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  • CLASSES

    Androgens
    Compounding Kits, Hormonal Agents

    BOXED WARNING

    Pulmonary oil microembolism

    Administration of testosterone undecanoate injection has been associated with cases of serious pulmonary oil microembolism (POME) reactions as well anaphylactoid reactions. Reported cases of POME reactions occurred during or immediately after intramuscular injection of testosterone undecanoate. Symptoms included: cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope. Most cases lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours, and some required emergency care and/or hospitalization. When administering testosterone undecanoate, clinicians should take care to inject deeply into the gluteal muscle, avoiding intravascular injection. In addition to POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported following the intramuscular injection of testosterone undecanoate. Patients with suspected hypersensitivity reactions should not be retreated with testosterone undecanoate. After every administration, monitor patient for 30 minutes and provide appropriate medical treatment in the event of serious POME or anaphylactoid reactions. Due to the risk of serious POME and anaphylaxis reactions, testosterone undecanoate injection (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed injection must be certified with the REMS Program for purposes of ordering or dispensing the product. Healthcare settings must also be certified with the REMS Program and must have the resources to provide emergency medical treatment in cases of serious POME and anaphylaxis. Further information is available at www.AveedREMS.com or call 1-855-755-0494 in the U.S.

    Cardiac disease, coronary artery disease, heart failure, hypertension, myocardial infarction, stroke, thromboembolism

    The FDA has alerted clinicians and the public of a possible increased cardiovascular risk associated with approved and unapproved uses of testosterone products.[58958] Testosterone is only approved for use in men with low testosterone concentrations due to medical conditions, and not exclusively due to aging. FDA labeled indications for testosterone replacement therapy include hypogonadism due to disorders of the testicles, pituitary gland, or brain. Before initiating testosterone, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least 2 separate days and that these serum testosterone concentrations are below the normal range. Clinicians should inform patients of the risk associated with therapy and counsel them on seeking immediate medical attention if they experience signs and symptoms of a cardiovascular event.[30060] [33698] [42603] [42676] [42931] [42932] [42691] [42677] [44211] [56803] [57334] [63592] Use testosterone with caution in men with coronary artery disease. Long-term clinical safety trials with testosterone products have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. Data from epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events, such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of these events in association with the use of testosterone replacement therapy in men.[30060] [33698] [42603] [42676] [42931] [42691] [42677] [42932] [44211] [56803] [57334] [63592] An observational study in the U.S. Veteran Affairs health system reported than 3 years after coronary angiography, 25.7% of patients receiving testosterone therapy suffered a severe and/or fatal cardiovascular event (MI, stroke, death) compared to 19.9% of patients not receiving therapy.[56670] A second observational study investigated the incidence of acute non-fatal MI following an initial testosterone prescription in both younger (55 years and younger) and older (65 years and older) adult males (n = 55,593). The incidence rate of MI occurring within 90 days following the initial testosterone prescription was compared to the incidence rate of MI occurring in the year leading up to the first prescription. Among older males, a 2-fold increase in the risk of MI was observed within the 90 day window; among younger males with a pre-existing history of heart disease, a 2- to 3-fold increased risk of MI was observed. In contrast, no increased risk was observed in younger males without a history of heart disease.[56671] Edema (due to sodium and fluid retention) with or without congestive heart failure may be a serious complication of testosterone therapy of any type in patients with preexisting cardiac disease. In addition to discontinuation of the drug, diuretic therapy may be required. Increased blood presssure has also been reported with testosterone therapy; patients receiving testosterone therapy who have a history of hypertension should be closely monitored.[30060] [33698] [42603] [42676] [42931] [42691] [42677] [42932] [44211] [56803] [57334] The testosterone enanthate subcutaneous injection carries a boxed warning, as it may cause hypertension that can increase the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular (CV) death. Because of this risk, use testosterone enanthate subcutaneous injection only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies. Before initiating testosterone enanthate subcutaneous injection, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled. Check BP approximately 6 weeks after initiating testosterone enanthate injection and periodically after that. Treat new-onset hypertension or exacerbations of pre-existing hypertension. Re-evaluate whether the benefits of treatment outweigh the risks in patients who develop cardiovascular risk factors or cardiovascular disease during treatment.[63592] In clinical trials, testosterone enanthate subcutaneous injection increased systolic blood pressure (BP) in the first 12 weeks of treatment by an average of 4 mmHg based on ambulatory blood pressure monitoring (ABPM) and by an average of 4 mmHg from baseline following 1 year of treatment on BP cuff measurements. In the 1-year trial, 10% of patients treated with this injection were started on antihypertensive medications or required changes to their antihypertensive medication regimen. These BP increases can increase the risk of MACE, with greater risk in patients with established cardiovascular disease or risk factors for CV disease. In some patients, the increase in BP may be too small to detect, but can still increase the risk for MACE.[63592] Additional risks associated with testosterone therapy of any type are venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE). 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 a venous thromboembolic event is suspected, discontinue treatment and initiate appropriate workup and management.[30060] [33698] [42603] [42676] [42931] [42691] [42677] [42932] [44211] [56803] [57334] [63592]

    Accidental exposure, females

    Accidental exposure to topical testosterone gel has occurred in pediatric patients after contact between the child and the application site in treated individuals. Strict adherence to the recommended handling of clothing and application site care can limit the risk of accidental exposure; patients should be encouraged to practice these recommendations to avoid exposing other persons to the drug. The FDA recommends taking precautions to minimize the potential for accidental exposure of topical testosterone products by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible. The adverse events reported from accidental exposure in pediatric patients include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. Accidental exposure to females of any age may result in virilization. In clinical studies, within 2 to 12 hours of application by male subjects, 15-minute sessions of vigorous skin-to-skin contact with a female partner resulted in serum female testosterone levels more than 2 times the female baseline values. When clothing covered the treated site on the male, the transfer of testosterone to the female was avoided.[42603] Testim testosterone gel is specifically contraindicated for use in females; the drug is for males only; the dosage form supplies testosterone in excess of what should be prescribed to females under certain endocrine situations.[42677] Most branded products are not indicated for use in females due to lack of controlled evaluations and/or the potential for virilizing effects.[30060] [33698] [42603] [42691] [42931] [56803] [63592] Female patients receiving other forms of testosterone therapy should be closely monitored for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). At high doses, virilization is common and is not prevented by concomitant use of estrogens. Some virilization may be judged to be acceptable during treatment for breast carcinoma; however, if mild virilism is evident, discontinuation of drug therapy is necessary to prevent long-term virilization.[42676]

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Primary androgen in humans synthesized by testes, ovaries, and adrenal cortex; available in a variety of dosage forms
    Primarily used in males with primary hypogonadism or with hypogonadism due to medical conditions; may be used for a limited duration for constitutional delay of puberty
    Not for use for low testosterone status exclusively due to aging in men due to potential risk for cardiovascular events and stroke

    COMMON BRAND NAMES

    Andro-L.A., Androderm, AndroGel, Aveed, AXIRON, Delatestryl, Depo-Testosterone, First - Testosterone, First - Testosterone MC, FORTESTA, Natesto, STRIANT, Testim, Testopel, Virilon, Vogelxo, XYOSTED

    HOW SUPPLIED

    Androderm/Testosterone Transdermal Film ER: 2mg, 4mg, 24h
    AndroGel/FORTESTA/Testim/Testosterone/Vogelxo Transdermal Gel: 0.5g, 1%, 1.62%, 10mg
    Andro-L.A./Aveed/Delatestryl/Depo-Testosterone/Testosterone Cypionate/Testosterone Enanthate/Virilon Intramuscular Inj Sol: 1mL, 100mg, 200mg, 250mg
    AXIRON/Testosterone Topical Sol: 1.5mL, 30mg
    Natesto Nasal Gel: 1actuation, 5.5mg
    STRIANT Buccal Tab ER: 30mg
    STRIANT Transmucosal Tab ER: 30mg
    Testopel Subcutaneous Imp: 75mg
    Testosterone Enanthate Subcutaneous Inj Sol: 0.5mL, 50mg, 75mg, 100mg

    DOSAGE & INDICATIONS

    For androgen replacement therapy in males with hypogonadism (primary and hypogonadotropic types).
    The safety and efficacy of testosterone in men with age-related hypogonadism (late-onset hypogonadism) have not been established.
    For the treatment of hypogonadism (primary and hypogonadotropic types).
    Subcutaneous dosage (testosterone enanthate subcutaneous injection only, i.e. Xyosted)
    Adult Males

    Initially, 75 mg subcutaneously in the abdominal region once weekly. Measure total testosterone trough concentrations (measure 7 days after the most recent dose) following 6 weeks of dosing, following 6 weeks after dose adjustment, and then periodically during treatment. A trough concentration between 350 ng/dL and 650 ng/dL generally provides testosterone exposures in the normal range during the entire dosing interval. DOSE ADJUSTMENTS: Decrease the dose by 25 mg is the total testosterone trough concentration is 650 ng/dL or greater. Increase the dose by 25 mg if the total testosterone trough concentration is less than 350 ng/dL. Maintain the same dose if the total testosterone trough concentration is 350 ng/dL to 649 ng/dL.[63592]

    Intramuscular dosage (testosterone undecanoate injection only; i.e., Aveed)
    Adult males

    Initially, 750 mg IM. After 4 weeks, give a repeat dose of 750 mg IM, then 750 mg IM every 10 weeks thereafter.

