Pronunciation: tes-TOS-ter-one
Class: Androgen Testosterone

Trade Names

Androderm
- Patch, transdermal 2 mg per 24 h
- Patch, transdermal 4 mg per 24 h

Testopel
- Pellet, implant 75 mg

Testosterone Cypionate (in oil)

Depo-Testosterone
- Injection, solution 100 mg/mL
- Injection, solution 200 mg/mL

Testosterone Enanthate (in oil)

Delatestryl
- Injection, solution 200 mg/mL

Testosterone Gel

AndroGel
- Gel, transdermal 1%
- Gel, transdermal 1.62%

Fortesta
- Gel, transdermal 10 mg per 0.5 g

Testim
- Gel, transdermal 1%

Testosterone Buccal System

Striant
- Mucoadhesive, buccal 30 mg

Testosterone Solution

Axiron
- Solution, transdermal 30 mg per 1.5 mL

Pharmacology

Promotes growth and development of male reproductive organs, maintains secondary sex characteristics, increases protein anabolism, and decreases protein catabolism.

Slideshow: Grapefruit and Medicines: A Possible Deadly Mix?

Pharmacokinetics

Absorption

Testosterone patch median T _max is 8 h. The transdermal products provide continuous transdermal delivery of testosterone for 24 h. Testosterone is slowly released following buccal application, reaching C _max within 10 to 12 h. Testosterone in oil injected IM is absorbed slowly from the lipid phase.

Distribution

98% is bound to proteins.

Metabolism

Testosterone is metabolized in the liver. The major active metabolites are estradiol and DHT.

Elimination

The half-life of testosterone when injected IM is approximately 8 days. Transdermal testosterone half-life is 10 to 100 min. Approximately 90% is excreted in urine, and approximately 6% is excreted in feces.

Special Populations

Renal Function Impairment

For testosterone transdermal, no formal studies were conducted in patients with renal insufficiency.

Hepatic Function Impairment

For testosterone transdermal, no formal studies were conducted in patients with hepatic insufficiency.

Elderly

There are no observed differences in the pharmacokinetics of testosterone transdermal based on age.

Children

For testosterone gel, no formal studies were conducted in pediatric patients.

Indications and Usage

Men

Replacement therapy in primary hypogonadism and hypogonadotropic hypogonadism (testosterone enanthate [ Delatestryl ], testosterone pellets [ Testopel ], testosterone gel [ AndroGel , Fortesta , Testim ], testosterone transdermal patch [ Androderm ], testosterone transdermal solution [ Axiron ], testosterone buccal system [ Striant ], testosterone cypionate [ Depo-Testosterone ]); stimulation of puberty (testosterone enanthate [ Delatestryl ], testosterone pellets [ Testopel ]).

Women

Ablation of ovaries in metastatic breast cancer (testosterone enanthate [ Delatestryl ]).

Contraindications

Hypersensitivity to any component of the product; serious cardiac, hepatic, or renal disease; men with carcinoma of the breast or prostate; women who are or may become pregnant or who are breast-feeding; testosterone gel and buccal system are contraindicated in women.

Dosage and Administration

Androgen Replacement Therapy
Adults

Buccal 30 mg applied to the gum region twice daily, morning and evening (approximately 12 h apart). Place in a comfortable position just above one of the incisor teeth.

IM 50 to 400 mg every 2 to 4 wk (testosterone enanthate, testosterone cypionate).

Subcutaneous 150 to 450 mg every 3 to 6 mo (testosterone pellets).

