyspnea, flu-like symptoms, hyperventilation, pharyngeal edema, pharyngolaryngeal pain, respiratory distress, rhinitis, snoring

Contraindications

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

Natesto, Striant, transdermal solution: Additional contraindications: Breastfeeding patients; patients who may become pregnant.

Aveed: Additional contraindications: Hypersensitivity to testosterone undecanoate, castor oil, benzyl benzoate.

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; patients who may become pregnant.

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

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

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

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.

Warnings/Precautions

Concerns related to adverse effects:

• Hypercalcemia: May cause hypercalcemia in patients with prolonged immobilization or cancer.

Disease-related concerns:

• 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.

• 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 patients, especially those with risk factors (eg, obesity or chronic lung disease). Withhold initial treatment in patients with untreated obstructive sleep apnea (ES [Bhasin 2018]).

Special populations:

• Older adults: Patients >65 years of age 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 (ES [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.

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 patients 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.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer’s labeling.

• Sesame oil: Some products may contain sesame oil.

• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI.

• Transdermal solution: Transdermal solution is not interchangeable with other topical testosterone products. Use in patients with BMI >35 kg/m2 has not been established.

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 males 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.

Warnings: Additional Pediatric Considerations

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Shehab 2009).

Metabolism/Transport Effects

Substrate of CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Agents with Blood Glucose Lowering Effects: Androgens may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

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

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

CycloSPORINE (Systemic): Androgens may enhance the hepatotoxic effect of CycloSPORINE (Systemic). Androgens may increase the serum concentration of CycloSPORINE (Systemic). Management: Consider avoiding concomitant use of androgens and cyclosporine. If concomitant use is unavoidable, monitor serum cyclosporine concentrations and for signs and symptoms of hepatotoxicity. Cyclosporine dose reductions may be required. Risk D: Consider therapy modification

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

Hypertension-Associated Agents: May enhance the hypertensive effect of Androgens. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Androgens may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Monitor for increased effects of vitamin K antagonists if an androgen is initiated/dose increased, or decreased effects if androgen is discontinued/dose decreased. Significant reductions in vitamin K antagonist dose are likely required. Risk D: Consider therapy modification

Reproductive Considerations

Use of some products is 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 with testosterone is not recommended for males desiring fertility within 6 to 12 months (ES [Bhasin 2018]).

Testosterone is a component of therapy for transgender males. Menstruation may be suppressed but ovulation may occur. Although treatment may cause temporary or permanent infertility, unintended pregnancies have been reported. Consider contraception in transgender males having sex with males. Successful planned pregnancies have been reported following cessation of testosterone therapy (ACOG 2021; Cheung 2019; ES [Hembree 2017]; Light 2014; Taub 2020). All available forms of contraception can be considered for patients receiving gender affirming testosterone therapy after evaluating the appropriateness of the method based on patient preferences and medical conditions (Bonnington 2020; Krempasky 2020).

Abuse of anabolic steroids may cause irregular menstruation and female infertility (ACOG 2011).

Testosterone has been evaluated for the treatment of hypoactive sexual desire disorder, primarily in postmenopausal patients. There are no FDA-approved formulations available for this indication. Transdermal products at 1% of the male dose may be an option in patients diagnosed following a formal biopsychosocial assessment, however robust long-term (>24 months) safety data are not available. Compounded testosterone products or off label use of pellets, IM injection and oral formulations is not recommended. Additional study is needed (Parish 2021).

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 persons 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.

Breastfeeding Considerations

Testosterone is present in breast milk.

Information related to the presence of testosterone in breast milk is available from case reports:

- Distribution of testosterone in breast milk was evaluated following use of the subcutaneous pellet in a breastfeeding woman. Prior to therapy, milk concentrations of testosterone were 96 pg/mL. Following SubQ implantation of the 100 mg pellet, milk samples ranged from 88 pg/mL (day 2) to 100 pg/mL (day 7 [morning]). Reported maternal serum samples ranged from <100 pg/mL (baseline), 2,830 pg/mL (day 2), and 1,480 pg/mL (day 7 [morning]). Adverse events were not observed in the breastfeeding male infant after 7 months of continuous maternal therapy (Glaser 2009).