    Intramuscular dosage (testosterone cypionate or testosterone enanthate)
    Adult males

    50 to 400 mg intramuscularly once every 2 to 4 weeks.

    Adolescents

    For the initiation of pubertal growth: 40 to 50 mg/m2 IM monthly until the growth rate falls to prepubertal levels. For the terminal growth phase: 100 mg/m2 IM monthly until growth ceases. Maintenance of virilization may be achieved with a dose of 100 mg/m2 IM twice monthly.

    Topical gel dosage (only for AndroGel 1%)

    AndroGel topical gels are not interchangeable. Dosage and administration for AndroGel 1% differs from AndroGel 1.62%.

    Adult males

    Initially 5 g of 1% gel (containing 50 mg of testosterone and delivering 5 mg of testosterone systemically) applied once daily (preferably in the morning) to clean, dry, intact skin of the upper arms and/or abdomen. Measure serum testosterone level 14 days later to ensure proper dosage. If the serum testosterone level is below the normal range or if the desired clinical response is not achieved, may increase to 7.5 g of gel once daily (containing 75 mg of testosterone and delivering 7.5 mg/day of testosterone systemically), and then to 10 g of gel once daily (containing 100 mg of testosterone and delivering 10 mg/day of testosterone systemically) as clinically indicated. The maximum dosage is 10 g/day of gel based on clinical trials.

    Topical gel dosage (only for AndroGel 1.62%)

    AndroGel topical gels are not interchangeable. Dosage and administration for AndroGel 1.62% differs from AndroGel 1%.

    Adult males

    Initially, 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet) applied once daily in the morning to clean, dry, intact skin of the shoulders and upper arms. Measure serum testosterone level at 14 and 28 days after starting or adjusting dose. DOSE ADJUSTMENT: If the serum testosterone level is less than 350 ng/dL, increase daily dose by 20.25 mg (1 pump actuation or a single 20.25 mg packet); if 350 to 750 ng/dL, no dose change; if greater than 750 ng/dL, reduce daily dose by 20.25 mg (1 pump actuation or a single 20.25 mg packet). Measure serum testosterone periodically thereafter. Max: 81 mg/day (4 pump actuations or 2 of the 40.5 mg packets).

    Topical gel dosage (only for Testim)
    Adult males

    Initially 5 grams gel (one tube containing 50 mg of testosterone and delivering 5 mg of testosterone systemically) applied once daily (preferably in the morning) to clean, dry, intact skin of the shoulders and/or upper arms. Measure morning serum testosterone levels roughly 14 days later to ensure proper dosage. DOSAGE ADJUSTMENT: If the serum testosterone level is below the normal range or if the desired clinical response is not achieved, may increase to 10 grams (2 tubes, delivering a total of 10 mg/day testosterone systemically) applied once daily. Max: 10 grams/day.

    Topical gel dosage (only for Fortesta)
    Adult males

    Initially, 40 mg (4 pump actuations) applied once daily in the morning to clean, dry, intact skin of the front and inner thighs. Titrate based on serum testosterone concentration drawn 2 hours after application on approximately days 14 and 35 after treatment initiation or dose adjustments. DOSE ADJUSTMENT: If the serum testosterone concentration is 2,500 ng/dL or greater, decrease the daily dose by 20 mg (2 pump actuations); if 1,250 to less than 2,500 ng/dL, decrease the daily dose by 10 mg (1 pump actuation); if 500 to less than 1,250 ng/dL, continue current dose; and if level less than 500 ng/dL, increase the daily dose by 10 mg (1 pump actuation). Minimum dose: 10 mg/day. Max: 70 mg/day.

    Topical solution dosage (i.e., Axiron and generics)
    Adult males

    Initially, 60 mg (2 pump actuations) applied once daily (preferably in the morning) to clean, dry, intact skin of the axilla. Measure serum testosterone concentration at 14 days later and draw 2 to 8 hours after application to ensure proper dosage. Target testosterone concentration: 300 to 1,050 ng/dL. DOSE ADJUSTMENT: If the testosterone concentration is less than 300 ng/dL, may increase to 90 mg once daily (3 pump actuations) or from 90 mg/day to 120 mg (4 pump actuations) once daily. If the serum testosterone concentration is more than 1,050 ng/dL while the patient is applying 60 mg/day, then decrease to 30 mg/day. If the serum concentration is more than 1,050 ng/dL while the patient is applying 30 mg/day (lowest) dose, then discontinue.

    Transdermal dosage (only for Androderm transdermal patch)
    Adult males

    Initiate with 1 patch of the 4 mg/day system (not two 2 mg/day systems) applied nightly to an area of dry, clean skin on the upper arms, thighs, back or abdomen. The patch should be worn for 24 hours. Approximately 2 weeks following initiation or any dose change, measure the early morning serum testosterone concentration following system application the previous evening. DOSE ADJUSTMENT: If the serum concentration is outside the target range of 400 to 930 ng/dL, increase the daily dose to 6 mg (i.e., one 4 mg/day and one 2 mg/day system) or decrease the daily dose to 2 mg (i.e., one 2 mg/day system), maintaining nightly application.

    Buccal Administration (only for Striant)
    Adult males

    Apply one 30 mg buccal system twice daily to the gum region just above the incisor tooth, approximately every 12 hours. When applying a new system, the old system should be removed and discarded. Follow package instructions to ensure adhesion. The site of application should be rotated to alternate sides of the mouth with each application.

    Intranasal administration (only for Natesto)
    Adult males

    Administer 11 mg gel (2 pump actuations; 1 actuation per nostril) intranasally 3 times daily for a total of 33 mg/day [administer once in the morning, once in the afternoon, and once in the evening (6 to 8 hours apart, preferably at the same times each day]. Measure serum total testosterone concentrations periodically, starting 1 month after initiating treatment. When total testosterone concentrations consistently exceed 1,050 ng/dL, discontinue testosterone therapy. If total testosterone concentration is consistently less than 300 ng/dL, consider alternate therapy.

    Subcutaneous dosage (Testopel Pellets)
    Adolescent and Adult males

    Generally, 150 to 450 mg (2 to 6 pellets) is inserted subcutaneously by a health care professional every 3 to 6 months. The dosage is based on individual requirements and the gradual reduction of the amount administered parenterally. Therapeutic effects of the pellets typically lasts for 3 to 4 months, but sometimes as long as 6 months.

    For the treatment of constitutional delay of growth and puberty (CDGP), a common cause of delayed puberty in males.
    Intramuscular dosage (testosterone cypionate or testosterone enanthate injection)
    Adolescent males

    50 to 200 mg intramuscularly once every 2 to 4 weeks for a limited period. Or, 40 to 50 mg/m2/dose intramuscularly monthly for 6 months. Patients are not routinely treated since these patients represent a normal variant in pubertal timing and usually have favorable outcomes for final height and reproductive capacity. Adolescent males are selected to receive a short course of testosterone therapy if psychological problems are exacerbated by the delay.

    Subcutaneous dosage (Testopel Pellets)
    Adolescent males

    Generally, 150 to 450 mg (2 to 6 pellets) is inserted subcutaneously by a health care professional every 3 to 6 months. For delayed puberty, the lower end of the dosing range is typically sufficient. Treatment is usually only required for 4 to 6 months. Patients are not routinely treated since these patients represent a normal variant in pubertal timing and usually have favorable outcomes for final height and reproductive capacity. Adolescent males are selected to receive a short course of testosterone therapy if psychological problems are exacerbated by the delay.