Transdermal

• Patch: Initial dosage is one 4 mg/day system (not two 2 mg/day systems) applied nightly for 24 hours. Approximately 2 weeks after starting or switching therapy, measure the morning serum testosterone concentration following system application the previous evening. If the serum concentration is outside the normal range, repeat sampling with assurance of proper system adhesion as well as appropriate application time. Confirmed serum concentrations outside the normal range of 400 to 930 ng/dL may require increasing the daily dose to 6 mg (ie, one 4 mg/day and one 2 mg/day system) or decreasing the daily dose to 2 mg (ie, one 2 mg/day system), maintaining nightly application.
• Gel:
  • AndroGel 1% / Testim : 5 g once daily in the morning; apply to the shoulders or upper arms ( AndroGel 1% may also be applied to the abdomen). Measure serum testosterone levels 14 d after initiation to ensure proper dosing. If the level is below the normal range or if the desired clinical response is not achieved, the dose may be increased to 7.5 g ( AndroGel 1% ) or 10 g ( Testim ) and from 7.5 g to 10 g ( AndroGel 1% ). Discontinue therapy if the serum testosterone concentration consistently exceeds the normal range at a daily dose of 5 g.
  • AndroGel 1.62% : 40.5 mg (2 pump actuations) applied once daily in the morning to the shoulders and upper arms. The dosage can be adjusted between 20.25 mg (1 pump actuation) and a maximum of 81 mg (4 pump actuations). Titrate based on the predose morning serum testosterone concentration from a single blood draw at approximately 14 and 28 d after starting treatment or following dose adjustment. For testosterone concentrations less than 350 ng/dL, increase the daily dose by 20.25 mg (1 pump actuation). For testosterone concentrations between 350 and 750 ng/dL, continue current dose. Decrease daily dose by 20.25 mg for concentrations more than 750 ng/dL.
  • Fortesta : 40 mg (4 pump actuations) applied once daily to the thighs in the morning. Titrate the dose between a minimum of 10 mg and a maximum of 70 mg based on the serum testosterone concentration from a single blood draw 2 h after application at approximately 14 and 35 d after starting treatment or following dose adjustment. For serum testosterone less than 500 ng/dL, increase the daily dosage by 10 mg (1 pump actuation). Continue the current dose for serum testosterone between 500 and 1,250 ng/dL. Decreased the daily dosage by 10 mg (1 pump actuation) or 20 mg (2 pump actuations) for concentrations between 1,250 and 2,500 ng/dL or 2,500 ng/dL or more, respectively.
• Solution:
  • Axiron : 60 mg (2 pump actuations) applied once daily to the axilla. Titrate the dose based on a single blood draw 2 to 8 h after application and at least 14 d after starting therapy or following dosage adjustment. Increase the dosage for 60 to 90 mg (3 pump actuations) for testosterone concentrations less than 300 ng/dL or from 90 to 120 mg (4 pump actuations). Decrease the dosage from 60 to 30 mg (1 pump actuation) for testosterone more than 1,050 ng/dL; discontinue treatment if the testosterone concentration consistently exceeds 1,050 ng/dL at the 30 mg dose.

Children (12 y and older)

IM 50 to 400 mg every 2 to 4 wk (testosterone cypionate).

Metastatic Breast Cancer in Women
Adults

IM 200 to 400 mg every 2 to 4 wk (testosterone enanthate).

Delayed Puberty
Adolescents

IM 50 to 200 mg every 2 to 4 wk for limited duration (testosterone enanthate).

Subcutaneous 150 to 450 mg every 4 to 6 mo (testosterone pellets).

General Advice

• Injection
• For IM administration deep into gluteal muscle only. Not for intradermal, IV, or intra-arterial administration. Avoid intravascular administration.
• Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.
• Dosage is adjusted according to the patient's response and the appearance of adverse reactions.

• Transdermal gel and solution
• Apply to clean, dry intact skin in the areas approved for the prescribed product. Do not apply to the genitals. Patients should wash their hands with soap and water immediately after application. The application site should be allowed to dry and then covered with clothing. For additional administration information (eg, pump priming), refer to the manufacturer's prescribing information.
• Avoid swimming, showering, or washing the application site for a minimum of 2 h (5 h for AndroGel 1%) after application.
• Children and women should avoid contact with the unwashed or unclothed application site. The application site should be washed with soap and water prior to any situation in which skin-to-skin contact with the application site is anticipated. If another person comes in direct contact with the unwashed or unclothed application site, they should immediately wash the area of contact with soap and water.

• Patch
• Open the pouch and remove the protective release liner. Apply the adhesive side of the patch to a clean, dry area of the skin on the back, abdomen, upper arms, or thighs. Press patch firmly in place, making sure there is good contact with the skin, especially around the edges.
• Avoid application over bony prominences or on a part of the body that may be subject to prolonged pressure during sleep or sitting. Do not apply to the scrotum.
• Rotate application sites, with an interval of 7 days between applications to the same site. Do not apply to sites that are oily, damaged, or irritated.
• Avoid swimming, showering, or washing the application site for a minimum of 3 h after application.
• Mild skin irritation may be ameliorated by treatment of the affected area with OTC topical hydrocortisone cream after patch removal.

