Dosing & Uses
Dosage Forms & Strengths
injectable solution (cypionate): Schedule III
- 100mg/mL (Depo-Testosterone)
- 200mg/mL (Depo-Testosterone)
injectable solution (enanthate): Schedule III
- 50 mg/0.5mL (Xyosted)
- 75 mg/0.5mL (Xyosted)
- 100 mg/0.5mL (Xyosted)
- 200mg/mL (generic)
injectable solution (undecanoate): Schedule III
- 750mg/3mL (Aveed)
pellet implant: Schedule III
- 75mg (Testopel)
- 12.5mg, 25mg, 37.5mg, 50mg (generic)
Hypogonadism
Primary hypogonadism (congenital or acquired): Testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter Syndrome, chemotherapy, or toxic damage from alcohol or heavy metals; these men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above 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 men have low testosterone serum concentrations but have gonadotropins in the normal or low range
Testosterone cypionate: 50-400 mg IM every 2-4 weeks
Testosterone enanthate (generic): 50-400 mg IM every 2-4 weeks
Testosterone undecanoate (restricted availability): 750 mg IM initial dose, repeat after 4 weeks, and then q10wk thereafter
Pellet: 150-450 mg SC every 3-6 months; 150 mg of pellet approximately equivalent to 25 mg of testosterone propionate weekly
Xyosted
- Starting dose: 75 mg SC qWeek
- Adjust dose based upon total testosterone minimum (trough) concentrations (Cmin) (measured 7 days after most recent dose) obtained following 6 weeks of dosing and periodically thereafter
- Trough concentration (350-650 ng/dL) generally provides testosterone exposures in normal range during entire dosing interval
- Decrease dose by 25 mg if (Cmin) is ≥650 ng/dL Increase dose by 25 mg if the total testosterone Cmin <350 ng/dL
- Maintain same dose if total testosterone Cmin ≥350 ng/dL and <650 ng/dL
Delayed Puberty in Males
Testosterone enanthate (generic): 50-200 mg IM every 2-4 weeks for 4-6 months
Inoperable Mammary Cancer in Women
Testosterone enanthate (generic): 200-400 mg IM every 2-4 weeks
Androgen Deficiency in HIV+ Patients (Orphan)
Physiologic testosterone replacement in androgen-deficient HIV+ patients with associated weight loss
Orphan sponsor
- Watson Laboratories, Research Park, 417 Wakara Way, Salt Lake City, UT 8410
Delayed Growth (Orphan)
Treatment of constitutional delay in growth and puberty in adolescent boys aged 14-17 years (testosterone undecanoate)
Orphan sponsor
- SOV Therapeutics, Inc, 101 Guymon Court, Morrisville, NC 27560
Dosing Considerations
Prior to initiation: Confirm diagnosis of hypogonadism by ensuring serum testosterone has been measured in the morning on at least 2 separate days and that these concentrations are below the normal range
Limitations of use (Xyosted, Depo-Testosterone, Aveed)
- Safety and efficacy not established in adult males with “age-related hypogonadism” (also referred as “late-onset hypogonadism”)
Dosage Forms & Strengths
injectable solution (cypionate): Schedule III
- 100mg/mL (Depo-Testosterone)
- 200mg/mL (Depo-Testosterone)
injectable solution (enanthate): Schedule III
- 200mg/mL (generic)
injectable solution (undecanoate): Schedule III
- 250mg/mL (Aveed)
pellet implant: Schedule III
- 75mg (Testopel)
- 12.5mg, 25mg, 37.5mg, 50mg (generic)
Hypogonadism
<12 years
- Safety and efficacy not established
≥12 years
- Testosterone cypionate: 50-400 mg IM every 2-4 weeks
- Testosterone enanthate (generic): 50-400 mg IM every 2-4 weeks
- Pellet: 150-450 mg SC every 3-6 months; 150 mg of pellet approximately equivalent to 25 mg of testosterone propionate weekly
Delayed Puberty in Males
<12 years
- Safety and efficacy not established
≥12 years
- 50-200 mg IM every 2-4 weeks for 4-6 months
Dosing Considerations
Limitations of use (Xyosted, Aveed)
- Safety and efficacy not established in adult males with “age-related hypogonadism” (also referred as “late-onset hypogonadism”) and males <18 years
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
Frequency Not Defined
Acne
Abnormal dreams
Aggressive behavior
Alopecia
Anaphylaxis
Anger
Amnesia
Anxiety
Bladder irritability
Breast soreness
Deep venous thrombosis
Excessive frequency and duration of erection
Fatigue
Growth acceleration
Gynecomastia
Headache
Hirsutism
Hot flashes
Hypersensitivity
Hypercholesterolemia
Hypertension
Insomnia
Liver function alterations
Male pattern baldness
Menstrual irregularities
Priapism
Pruritus
Rash
Seborrhea
Suppression of factors II, V, VII, X
Vasodilation
Virilization
Water retention
Postmarketing Reports
Vascular Disorders: Venous thromboembolism
Reproductive system: Azoospermia, benign prostatic hyperplasia
Warnings
Black Box Warnings
Blood pressure increase
- Xyosted only
- Blood pressure (BP) increases reported that can increase the risk for major adverse cardiovascular events (MACE) (eg. nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) with greater risk for MACE in patients with cardiovascular risk factors or established cardiovascular disease
- Before initiating treatment, consider patient’s baseline cardiovascular risk and ensure adequate blood pressure controlled