    For palliative treatment of breast cancer that is inoperable in women.
    Intramuscular dosage (testosterone cypionate or testosterone enanthate)
    Adults

    200 to 400 mg intramuscularly once every 2 to 4 weeks.

    MAXIMUM DOSAGE

    Adults

    Dependent on indication for therapy.

    Elderly

    Dependent on indication for therapy.

    Adolescents

    Dependent on indication for therapy.

    Children

    Dependent on indication for therapy.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Generally, androgen use is contraindicated in patients with severe hepatic dysfunction. Specific guidelines for dosage adjustment in hepatic impairment are not available; use caution in patients with mild to moderate hepatic disease.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Other Oral Formulations

    Buccal Administration
    Striant Buccal System:
    Wash hands before and after application.
    The patient must not swallow the system.
    Application: Apply the Striant buccal system to the upper gum just above the incisor tooth on either side of the mouth, rotating the site of application to alternate sides of the mouth with each application. The rounded side surface of the buccal system should be placed against the gum and held firmly in place with a finger over the lip and against the product for 30 seconds to ensure adhesion. To remove, gently slide the buccal system downwards from the gum towards the tooth to avoid scratching the gum.

    Injectable Administration

    Many testosterone injections are for intramuscular use only. Do NOT administer intravenously or intravascularly.
    One testosterone enanthate injection product (Xyosted) is administered via subcutaneous injection only. Do NOT administer intravenously. Avoid intramuscular or intravascular injection.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Testosterone cypionate in oil injection:
    Testosterone cypionate injection is a clear, colorless to pale yellow solution in cottonseed oil. Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.
    Inject deep into the gluteal muscle. Take care to avoid intravascular injection.
    For subsequent injections, alternate injection site.
     
    Testosterone enanthate in oil injection:
    Testosterone enanthate injection is a clear, colorless to pale yellow solution in sesame oil.
    Inject deep into the gluteal muscle. Take care to avoid intravascular injection.
    Inject testosterone enanthate slowly. Use of a wet needle or wet syringe may cause the testosterone enanthate solution to become cloudy but will not alter potency.
    For subsequent injections, alternate injection site.
     
    Testosterone undecanoate injection (Aveed injection):
    Testosterone undecanoate injection is a clear, yellowish, sterile oily solution in refined castor oil.
    Withdraw 3 mL (750 mg) of the solution from the vial. Expel excess air bubbles from the syringe. Replace the syringe needle used to draw up the solution from the vial with a new intramuscular needle before injection.
    The site for injection is the gluteus medius muscle site located in the upper outer quadrant of the buttock. Care must be taken to avoid the needle hitting the superior gluteal arteries and sciatic nerve.
    Inject testosterone undecanoate slowly and deeply into the gluteus medius muscle as follows. Take care to avoid intravascular injection.
    Following antiseptic skin preparation, enter the gluteus medius muscle and maintain the syringe at a 90-degree angle with the needle in its deeply imbedded position.
    Grasp the barrel of the syringe firmly with 1 hand. With the other hand, pull back on the plunger and aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, immediately withdraw and discard the syringe and prepare another dose.
    If no blood is aspirated, reinforce the current needle position to avoid any movement of the needle and slowly (over 60 to 90 seconds) depress the plunger carefully and at a constant rate, until all the medication has been delivered. Be sure to depress the plunger completely with sufficient controlled force.
    Withdraw the needle. Immediately upon removal of the needle from the muscle, apply gentle pressure with a sterile pad to the injection site. If there is bleeding at the site of injection, apply a bandage.
    Monitor patient for 30 minutes following each injection in order to provide appropriate medical treatment in the event of serious pulmonary oil microembolism (POME) reaction or anaphylaxis.
    Discard any unused portion in the vial.
    For subsequent injections, alternate injection site between the right and left buttocks.

    Subcutaneous Administration

    Testosterone Enanthate Subcutaneous Injection (Xyosted)
    Testosterone enanthate injection is a clear, colorless to pale yellow solution in sesame oil. The product is a single-use auto-injector for weekly administration.
    For subcutaneous injection only.
    Do not use if the medicine is cloudy or if visible particles are present. You may notice an air bubble, this is normal.
    Do not remove the cap until ready to inject.
    Wash hands with soap and water.
    Wipe the abdomen injection site with an alcohol swab. Allow the site to dry on its own. Only use the left or right side of the abdomen for injection sites. Do not use the area within 2 inches around the navel. Do not use in areas where the skin is tender, bruised, red, scaly, or hard. Avoid areas with scars, tattoos, or stretch marks.
    Administering injection using Autoinjector:
    Twist the cap to remove it. You may notice a few drops of liquid, this is normal. The auto-injector should be used or discarded after the cap is removed. Do not re-cap for later use.
    Do not touch the needle end of the auto-injector with your hand or fingers after the cap is removed, doing so can cause injection and injury to your hands.
    Position the auto-injector and gently squeeze the abdomen injection site to create a raised area. Hold that area firmly until after the injection is complete. Place the needle end of the auto-injector on the abdomen injection site. Keep the auto-injector straight at a 90-degree angle to the abdomen injection site.
    Firmly push the auto-injector down on the abdomen site and continue to hold it down after you hear the "click". While holding the auto-injector down, slowly count from 1 to 10 to allow all of the medicine to be delivered. Keep holding the auto-injector down for a total of 10 seconds even if the injection is complete and the viewing window turns orange sooner.
    It is normal if there is slight bleeding from the site after injection. If this occurs, hold a cotton ball or gauze on the area for a few seconds. Do not rub the area.
    After injecting, inspect the viewing window of the auto-injector. It should be orange confirming the dose was administered. If the viewing window is not orange, do not use another auto-injector and do not attempt another injection. Call the healthcare provider or call the Xyosted information number 1-844-996-7833 for assistance.
    Rotate injection sites with each injection.
    Disposal: After completing the injection, dispose of the auto-injector and cap in an FDA-cleared sharps disposal container immediately after use; do not dispose of the auto-injector in the household trash.[63592]

    Other Injectable Administration

    Subcutaneous Implants
    Testosterone implant pellets (Testopel)
    Testosterone pellets are for subcutaneous implantation. Pellets may extrude or migrate from the insertion site if superficially implanted or if aseptic technique is not used.

    Topical Administration

    Apply topically for transdermal absorption as transdermal patches, skin gels, solutions, or ointments.
    Wash hands before and after application of any of these dosage forms. Take care not to touch the eyes or other mucous membranes.

    Cream/Ointment/Lotion Formulations

    General Administration Notes:
    For all products, allow the site to dry a few minutes before putting on clothing.
    In order to maintain serum testosterone levels in the normal range, washing, showering, and swimming should be avoided for 5 to 6 hours after applying AndroGel 1% and for 2 hours after applying Androgel 1.62%, Testim, or Fortesta.
    Direct contact of the gel-medicated skin with the skin of another person can result in the transfer of residual testosterone and absorption by the other person. This is particularly important for women or children that may come into contact with the treated area. Even a few minutes of contact may result in transfer of the drug. It is recommended that the treated area be clothed at all times prior to washing off residual drug. If direct skin-to-skin contact with another person is anticipated, the application sites must be washed thoroughly with soap and water. If another person comes in direct skin-to-skin contact with unwashed or unclothed treated skin, that person should wash the general area of contact with soap and water as soon as possible.
    Patients should be advised that topical gels are typically flammable; therefore, fire, flame, and smoking should be avoided during use.
     
    Administration of Specific Products:
    AndroGel 1% packet: Open packets needed for proper dosing. Squeeze the entire contents of the dose into the palm of the hand and then immediately apply to the skin site; alternatively, squeeze a portion of the gel from the packet into the palm of the hand and apply to the application sites, repeating until the entire contents of the packet have been applied. Apply once daily (preferably in the morning) to clean, dry skin on the shoulders, upper arm or the abdomen. Do not apply to the genitals.
     
    AndroGel 1% Pump: Each actuation of the metered dose pump dispenses 1.25 g of gel when fully depressed once (i.e., 4 pumps = 5 g; 6 pumps = 7.5 g; 8 pumps = 10 g) The pump must be primed before the first use by fully depressing the pump mechanism 3 times, and discarding any gel that is released during the priming. The entire dosage needed may be pumped into the palm of the hand and then immediately apply to the skin site or each individual actuation may be delivered into the palm of the hand and applied to the application sites, repeating until the entire dose has been applied. Alternatively, the gel can be directly applied to the application site which can prevent loss of product that may occur during transfer from the palm of the hand onto the application site. Apply once daily (preferably in the morning) to clean, dry skin on the shoulders, upper arm or the abdomen. Do not apply to the genitals.
     
