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Testosterone Enanthate

Pronunciation

Class: Androgens
Note: This monograph also contains information on Testosterone, Testosterone Cypionate
VA Class: HS100
CAS Number: 58-22-0
Brands: Androderm, AndroGel, Delatestryl, Striant, Testim

Warning(s)

Special Alerts:

[Posted 01/31/2014] ISSUE: FDA is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. FDA is providing this alert while it continues to evaluate the information from these studies and other available data. FDA will communicate final conclusions and recommendations when the evaluation is complete.

BACKGROUND: Testosterone is a hormone essential to the development of male growth and masculine characteristics. Testosterone products are FDA-approved only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition.

RECOMMENDATION: At this time, FDA has not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, or death. Patients should not stop taking prescribed testosterone products without first discussing any questions or concerns with their health care professionals. Health care professionals should consider whether the benefits of FDA-approved testosterone treatment is likely to exceed the potential risks of treatment. The prescribing information in the drug labels of FDA-approved testosterone products should be followed.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.

For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for testosterone to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of testosterone and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Warning(s)

  • Risk of virilization in children and women following secondary exposure to testosterone in topically administered testosterone gel.157 166 170 171 Advise children and women to avoid contact with application sites of men using testosterone gel.166 170 171 (See Virilization in Children and Women from Secondary Exposure to Testosterone under Cautions.)

  • Advise men using testosterone gel to strictly adhere to recommended instructions for use.170 171 (See Administration under Dosage and Administration.)

Introduction

Androgenic anabolic steroid hormone; the principal endogenous androgen.a

Uses for Testosterone Enanthate

Male Hypogonadism

Management of congenital or acquired primary hypogonadism such as that resulting from orchidectomy or from testicular failure caused by cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals.117 133 135 157 161 162 a

Management of congenital or acquired hypogonadotropic hypogonadism such as that resulting from idiopathic gonadotropin or gonadotropin-releasing hormone (luteinizing hormone-releasing hormone) deficiency or from pituitary-hypothalamic injury caused by tumors, trauma, or radiation.117 133 135 157 161 162 a Should be used in the treatment of hypogonadotropic hypogonadism only in patients uninterested in or unable to achieve fertility.f

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Considered the androgen of choice for the treatment of androgen deficiency (e.g., hypogonadism) and AIDS wasting in HIV-infected men.126

May be used to stimulate puberty when the diagnosis is well established in carefully selected males with delayed puberty (designated an orphan drug by FDA for this use).a 162

Some experts (e.g., American College of Rheumatology) recommend that men who develop low serum testosterone concentrations (<300 ng/mL) while receiving long-term corticosteroid therapy receive testosterone replacement therapy in an attempt to treat hypogonadism and possibly reduce the risk of corticosteroid-induced osteoporosis.122

Clinical evidence to date regarding testosterone therapy in aging men suggests some beneficial effects (e.g., on body composition, strength, bone density, frailty, cognitive function, mood, sexual function, quality of life), but risks relating to benign prostatic hyperplasia and prostate cancer need to be quantified.156 The Institute of Medicine states that the nature and extent of therapeutic benefits in older men require additional study.156

Not indicated for the treatment of erectile dysfunction in men with normal testosterone concentrations.158

Breast Cancer

Palliative treatment of androgen-responsive, advanced, inoperable, metastatic (skeletal) breast cancer in women who are 1–5 years postmenopausal and in premenopausal women who have benefited from oophorectomy.a 162

Poorly tolerated (see Virilization under Cautions); other hormonal agents (e.g., tamoxifen, anastrozole, letrozole, exemestane) currently are preferred for this use.d e

Misuse and Abuse

Has been misused and abused by athletes, bodybuilders, weight lifters, and others to enhance athletic performance or physique.100 101 102 103 104 105 106 107 108 109 110 111 112 114 115 116 120

Medical and sports experts (e.g., International Olympic Committee) consider such use to be inappropriate and unacceptable because of known adverse effects and potential long-term sequelae and because such use by athletes is contrary to the rules and ethical principles of athletic competition.101 102 107 114 115 116

Testosterone Enanthate Dosage and Administration

General

Male Hypogonadism

  • Individualize dosage according to the condition being treated; the severity of symptoms; the patient’s age, gender, and history of prior androgenic therapy; and the specific testosterone preparation being used.a

  • Monitor every 3–4 months during the first year of testosterone replacement and periodically thereafter (e.g., every 4–6 months) for response and tolerance.123

Delayed Puberty

  • Prior to initiation of therapy, fully discuss the potential risk of therapy with the patient and his parents.a 162

  • Take into consideration the chronological and skeletal ages of the patient, both in determining the initial dosage and in adjusting the dosage.117 162 a

  • Perform radiographic examination of the hand and wrist at 6-month intervals to determine the rate of bone maturation and to assess the effect of therapy on the epiphyseal centers.117 162 a (See Pediatric Use under Cautions.)