Storage/Stability

Store transdermal gel and solution between 59° and 86°F. Do not freeze. Store transdermal patches in protective pouch, between 68° and 77°F. Protect patches from excessive heat or pressure, which can cause bursting of the drug reservoir. Store blister packs ( Striant ) between 68° and 77°F. Protect from heat and moisture. Do not remove the buccal system from the blister pack until ready to apply. Store vials and prefilled syringes between 68° and 77°F. Protect from light. Store pellets in a cool place.

Drug Interactions

Anticoagulants (eg, warfarin)

The anticoagulant effect of warfarin may be increased. Monitor coagulation parameters and adjust the warfarin dose as needed.

Carbamazepine

Carbamazepine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Closely monitor carbamazepine plasma concentrations and the patient's clinical status for symptoms of carbamazepine toxicity. Adjust the carbamazepine dose as needed.

Corticotropin, corticosteroids

Use with caution because of increased risk of edema.

Insulin, oral hypoglycemics

May decrease glucose levels and antidiabetic drug requirements. Monitor blood glucose and adjust the insulin dose as needed.

Triamcinolone

Pretreatment with triamcinolone ointment reduced testosterone absorption from the transdermal patch system.

Laboratory Test Interactions

Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T ₄ serum levels and increased resin uptake of T ₃ and T ₄ . Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Adverse Reactions

Cardiovascular

Hot flashes (postmarketing).

Transdermal gel/solution

Hypertension (3%); diastolic BP decreased, hot flushes (1%).

CNS

Amnesia, anxiety, depression, dizziness, generalized paresthesia, headache, hostility, increased or decreased libido, insomnia, malaise, sleep apnea (postmarketing).

Buccal

Headache (3%).

Transdermal gel/solution

Headache (6%); asthenia, decreased libido, emotional lability, nervousness (3%); insomnia (2% or less); abnormal dreams, depression, mood swings (1%).

Dermatologic

Acne, hirsutism, male pattern baldness, seborrhea; discolored hair, erythema, paresthesia, rash (postmarketing).

Transdermal gel/solution

Acne (8%); contact dermatitis, dry skin, pruritus (2%); alopecia (1%).

EENT

Transdermal gel/solution

Lacrimation increased, smell disorder, taste disorder (1%); vitreous detachment (postmarketing).

Endocrine

Inhibition of gonadotropin secretion.

GI

Nausea.

Transdermal gel/solution

Diarrhea, vomiting (4%).

Transdermal patch

Diarrhea, gastroesophageal reflux disease (less than 3%).

Genitourinary

Amenorrhea and other menstrual irregularities, virilization (including deepening of the voice and clitoral enlargement) (women); excessive frequency and duration of penile erection, gynecomastia, oligospermia (men).

Transdermal gel/solution

Increase in prostate-specific antigen (18%); enlarged prostate (12%); prostate disorder (5%); urinary symptoms (4%); breast pain, gynecomastia, testis disorder (3%); benign prostatic hyperplasia (2% or less); prostate carcinoma, spontaneous penile erection (1%); priapism (postmarketing).

Transdermal patch

Prostatitis, polyuria (less than 3%).

Hematologic-Lymphatic

Polycythemia, suppression of clotting factors II, V, VII, and X.

Transdermal gel/solution

Anemia (3%).

Transdermal patch

Hemarthrosis, hematuria (less than 3%).

Hepatic

Alterations in LFTs, cholestatic jaundice, hepatocellular neoplasms, peliosis hepatitis.

Hypersensitivity

Anaphylactoid reactions, hypersensitivity (including skin manifestations).

Lab Tests

Transdermal gel/solution

Decreased or increased HDL, elevated AST or ALT, elevated cholesterol, elevated cholesterol/LDL ratio, elevated glucose, elevated hemoglobin or hematocrit, elevated serum creatinine, elevated testosterone, elevated total bilirubin, elevated triglycerides, hyperlipidemia, hypokalemia (6% to 9%).

