Testosterone cypionate

Testosterone is injected into a muscle. Testosterone injection is usually given every 2 to 4 weeks.

Misuse of testosterone can cause dangerous or irreversible effects, such as enlarged breasts, small testicles, infertility, high blood pressure, heart attack, stroke, liver disease, bone growth problems, addiction, and mental effects such as aggression and violence.

Testosterone injections should be given only by a healthcare professional.

The length of treatment with testosterone injection will depend on the condition being treated.

Testosterone will not enhance athletic performance and should not be used for that purpose.

While receiving testosterone, you will need frequent blood tests.

Testosterone can affect bone growth in boys who are treated for delayed puberty. Bone development may need to be checked with x-rays every 6 months during treatment.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Androgenic anabolic steroid hormone; the principal endogenous androgen.a

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 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

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 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 was 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

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

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 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 Manufacturer of testosterone transdermal system (Androderm) recommends evaluation for prostate cancer prior to therapy initiation, 3–6 months after initiation, and then in accordance with current standards of care.133

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

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

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

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

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

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

Long-term safety studies not conducted to date to determine the cardiovascular effects of testosterone replacement therapy in men.133 Epidemiologic data and results from randomized, controlled clinical trials inconclusive to date for determining risk of serious adverse cardiovascular events (i.e., nonfatal MI, nonfatal stroke, death) with testosterone use compared with nonuse.133

Based on review of data, FDA concluded that testosterone therapy is associated with possible increased risk of serious adverse cardiovascular events.175 177 178 179 180 181 182 183 Inform patients of this potential increased cardiovascular risk when deciding whether to use or continue to use therapy.133

Unclear whether potential cardiovascular risk is confined to a certain subset of patients; some experts suggest that clinicians use testosterone therapy with caution in patients at high risk for cardiovascular disease (e.g., older men, those with diabetes mellitus or obesity).176 Additional evidence needed to further elucidate the cardiovascular risk associated with testosterone use.175 176

Cardiovascular events (e.g., MI, stroke) reported during postmarketing experience with testosterone transdermal system (Androderm).133 Advise patients to immediately report symptoms suggestive of MI or stroke (e.g., chest pain, shortness of breath, unilateral weakness, difficulty talking) to their clinician.175

Venous thromboembolism (i.e., PE, DVT) reported during postmarketing experience with testosterone preparations, including testosterone transdermal system (Androderm).133 185 Evaluate patients reporting symptoms of pain, edema, warmth, erythema in a lower extremity for DVT, or presenting with acute shortness of breath for PE.133 If venous thromboembolism suspected, discontinue drug and institute appropriate evaluation and management.133

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.

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

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 discontinuance 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 Manufacturer of testosterone transdermal system (Androderm) recommends performing hematocrit determinations 3–6 months after therapy initiation and annually thereafter.133

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

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

Skin burns may occur at application site of testosterone transdermal system (Androderm) if worn during MRI, since system contains aluminum.133 Advise patients to remove the transdermal system before undergoing MRI.133

Specific Populations

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 was 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

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

Safety and efficacy not established for topical testosterone gel,157 166 extended-release buccal (transmucosal) testosterone tablets,161 or testosterone transdermal system in children <18 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

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), topical testosterone gel (AndroGel), and testosterone transdermal system (Androderm) have not included sufficient numbers of adults ≥65 years of age to determine whether geriatric patients respond differently than younger adults.133 162 166

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, AndroGel, and Androderm to determine the potential risks of cardiovascular disease, prostate cancer, and prostatic hyperplasia in geriatric adults.133 162 166

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

Storage

Buccal (Transmucosal)

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

Topical

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

20–25°C.133 Protect from excessive heat.133

Parenteral

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Risk of MI or stroke.133 175 Contact clinician if symptoms suggestive of MI or stroke (e.g., chest pain, shortness of breath, unilateral weakness, difficulty talking) occur.175

• 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.133 157 166 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.133 157 166

• Importance of informing patients that changes in urinary habits may occur with testosterone therapy, including increased urinary frequency, urgency, incontinence, nocturia.133

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

• 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.)

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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.

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

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

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

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

1. Known hypersensitivity to the drug
2. Males with carcinoma of the breast
3. Males with known or suspected carcinoma of the prostate gland
4. Women who are or who may become pregnant
5. Patients with serious cardiac, hepatic or renal disease

General

Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or excessive sexual stimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage. If any of these effects appear, the androgen should be stopped and if restarted, a lower dosage should be utilized.

Testosterone Cypionate should not be used interchangeably with testosterone propionate because of differences in duration of action.

Testosterone Cypionate is not for intravenous use.

Information for patients

Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, ankle swelling, too frequent or persistent erections of the penis.

Laboratory tests

Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in patients receiving long-term androgen administration.

Serum cholesterol may increase during androgen therapy.

Drug interactions

Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia.

Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.

In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

Drug/Laboratory test Interferences

Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Carcinogenesis

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

Pregnancy

Pregnancy Category X

(See CONTRAINDICATIONS.)

Benzyl alcohol can cross the placenta. See WARNINGS.

Nursing mothers

Testosterone Cypionate Injection is not recommended for use in nursing mothers.

Pediatric use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.