testosterone (Rx)

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

Contraindications

Hypersensitivity to product or formulation components

Men with carcinoma of the breast or known or suspected carcinoma of the prostate

Men with hypogonadal conditions (eg, “age-related hypogonadism”) that are not associated with structural or genetic etiologies; efficacy has not been established for these conditions, and testosterone can increase BP which can increase the risk of MACE

Women: Pregnancy or prospect of pregnancy

Cautions

May increase blood pressure (BP); before initiating, consider baseline cardiovascular (CV) risk and ensure BP is adequately controlled; check BP ~3 weeks after initiating or increasing dose and periodically thereafter; treat new-onset hypertension or exacerbations; reassess whether the benefits of continued treatment outweigh risks

Increased hematocrit (polycythemia) reflective of increases in RBC mass may require lower dose or discontinuation; evaluate hematocrit ~q3Months, and if elevated hold testosterone until hematocrit returns to normal; if testosterone restarted and again hematocrit increase, permanently discontinue testosterone; increased RBC mass may increase thromboembolic risk

Patients with BPH treated with androgens are at an increased risk for worsening of BPH signs and symptoms

Androgens may increase risk for prostate cancer; evaluate patients for prostate cancer before initiating and during treatment with testosterone

Venous thromboembolic events (VTE) reported, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone replacement; evaluate patients who report symptoms of pain, edema, warmth, and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE; if VTE suspected, discontinue testosterone and initiate appropriate workup and management

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 testosterone associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice); peliosis hepatis can be life-threatening or fatal; long-term therapy with IM testosterone enanthate has produced multiple hepatic adenomas; although not reported with other administration routes, monitor for signs or symptoms of hepatic dysfunction; promptly discontinue testosterone if jaundice occurs while evaluating cause

Gynecomastia may develop and persist in patients treated for hypogonadism

May alter serum lipid profile and require dose adjustment of lipid lowering drugs or discontinuing testosterone; monitor lipid profile, especially after starting testosterone

Androgens may promote sodium and water retention; edema, with or without CHF, may be a serious complication if pre-existing cardiac, renal, or hepatic disease exists; may necessitate discontinuing drug; consider diuretic therapy

Large doses may suppress spermatogenesis

May potentiate sleep apnea in some patients, especially patients who are obese or with chronic lung disease

Use androgens cautiously in patients with cancer with risk of hypercalcemia (and associated hypercalciuria); monitor serum calcium concentrations regularly during treatment

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

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

Aveed only: Serious POME reactions reported to occur during or immediately after IM injection of testosterone undecanoate 1000 mg (see Black Box Warnings)

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 risk

• Long term clinical safety trials have not been conducted to assess CV outcomes of testosterone replacement therapy
• As of March 2019, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of MACE (eg, non-fatal MI or stroke, CV death) with testosterone use compared with non-use
• Some studies, but not all, reported an increased risk of MACE associated with testosterone replacement therapy
• Testosterone can cause BP increases that can increase the risk of MACE

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

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.

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

Oral Administration

Jatenzo only

Take with food

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

The various testosterone salts are not interchangeable; check prescribing information if switching product

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

Jatenzo: Avoid exposing the capsules to moisture (store in a dry place)