- A case report describes milk concentrations of testosterone in a lactating male who initiated gender affirming testosterone therapy when the infant was 13 months of age. SUBQ testosterone cypionate 50 mcg was administered weekly; milk and infant serum testosterone were measured prior to the first dose and over the first month of therapy. Milk concentrations were 0.462 ng/dL (baseline), 20.85 ng/dL (14 days after therapy initiated), and 12.36 ng/dL (28 days after the first dose of testosterone). Infant serum concentrations were <7 ng/dL at all time points. In comparison, the total testosterone concentration in the parent serum were 14 ng/dL at baseline and increased to 430 ng/dL after 28 days. It was not stated how much milk was ingested by the infant (Oberhelm 2020).

Because of the potential for secondary exposure, all persons should avoid skin-to-skin contact to areas where testosterone has been applied topically on another person.

High levels of endogenous maternal testosterone, such as those caused by certain ovarian cysts, suppress milk production. Maternal serum testosterone levels generally fall following pregnancy and return to normal once breastfeeding is stopped (Betzold 2004; Hoover 2002). Some products are specifically contraindicated while breastfeeding. Because testosterone may suppress milk production, reinitiating treatment in transgender males after pregnancy is not recommended until chestfeeding is complete (ACOG 2021).

Monitoring Parameters

Prior to treatment initiation: Confirm hypogonadism by measuring serum total testosterone on at least 2 separate mornings following overnight fasting. LFTs, lipid panel, hemoglobin and hematocrit (withhold initial treatment with hematocrit >48% or >50% in males living at higher altitudes) (ES [Bhasin 2018]). Evaluate cardiovascular risk factors. PSA and prostate exam in males 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 males at high risk of prostate cancer (ES [Bhasin 2018]); BP.

During treatment:

BP (3 to 6 weeks after initiation or dosage adjustments, and periodically thereafter), LFTs, lipid panel, hemoglobin and hematocrit (at 3 to 6 months, at 12 months, then annually); discontinue therapy if hematocrit exceeds 54% (ES [Bhasin 2018]). Monitor urine and serum calcium and signs of virilization in females 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. Monitor for symptoms of pain, edema, warmth, and erythema in the lower extremity (evaluate for deep vein thrombosis) and acute shortness of breath (evaluate for pulmonary embolism).

Bone mineral density:

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

Males with hypogonadism and osteoporosis or low trauma fracture: Monitor after 1 to 2 years of therapy (ES [Bhasin 2018]).

Prostate-specific antigen (PSA): In males 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 (ES [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) (ES [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]; ES [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, testosterone enanthate IM injection: Measure testosterone level midway between injections (ES [Bhasin 2018]).

Testosterone enanthate SUBQ injection (Xyosted): 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 (ES [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.

Kyzatrex: Measure testosterone 3 to 5 hours after morning dose beginning 7 days after initiating therapy or after dosage adjustments and then periodically thereafter.

Tlando: Measure testosterone 8 to 9 hours after morning dose beginning 3 to 4 weeks after initiating therapy and periodically thereafter. Discontinue therapy if total serum testosterone is consistently outside the normal range.

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 (ES [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.

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.

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

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

Hormone therapy for transgender males (assigned female at birth) (off-label use): Routine cancer and laboratory screening as in nontransgender 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 (eg, 320 to 1,000 ng/dL) (ES [Hembree 2017]).

Reference Range

Total testosterone normal reference range for males (CDC-certified labs) (Travison 2017):

2.5th and 97.5th percentile: 264 to 916 ng/dL

5th and 95th percentile: 303 to 852 ng/dL

Note: Due to diurnal fluctuations, diagnostic measurements should be obtained on at least 2 separate mornings while patient is fasting. Results from laboratories that are not CDC certified or otherwise standardized according to an accuracy-based quality control program may vary considerably (ES [Bhasin 2018]).