Breast Cancer

  • Administer only under supervision of a qualified clinician experienced in the treatment of breast cancer.162 a

  • May occasionally appear to accelerate progression of the disease;162 a monitor patients closely.162

  • Discontinue the drug if hypercalcemia occurs, since this may indicate progression of metastases to the bone.162

Administration

Administer testosterone topically or intrabuccally.133 157 161 166

Administer testosterone cypionate and testosterone enanthate by deep IM injection;117 162 not for IV administration.117

IM Administration

Administer by deep IM injection into the upper outer quadrant of the gluteus maximus.117 162

Topical Administration

Gel

AndroGel: Apply gel topically once daily, preferably in the morning, to clean, dry, intact skin on the shoulders and upper arms and/or abdomen.166 Do not apply to the genitals.166

AndroGel unit-dose packet: Upon opening the unit-dose packet, squeeze the entire contents into the palm of the hand and immediately apply to the application site.135 Alternatively, squeeze a portion of the contents into the palm of the hand and immediately apply to application site; repeat procedure until entire contents of the packet has been applied.135

AndroGel metered-dose pump: Collect gel in the palm of the hand by pressing the pump firmly and fully; apply to application site.135 This can be done one pump actuation at a time or after completion of all pump actuations needed for the daily dose.135 Alternatively, apply the gel directly to application site (direct application prevents loss of gel during transfer to hand).135 Prime pump by depressing 3 times before using the pump for the first dose; discard gel so that household members or pets are not exposed to the gel (i.e., rinse down sink).135

Testim: Apply gel topically once daily, preferably in the morning, to clean, dry, intact skin on the shoulders and/or upper arms157 Do not apply to abdomen or genitals.157 Upon opening the unit-dose tube, squeeze the entire contents into the palm of the hand and immediately apply to the application site.157

Immediately wash hands with soap and water after application of the gel.157 166 170 171

Allow the application site to dry for a few minutes after application of gel.166 170 171 After the gel has dried, cover site with clothing (e.g., a shirt) to prevent transfer to another individual.157 166

Manufacturer of AndroGel recommends waiting ≥5–6 hours166 and the manufacturer of Testim recommends waiting ≥2 hours after application before showering or swimming.157 However, showering or swimming after the elapse of just 1 hour should have a minimal effect on the amount of testosterone gel absorbed if done very infrequently.135

Wash the application site(s) thoroughly with soap and water to remove any testosterone residue prior to situations in which skin-to-skin contact with other individuals is anticipated at the site of testosterone gel application.170 171 If unwashed or unclothed skin at the site of testosterone gel application comes in contact with the skin of another individual, wash the general area of contact with soap and water as soon as possible.157 166 170 171

Consider the possibility of secondary exposure to testosterone topical gel.157 166 170 171 (See Virilization in Children and Women from Secondary Exposure to Testosterone under Cautions.)

Transdermal System

Apply the transdermal system to clean, dry area of skin on the back, abdomen, upper arm, or thigh by firmly pressing the system with the adhesive side touching the skin.133 Do not apply to the scrotum or to oily, damaged, or irritated areas of the skin.133 134

To avoid burn-like blisters, do not apply systems over bony prominences or on a part of the body that may be subject to prolonged pressure during sleep or sitting (e.g., the deltoid region of the upper arm, the greater trochanter of the femur, the ischial tuberosity).133

Apply once daily at night (e.g., 10 p.m.).133 Leave transdermal system in place for 24 hours; after 24 hours, remove system and apply a new system.133 Apply system immediately after removal from its protective pouch and removal of the protective liner.133

To minimize and/or prevent potential skin irritation, apply each transdermal system at a different site, with ≥1 week between applications to a particular site.133

Mild skin irritation may be ameliorated with topical hydrocortisone 0.5 or 1% cream after system removal; alternatively, apply a small amount of triamcinolone acetonide 0.1% cream to the skin under the drug reservoir (do not use ointment formulations because they may reduce testosterone absorption).133 143

Transdermal system does not need to be removed during sexual intercourse or while showering or bathing.133

Intrabuccal Administration

Press the extended-release buccal (transmucosal) tablet against the gum above the upper left or right incisor twice daily (morning and evening) about 12 hours apart.161 These tablets will adhere to the gum and do not dissolve completely; do not chew or swallow.161 Dislodge and remove the tablet after 12 hours.161 Alternate application sites above the left and right upper incisors.161

