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Testosterone

Pronunciation

Pronunciation

(tes TOS ter one)

Index Terms

  • Delatestryl
  • Testosterone Cypionate
  • Testosterone Enanthate
  • Testosterone Undecanoate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Cream, Transdermal:

First-Testosterone MC: 2% (60 g) [contains benzyl alcohol, sesame oil]

Gel, Nasal:

Natesto: 5.5 mg/actuation (7.32 g)

Gel, Transdermal:

AndroGel: 25 mg/2.5 g (1%) (2.5 g); 50 mg/5 g (1%) (5 g); 20.25 mg/1.25 g (1.62%) (1.25 g); 40.5 mg/2.5 g (1.62%) (2.5 g) [contains alcohol, usp]

AndroGel Pump: 12.5 mg/actuation (1%) (75 g); 20.25 mg/actuation (1.62%) (75 g) [contains alcohol, usp]

Fortesta: 10 mg/actuation (2%) (60 g) [odorless; 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); 50 mg/5 g (1%) (5 g); 10 mg/actuation (2%) (60 g); 12.5 mg/actuation (1%) (75 g); 50 MG/5GM (1%) (5 g)

Miscellaneous, Buccal:

Striant: 30 mg (60 ea)

Ointment, Transdermal:

First-Testosterone: 2% (60 g) [contains benzyl alcohol, butylated hydroxytoluene (bht), petrolatum, sesame oil]

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)

Pellet, Implant [preservative free]:

Generic: 12.5 mg (1 ea); 25 mg (1 ea); 37.5 mg (1 ea); 50 mg (1 ea)

Solution, Transdermal:

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

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)]

Brand Names: U.S.

  • Androderm
  • AndroGel
  • AndroGel Pump
  • Aveed
  • Axiron
  • Depo - Testosterone
  • First - Testosterone
  • First - Testosterone MC
  • Fortesta
  • Natesto
  • Striant
  • Testim
  • Testopel
  • Vogelxo
  • Vogelxo Pump

Pharmacologic Category

  • Androgen

Pharmacology

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

Absorption

Transdermal gel: ~10% of applied dose

Metabolism

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

Excretion

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

Time to Peak

IM undecanoate: 7 days (median; range: 4 to 42 days); Intranasal: ~40 minutes; Transdermal system: 8 hours (range: 4 to 12 hours); Buccal system: 10 to 12 hours; Oral capsule [Canadian product]: 4 to 5 hours

Duration of Action

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

Half-Life Elimination

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

Protein Binding

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

Use: Labeled Indications

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

Delayed puberty: Injection (enanthate); pellet: Androgen replacement in carefully selected males with delayed puberty. Generally observed in males with a familial pattern of delayed puberty; not secondary to a pathological disorder.

Hypogonadism, hypogonadotropic (congenital or acquired): Buccal; Gel (nasal, transdermal); Injection (cypionate, enanthate, undecanoate); Patch (transdermal); Pellet; Solution (transdermal): Gonadotropin or luteinizing hormone-releasing hormone deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation. Generally observed in men with low serum testosterone and gonadotropins in the normal or low range.

Hypogonadism, primary (congenital or acquired): Buccal; Gel (nasal, transdermal); Injection (cypionate, enanthate, undecanoate); Patch (transdermal); Pellet; Solution (transdermal): 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. Generally observed in men with low serum testosterone and gonadotropins (follicle-stimulating hormone, luteinizing hormone) above the normal range.

Replacement therapy (capsule [Canadian product]): Testosterone replacement in adult males for conditions associated with a deficiency or absence of endogenous testosterone.

Limitations of use: In adult males, testosterone is indicated as replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Use in age-related hypogonadism (or late-onset hypogonadism) has not been established.

Contraindications

Breast cancer (males); prostate cancer (known or suspected); pregnant women or women who may become pregnant

Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Vogelxo: Additional contradiction: Breast-feeding women

Andriol [Canadian product]: Additional contraindications: Hypersensitivity to any component of the formulation; use in women

Aveed: Additional contraindications: Hypersensitivity to testosterone undecanoate, castor oil, benzyl benzoate; breast-feeding women

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

Testosterone enanthate: Additional contraindications: Hypersensitivity to any component of the formulation

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.

