Testosterone

Striant is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

• Primary hypogonadism (congenital or acquired) – testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
• Hypogonadotropic hypogonadism (congenital or acquired) –Gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency, or pituitary hypothalamic injury from tumors, trauma, or radiation. These patients have low serum testosterone levels but have gonadotropins in the normal or low range.

Limitations of use

• Safety and efficacy of Striant in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
• Safety and efficacy of Striant in males less than 18 years old have not been established [see Use in Specific Populations].

Adverse events are reported in this section by product. Adverse events reported during use of a given product may occur in patients who are treated with any TESTODERM (testosterone (transdermal)) product.

Adverse Events with TESTODERM (testosterone (transdermal)) TTS
In clinical studies of 457 participants (116 hypogonadal males and 341 healthy adult males) treated for up to 6 weeks with TESTODERM (testosterone (transdermal)) TTS, the most commonly reported adverse events were application site reactions of transient itching (12%) and moderate or severe erythema (3%).

Adverse events reported by less than 1% of TESTODERM (testosterone (transdermal)) TTS users in clinical trials that were of probable or unknown relationship to drug were:

Topical Reactions
Of 457 study participants, 3 men (1%) discontinued prematurely because of application site reactions.

There were no clinically significant differences in skin tolerability in younger (

Testosterone is a naturally occurring "male" sex hormone necessary for many processes in the body.

Testosterone buccal system is used to treat men with low testosterone levels.

Testosterone buccal system may also be used for purposes other than those listed in this medication guide.

Testosterone is a prescription medication used to treat low testosterone levels (hypogonadism) in men who do not produce enough natural testosterone. It may also be used to treat delayed puberty in adolescent males. Testosterone may also be administered to women to treat certain types of cancer.

Testosterone is a hormone that is usually produced by the body. It controls the growth, development, and function of male sexual organs and characteristics.

This medication comes in several topical forms for the skin, nose, and mouth that are applied to the body one to three times daily, depending on the dosage form.

This medication is also available in an injectable form to be given directly into a muscle (IM) by a healthcare professional.

Common side effects of testosterone include irritation and redness at the site of application, headache, acne, stomach pain, nervousness, hair loss, changes in mood and behavior, and changes in the ability to taste or smell.

Testosterone may be found in some form under the following brand names:

• Androderm

• AndroGel

• Aveed

• Axiron

• Delatest

• Delatestadiol

• Delatestryl

• Dep Androgyn

• Depo-Testadiol

• Depo-testosterone

• Depotest

• Depotestogen

• Duo-Cyp

• Dura-Dumone

• Duratest

• Duratestrin

• Estra-Testrin

• Everone

• Fortesta

• Histerone

• Meditest

• Natesto

• Striant

• Testamone-100

• Testim

• Testoderm

• Testolin

• Testopel

• Testro

• Testro AQ

• Testro-L.A.

• Virilon IM

• Virormone Injection

• Vogelxo

Before taking testosterone, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to testosterone or to any of its ingredients
• have or have had prostate cancer or an enlarged prostate
• have or have had breast cancer
• have sleep apnea
• have heart problems
• have diabetes
• have kidney disease
• have lung disease
• have liver disease
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

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

• 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

The following adverse reactions in the male have occurred with some androgens:
 
Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages.
 
Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne.
 

Cardiovascular Disorders – myocardial infarction, stroke

Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
 
Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis (see WARNINGS).
 
Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.
 
Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
 
Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions.
 
Vascular Disorders: venous thromboembolism

Miscellaneous: Inflammation and pain at the site of intramuscular injection.

Testosterone cypionate injection, USP is available as follows:

100 mg/mL         

10 mL Multiple-dose vials      NDC 62756-017-40

200 mg/mL

1 mL Single-dose vials           NDC 62756-015-40
10 mL Multiple-dose vials      NDC 62756-016-40

Vials should be store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Industries Ltd.

Halol-Baroda Highway,

Halol-389 350, Gujarat, India

ISS. 08/2017

PJPI0281I

(tes TOS ter one)

• Androgen

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

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

During treatment:

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

Bone mineral density:

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

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

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

Formulation-specific monitoring:

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

AndroGel 1.62%: Morning serum testosterone levels after 14 and 28 days of starting therapy or dose adjustments and periodically thereafter.

Androderm: Morning serum testosterone levels (following application the previous evening) ~14 days after start of therapy or dose adjustments.

Aveed: Monitor for 30 minutes after injection; appropriate treatment should be available in the event of a serious POME reaction or anaphylaxis. Measure testosterone level just prior to each subsequent injection and adjust dosing interval to maintain serum testosterone in mid-normal range (Endocrine Society [Bhasin 2010]).

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

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

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

Striant: Examine application area of gums; total serum testosterone 4 to 12 weeks after initiating treatment, prior to morning dose. Discontinue therapy if the total serum testosterone are consistently outside of the normal range (300 to 1,050 ng/dL).

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

Testopel: Measure at the end of the dosing interval (Endocrine Society [Bhasin 2010]).

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

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

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