Consult manufacturer’s patient information for instructions on proper intrabuccal administration and removal of the tablet.161

If the tablet fails to properly adhere to the gum or falls off within the first 8 hours, replace the old tablet with a new one.161 The new tablet may remain in place until the time of the next regularly scheduled dose (i.e., 12 hours after the original buccal tablet was administered).161 If the buccal tablet falls off after 8 hours but before 12 hours, replace the original tablet with one that can serve as the second dose for that day.161

Dosage

Available as testosterone; dosage expressed in terms of testosterone.133 135 157 161 Also available as testosterone enanthate or testosterone cypionate; dosage expressed in terms of the salts.117 162

AndroGel unit-dose packets contain 2.5 or 5 g of gel (25 or 50 mg of testosterone).135 Each depression of the metered-dose pump delivers 1.25 g of gel (12.5 mg of testosterone) after priming.135

Testim unit-dose tubes contain 5 g of gel (50 mg of testosterone).157

Pediatric Patients

Male Hypogonadism
Delayed Puberty
IM

Dosage regimens vary.117 162 a Some clinicians recommend that lower dosages be used initially, followed by gradual increases in dosage as puberty progresses; subsequently, the dosage may be decreased to maintenance levels.117 162 a Other clinicians state that higher dosages are required initially to induce pubertal changes and lower dosages can then be used for maintenance therapy after puberty.117 162 a

Usual dosage of testosterone enanthate: 50–200 mg every 2–4 weeks for a limited period of time (e.g., 4–6 months).a 162

Adults

Male Hypogonadism
IM

Usual dosage: 50–400 mg of testosterone cypionate or testosterone enanthate every 2–4 weeks.117 162

Some clinicians recommend testosterone cypionate or testosterone enanthate dosage of 50–100 mg every 7–10 days or 100–150 mg every 2 weeks.f While dosage of 300 mg every 3 weeks also may be considered for convenience, such dosing is associated with wider testosterone fluctuations and generally is inadequate to ensure a consistent clinical response.123 Serum total testosterone concentrations generally should exceed lower limit of normal (in the range of 250–300 ng/dL) just before the next dose.123

Adult males with prepubertal onset of hypogonadism who are going through puberty for the first time with testosterone replacement: Initially, 50 mg every 3–4 weeks;f increase dosage gradually in subsequent months as tolerated up to full replacement within 1 year.123

Attainment of full virilization may require up to 3–4 years of IM testosterone replacement.123

Topical (Gel)

AndroGel and Testim: Apply 50 mg of testosterone (5 g of 1% gel) once daily, preferably in the morning; this dose delivers about 5 mg of testosterone systemically.135 157 Adjust dosage according to serum testosterone concentrations obtained at regular intervals after initiating daily application of AndroGel166 and approximately 14 days after initiating Testim.157

AndroGel: If serum testosterone concentrations are below the normal range or the clinical response is inadequate, the dosage can be increased initially to 75 mg of testosterone (7.5 g of 1% gel) and, if necessary, subsequently to 100 mg of testosterone (10 g of 1% gel).135 If serum testosterone concentrations exceed the normal range, the daily dosage may be decreased.166 If serum testosterone concentrations consistently exceed the normal range at a daily dosage of 50 mg of testosterone (5 g of 1% gel), discontinue application of the gel.166

Testim: If serum testosterone concentrations are below the normal range or the clinical response is inadequate, may increase dosage to 100 mg of testosterone (10 g of 1% gel).157

Topical (Transdermal System)

Usual initial dosage is 1 system delivering 5 mg/24 hours or 2 systems delivering 2.5 mg/24 hours applied to the skin nightly.133

Adjust dosage according to morning serum testosterone concentrations.133 Depending on requirements, increase dosage to 7.5 mg once daily (administered nightly as 1 system delivering 5 mg/24 hours plus 1 system delivering 2.5 mg/24 hours or as 3 systems delivering 2.5 mg/24 hours) or decrease dosage to 2.5 mg once daily (administered nightly as 1 system delivering 2.5 mg/24 hours).133

Intrabuccal

30 mg (1 extended-release transmucosal tablet) twice daily (morning and evening) about 12 hours apart.161 Serum testosterone concentration may be determined just prior to the morning dose at 4–12 weeks after initiation of intrabuccal therapy; if total serum testosterone concentration is excessive, discontinue intrabuccal therapy and consider alternative treatments.161

Breast Cancer
IM

200–400 mg of testosterone cypionate or testosterone enanthate every 2–4 weeks.162 a