- Starting ~6 weeks after initiating therapy, periodically monitor for and treat new onset hypertension or exacerbations of pre-existing hypertension
- Re-evaluate whether benefits outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease while on treatment
- Due to this risk, use only for treatment of men with hypogonadal conditions associated with structural or genetic etiologies
Serious pulmonary oil microembolism reactions and anaphylaxis
- Aveed only
- Serious pulmonary oil microembolism reactions (POME) (eg, urge to cough, dyspnea, throat tightening, chest pain, dizziness, syncope reactions and episodes) of anaphylaxis reported during or immediately after administration; may occur after first dose
- Observe patients for 30 minutes in healthcare setting to provide immediate medical treatment in event of serious POME reactions or anyphylaxis
- Because of risks of serious POME reactions and anaphylaxis, testosterone undecanoate is available through restricted program under a risk evaluation and mitigation strategy (REMS) called the Aveed REMS Program
Contraindications
Hypersensitivity to product or formulation components
Men with carcinoma of the breast or known or suspected carcinoma of the prostate
Severe cardiac, hepatic, or renal disease
Women: Pregnancy or prospect of pregnancy
Cautions
Do not use testosterone cypionate interchangeably with testosterone propionate
Breast cancer patients: Risk of hypercalcemia; discontinue if this condition develops
Long term use (>10 years) of parenteral testosterone for male hypogonadism may increase the risk of breast cancer
Caution in history of myocardial infarction (MI) or coronary artery disease (CAD); some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy
Testosterone has been subject to abuse, typically at doses higher than recommended for approved indication and in combination with other anabolic androgenic steroids; anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions; if testosterone abuse suspected, check serum testosterone concentrations to ensure they are within therapeutic range; consider possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events
Prolonged use of high-dose androgens associated with peliosis hepatitis and hepatic neoplasms (including hepatic cancer)
Risk of cholestatic hepatitis with jaundice; discontinue if this condition develops
Increased risk of benign prostatic hyperplasia (BPH) and prostate cancer; monitor patients with BPH for worsening of signs and symptoms of BPH
Risk of gynecomastia
May alter serum lipid profile (use caution in history of MI or coronary artery disease)
Use with caution in patients with diseases that may be exacerbated by fluid retention, including cardiac, hepatic, or renal dysfunction; testosterone may cause fluid retention; treatment of androgen deficiency syndromes is not recommended for men with uncontrolled or poorly controlled heart failure
May accelerate bone maturation and premature closure of epiphyses in children; in prebubertal children perform radiographic examination
Large doses may suppress spermatogenesis
May potentiate sleep apnea in some patients
Risk of priapism, excessive sexual stimulation, or acute urethral obstruction in patients with BPH
May decrease concentrations of thyroxine-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4; free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction
Increased hematocrit (polycythemia), reflective of increased red blood cell mass, may require discontinuation; increases risk for thromboemolism; monitor serum testosterone, prostate specific antigen (PSA), liver function, lipid concentrations, hematocrit and hemoglobin periodically
Skin burns reported at application site in patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI); because transdermal testosterone patch contains aluminum, it is recommended to remove system before undergoing MRI
Venous thromboembolism, including DVT and PE reported in patients using testosterone products; these observations have included patients with and without polycythemia; evaluate signs or symptoms consistent with DVT or PE; if venous thromboembolic event suspected, discontinue treatment with testosterone and initiate appropriate workup and management
Serious POME reactions reported to occur during or immediately after IM injection of testosterone undecanoate 1000 mg (4 mL) (see Black Box Warnings)
Due to lack of controlled evaluations in women and potential virilizing effects, not indicated for use in women
Depression and suicidal ideation and behavior, including completed suicide, have occurred during clinical trials
Testopel only: Postmarketing cases associated pellet(s) insertion with implant site infection (cellulitis and abscess), and/or pellet extrusion at or near implantation site; most reported cases occurred within the first month after implantation
Cardiovascular risks