Dosing: Adult

Note: In adult men with androgen deficiency syndromes (eg, hypogonadism), withhold initial treatment with hematocrit >50% (discontinue therapy if hematocrit exceeds 54%), hyperviscosity, untreated obstructive sleep apnea, uncontrolled severe heart failure, or with severe untreated BPH with IPSS symptom score >19 (Endocrine Society [Bhasin 2010]).

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

Delayed puberty (males):

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

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

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

IM (testosterone enanthate or testosterone cypionate): 50 to 400 mg every 2 to 4 weeks (FDA-approved dosing range); 75 to 100 mg/week or 150 to 200 mg every 2 weeks (Endocrine Society [Bhasin 2010])

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

Intranasal: Testosterone gel: Natesto: 11 mg (2 pump actuations; 1 actuation per nostril) administered 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 >1050 ng/mL

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

Topical:

Buccal: 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.

Gel:

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

Dose adjustment based on 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. Dosage range: 20.25 mg to 81 mg daily.

Dose adjustment based on testosterone levels:

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

≥350 ng/dL to ≤750 ng/dL: Maintain current dose

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

Fortesta: 40 mg once daily in the morning. Apply to the thighs. Dosing range: 10 to 70 mg daily

Dose adjustment based on serum testosterone levels:

≥2500 ng/dL: Decrease dose by 20 mg daily

≥1250 to <2500 ng/dL: Decrease dose by 10 mg daily

≥500 and <1250 ng/dL: Maintain current dose

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

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

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

Dose adjustment based on testosterone levels: 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 daily). Apply to the axilla at the same time each morning.

Dose adjustment based on serum testosterone levels:

>1050 ng/dL: Decrease 60 mg daily dose to 30 mg daily; if levels >1050 ng/dL persist after dose reduction, discontinue therapy

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

Transdermal system (Androderm):

Initial: 4 mg daily (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 daily

400 to 930 ng/dL: Continue 4 mg daily

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

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

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

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

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

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

Replacement therapy (males): Oral capsule (Andriol [Canadian product]): Initial: 120 to 160 mg daily in 2 divided doses for 2 to 3 weeks; adjust according to individual response and/or testosterone levels; usual maintenance dose: 40 to 120 mg daily (in divided doses)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Delayed puberty (adolescent males):

IM (testosterone enanthate): Refer to adult dosing.

Pellet (for subcutaneous implantation): Refer to adult dosing.

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

IM (testosterone enanthate or testosterone cypionate): Refer to adult dosing.

Pellet (for subcutaneous implantation): Refer to adult dosing.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

Reconstitution

Injection:

Testosterone enanthate, testosterone cypionate: Warm to room temperature; shaking vial will help redissolve crystals that have formed after storage.

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

Administration

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

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

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

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

Oral, capsule (Andriol [Canadian product]): Administer with meals. Should be swallowed whole; do not crush or chew.

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

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.

Topical gel and solution: 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 these products are not interchangeable.

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

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

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

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

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

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

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Dietary Considerations

Food and beverages have not been found to interfere with buccal system; ensure system is in place following eating, drinking, or brushing teeth.

Storage

Andriol [Canadian product]: Store between 15°C and 30°C; protect from light and moisture; do not refrigerate.

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

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

AndroGel 1.62%, Natesto, Testim, Vogelxo: Store at 20°C and 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Aveed: Store at 25ºC (77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF) Store in original container.

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

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

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

Testopel: Store in a cool location.

Testosterone enanthate injection: Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

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

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

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

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

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

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

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

Test Interactions

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

Adverse Reactions

Frequency not always defined.

Cardiovascular: Hypertension (≥3%), increased blood pressure (1%), decreased blood pressure, deep vein thrombosis, edema, vasodilatation

Central nervous system: Headache (1% to ≥3%), fatigue (2%), irritability (2%), insomnia (≤2%), mood swings (≤2%), aggressive behavior (1%), taste disorder (1%), altered sense of smell (≤1%), abnormal dreams, amnesia, anxiety, chills, depression, dizziness, emotional lability, excitement, hostility, malaise, nervousness, outbursts of anger, paresthesia, seizure, sleep apnea, suicidal ideation

Dermatologic: Acne vulgaris (5%), hyperhidrosis (1%), alopecia, contact dermatitis, diaphoresis, erythema, folliculitis, hair discoloration, pruritus, seborrhea, skin rash, xeroderma