Special Populations

No special population dosage recommendations at this time.157 166

Cautions for Testosterone Enanthate

Contraindications

  • Men with breast cancer or known or suspected prostate cancer.117 133 157 161 162 166

  • Known hypersensitivity to testosterone, testosterone cypionate, testosterone enanthate, or any ingredient in the formulation.117 133 157 161 162 166 a

  • Some manufacturers state that testosterone is contraindicated in patients with serious cardiac, renal, or hepatic disease.117

  • Manufacturers of testosterone cypionate and testosterone enanthate injections (preparations indicated for the treatment of breast cancer) state that androgens are contraindicated in women who are or may become pregnant.117 162

  • Manufacturers of testosterone gel (AndroGel, Testim) state that testosterone is contraindicated in women who are or may become pregnant, or who are breastfeeding.157 166

  • Manufacturers of buccal and transdermal testosterone preparations state that these preparations should not be used in women.133 161

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity

May cause fetal harm;117 133 157 162 166 dose-related virilization of the external genitalia (e.g., clitoral hypertrophy, abnormal vaginal development, fusion of genital folds to form a scrotal-like structure) of female fetus reported, particularly when exposure to androgens occurs during the 1st trimester.162 166 a

Virilization in Children and Women from Secondary Exposure to Testosterone

Virilization in children and women can occur following secondary exposure to testosterone in topically administered gel.170 171 172 173 Enlargement of penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age reported in children 9 months to 5 years of age during postmarketing surveillance of testosterone gel.167 168 169 170 171 172 173 Direct contact of children with testosterone gel application sites on men's skin reported in most cases.170 172 173 Secondary exposure to testosterone also possible from contact with items (e.g., shirts, bed linens) of men receiving testosterone gel.170 172 173 Signs and symptoms generally resolved with removal of testosterone exposure.169 170 171 172 In some cases, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronologic age.169 170 171

Children and women should avoid contact with application sites on the skin of men using testosterone gel.166 170 171 Consider also the possibility of secondary exposure from contact with items (e.g., shirts, bed linens) of men using testosterone gel.170 172 173

Risk of testosterone transfer in some cases increased by lack of adherence to precautions for appropriate use of testosterone gel.170 Advise men using topical gel to strictly adhere to the recommended instructions for use and appropriate precautions from the manufacturers to minimize the potential for secondary exposure to testosterone in other individuals.170 171 (See Administration under Dosage and Administration.)

If unwashed or unclothed skin to which testosterone gel has been applied comes in contact with the skin of another individual, wash the general area of contact with soap and water as soon as possible.157 166

Inform clinicians of inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, substantial increases in acne, or other signs of virilization in women.166 170 171 Consider the possibility of secondary exposure to testosterone as the cause of virilization in these patients.166 170 171 Discontinue testosterone gel promptly at least until the cause of virilization in such children and women is identified.170 171

Hepatic Effects

Potentially serious and/or life-threatening adverse hepatic effects (e.g., peliosis hepatis, hepatic adenomas, hepatocellular carcinoma, cholestatic hepatitis, jaundice) associated with prolonged use of high dosages of androgens (e.g., testosterone enanthate).117 133 134 135 157 161 162 Abnormal liver function tests (e.g., ALT, AST, gamma-glutamyltranspeptidase [GGTP], bilirubin) reported with AndroGel during postmarketing surveillance.166

If cholestatic jaundice or hepatitis occurs or if liver function test results become abnormal during therapy, discontinue the drug and investigate the etiology of these disorders.162 Drug-induced jaundice usually is reversible following discontinuance of the drug.162 Discontinuance of androgen therapy following development of hepatocellular carcinoma does not always result in regression of the tumor.117 133 135 157 161 162

GU Effects

Priapism or excessive sexual stimulation possible, especially in geriatric men.117 133 135 a Oligospermia and decreased ejaculatory volume may also occur in men receiving excessive dosage or prolonged administration of testosterone.117 a If any of these adverse effects occur, discontinue the drug temporarily.117 a If therapy is restarted, use lower dosages.117 a

Possible increased risk for the development of prostatic hyperplasia and prostate cancer, particularly in geriatric patients.117 133 134 135 157 161 162 Testosterone therapy has been associated with increases in PSA (of 0.3 ng/mL) in men with hypogonadism.135 163 Increased serum PSA concentrations observed in 18% of hypogonadal men receiving AndroGel for up to 42 months; most increases occurred within the first year of therapy.166 Evaluate geriatric patients and other patients with known clinical or demographic risk factors for prostate cancer for the presence of the disease prior to initiation of testosterone replacement therapy.133 135 157 161 162 Perform rectal prostate examinations at baseline and periodically thereafter.123 Baseline and annual determinations of PSA also recommended in older men, particularly in those >50 years of age.123