    Androgel 1.62% packet: Open packets needed for proper dosing. Squeeze the entire contents of the dose into the palm of the hand and then immediately apply to the skin site or squeeze a portion of the gel from the packet into the palm of the hand and apply to the application sites, repeating until the entire contents of the packet have been applied. Alternatively, the gel can be directly applied to the application site which can prevent loss of product that may occur during transfer from the palm of the hand onto the application site. Apply dose once daily in the morning to clean, dry skin of the shoulders and upper arms. Limit the application site to the area that will be covered by a short sleeve T-shirt. Do not apply to other parts of the body including the abdomen, genitals, chest, armpits or knees.
     
    AndroGel 1.62% Pump: Each actuation of the metered dose pump dispenses 20.25 mg when fully depressed once (i.e., 1 pump = 20.25 mg; 2 pumps = 40.5 mg; 3 pumps = 60.75 mg; 4 pumps = 81 mg). The pump must be primed before the first use by fully depressing the pump mechanism 3 times, and discarding any gel that is released during the priming. Once primed, apply dose once daily in the morning to clean, dry skin of the shoulders and upper arms. Limit the application site to the area that will be covered by a short sleeve T-shirt. Do not apply to other parts of the body including the abdomen, genitals, chest, armpits or knees. Each individual actuation may be pumped into the palm of the hand and then applied to the skin site or pumped directly onto the application site. Regardless of method, apply the gel from one pump actuation to one shoulder and upper arm area, then apply each additional actuation to the alternate shoulder and upper arm area, repeating the application site as needed for dosage increases.
     
    Testim packet: Open packets needed for proper dosing. Squeeze the entire contents of the dose into the palm of the hand and then immediately apply to the skin site; alternatively, squeeze a portion of the gel from the packet into the palm of the hand and apply to the application sites, repeating until the entire contents of the packet have been applied. Apply once daily (preferably in the morning) to clean, dry skin on the shoulders and/or upper arm. Do not apply to the genitals or abdomen.
     
    Fortesta gel: Apply gel to clean, dry, intact skin of the front and inner thighs. Do not apply to the genitals or other parts of the body. Using one finger, gently rub gel evenly onto the front and inner area of each thigh as directed. Avoid the area adjacent to the scrotum, and limit the application site to the area that will be covered by shorts or pants. Allow the gel to dry completely and cover with clothing. The pump must be primed before the first use by fully depressing the pump mechanism 8 times and discarding any gel that is released during the priming. Once primed, each actuation of the metered dose pump delivers 10 mg of testosterone. Apply the gel from one actuation (1 pump = 10 mg testosterone) to one thigh, then apply each additional actuation to the alternate thigh, repeating the application site as needed for dosage increases.

    Transdermal Patch Formulations

    Androderm Transdermal System:
    Apply patch to a dry, clean area of skin on the upper arms, thighs, back or abdomen immediately after opening the pouch and removing the protective release liner. If the liner is difficult to pull off or if you see adhesive sticking to the liner, DO NOT use the patch, throw it away and get a new one.
    Press the system firmly in place, making sure there is good contact with the skin, especially around the edges.
    Do not apply to the scrotum or bony areas of the body. Do not apply to an area that is oily, damaged, or irritated. Also, avoid applying 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, and the ischial tuberosity).
    Washing, showering, and swimming should be avoided for a minimum of 3 hours after application.
    Rotate sites daily and do not reuse a site for 7 days.
    Removal of the Androderm patch before undergoing magnetic resonance imaging (MRI) is recommended because the patch contains aluminum.
    Mild skin irritation may be ameliorated by treatment of the affected skin with over-the-counter topical hydrocortisone cream applied after system removal. Additionally, applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the central drug reservoir of the Androderm transdermal system has been shown to reduce the incidence and severity of skin irritation. The administration of 0.1% triamcinolone acetonide cream does not significantly alter transdermal absorption of testosterone from the system. Ointment formulations should not be used for pretreatment as they may significantly reduce testosterone absorption.

    Other Topical Formulations

    Axiron topical solution:
    Using the provided applicator, apply the solution to clean, dry, intact skin of the axilla, preferably at the same time each morning. Do not apply to any other part of the body including the scrotum, penis, abdomen, shoulders, or upper arms. Allow the solution to dry completely before dressing. If an antiperspirant or deodorant is used for personal hygiene, apply these products at least 2 minutes before applying the topical solution. The pump must be primed before the first use by fully depressing the pump mechanism 3 times, and discarding any solution that is released during the priming. To dispense the solution, position the nozzle over the applicator cup and carefully depress the pump once fully; the cup should be filled with no more than 1 pump actuation (30 mg testosterone). With the applicator upright, place it up into the axilla and wipe steadily down and up into the axilla. Do not use fingers or hand to rub the solution. If multiple applications are necessary for the required dose, alternate application between the left and right axilla. When repeat application to the same axilla is necessary, allow the solution to dry completely before the next application. After use, rinse the applicator under running water and pat dry with tissue. Wash hands with soap and water.
    Following application, allow the site to dry a few minutes before putting on clothing.
    Direct contact of the medicated skin with the skin of another person can result in the transfer of residual testosterone and absorption by the other person. To reduce accidental transfer, the patient should cover the application site(s) with clothing (e.g., a T-shirt) after the solution has dried. The application site should be washed with soap and water prior to any skin-to-skin contact regardless of the length of time since application. In the case of direct contact, the other person should wash the area of contact with soap and water as soon as possible.
    Patients should be advised that the topical solution is flammable; therefore, fire, flame, and smoking should be avoided during use.
    Advise patients to avoid swimming or washing the application site until 2 hours following application of solution.

    Extemporaneous Compounding-Topical

    Extemporaneous compounding of a Testosterone Ointment or Cream:
    NOTE: The extemporaneous compounded testosterone ointment or cream is not approved by the FDA for topical administration.
     
    Ointment:
    Extemporaneously prepare 15 grams of a 2% ointment by using 3 mL of 100 mg/mL testosterone propionate injection and 12 grams of white petrolatum.
    To make 15 grams of a 5% ointment, use 7.5 mL of 100 mg/mL testosterone propionate injection and 7.5 grams of white petrolatum.
     
    Cream:
    Several commercial compounding kits are available. Follow the directions supplied with each kit for preparation instructions.

    Other Administration Route(s)

    Intranasal Administration
    Natesto Nasal Gel:
    Wash hands before and after application.
    For intranasal use only; do not administer to other parts of the body.
    For first time use of the Natesto nasal gel, prime the pump by depressing the pump 10 times over the sink and discarding any dispensed product. Wipe the tip of the dispenser clean with a dry tissue.
    Before administration, instruct patient to blow their nose and remove dispenser cap.
    Place the right index finger on the pump of the actuator and while in front of a mirror, slowly advance the tip of the actuator into the left nostril upwards until the finger on the pump reaches the base of the nose. Tilt the actuator so that the opening on the tip of the actuator is in contact with the lateral wall of the nostril to ensure that the gel is applied to the nasal wall.
    Slowly depress the pump until it stops; depress pump completely to administer a full actuation. Each actuation of the metered dose pump dispenses 5.5 mg of testosterone.
    Remove the actuator from the nose while wiping the tip along the inside of the lateral nostril wall to fully transfer the gel.
    Using the left index finger, repeat steps for administration of the next actuation, this time to the lateral wall of the right nostril.
    Wipe the tip of the actuator with a dry tissue, replace dispenser cap.
    Two actuations total (1 actuation in each nostril) will deliver 11 mg of testosterone.
    Press on the nostrils at a point just below the bridge of the nose and lightly massage.
    Do not blow the nose or sniff for 1 hour after administration of the intranasal gel.
    If any gel gets on the hands, it is recommended to wash hands with warm water and soap.
    Replace the nasal gel dispenser when the top of the piston inside the dispenser reaches the arrow at the top of the inside label. The inside label may be found by unwrapping the outer flap from around the container.