Local

IM

Inflammation and pain at injection site.

Buccal

Gum or mouth disorder (9%); bitter taste (4%); gum pain, gum tenderness (3%); gum edema, taste perversion (2%).

Transdermal gel/solution

Application-site reactions (16%); application-site irritation (8%); application-site erythema (7%).

Transdermal patch

Application-site reactions (28%); application-site pruritus (17%); application-site vesicles (6%); application-site erythema or exfoliation (less than 3%).

Metabolic-Nutritional

Electrolyte changes (eg, calcium, nitrogen, phosphorus, potassium, sodium), increased serum cholesterol, increased weight, retention of calcium, chloride, potassium, sodium, and inorganic phosphates (postmarketing).

Musculoskeletal

Transdermal patch

Back pain (6%).

Respiratory

Dyspnea (postmarketing).

Miscellaneous

Edema (postmarketing).

Transdermal patch

Chills (less than 3%).

Precautions

Warnings Secondary exposure Virilization has been reported in children who were secondarily exposed to testosterone transdermal gel or solution. Children should avoid contact with unwashed or unclothed application sites in men using testosterone transdermal gel or solution. Advise patients to strictly adhere to recommended instructions for use.

Monitor Periodically monitor serum testosterone concentrations. Regularly monitor urine and serum calcium concentrations in women with disseminated breast cancer. Observe women for signs of virilization (eg, clitoral enlargement, deepening of voice). In patients with delayed puberty, monitor effect on bone maturation by assessing bone age of the wrist and hand every 6 mo. In patients receiving high doses, periodically check Hgb and Hct for polycythemia. Periodically monitor liver function and serum lipid profile. Monitor for signs and symptoms of worsening benign prostatic hyperplasia. Evaluate patients for prostate cancer prior to initiation and periodically thereafter, based on current guidelines for eugonadal men.

Pregnancy

Category X . Contraindicated in pregnancy.

Lactation

Undetermined. Testosterone transdermal products, cypionate, and buccal are not indicated for women.

Children

Use drug with great caution; may affect bone maturation.

Testosterone cypionate

Safety and efficacy not established in children younger than 12 y. This product contains benzyl alcohol, which has been reported to be associated with a fatal “gasping syndrome” in premature infants.

Testosterone transdermal products and buccal system

Safety and efficacy not established.

Elderly

Elderly men may be at increased risk of developing prostatic hypertrophy or carcinoma.

Renal Function

Contraindicated in patients with serious renal impairment (cypionate).

Hepatic Function

Contraindicated in patients with serious hepatic impairment (cypionate).

Acute intermittent porphyria

Acute intermittent porphyria has been reported. Use drug with caution in patients known to have this condition.

Athletic performance

Abuse of these agents to enhance athletic performance has potential risk of serious adverse reactions.

Benign prostatic hyperplasia

May worsen.

Edema

Edema with or without CHF may be a serious complication in patients with preexisting cardiac, hepatic, or renal disease. Use with caution in patients with conditions affected by fluid retention (eg, asthma, cardiac or renal impairment, epilepsy).

Gynecomastia

Frequently occurs and may persist.

Hepatic effects

Prolonged use of high doses of androgens may result in potentially life-threatening peliosis, cholestatic jaundice, hepatitis, hepatic neoplasms, or hepatocellular carcinoma; cholestatic hepatitis and jaundice occur with 17-alpha-alkyl-androgens at a relatively low dose.

Hypercalcemia

Androgen therapy may cause hypercalcemia by stimulating osteolysis in patients with breast cancer and immobilized patients.

IM administration

Transient reactions involving urge to cough, coughing fits, and respiratory distress immediately following injection of an oil-based depot preparation may occur.

Oligospermia and reduced ejaculatory volume

May occur after prolonged use.

Polycythemia

Increases in hematocrit reflective of increase in red blood cell mass may require lowering of dose or discontinuation of testosterone.

Priapism/Excessive sexual stimulation

May occur.

Product interchange

Do not interchange products because of their differences in duration of action.

Prostate cancer

Risk may be increased.

Serum cholesterol

Levels may increase with androgen use; use drug with caution in patients with history of MI or coronary artery disease.