Acute urethral obstruction possible in patients with benign prostatic hypertrophy who receive IM testosterone cypionate.117

Gynecomastia frequently develops and occasionally persists.117 135 157 161 162 Consider concomitant use of an aromatase inhibitor or surgery.123

Postmarketing reports with AndroGel include impaired urination, prostatic enlargement, testicular atrophy, oligospermia, priapism, gynecomastia, and mastodynia.166

Fluid Retention

Edema, with or without CHF, possible as a result of sodium and water retention and may be a serious complication in patients with preexisting cardiac, renal, and/or hepatic disease.117 133 157 161 162 166 (See Contraindications under Cautions.)

If edema occurs and is considered a serious complication, discontinue the drug and, if necessary, initiate diuretic therapy.133 135 157 161 162 a

Hypercalcemia

Possible hypercalcemia resulting from osteolysis, especially in immobile patients and in women with metastatic breast cancer.161 166 a In patients with cancer, hypercalcemia may indicate progression of metastases to the bone.161 a Monitor urine and serum calcium concentrations frequently during the course of androgen therapy in women with metastatic breast cancer.162 166

If hypercalcemia occurs, discontinue the drug and institute appropriate measures to reduce serum calcium concentrations.162 a

Sleep Apnea

May potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.157 161 166

If manifestations of sleep apnea occur or worsen during therapy, perform sleep studies.123 144 If sleep apnea is confirmed, decrease the dosage or discontinue the drug.123 144

Some clinicians consider a history of sleep apnea to be a relative contraindication to testosterone therapy.123

Misuse and Abuse

Potential for serious adverse effects (e.g., increased aggression,100 101 102 104 107 108 109 116 antisocial behavior,100 101 102 104 107 108 109 116 manic episode,102 104 105 106 107 108 112 114 depression,102 104 105 106 107 108 112 114 changes in libido,101 102 107 109 116 increased risk of cardiovascular disease,100 101 102 104 107 108 111 112 114 116 119 hepatotoxicity100 101 102 104 107 108 109 110 112 114 116 ) associated with misuse and abuse of androgens (see Misuse and Abuse under Uses); testosterone preparations currently subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990 and 2004, as schedule III (C-III) drugs.113 164

Flammability

Testosterone gels contain alcohol and are flammable until dry; keep away from open flame.166

Sensitivity Reactions

Allergic contact dermatitis possible with transdermal systems.133 137 142 Topical application of testosterone gel (i.e., AndroGel) is not associated with phototoxicity.135 Hypersensitivity reactions (e.g., anaphylactoid reactions, skin manifestations) rarely reported with testosterone.a

General Precautions

Virilization in Women Receiving Testosterone Therapy

Virilization, including deepening of the voice, hirsutism, and clitoral enlargement, occurs commonly in females receiving testosterone therapy; these changes may not be reversible following discontinuance of the drug.162 a

Monitor women receiving testosterone therapy for signs of virilization (e.g., deepening of the voice, hirsutism, clitoromegaly, menstrual irregularities).161 If virilization occurs, discontinue therapy.161

See Virilization in Children and Women from Secondary Exposure to Testosterone under Cautions.

Lipid Abnormalities

Androgens may alter serum cholesterol concentration.117 162 Although lipid abnormalities generally do not develop during testosterone replacement therapy because of aromatization of testosterone to estradiol,123 consider the possibility that such changes could occur and use testosterone with caution in patients with a history of MI or CAD.162

Perform a lipid profile at baseline and after 6–12 months; adjust therapy accordingly.123 135 157 161 162 Changes in serum lipid profiles may require dosage adjustment or discontinuance of testosterone therapy.166

Hematologic Effects

Supraphysiologic concentrations of testosterone can stimulate erythropoiesis123 166 and may increase the risk for a thromboembolic event.166 Increases in hematocrit may require dosage reduction or discontinuation of testosterone.166 To detect polycythemia, perform periodic hemoglobin and hematocrit determinations in patients receiving long-term therapy.117 123 133 135 157 161 162

Some clinicians consider hyperviscosity to be a relative contraindication to testosterone therapy.123

Transfer of Topically Administered Testosterone to Other Individuals

Possible transfer of testosterone from patients treated with topical gel to their sexual partners or other individuals in close physical contact.157 166 (See Pregnancy and also see Virilization in Children and Women from Secondary Exposure to Testosterone under Cautions.)