    STORAGE

    Androderm:
    - Do not store outside the pouch provided
    - Store between 68 to 77 degrees F
    AndroGel:
    - Flammable, keep away from heat and flame
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Andro-L.A.:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Aveed:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container
    AXIRON:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Delatestryl:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Depo-Testosterone:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    First - Testosterone:
    - Store at room temperature (between 59 to 86 degrees F)
    First - Testosterone MC:
    - Store at room temperature (between 59 to 86 degrees F)
    FORTESTA:
    - Do not freeze
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton
    Natesto:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    STRIANT:
    - Avoid exposure to heat
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Testim:
    - Flammable, keep away from heat and flame
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Testopel:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a cool, dry place
    Virilon:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vogelxo:
    - Flammable, keep away from heat and flame
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    XYOSTED:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not refrigerate
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Benzoic acid hypersensitivity, benzyl alcohol hypersensitivity, polyoxyethylated castor oil hypersensitivity, serious hypersensitivity reactions or anaphylaxis, sesame oil hypersensitivity, soya lecithin hypersensitivity

    There is a risk of serious hypersensitivity reactions or anaphylaxis with the use of testosterone undecanoate (Aveed) oil for injection. These allergic reactions can occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose. Observe patients in the healthcare setting for 30 minutes after an Aveed injection in order to provide appropriate medical treatment in the event of serious hypersensitivity reactions or anaphylaxis. The Aveed injection contains benzyl benzoate, the ester of benzyl alcohol and benzoic acid, and refined castor oil. Therefore, testosterone undecanoate use is contraindicated in patients with polyoxyethylated castor oil hypersensitivity, benzoic acid hypersensitivity, or benzyl alcohol hypersensitivity. Patients with suspected hypersensitivity reactions should not be re-treated with testosterone undecanoate injection. The testosterone enanthate injections are contraindicated in patients with sesame oil hypersensitivity. The manufacturers of certain testosterone products (i.e., AndroGel and Striant) state that their products are contraindicated in patients with soybean, soy, or soya lecithin hypersensitivity because they are derived partially from soy plants.

    Intravenous administration

    Do not inject any testosterone products via intravenous administration. Respiratory adverse events have been reported immediately after injection of testosterone enanthate and testosterone undecanoate. Care should be taken to ensure proper administration of the selected testosterone product.

    Pulmonary oil microembolism

    Administration of testosterone undecanoate injection has been associated with cases of serious pulmonary oil microembolism (POME) reactions as well anaphylactoid reactions. Reported cases of POME reactions occurred during or immediately after intramuscular injection of testosterone undecanoate. Symptoms included: cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope. Most cases lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours, and some required emergency care and/or hospitalization. When administering testosterone undecanoate, clinicians should take care to inject deeply into the gluteal muscle, avoiding intravascular injection. In addition to POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported following the intramuscular injection of testosterone undecanoate. Patients with suspected hypersensitivity reactions should not be retreated with testosterone undecanoate. After every administration, monitor patient for 30 minutes and provide appropriate medical treatment in the event of serious POME or anaphylactoid reactions. Due to the risk of serious POME and anaphylaxis reactions, testosterone undecanoate injection (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed injection must be certified with the REMS Program for purposes of ordering or dispensing the product. Healthcare settings must also be certified with the REMS Program and must have the resources to provide emergency medical treatment in cases of serious POME and anaphylaxis. Further information is available at www.AveedREMS.com or call 1-855-755-0494 in the U.S.

    Breast cancer, prostate cancer, prostatic hypertrophy

    Testosterone can stimulate the growth of cancerous tissue and is contraindicated in male patients with prostate cancer or breast cancer. Men with prostatic hypertrophy should be treated with caution because androgen therapy may cause a worsening of the signs and symptoms of benign prostatic hypertrophy and may increase the risk for development of malignancy. Patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In patients receiving testosterone therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men.

    Cardiac disease, coronary artery disease, heart failure, hypertension, myocardial infarction, stroke, thromboembolism

    The FDA has alerted clinicians and the public of a possible increased cardiovascular risk associated with approved and unapproved uses of testosterone products.[58958] Testosterone is only approved for use in men with low testosterone concentrations due to medical conditions, and not exclusively due to aging. FDA labeled indications for testosterone replacement therapy include hypogonadism due to disorders of the testicles, pituitary gland, or brain. Before initiating testosterone, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least 2 separate days and that these serum testosterone concentrations are below the normal range. Clinicians should inform patients of the risk associated with therapy and counsel them on seeking immediate medical attention if they experience signs and symptoms of a cardiovascular event.[30060] [33698] [42603] [42676] [42931] [42932] [42691] [42677] [44211] [56803] [57334] [63592] Use testosterone with caution in men with coronary artery disease. Long-term clinical safety trials with testosterone products have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. Data from epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events, such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of these events in association with the use of testosterone replacement therapy in men.[30060] [33698] [42603] [42676] [42931] [42691] [42677] [42932] [44211] [56803] [57334] [63592] An observational study in the U.S. Veteran Affairs health system reported than 3 years after coronary angiography, 25.7% of patients receiving testosterone therapy suffered a severe and/or fatal cardiovascular event (MI, stroke, death) compared to 19.9% of patients not receiving therapy.[56670] A second observational study investigated the incidence of acute non-fatal MI following an initial testosterone prescription in both younger (55 years and younger) and older (65 years and older) adult males (n = 55,593). The incidence rate of MI occurring within 90 days following the initial testosterone prescription was compared to the incidence rate of MI occurring in the year leading up to the first prescription. Among older males, a 2-fold increase in the risk of MI was observed within the 90 day window; among younger males with a pre-existing history of heart disease, a 2- to 3-fold increased risk of MI was observed. In contrast, no increased risk was observed in younger males without a history of heart disease.[56671] Edema (due to sodium and fluid retention) with or without congestive heart failure may be a serious complication of testosterone therapy of any type in patients with preexisting cardiac disease. In addition to discontinuation of the drug, diuretic therapy may be required. Increased blood presssure has also been reported with testosterone therapy; patients receiving testosterone therapy who have a history of hypertension should be closely monitored.[30060] [33698] [42603] [42676] [42931] [42691] [42677] [42932] [44211] [56803] [57334] The testosterone enanthate subcutaneous injection carries a boxed warning, as it may cause hypertension that can increase the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular (CV) death. Because of this risk, use testosterone enanthate subcutaneous injection only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies. Before initiating testosterone enanthate subcutaneous injection, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled. Check BP approximately 6 weeks after initiating testosterone enanthate injection and periodically after that. Treat new-onset hypertension or exacerbations of pre-existing hypertension. Re-evaluate whether the benefits of treatment outweigh the risks in patients who develop cardiovascular risk factors or cardiovascular disease during treatment.[63592] In clinical trials, testosterone enanthate subcutaneous injection increased systolic blood pressure (BP) in the first 12 weeks of treatment by an average of 4 mmHg based on ambulatory blood pressure monitoring (ABPM) and by an average of 4 mmHg from baseline following 1 year of treatment on BP cuff measurements. In the 1-year trial, 10% of patients treated with this injection were started on antihypertensive medications or required changes to their antihypertensive medication regimen. These BP increases can increase the risk of MACE, with greater risk in patients with established cardiovascular disease or risk factors for CV disease. In some patients, the increase in BP may be too small to detect, but can still increase the risk for MACE.[63592] Additional risks associated with testosterone therapy of any type are venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE). 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 a venous thromboembolic event is suspected, discontinue treatment and initiate appropriate workup and management.[30060] [33698] [42603] [42676] [42931] [42691] [42677] [42932] [44211] [56803] [57334] [63592]

    Obesity, pulmonary disease, sleep apnea

    The treatment of hypogonadal men with testosterone esters may potentiate sleep apnea, especially in patients that have risk factors for apnea such as obesity or chronic pulmonary disease.[30060] [33698] [42603] [42676] [42931] [42932] [42691] [42677] [44211] [56803] [57334] [63592] In addition, the safety and efficacy of testosterone topical solution and intranasal gel in obese males with a body mass index (BMI) greater than 35 kg/m2 has not been established.[42603] [57334]

    Polycythemia

    In patients receiving testosterone, check that hematocrit is not elevated prior to initiating therapy. Patients receiving high doses of testosterone are at risk for polycythemia. Periodically, patients receiving testosterone should have their hemoglobin and hematocrit concentrations measured to detect polycythemia. Evaluate hematocrit approximately every 3 to 6 months during therapy. If hematocrit becomes elevated, interrupt therapy until the hematocrit decreases to an acceptable level. A dose decrease may be warranted. If therapy is restarted and again causes hematocrit to become elevated, discontinue therapy permanently. Any increase in red blood cell mass may increase the risk of thromboembolic events.[30060] [33698] [42603] [42931] [42691]  [42677]  [44211] [56803] [57334] [63592]

    Hepatic disease, renal disease

    Androgens may promote retention of sodium and water. Edema may be a serious complication in patients with preexisting renal disease or hepatic disease. Testosterone should generally be avoided in patients with severe hepatic disease. Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. These events have not been reported with the use of topical, nasal, or transdermal testosterone products.[30060] [33698] [42603] [42931] [42691] [42677] [44211] [56803] [57334] [63592]

    Diabetes mellitus

    Androgen therapy, such as testosterone, can result in changes in insulin sensitivity or glycemic control and should be used with caution in patients with diabetes mellitus. The metabolic effects of androgens may decrease blood glucose and, therfore may decrease antidiabetic agent dosage requirements. Close monitoring of blood glucose is recommended.          