Endocrine & metabolic: Increased plasma estradiol concentration (3%), weight gain (1%), gynecomastia (≤1%), hot flash (≤1%), change in libido, decreased gonadotropin, fluid retention, hirsutism (increase in pubic hair growth), hypercalcemia, hyperchloremia, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hypernatremia, hypoglycemia, hypokalemia, inorganic phosphate retention, menstrual disease (including amenorrhea)

Gastrointestinal: Diarrhea (≥3%), gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal irritation, increased appetite, nausea, vomiting

Following buccal administration (most common): Dysgeusia, gingival pain, gingival swelling, mouth irritation (including gums), unpleasant taste

Genitourinary: Prostate specific antigen increase (5% to 11%), prostatitis (≥3%), ejaculatory disorder (1%), prostate induration (1%), spontaneous erections (≤1%), benign prostatic hypertrophy, difficulty in micturition, hematuria, impotence, irritable bladder, mastalgia, oligospermia, priapism, testicular atrophy, urinary tract infection, virilization

Hepatic: Abnormal hepatic function tests, cholestatic hepatitis, cholestatic jaundice, hepatic insufficiency, hepatic necrosis, hepatocellular neoplasms, increased serum bilirubin, peliosis hepatis

Hematologic & oncologic: Increased hematocrit (1% to 3%), increased hemoglobin (2%), malignant neoplasm of prostate (1%), anemia, clotting factors suppression, hemorrhage, leukopenia, polycythemia, prostate carcinoma

Hypersensitivity: Anaphylactoid reaction, hypersensitivity reaction (including pulmonary oil microembolism)

Local: Pain at injection site (5%), erythema at injection site (1%), application site reaction (gel, solution), inflammation at injection site

Transdermal system: Application site pruritus (17% to 37%), application site vesicles (including burn-like blisters under system; 6% to 12%), application site erythema (≤7%), local allergic contact dermatitis (4%), application site burning (3%), application site induration (3%), local skin exfoliation (<3%)

Neuromuscular & skeletal: Arthralgia (≥3%), back pain (≥3%), abnormal bone growth (accelerated), hemarthrosis, hyperkinesia, weakness

Ophthalmic: Increased lacrimation

Renal: Increased serum creatinine, polyuria

Respiratory: Bronchitis (≥3%), nasopharyngitis (≥3%), sinusitis (≥3%), upper respiratory tract infection (≥3%), dyspnea

<1% (Limited to important or life-threatening): Injection, gel: Abnormal erythropoiesis, abscess at injection site, anaphylaxis, androgenetic alopecia, asthma, atrial fibrillation, cardiac failure, cerebrovascular accident, chronic obstructive pulmonary disease, cognitive dysfunction, decreased libido, diabetes mellitus, epididymitis, hearing loss (sudden), hematoma at injection site, hepatic neoplasm, hepatotoxicity (idiosyncratic) (Chalasani 2014), hyperparathyroidism, hypersensitivity angiitis, increased intraocular pressure, Korsakoff's psychosis (nonalcoholic), migraine, myocardial infarction, personality disorder, prolonged prothrombin time, prostatic intraepithelial neoplasia, renal disease, reversible ischemic neurological deficit, spermatocele, systemic lupus erythematosus, tachycardia, thrombocytopenia, thrombosis, urinary incontinence, venous insufficiency, vesicobullous rash, virilization (of children, following secondary exposure to topical gel [advanced bone age, aggressive behavior, enlargement of clitoris requiring surgery, enlargement of penis, increased erections, increased libido, pubic hair development]), vitreous detachment

ALERT: U.S. Boxed Warning

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 (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.

Warnings/Precautions

Concerns related to adverse effects:

• Breast cancer: Long term use (>10 years) of parenteral testosterone for male hypogonadism may increase the risk of breast cancer (Medras 2006).

• Cardiovascular events: Available studies are inconclusive regarding the risk of developing major adverse cardiovascular events (MACE) such as nonfatal MI, stroke, or cardiovascular death following testosterone use. Some studies have suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy (Basaria 2010; Finkle 2014; Vigen 2013), although the overall evidence does not demonstrate an increased or decreased cardiovascular risk (Endocrine Society [Bhasin 2010]; Corona 2014; Morgentaler 2015). The Endocrine Society suggests it may be prudent to avoid testosterone therapy in men who have experienced a cardiovascular event (eg, MI, stroke, acute coronary syndrome) in the past six months (The Endocrine Society 2014). Evaluate patients for cardiovascular risk factors prior to initiating therapy and monitor closely during therapy for cardiovascular events.