Androderm transdermal system has an occlusive backing that prevents the partner from coming in contact with testosterone in the system; the system does not need to be removed during sexual intercourse.133 Transfer of the transdermal system itself from the patient’s body to that of his partner is unlikely.133

Specific Populations

Pregnancy

Category X.117 133 135 157 161 162 (See Fetal/Neonatal Morbidity and also see Contraindications under Cautions.)

Avoid transfer of testosterone from topical preparations of the drug to pregnant women.157 166 (See Virilization in Children and Women from Secondary Exposure to Testosterone under Cautions.)

If unwashed or unclothed skin to which testosterone topical gel has been applied comes in direct contact with the skin of a pregnant woman, wash the general area of contact with soap and water as soon as possible.157 166

Lactation

Not known whether testosterone is distributed into milk.162 Potential for serious adverse reactions in nursing infants.162 166 Testosterone also may adversely affect lactation.166 Discontinue nursing or testosterone enanthate injection taking into account the importance of the drug to the woman.162 Use of testosterone gel, transdermal system, and buccal tablets not recommended.117 133 157 161 166

Pediatric Use

Safety and efficacy not established for topical testosterone gel 157 166 or extended-release buccal (transmucosal) testosterone tablets in children <18 years of age;161 testosterone transdermal systems in males <15 years of age;133 or testosterone cypionate in children <12 years of age.117 Secondary exposure to testosterone in children can occur with use of testosterone gel in other individuals.170 171 (See Virilization in Children and Women from Secondary Exposure to Testosterone under Cautions.)

Testosterone enanthate injection may accelerate bone maturation without producing compensatory gain in linear growth, possibly resulting in compromised adult stature.162 a The younger the child, the greater the risk of testosterone compromising final mature stature.162 a Use with extreme caution in children and only under the supervision of a specialist who is aware of the adverse effects of testosterone on bone maturation.162 a 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.162 a

Geriatric Use

Possible increased risk of developing prostatic hypertrophy and prostate cancer during androgen therapy.117 133 157 166 161 a (See GU Effects under Cautions.)

Total amount of testosterone delivered over 24 hours in men 65–79 years of age following application of transdermal testosterone system (Androderm) was approximately 20% less than the average amount delivered in younger patients.133

Clinical studies evaluating testosterone enanthate injection (Delatestryl) and topical testosterone gel (AndroGel) have not included sufficient numbers of adults ≥65 years of age to determine whether geriatric patients respond differently than younger adults.162 166

No substantial differences in safety and efficacy of extended-release buccal (transmucosal) testosterone tablets (Striant)in geriatric patients relative to younger adults.161 Pharmacokinetic differences observed between geriatric and younger adults in studies with Striant, but not known whether these differences are clinically important.161

Insufficient long-term safety data with Delatestryl and AndroGel to determine the potential risks of cardiovascular disease, prostate cancer, and prostatic hyperplasia in geriatric adults.162 166

Common Adverse Effects

Acne, flushing of the skin, gynecomastia, increased or decreased libido, habituation, edema,a local irritation at the site of application (with topical or intrabuccal administration).133 137 138 139 140 143 157 161 166

Interactions for Testosterone Enanthate

Specific Drugs

Drug

Interaction

Comment

Anticoagulants, oral

Testosterone may potentiate the action of oral anticoagulantsa and decrease anticoagulant requirements117 133 162

Monitor INR and prothrombin time closely when androgen therapy is initiated or discontinued in patients receiving oral anticoagulants and adjust anticoagulant dosage as needed133 162 166 a

Corticotropin (ACTH) and corticosteroids

Increased risk of fluid retention and edema157 161 162 166

Use with caution, particularly in patients with cardiac, renal, and/or hepatic disease157 161 162 166

Insulin

Testosterone may decrease blood glucose concentrations and, therefore, insulin requirements in patients with diabetes117 133 157 161 162 166

Changes in insulin sensitivity or glycemic control may occur in patients receiving androgens166

Propranolol

IM testosterone cypionate may increase clearance of propranolol.135 157 174 Not known whether topically administered testosterone gel has potential for this interaction135 157

Oxyphenbutazone

Increased serum concentrations reported with concurrent androgen administration157

Testosterone Enanthate Pharmacokinetics

Absorption

Bioavailability

Testosterone is absorbed systemically through the skin following topical application as a gel135 157 or transdermal system123 133 137 145 146 147 148 149 150 151 152 and through the gum and cheek following administration as an extended-release buccal (transmucosal) tablet.161

Following oral administration, bioavailability is low secondary to metabolism in the GI mucosa during absorption and on first pass through the liver.a

Following topical application of testosterone gel (AndroGel 1%, Testim 1%) to the skin, the skin surface serves as a reservoir for sustained release of the hormone into systemic circulation; approximately 10% of a testosterone dose applied topically to the skin as the 1% gel is absorbed into systemic circulation.135 157