    Hypercalcemia

    Testosterone has induced osteolysis and should be used with caution in patients with hypercalcemia, which can be exacerbated in patients with metastatic breast cancer.       

    Depression, suicidal ideation

    Use testosterone with caution in patients with a history of depression. Depression and suicidal ideation and behavior, including completed suicide, have occurred during clinical trials in patients treated with testosterone enanthate subcutaneous injection. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behavior, new or worsening depression, anxiety, or other mood changes.

    Substance abuse

    Testosterone is subject to substance abuse. Physical and psychological dependence (i.e., addiction) are possible. Testosterone abuse is typically observed at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice. Testosterone abuse can lead to serious cardiovascular and psychiatric adverse reactions. Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented. If testosterone abuse is suspected, monitor serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone concentrations may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

    Magnetic resonance imaging (MRI)

    Because some testosterone transdermal systems (e.g., Androderm) contain aluminum or other metal components, patients should be instructed to remove the patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered.

    Nasal polyps, nasal septal perforation, nasal surgery, nasal trauma, rhinorrhea, Sjogren's syndrome

    Intranasal formulations of testosterone (e.g., Natesto) are not recommended for individuals with a history of nasal disorders such as nasal polyps; nasal septal perforation; nasal surgery; nasal trauma resulting in nasal fracture within the previous 6 months or nasal fracture that caused a deviated anterior nasal septum; sinus surgery or sinus disease. In addition, the safety and efficacy of intranasal testosterone has not been evaluated in individuals with mucosal inflammatory disorders such as Sjogren's syndrome. Patients with rhinorrhea (rhinitis) who are receiving intranasal formulations of testosterone may experience decreased medication absorption secondary to nasal discharge. These patients may experience a blunted or impeded response to the intranasal medication. In clinical evaluation, serum total testosterone concentrations were decreased by 21% to 24% in males with symptomatic allergic rhinitis, whether treated with nasal decongestants or left untreated. Treatment with intranasal testosterone should be delayed until symptoms resolve in patients with nasal congestion, allergic rhinitis, or upper respiratory infection. If severe rhinitis symptoms persist, an alternative testosterone replacement therapy is advised.

    Infertility

    Testosterone replacement therapy may reversibly reduce spermatogenesis in men, causing temporary infertility. The frequency of this potential adverse effect is not known. Oligospermia may occur in some men at high dosages.

    Accidental exposure, females

    Accidental exposure to topical testosterone gel has occurred in pediatric patients after contact between the child and the application site in treated individuals. Strict adherence to the recommended handling of clothing and application site care can limit the risk of accidental exposure; patients should be encouraged to practice these recommendations to avoid exposing other persons to the drug. The FDA recommends taking precautions to minimize the potential for accidental exposure of topical testosterone products by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible. The adverse events reported from accidental exposure in pediatric patients include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. Accidental exposure to females of any age may result in virilization. In clinical studies, within 2 to 12 hours of application by male subjects, 15-minute sessions of vigorous skin-to-skin contact with a female partner resulted in serum female testosterone levels more than 2 times the female baseline values. When clothing covered the treated site on the male, the transfer of testosterone to the female was avoided.[42603] Testim testosterone gel is specifically contraindicated for use in females; the drug is for males only; the dosage form supplies testosterone in excess of what should be prescribed to females under certain endocrine situations.[42677] Most branded products are not indicated for use in females due to lack of controlled evaluations and/or the potential for virilizing effects.[30060] [33698] [42603] [42691] [42931] [56803] [63592] Female patients receiving other forms of testosterone therapy should be closely monitored for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). At high doses, virilization is common and is not prevented by concomitant use of estrogens. Some virilization may be judged to be acceptable during treatment for breast carcinoma; however, if mild virilism is evident, discontinuation of drug therapy is necessary to prevent long-term virilization.[42676]

    Contraception requirements, labor, obstetric delivery, pregnancy, reproductive risk

    Testosterone is contraindicated during human pregnancy. Testosterone should not be administered during human pregnancy due to the possibility of virilization of the external genitalia of the female fetus. This virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is related to the amount of drug given and the age of the fetus, and is most likely to occur in the female fetus when the drugs are given in the first trimester. Contraception requirements are recommended in females who are receiving testosterone who are pre-menopausal; women of childbearing potential who are receiving testosterone treatments should utilize adequate contraception. If the patient becomes pregnant while taking these drugs, she should be apprised of the potential reproductive risk to the fetus. Because testosterone is not used during pregnancy, there should be no particular reason to administer the products to women during labor or obstetric delivery; safety and efficacy in these settings have not been established. Most products containing testosterone are for use in men only.

    Breast-feeding

    Testosterone topical solution, transdermal patches, and gels are contraindicated in lactating women who are breast-feeding. It is recommended that other testosterone formulations be avoided during breast-feeding.  Testosterone distribution into breast milk has not been determined; it is unclear if exposure would exceed levels of the hormone normally found in human milk. Significant exposure to testosterone via breast-feeding may have adverse androgenic effects on the infant and the drug may also interfere with proper establishment of lactation in the mother. Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy.

    Geriatric

    Testosterone replacement is not indicated in geriatric patients who have age-related low testosterone due to aging because there is insufficient safety and efficacy information to support such use. According to the Beers Criteria, testosterone is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided due to the potential for cardiac problems and its contraindication in men with prostate cancer. The Beers expert panel considers use of testosterone for confirmed hypogonadism with clinical symptoms as acceptable in geriatric patients.

    Children, infants, neonates

    Generally, the use of testosterone in prepubertal children should be undertaken with caution. The safety and efficacy Depo-Testosterone injection has not be established in children less than 12 years , and Androdem patches have not been evaluated in pediatric patients less than 15 years. The safety and efficacy of testosterone topical products Androgel, Axiron, Fortesta, and Testim as well as Striant buccal tablets, Natesto intranasal gel, Aveed injectable testosterone undecenoate, and Xyosted injectable testosterone enanthate have not been established in neonates, infants, children, and adolescents less than 18 years old. Testosterone may accelerate bone maturation without stimulating compensatory linear growth, sometimes resulting in compromised adult stature. If testosterone is administered to prepubertal males, radiographic examinations of the hand and wrist should be performed every 6 months to assess the rate of bone maturation and the effect of the drug on epiphyseal centers. Once the epiphyses have closed, growth is terminated. Even after discontinuation of treatment, epiphyseal closure can be enhanced for several months. Accidental exposure to topical testosterone gel has also occurred in pediatric patients after skin to skin contact between the child and the application site in treated individuals. The adverse events reported include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. The FDA recommends taking precautions to minimize the potential for accidental exposure by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible.