• Dyslipidemia: May alter serum lipid profile; use caution with history of MI or coronary artery disease.

• Gynecomastia: May cause gynecomastia, which may persist in patients treated for hypogonadism.

• Hepatic effects: Prolonged use of high doses of oral androgens has been associated with serious hepatic effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, jaundice). Prolonged use of intramuscular testosterone enanthate has been associated with multiple hepatic adenomas. Discontinue therapy if signs or symptoms of hepatic dysfunction (such as jaundice) develop.

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

• Oligospermia: Large doses may suppress spermatogenesis; oligospermia may occur. Discontinue therapy if this occurs, if restarted, a lower dose should be used.

• Polycythemia: May increase hematocrit requiring dose adjustment or discontinuation. Withhold initial treatment in patients with hematocrit >50%. Discontinue therapy if hematocrit exceeds 54%; may reinitiate at lower dose (Endocrine Society [Bhasin 2010]).

• Priapism: Priapism or excessive sexual stimulation may occur; discontinue therapy if this occurs, if restarted, a lower dose should be used.

• Prostate cancer: May increase the risk of prostate cancer. Withhold therapy pending urological evaluation in patients with palpable prostate nodule or induration, PSA >4 ng/mL, or PSA >3 ng/mL in men at high risk of prostate cancer (Endocrine Society [Bhasin 2010]).

• Venous thromboembolism: Venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported with testosterone products. Evaluate patients with symptoms of pain, edema, warmth, and erythema in the lower extremity for DVT and those with acute shortness of breath for PE. Discontinue therapy if a venous thromboembolism is suspected.

Disease-related concerns:

• Benign prostatic hyperplasia (BPH): Androgens may worsen BPH; do not use in patients with severe lower urinary tract symptoms [(AUA)/International Prostate Symptom Score (IPSS) > 19] (Endocrine Society [Bhasin 2010]). Discontinue therapy if urethral obstruction develops in patients with BPH (use lower dose if restarted).

• Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including cardiac, hepatic, or renal dysfunction; testosterone may cause fluid retention. Treatment of androgen deficiency syndromes is not recommended for men with uncontrolled or poorly controlled heart failure (Endocrine Society [Bhasin 2010]).

• Sleep apnea: May potentiate sleep apnea in some male patients, especially those with risk factors (eg, obesity or chronic lung disease). Withhold initial treatment in patients with untreated obstructive sleep apnea (Endocrine Society [Bhasin 2010]).

Concurrent drug therapy issues:

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

Special populations:

• Elderly: Geriatric patients may be at greater risk for prostatic hyperplasia, prostate cancer, fluid retention, and transaminase elevations.

• 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. Gels, solution, transdermal, and buccal system have not been evaluated in males <18 years of age; safety and efficacy of testosterone cypionate injection have not been established in males <12 years of age.

• Women: During treatment for metastatic breast cancer, women should be monitored for signs of virilization; discontinue if mild virilization is present to prevent irreversible symptoms.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Castor oil: Some products may contain castor oil.

• Gel, intranasal: Use of the intranasal gel is not recommended in patients with sinus disease, mucosal inflammatory disorders (eg, Sjogren syndrome), or with a history of nasal disorders, nasal or sinus surgery, nasal fracture within the previous 6 months, or nasal fracture that caused a deviated anterior nasal septum. Safety and efficacy have not been established in males with a BMI >35 kg/m2.

• Gel, topical: Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure; these products are not interchangeable.

• Injection: Testosterone cypionate should not be used interchangeably with testosterone propionate due to differences in duration of action.

• Pulmonary oil microembolism: Testosterone undecanoate injection: [US Boxed Warning]: Serious pulmonary oil microembolism (POME) reactions and anaphylaxis have been reported with testosterone undecanoate injection. Reactions include anaphylaxis, chest pain, urge to cough, dizziness, dyspnea, throat tightening, and syncope; may be life threatening. Reactions may occur after any injection during the course of therapy, including the first dose. Patients must be monitored for 30 minutes after injection. Due to the risk of serious POME reactions, Aveed is only available through the Aveed REMS program. To minimize risk of adverse reactions, inject deeply into gluteal muscle.

• Solution: Axiron is not interchangeable with other topical testosterone products. Use in males with BMI >35 kg/m2 has not been established.