Cypionate and enanthate esters of testosterone are absorbed slowly from the lipid tissue phase at the IM injection site,117 162 a achieving peak serum concentrations about 72 hours after IM injection.a

Onset

Increases in serum testosterone concentrations are apparent within 30 minutes of topical application of a 100-mg testosterone dose of AndroGel gel; physiologic concentrations generally are achieved within 4 hours.135

Physiologic concentrations are achieved within 24 hours of topical application of a 50- or 100-mg testosterone dose Testim gel; percutaneous absorption continues for the entire 24-hour dosing interval.157

Following topical application of the transdermal testosterone system, peak plasma concentrations are achieved in 6–12 hours.133

Following application of an extended-release buccal (transmucosal) tablet, peak plasma concentrations are achieved in 10–12 hours.162

Duration

Following discontinuance of daily topical application of AndroGel gel, serum testosterone concentrations remain within the normal range for 24–48 hours but return to pretreatment levels by the 5th day after the last application.135

Testosterone concentrations return toward baseline within about 24 hours following removal of the transdermal system.133

Following removal of the extended-release buccal (transmucosal) tablet, serum testosterone concentrations decline to below normal range within 2–4 hours.161

Testosterone cypionate and enanthate have a prolonged (up to 2–4 weeks) duration of action following IM administration.a

Plasma Concentrations

Administration of 10 or 5 g of AndroGel gel daily results in average daily serum testosterone concentrations of 794 or 566 ng/dL, respectively, at day 30.135

Administration of 10 or 5 g of Testim gel daily results in average daily serum testosterone concentrations of 612 or 365 ng/dL, respectively, at day 30.157

In patients receiving the transdermal system, average daily serum testosterone concentrations reportedly are 498 ng/dL at steady state.133

In patients receiving the extended-release buccal tablet, average daily serum testosterone concentrations are 520–550 ng/dL at steady state.161

Distribution

Plasma Protein Binding

Approximately 30–40% of testosterone in plasma is bound to sex hormone binding globulin (SHBG), 2% remains unbound (free), and the rest is bound to albumin and other proteins.123 135 157 161

Special Populations

SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life.135 161

Elimination

Metabolism

Metabolized principally in the liver to various 17-ketosteroids via 2 different pathways.162 a

Elimination Route

Excreted principally in urine (90%) and also in feces (6%).117 133 135 157 161 162 a

Half-life

Testosterone: Plasma half-life ranges from 10–100 minutes.133 135 157 162 a

Testosterone cypionate after IM injection: Plasma half-life is approximately 8 days.117

Stability

Storage

Buccal (Transmucosal)

Extended-release Tablets

20–25°C.161 Protect from heat and moisture.161

Topical

Gel

25°C (may be exposed to 15–30°C).135 157

Transdermal System

25°C (may be exposed to 15–30°C).b

Parenteral

Injection

20–25°C.117 162 Protect from light;117 do not freeze.a

A precipitate may form if testosterone cypionate or testosterone enanthate injection is stored at low temperatures; the precipitate will dissolve after shaking and warming to room temperature.117 162

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Injection

Use of a wet needle or syringe may cause testosterone enanthate solutions to become cloudy; potency is not affected.162

Actions

  • Replaces diminished or absent endogenous testicular hormone in hypogonadal males.117 133 135 a

  • Endogenous androgens are essential hormones that are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics.117 133 135 157 161 162 a

  • Androgens are responsible for the growth spurt that occurs during adolescence and for the eventual termination of linear growth that results from fusion of the epiphyseal growth centers.117 133 135 157 161 162 a

  • Large doses of androgens may suppress spermatogenesis.117 133 135 157 161 162 a

  • Increases protein anabolism and decreases amino acid catabolism; improves nitrogen balance only when there is sufficient intake of calories and protein.117 133 135 157 161 162 a

  • Androgens reportedly stimulate the production of erythrocytes, apparently by enhancing production of erythropoietic-stimulating factor.117 133 135 157 161 162 a

Advice to Patients

  • Risk of virilization in females.133 157 161 162 166 Advise female patients receiving testosterone therapy and female partners of patients treated with topical testosterone preparations (e.g., gel, transdermal systems) to contact their clinician if they notice changes in body hair distribution, substantial increases in acne, or other manifestations of virilization.117 133 157 161 162 166

  • Risk of virilization in children resulting from secondary exposure to testosterone.166 167 168 169 170 171 172 173 Contact clinician if inappropriate changes in genital size, development of pubic hair, increased erections and libido, or aggressive behavior occur in children when transfer of topically administered testosterone gel from another individual is possible.117 133 157 161 162 166