    ADVERSE REACTIONS

    Severe

    erythrocytosis / Delayed / 1.3-14.0
    prostatic hypertrophy / Delayed / 1.0-5.0
    pulmonary oil microembolism / Rapid / 0-0.3
    feminization / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    breast cancer / Delayed / Incidence not known
    stroke / Early / Incidence not known
    thromboembolism / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    apnea / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    hearing loss / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    epiphyseal closure / Delayed / Incidence not known
    virilization / Delayed / Incidence not known

    Moderate

    hypertension / Early / 1.0-12.7
    erythema / Early / 0-7.0
    contact dermatitis / Delayed / 1.6-4.0
    dysuria / Early / 0-3.0
    prostatitis / Delayed / 0-3.0
    hematuria / Delayed / 0-3.0
    depression / Delayed / 1.0-3.0
    confusion / Early / 0-3.0
    peripheral edema / Delayed / 0-2.7
    polycythemia / Delayed / 0-2.0
    edema / Delayed / 0-1.0
    memory impairment / Delayed / 0-1.0
    hostility / Early / 0-1.0
    amnesia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    wheezing / Rapid / 0-1.0
    bullous rash / Early / 0-1.0
    stomatitis / Delayed / 0-1.0
    impotence (erectile dysfunction) / Delayed / Incidence not known
    priapism / Early / Incidence not known
    infertility / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    peliosis hepatis / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    furunculosis / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 1.9-37.0
    pharyngitis / Delayed / 3.8-8.7
    skin irritation / Early / 0-8.0
    acne vulgaris / Delayed / 1.0-8.0
    rhinorrhea / Early / 3.8-7.8
    epistaxis / Delayed / 3.8-6.5
    vesicular rash / Delayed / 0-6.0
    headache / Early / 1.0-6.0
    nasal irritation / Early / 3.8-5.9
    parosmia / Delayed / 5.8-5.8
    nasal dryness / Early / 4.2-4.2
    dysgeusia / Early / 0-4.1
    nausea / Early / 0-4.0
    vomiting / Early / 0-4.0
    nasal congestion / Early / 3.9-3.9
    sinusitis / Delayed / 3.8-3.8
    mastalgia / Delayed / 0-3.0
    gynecomastia / Delayed / 1.0-3.0
    libido decrease / Delayed / 0-3.0
    infection / Delayed / 0-3.0
    polyuria / Early / 0-3.0
    fatigue / Early / 0-3.0
    emotional lability / Early / 1.0-3.0
    gastroesophageal reflux / Delayed / 0-3.0
    diarrhea / Early / 0-3.0
    insomnia / Early / 0-2.3
    irritability / Delayed / 0-2.0
    abdominal pain / Early / 0-2.0
    rash / Early / 0-2.0
    abnormal dreams / Early / 0-1.3
    hyperhidrosis / Delayed / 0-1.3
    appetite stimulation / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    hair discoloration / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    folliculitis / Delayed / 0-1.0
    gingivitis / Delayed / 0-1.0
    dental pain / Delayed / 0-1.0
    xerostomia / Early / 0-1.0
    lacrimation / Early / 0-1.0
    libido increase / Delayed / 10.0
    oligospermia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    nocturia / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    chills / Rapid / Incidence not known
    arthralgia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    back pain / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    oligomenorrhea / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Concomitant use of androgens or estrogens with abarelix is relatively contraindicated, as both could counteract the therapeutic effect of abarelix.
    Acarbose: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Alogliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Alogliptin; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Alogliptin; Pioglitazone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Alpha-glucosidase Inhibitors: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Ambrisentan: (Moderate) Ambrisentan is a substrate for P-glycoprotein (P-gp). The inhibition of P-gp, by drugs such as testosterone, may lead to a decrease in the intestinal metabolism and an increase in the oral absorption of ambrisentan. If ambrisentan is coadministered with a P-gp inhibitor, patients should be monitored closely for adverse effects.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if systemic testosterone and aprepitant, fosaprepitant are used concurrently and monitor for an increase in testosterone-related adverse effects for several days after administration of a multi-day aprepitant regimen. Topical preparations of testosterone are not expected to have this interaction. Testosterone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of testosterone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Atazanavir: (Minor) The plasma concentrations of testosterone may be significantly elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4. Testosterone is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Minor) Plasma concentrations of testosterone may be significantly elevated when administered with cobicistat. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while testosterone is a CYP3A4 and P-gp substrate. (Minor) The plasma concentrations of testosterone may be significantly elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4. Testosterone is a CYP3A4 substrate.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering testosterone with boceprevir due to an increased potential for testosterone-related adverse events. If testosterone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of testosterone. Testosterone is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated testosterone plasma concentrations.
    Cabozantinib: (Minor) Monitor for an increase in testosterone-related adverse reactions if coadministration of a systemic testosterone preparation with cabozantinib is necessary. Testosterone is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Interactions are not expected with topical testosterone preparations.
    Canagliflozin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Canagliflozin; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Carvedilol: (Moderate) Altered concentrations of testosterone and/or carvedilol may occur during coadministration. Carvedilol and testosterone are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Cobicistat: (Minor) Plasma concentrations of testosterone may be significantly elevated when administered with cobicistat. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while testosterone is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Minor) Plasma concentrations of testosterone may be significantly elevated when administered with cobicistat. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while testosterone is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Plasma concentrations of testosterone may be significantly elevated when administered with cobicistat. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while testosterone is a CYP3A4 and P-gp substrate.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and testosterone is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and testosterone is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions. Topical preparations of testosterone are not expected to have this interaction.
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and testosterone, a CYP3A4/P-gp substrate. Concurrent use may result in elevated testosterone serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as testosterone, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with testosterone. Treatment with testosterone may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Corticosteroids: (Moderate) Coadministration of corticosteroids and testosterone may increase the risk of edema, especially in patients with underlying cardiac or hepatic disease. Corticosteroids with greater mineralocorticoid activity, such as fludrocortisone, may be more likely to cause edema. Administer these drugs in combination with caution.
    Cyclosporine: (Moderate) Androgens may increase concentrations of cyclosporine, potentially increasing the risk of nephrotoxicity. Until further data are available, close monitoring of cyclosporine serum concentrations is prudent during coadministration with androgens.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with testosterone, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE), or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like testosterone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with testosterone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: (Minor) Systemic exposure of testosterone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of testosterone; monitor patients for potential adverse effects.
    Dapagliflozin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Dapagliflozin; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Dapagliflozin; Saxagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Darbepoetin Alfa: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to darbepoetin alfa, reducing the amount required to treat anemia.
    Darunavir: (Minor) The plasma concentrations of testosterone may be significantly elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4. Testosterone is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Minor) Plasma concentrations of testosterone may be significantly elevated when administered with cobicistat. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while testosterone is a CYP3A4 and P-gp substrate. (Minor) The plasma concentrations of testosterone may be significantly elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4. Testosterone is a CYP3A4 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Minor) Plasma concentrations of testosterone may be significantly elevated when administered with cobicistat. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while testosterone is a CYP3A4 and P-gp substrate. (Minor) The plasma concentrations of testosterone may be significantly elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4. Testosterone is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of testosterone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of testosterone, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor; it also inhibits P-gp. In addition, testosterone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of testosterone with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of testosterone, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor; it also inhibits P-gp. Paritaprevir also inhibits P-gp. In addition, testosterone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of testosterone with ritonavir may result in elevated plasma concentrations of testosterone and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and P-gp inhibitor. In addition, testosterone inhibits P-gp; ritonavir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together.
    Degarelix: (Major) Concomitant use of androgens with degarelix is relatively contraindicated, as androgens could counteract the therapeutic effect of degarelix.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Testosterone is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Edoxaban: (Moderate) Coadministration of edoxaban and testosterone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and testosterone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of testosterone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Minor) Administering testosterone with grazoprevir may result in elevated testosterone plasma concentrations. Testosterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Coadministration of testosterone and eliglustat may result in increased plasma concentrations of testosterone. Monitor patients closely for testosterone-related adverse effects. Testosterone is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Empagliflozin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Empagliflozin; Linagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Empagliflozin; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Epoetin Alfa: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Ertugliflozin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Ertugliflozin; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Ertugliflozin; Sitagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with testosterone. Testosterone is an inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Everolimus: (Major) Everolimus is an inhibitor and substrate of CYP3A4 and Pgp. Coadministration with inhibitors of Pgp, such as testosterone, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, testosterone is a substrate of CYP3A4. The effect of everolimus on testosterone pharmacokinetics has not been established; however, pharmacokinetic studies showed no significant impact of the coadministration of everolimus with the CYP3A4 and Pgp substrate atorvastatin.
    Fluconazole: (Minor) Testosterone concentrations may increase during fluconazole administration. Fluconazole is an inhibitor of CYP3A4, the hepatic microsomal isoenzyme responsible for metabolism of testosterone. The clinical significance of this interaction is unclear at this time.