Total testosterone therapeutic goal: 350 to 600 ng/dL (midnormal range for most labs) is a reasonable target for most patients on testosterone therapy to minimize potential for over- or under-treatment (AUA [Mulhall 2018]; ES [Bhasin 2018]). 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]).

Free testosterone: The normal free testosterone reference range varies by laboratory and a CDC harmonized standard has not yet been established; therefore, the Endocrine Society recommends referring to ranges established within each local laboratory (ES [Bhasin 2018]).

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

Duration (route and ester dependent): IM: Cypionate and enanthate esters: 2 to 4 weeks; Undecanoate: 10 weeks; Transdermal gel: 24 hours.

Absorption: Transdermal gel: ~10% of applied dose.

Protein binding: 98%; bound to sex hormone-binding globulin (40%) and albumin.

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

Bioavailability: Oral capsule: Jatenzo: Absolute bioavailability not reported; relative bioavailability decreased 25% when taken with lower fat content meal (eg, 15 g) versus higher fat content meal (eg, ≥30 g); Tlando: Absolute bioavailability not reported; administration in fasting conditions resulted in approximately 65% lower Cmax and 38% lower AUC compared to administration with food (high fat meal); 40 mg capsule [Canadian product]: ~7% (absolute bioavailability).

Half-life elimination: Variable: 10 to 100 minutes; Testosterone cypionate: ~8 days.

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; Kyzatrex: ~4 hours; Tlando: ~5 hours; 40 mg capsule [Canadian product]: 4 to 5 hours; SUBQ (Xyosted): 11.9 hours (median; range: 5.8 to 168.7 hours) following weekly administration for 12 weeks.

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

Pricing: US

Capsules (Jatenzo Oral)

158 mg (per each): $9.63

198 mg (per each): $9.63

237 mg (per each): $19.25

Capsules (Kyzatrex Oral)

100 mg (per each): $2.00

150 mg (per each): $2.00

200 mg (per each): $2.00

Capsules (Tlando Oral)

112.5 mg (per each): $6.95

Gel (AndroGel Pump Transdermal)

20.25 MG/ACT (1.62%) (per gram): $9.94

Gel (AndroGel Transdermal)

25 MG/2.5GM (1%) (per gram): $9.97

Gel (Fortesta Transdermal)

10 MG/ACT (2%) (per gram): $8.28

Gel (Natesto Nasal)

5.5 mg/ACT (per gram): $45.10

Gel (Testim Transdermal)

50 MG/5GM (1%) (per gram): $4.74

Gel (Testosterone Transdermal)

10 MG/ACT (2%) (per gram): $6.83 - $7.87

12.5 MG/ACT (1%) (per gram): $2.75 - $3.00

20.25 MG/ACT (1.62%) (per gram): $1.42 - $9.44

20.25 MG/1.25GM (1.62%) (per gram): $10.75 - $18.94

25 MG/2.5GM (1%) (per gram): $5.83

40.5 MG/2.5GM (1.62%) (per gram): $5.81 - $9.74

50 MG/5GM (1%) (per gram): $2.75 - $3.88

Gel (Vogelxo Pump Transdermal)

12.5 MG/ACT (1%) (per gram): $3.56

Gel (Vogelxo Transdermal)

50 MG/5GM (1%) (per gram): $3.56

Patch, 24-hour (Androderm Transdermal)

2 mg/24 hrs (per each): $12.32

4 mg/24 hrs (per each): $24.64

Pellet (Testopel Implant)

75 mg (per each): $129.82

Solution (Aveed Intramuscular)

750 mg/3 mL (per mL): $623.04

Solution (Depo-Testosterone Intramuscular)

100 mg/mL (per mL): $9.26

200 mg/mL (per mL): $25.20

Solution (Testosterone Cypionate Intramuscular)

100 mg/mL (per mL): $5.91 - $8.98

200 mg/mL (per mL): $21.60 - $67.50

Solution (Testosterone Enanthate Intramuscular)

200 mg/mL (per mL): $17.93

Solution (Testosterone Transdermal)