Sleep apnea

Treatment of hypogonadal men may potentiate sleep apnea, particularly in patients with risk factors (eg, chronic lung diseases, obesity).

Urethral obstruction

May develop in patients with benign prostatic hypertrophy.

Virilization

May occur in women using high-dose androgens.

Overdosage

Symptoms

Cerebrovascular accident (testosterone enanthate).

Patient Information

• Advise patients to read patient information leaflet before using the first time and with each refill.
• Instruct patients with diabetes to monitor blood glucose more frequently when drug is started or dose is changed, and to inform their health care provider of significant changes in readings.
• Caution patients that testosterone has not been shown to be safe or effective for enhancing athletic performance and, because of potential for serious health risks, to not use for this purpose.
• Instruct patients to inform their health care provider if any of the following occurs: ankle swelling; any change in skin color; breast enlargement; breathing problems, including any associated with sleep; changes in body hair distribution, increase in acne, or other unusual changes in female partner; difficulty urinating; mood changes; too frequent or persistent erections of the penis; unexplained nausea and/or vomiting.
• Inform male adolescent patients receiving androgens for delayed puberty to have bone development checked every 6 mo.

• Buccal system
• Review application and removal process with patient.
• Instruct patients to apply buccal system twice daily, morning and evening (approximately 12 h apart).
• Caution patients not to chew or swallow the buccal system.
• Advise patients to avoid dislodging the buccal system and check to see if the system is in place following brushing teeth, using mouthwash, and eating or drinking.
• Advise patients that if the buccal system fails to properly adhere to the gum or falls off during the 12-hour dosing interval, the old system should be discarded and a new one applied. If the buccal system falls out of position within 4 h of the next dose, a new system should be applied and may remain in place until the time of the next regularly scheduled dose.
• Advise patients to regularly inspect gum region where the buccal system is applied and to report any abnormality (including gum tenderness or irritation) to their health care provider.

• Transdermal gel/solution
• Instruct patients to apply once daily at approximately the same time each day. Advise patient that application every morning is preferred. Advise patient that if bathing or showering in the morning, to apply afterward.
• Caution patients that product is flammable and not to use near fire or open flame.
• Instruct patients in proper application.
• Caution patients not to apply gel to scrotum, penis, or skin that is not normal (eg, inflamed or irritated).
• Advise patients not to swim or bathe within 2 h (5 h for AndroGel 1%) of application because swimming or bathing too soon after application may reduce effectiveness.
• Instruct patients to wash application site thoroughly with soap and water to remove drug residue before any situation in which direct skin-to-skin contact is anticipated.
• Advise patients in the event that unwashed or unclothed skin to which the product has been applied comes in contact with the skin of another person, especially a pregnant or breast-feeding woman, to thoroughly wash the general area of contact on the other person with soap and water as soon as possible.

• Injection and pellets
• Advise patients that medication will be prepared and administered by a health care provider in a medical setting.
• Advise patients to report pain, tenderness, or signs of inflammation at injection/implantation site to their health care provider.

• Transdermal system
• Instruct patients to apply patch once daily at approximately the same time each day. Advise patient that application at night is preferred.
• Instruct patients in proper application of patch: open packet and remove patch immediately prior to application; remove release liner to expose adhesive side of patch; apply to clean, dry skin area of back, abdomen, thigh, or upper arm using firm pressure with fingers or palm, making sure there is good contact with the skin, especially around the edge of the patch.
• Instruct patients that the application site should be rotated, with an interval of 7 days between application to the same site.
• Advise patients that the patch should be removed before undergoing an MRI.
• Caution patients not to apply patch to scrotum, penis, skin that is not normal (eg, inflamed or irritated), skin over a bony prominence, or skin that could be subject to prolonged pressure during sleep or sitting.
• Instruct patients to discard used patches in household trash in a manner that prevents accidental ingestion by children or pets.
• Advise patients that patch does not have to be removed during sexual intercourse, nor while showering, bathing, or swimming. Swimming or showering should be avoided for at least 3 h after application.
• Advise patients that mild skin irritation can be relieved by using OTC hydrocortisone. Instruct patients to notify their health care provider if irritation persists or worsens.

Copyright © 2009 Wolters Kluwer Health.