  • Importance of children and women avoiding contact with application sites on the skin of men using testosterone gel.170 171 If contact with unwashed or unclothed skin at the site of testosterone gel application occurs with the skin of another individual, importance of washing the general area of contact with soap and water as soon as possible.135 157 170 171

  • Importance of promptly discontinuing testosterone gel when virilization occurs in children or women in contact with men using testosterone gel products until the cause of virilization is identified.170 171

  • Risk of developing benign prostatic hyperplasia or prostate cancer.157 166 Importance of evaluating patients for prostate cancer, especially geriatric patients and those with clinical or demographic characteristics associated with increased risk, prior to initiating and during testosterone therapy.157 166

  • Risk of priapism; importance of adult or adolescent males informing their clinician if too frequent or persistent penile erections occur.117 133 135 157 161 162

  • Importance of periodic assessments to determine the rate of bone maturation in prepubertal males receiving testosterone therapy for delayed puberty.161

  • Importance of patients informing their clinician of nausea, vomiting, changes in skin color, ankle swelling, or breathing disturbances (e.g., sleep apnea).117 133 135 157 161 162

  • Importance of instructing patients in the proper use (see Administration under Dosage and Administration) and disposal of testosterone preparations and of providing patients a copy of manufacturer’s patient information.133 135 157 161

  • Importance of advising patients receiving therapy with extended-release buccal tablets to regularly inspect the gum region where the tablet is applied and to report any abnormality to their clinician.161

  • For patients using gel preparations, importance of strictly adhering to the recommended instructions for use and precautions from the manufacturers.170 171

  • For patients using gel preparations, importance of washing hands immediately with soap and water following application of gel and covering the application site with clothing after allowing gel to dry.166 170

  • For patients using gel preparations, importance of avoiding fire, flames, and smoking until gel has dried.166

  • Importance of women informing their clinician if they are or plan to become pregnant or to breast-feed.117 133 135 157 161 162

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.117 133 135 157 161 162

  • Importance of informing patients of other important precautionary information.117 133 135 157 161 162 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Most preparations containing testosterone or its salts, esters, or ethers are subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990 and 2004, as schedule III (C-III) drugs.113 164 However, manufacturers of certain preparations containing androgenic anabolic steroid hormones (principally combinations that also include estrogens) have applied for and obtained for their products(s) an exemption from the record-keeping and other regulatory requirements of the Federal Controlled Substances Act.121 165 Under provisions of the Act, specific products can be exempted from such control by the Attorney General, in consultation with the Secretary of Health and Human Services, if the product is determined not to possess any significant potential for abuse because of concentration, preparation, combination, and/or delivery system. Because regulatory requirements for a given preparation containing an androgenic anabolic steroid may be subject to change based on these provisions, the manufacturer should be contacted when specific clarification about a preparation’s status is required.

Testosterone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Buccal (Transmucosal)

Tablets, extended-release

30 mg

Striant ( C-III)

Columbia

Topical

Gel

1%

AndroGel ( C-III)

Unimed

Testim ( C-III)

Auxilium

Transdermal system

2.5 mg/24 hour (12.2 mg/37 cm2)

Androderm ( C-III)

Watson

5 mg/24 hour (24.3 mg/44 cm2)

Androderm (C-III)

Watson

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Testosterone Cypionate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (in oil)

200 mg/mL*

Testosterone Cypionate ( C-III)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Testosterone Enanthate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (in oil)

200 mg/mL*

Delatestryl ( C-III)

Indevus

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Testosterone Propionate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

powder (c-iii)*

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Androderm 2MG/24HR Patches (WATSON LABS): 60/$352.00 or 180/$1,026.01

Androderm 4MG/24HR Patches (WATSON LABS): 30/$332.00 or 90/$965.99

AndroGel 50MG/5GM Gel (ABBOTT): 150/$368.97 or 450/$1,015.95

AndroGel Pump 1% Gel (ABBOTT): 150/$360.97 or 450/$986.92

AndroGel Pump 20.25 MG/ACT(1.62%) Gel (UNIMED): 75/$326.45 or 225/$959.76

First-Testosterone 2% Ointment (CUTIS PHARMA): 60/$55.99 or 180/$145.97

First-Testosterone MC 2% Cream (CUTIS PHARMA): 60/$53.19 or 180/$139.62

Striant 30MG Misc (ACTIENT PHARMACEUTICALS): 60/$357.90 or 180/$1,027.07

Testim 1% Gel (AUXILIUM PHARMACEUTICALS): 150/$330.00 or 450/$949.94

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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