- Evaluate patients for cardiovascular risk factors prior to initiating therapy and monitor closely for cardiovascular events during therapy; it may be prudent to avoid testosterone therapy in men who have experienced a cardiovascular event
- January 31, 2014: FDA is investigating risk of stroke, MI, and death in men taking prescription testosterone drugs; investigation was prompted by findings from 2 studies suggesting increased risk of MI in men who take testosterone
- In one study, analysis of 55,593 men with history of MI showed that men >65 years had 2-fold increase in MI risk within 90 days of filling initial prescription for testosterone drug; among younger men (<65 years) with history of heart disease, MI risk was increased 2- to 3-fold
- This study confirmed results of earlier, much smaller study, which found that older men, many with underlying heart disease, had 30% increased chance of death, MI, and stroke after receiving testosterone therapy
Drug interactions overview
- In diabetic patients, metabolic effects of androgens may decrease blood glucose and, therefore, may necessitate a decrease in dose of antidiabetic medication
- Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking warfarin, especially at initiation and termination of androgen therapy
- Concurrent use of testosterone with corticosteroids may result in increased fluid retention and carefully monitor, particularly in patients with cardiac, renal or hepatic disease.
- Some prescription medications and nonprescription analgesic and cold medications contain drugs known to increase blood pressure; coadministration of these medications may lead to additional increases in blood pressure
Pregnancy & Lactation
Pregnancy
Contraindicated in pregnant women
Teratogenic; may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action
Exposure of a female fetus to androgens may result in varying degrees of virilization
Animal data
- In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring
- These studies did not meet current standards for nonclinical development toxicity studies
Infertility
- During treatment with large doses of exogenous androgens, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis
- Observed reduced fertility in some men taking testosterone replacement therapy; impact on fertility may be irreversible
Lactation
Not indicated for women
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Endogenous androgen; promotes growth and development of male sex organs and maintains secondary sex characteristics in androgen-deficient males
Absorption
Peak plasma concentration: 790 ng/dL (Xyosted)
Peak plasma time: 11.9 hr (Xyosted)
AUC: 92,955 ng·hr/dL (Xyosted)
Steady state reached: 14 days (Aveed)
Distribution
Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin
Protein bound
- Xyosted and Aveed: ~40% (SHBG), 2% (free), and remaining is loosely bound to albumin and other proteins
- Depo-Testosterone and Testopel: 98% (SHBG); 2 % (free)
Metabolism
Testosterone undecanoate: Metabolized to testosterone via ester cleavage of undecanoate group
Testosterone enanthate: Metabolized to testosterone via ester cleavage of enanthate group
Testosterone is metabolized to various 17-keto steroids through two different pathways; major active metabolites of testosterone are estradiol and DHT
Elimination
Half-life: 8 days (Depo-Testosterone); 10-100 minutes (Testopel)
Excretion: Urine (90%); feces (6%)
Inactivation of testosterone occurs primarily in the liver
Administration
Implant Administration
Testopel only
Number of pellets to implant depends upon minimal daily requirements of testosterone propionate determined by a gradual reduction of amount administered parenterally
With lower requirements by injection, correspondingly lower amounts may be implanted; found approximately one-third of material is absorbed in the first month, one-fourth in the second month and one-sixth in the third month
Adequate effect of pellets ordinarily continues for 3-4 months, sometimes as long as 6 months
SC Administration
Xyosted only
SC use only; administer in abdominal region only
Avoid IM or IV injection
Visually inspect for particulate matter and discoloration prior to administration
Do not use if liquid is cloudy or if visible particles are present
Do not use if seal is broken
IM Administration
Depo-Testosterone and Aveed only
IM use only; administer IM deep in the gluteal muscle
Do not give IV
Between consecutive injections, alternate injection site between left and right buttock
Visually inspect for particular matter and discoloration prior to administration
Warming and shaking the vial redissolves any crystals that may have formed during storage at temperatures lower than recommended
Storage
All formulations: Store at room temperature 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in its original carton until the date indicated
Xyosted: Protect from light
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Patient Handout
Formulary
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