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

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• Abuse/misuse/diversion: Anabolic steroids may be abused; abuse may be associated with adverse physical and psychological effects. Dependence may occur when used outside of approved dosage/indications.

• Secondary exposure: Testosterone may be transferred to another person following skin-to-skin contact with the application site. [US Boxed Warning]: Virilization in children has been reported following contact with unwashed or unclothed application sites of men using topical testosterone. Patients should strictly adhere to instructions for use in order to prevent secondary exposure. Children and women should avoid contact with application sites of men using topical products. Symptoms of virilization generally regress following removal of exposure; however, in some children, enlarged genitalia and bone age did not fully return to age appropriate normal. Signs of inappropriate virilization in women or children following secondary exposure to topical testosterone should be brought to the attention of a healthcare provider.

Monitoring Parameters

Prior to treatment initiation: Confirm hypogonadism by measuring morning serum testosterone on at least 2 separate days. Liver function tests, lipid panel, hemoglobin and hematocrit (withhold initial treatment with hematocrit >50%) (Endocrine Society [Bhasin 2010]). PSA and prostate exam in men >40 years of age with baseline PSA >0.6 ng/mL.

During treatment:

Liver function tests, lipid panel, hemoglobin and hematocrit (at 3 to 6 months then annually); discontinue therapy if hematocrit exceeds 54% (Endocrine Society [Bhasin 2010]). Monitor urine and serum calcium and signs of virilization in women treated for breast cancer. Serum glucose (may be decreased by testosterone, monitor patients with diabetes). Evaluate males for response to treatment and adverse events 3 to 6 months after initiation and then annually; monitor for cardiovascular events closely during therapy. Monitor serum testosterone 3 to 6 months after initial dose titration (if applicable) then annually.

Bone mineral density:

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

Hypogonadal men with osteoporosis or low trauma fracture: Monitor after 1 to 2 years of therapy (Endocrine Society [Bhasin 2010]).

PSA: In men >40 years of age with baseline PSA >0.6 ng/mL, PSA and prostate exam at 3 to 6 months, then as based on current guidelines. Withhold treatment pending urological evaluation in patients with palpable prostate nodule or induration or PSA >4 ng/mL or if PSA >3 ng/mL in men at high risk of prostate cancer (Endocrine Society [Bhasin 2010]).

Formulation-specific monitoring:

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

AndroGel 1.62%: Morning 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.

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 serum testosterone in mid-normal range (Endocrine Society [Bhasin 2010]).

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

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

Natesto: Measure total serum testosterone periodically, beginning 1 month after initiating therapy. Discontinue therapy if the total serum testosterone consistently exceeds 1,050 ng/dL. If total serum testosterone is consistently <300 ng/dL consider an alternative therapy.

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 are consistently outside of the normal range (300 to 1,050 ng/dL).

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

Testopel: Measure at the end of the dosing interval (Bhasin 2010).

Testosterone cypionate injection: Measure testosterone level midway between injections. Adjust dose or frequency if testosterone concentration is <400 ng/dL or >700 ng/dL (Endocrine Society [Bhasin 2010]).

Testosterone enanthate injection: Measure testosterone level midway between injections. Adjust dose or frequency if testosterone concentration is <400 ng/dL or >700 ng/dL (Endocrine Society [Bhasin 2010]).

Vogelxo: Measure serum testosterone ~14 days after initiation of therapy, in the morning, prior to application.

Pregnancy Risk Factor

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Pregnancy Considerations

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

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

Large doses of testosterone may suppress spermatogenesis. Treatment of hypogonadotropic hypogonadism is not recommended for men desiring fertility (Endocrine Society [Bhasin 2010]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pharyngitis, acne, diarrhea, emotional instability, decreased libido, sexual dysfunction, loss of strength and energy, insomnia, skin irritation, bad taste, or back pain. Have patient report immediately to prescriber angina, cough or need to cough, dizziness, passing out, shortness of breath, throat tightness, priapism, polyuria, urinary retention, change in amount of urine passed, mood changes, enlarged breasts, breast pain, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), shortness of breath, excessive weight gain, swelling of arms or legs, nausea, vomiting, bruising, bleeding, severe fatigue, severe headache, coughing up blood, skin discoloration, testicular irregularities, gingival changes, severe mouth irritation, nosebleed, nasal dryness, rhinitis, rhinorrhea, nasal scabs, sneezing, severe injection site irritation, or signs of virilization (in females a deep voice, facial hair, pimples, or period changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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