30 mg/ACT (per mL): $3.37 - $6.88

Solution Auto-injector (Xyosted Subcutaneous)

50 mg/0.5 mL (per 0.5 mL): $173.21

75 mg/0.5 mL (per 0.5 mL): $173.21

100 mg/0.5 mL (per 0.5 mL): $173.21

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Andriol (EG, MX, UA);
  • Androderm (AU, BB, NZ);
  • AndroForte (AU);
  • Androgel (AE, BE, BH, CU, CZ, EE, FR, HK, HN, HU, IT, LB, MY, NL, PL, RU, SA, SG, TH, TW, UA, VN);
  • Andromen (EG);
  • Andropatch (GR);
  • Aquaviron (IN);
  • Axiron (AU);
  • Depo-Test (TH);
  • Depo-Testosterone (BB, ZA);
  • Hormon-M (TW);
  • Intrinsa Patch (IE);
  • Itnogen (ES);
  • Jenasteron (KR);
  • Nebido (AT, BE, BG, BH, DE, DK, EE, EG, FR, HK, HR, HU, ID, IE, IL, IS, KW, LB, LT, LU, LV, MY, NL, NO, PL, QA, RO, UA, VN);
  • Omnadren (PL, UA);
  • Primoteston Depot (AU, BF, BJ, CI, EC, ET, GH, GM, GN, KE, KR, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);
  • Primotestone Depot (AE);
  • Proviron Depot (VE);
  • Reandron (ES);
  • Sustanon (BH, JO, SA);
  • Testex (ES);
  • Testim (BE, DK, ES, GB, HU, IE, IS, LU, LV, MT, NO, PL, SI, SK);
  • Testocaps (LU);
  • Testoderm (AT);
  • Testogel (BG, DK, IE, IS, TR);
  • Testom (RO);
  • Testopatch (FR);
  • Testosteron Ferring (AT);
  • Testosteronum propionicum (PL);
  • Testotop (LU);
  • Testoviron (CY, JO, PK, SI, TR);
  • Testoviron Depot (HK, LK, QA, SA);
  • Testoviron-Depot (AR, CH, CO, DE, IL, PE, PT, PY, SE, UY);
  • Tostran (GB, IE);
  • Tostrex (ID);
  • Tostrex Gel (KR);
  • Virormone (AE, BH, CY, IQ, IR, JO, LY, OM, SA, SY, YE);
  • Vivrone (PH);
  • Y45 (BD)


For country abbreviations used in Lexicomp (show table)
  1. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767. [PubMed 30693946]
  2. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]
  3. American College of Obstetricians and Gynecologists (ACOG) Committee on Gynecologic Practice and Committee on Health Care for Underserved Women. ACOG Committee Opinion No. 823: Health care for transgender and gender diverse individuals. Obstet Gynecol. 2021;137(3):e75-e88. doi:10.1097/AOG.0000000000004294 [PubMed 33595253]
  4. American College of Obstetricians and Gynecologists (ACOG) Committee on Gynecologic Practice. ACOG Committee Opinion No. 484: Performance enhancing anabolic steroid abuse in women. Obstet Gynecol. 2011;117(4):1016-1018. doi:10.1097/AOG.0b013e3182192281 [PubMed 21422881]
  5. American Urological Association (AUA). AUA Position statement on testosterone therapy. 2014. Available at https://www.auanet.org/guidelines/archived-documents/testosterone-therapy [PubMed AUA.1]
  6. Androderm (testosterone transdermal system) [prescribing information]. Madison, NJ: Allergan USA Inc; May 2020.
  7. Androderm (testosterone transdermal system) [product monograph]. Markham, Ontario, Canada: Allergan Inc; February 2018.
  8. AndroGel 1% (testosterone) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2019.
  9. AndroGel 1.62% (testosterone) [prescribing information]. North Chicago, IL: AbbVie Inc; November 2020.
  10. Aveed (testosterone undecanoate) [prescribing information]. Malvern, PA: Endo Pharmaceuticals Inc; August 2021.
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