    Fosamprenavir: (Moderate) Concomitant use of testosterone and fosamprenavir may result in elevated fosamprenavir and altered testosterone plasma concentrations. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and a substrate/inhibitor of the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is substrate/inducer of P-gp and a potent inhibitor/moderate inducer of CYP3A4.
    Glipizide; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Glyburide; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Goserelin: (Major) Goserelin inhibits steroidogenesis. Concomitant use of androgens, like fluoxymesterone, with goserelin is relatively contraindicated and would defeat the purpose of goserelin therapy.
    Histrelin: (Major) Avoid concurrent use of androgens with gonadotropin releasing hormone (GnRH) agonists such as histrelin. Histrelin inhibits steroidogenesis; concomitant use with androgens may counteract this therapeutic effect.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Testosterone cypionate has been shown to increase the clearance of propranolol in one study. Monitor patients taking testosterone and proprantolol together for decreased therapeutic efficacy of propranolol.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with testosterone, a CYP3A substrate, as testosterone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Incretin Mimetics: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Insulins: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Isavuconazonium: (Moderate) The plasma concentrations of testosterone may be elevated when administered concurrently with isavuconazonium. Clinical monitoring for adverse effects, such as libido changes and other hormone-induced effects, is recommended during coadministration. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp.
    Ixabepilone: (Minor) Testosterone is an inhibitor of and substrate for P-glycoprotein (Pgp). Ixabepilone is a mild inhibitor of and substrate for Pgp. Concomitant use of these agents may cause an increase in ixabepilone concentrations and/or an increase in testosterone concentrations. Caution is recommended if ixabepilone is coadministered with a Pgp inhibitor.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Leuprolide: (Major) Leuprolide inhibits steroidogenesis. While no drug interactions have been reported with leuprolide, therapy with androgens would be relatively contraindicated and would counteract the therapeutic effect of leuprolide.
    Leuprolide; Norethindrone: (Major) Leuprolide inhibits steroidogenesis. While no drug interactions have been reported with leuprolide, therapy with androgens would be relatively contraindicated and would counteract the therapeutic effect of leuprolide.
    Linagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Linagliptin; Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with testosterone, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with testosterone, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of testosterone with lopinavir; ritonavir may result in elevated plasma concentrations of testosterone and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and P-gp inhibitor, while lopinavir also inhibits P-gp. In addition, testosterone inhibits P-gp; ritonavir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of testosterone with ritonavir may result in elevated plasma concentrations of testosterone and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and P-gp inhibitor. In addition, testosterone inhibits P-gp; ritonavir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may alter the exposure of testosterone. Testosterone is a substrate of CYP3A and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of testosterone metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Maraviroc: (Moderate) Use caution and careful monitoring with the coadministration of maraviroc and testosterone as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); testosterone is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Meglitinides: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metformin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metformin; Pioglitazone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metformin; Repaglinide: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metformin; Rosiglitazone: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metformin; Saxagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Metformin; Sitagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Methoxy polyethylene glycol-epoetin beta: (Moderate) Androgens are known to stimulate erythropoiesis. Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient's response to MPG-epoetin beta, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Miglitol: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Mitotane: (Moderate) Use caution if mitotane and testosterone are used concomitantly, and monitor for decreased efficacy of testosterone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and testosterone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of testosterone. Topical preparations of testosterone are not expected to have this interaction.
    Nafarelin: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,nafarelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Testosterone inhibited the formation of paclitaxel metabolites in vitro. Combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of testosterone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of testosterone, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor; it also inhibits P-gp. In addition, testosterone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of testosterone with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of testosterone, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor; it also inhibits P-gp. Paritaprevir also inhibits P-gp. In addition, testosterone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of testosterone with ritonavir may result in elevated plasma concentrations of testosterone and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and P-gp inhibitor. In addition, testosterone inhibits P-gp; ritonavir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together.
    Oritavancin: (Minor) Testosterone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of testosterone may be reduced if these drugs are administered concurrently.
    Oxymetazoline: (Moderate) The drug interaction potential between intranasal testosterone (e.g., Natesto) and other intranasally administered drugs other than sympathomimetic decongestants is unknown. Therefore, concomitant use of intranasal testosterone with intranasal drugs other than sympathomimetic decongestants (e.g., oxymetazoline) is not recommended. Eighteen males with seasonal allergic rhinitis were treated with intranasal testosterone and randomized to receive oxymetazoline (30 minutes prior to intranasal testosterone) or no treatment. In general, serum total testosterone concentrations were decreased by 21-24% in males with symptomatic allergic rhinitis, due to the underlying condition. A mean decrease in AUC and Cmax (2.6% and 3.6%, respectively) for total testosterone was observed in males with symptomatic seasonal rhinitis when treated with oxymetazoline compared to untreated patients. Concomitant use of oxymetazoline does not impact the absorption of testosterone.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4 and a substrate for P-glycoprotein (Pgp). Testosterone is a substrate for CYP3A4 and an inhibitor of Pgp. Concurrent administration of testosterone and pazopanib may result in increased pazopanib concentrations and/or increased testosterone concentrations. Use caution when concurrent administration of testosterone and pazopanib is necessary.
    Posaconazole: (Major) Posaconazole and testosterone should be coadministered with caution due to an increased potential for adverse events. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and testosterone, ultimately resulting in an increased risk of adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of testosterone. Further, both testosterone and posaconazole are inhibitors and substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug.
    Pramlintide: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Propranolol: (Moderate) Testosterone cypionate has been shown to increase the clearance of propranolol in one study. Monitor patients taking testosterone and proprantolol together for decreased therapeutic efficacy of propranolol.
    Ranolazine: (Moderate) Testosterone is an inhibitor of P-glycoprotein transport. Ranolazine is a substrate of P-glycoprotein, and inhibitors of P-glycoprotein may increase the absorption of ranolazine. In addition, ranolazine inhibits CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4 such as testosterone.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and testosterone, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ritonavir: (Moderate) Concurrent administration of testosterone with ritonavir may result in elevated plasma concentrations of testosterone and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and P-gp inhibitor. In addition, testosterone inhibits P-gp; ritonavir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and testosterone may result in increases in rivaroxaban exposure and may increase bleeding risk. Testosterone is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Romidepsin: (Moderate) Romidepsin is a substrate for P-glycoprotein. Testosterone is an inhibitor of P-gp. Concurrent administration of romidepsin with an inhibitor of P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Sapropterin: (Minor) Caution is advised with the concomitant use of sapropterin and testosterone as coadministration may result in increased systemic exposure of testosterone. Testosterone is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of testosterone.
    Saw Palmetto, Serenoa repens: (Major) Drug interactions with Saw palmetto, Serenoa repens have not been specifically studied or reported. Saw palmetto extracts appear to have antiandrogenic effects. The antiandrogenic effects of Saw palmetto, Serenoa repens would be expected to antagonize the actions of androgens; it would seem illogical for patients taking androgens to use this herbal supplement.
    Saxagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    SGLT2 Inhibitors: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Simvastatin; Sitagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Sitagliptin: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with testosterone. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp).
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of testosterone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with testosterone. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp).
    Somatropin, rh-GH: (Moderate) Somatropin can induce (i.e., increase) the activity of cytochrome-mediated metabolism of antipyrine clearance in man. Thus, this predicts that somatropin may affect other drugs metabolized via this pathway, like testosterone.
    Soy Isoflavones: (Moderate) Theoretically, the soy isoflavones may counteract the activity of the androgens.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, CYP1A2, and potentially CYP2C9. Co-administration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes, including testosterone.
    Sulfonylureas: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering testosterone with telaprevir due to an increased potential for testosterone-related adverse events. Coadministration may result in elevated testosterone plasma concentrations. If testosterone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of testosterone. Testosterone is a substrate of the drug efflux transporter P-glycoprotein (P-gp) and of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor of both the efflux protein and the isoenzyme.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and testosterone is necessary, as the systemic exposure of testosterone may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of testosterone as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of testosterone if necessary. Testosterone is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and testosterone is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with testosterone, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as testosterone, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as testosterone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Thiazolidinediones: (Moderate) Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may decrease antidiabetic agent dosage requirements. Moniitor blood glucose and HbA1C when these drugs are used together.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and testosterone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and testosterone is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tolvaptan: (Major) Tolvaptan is a substrate for P-gp. Testosterone is an inhibitor of P-gp. Coadministration may result in increased exposure of tolvaptan; a reduction in the dose of tolvaptan may be required.
    Triptorelin: (Major) Gonadotropin releasing hormone (GnRH) agonists (i.e.,triptorelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and testosterone may result in altered concentrations of testosterone and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4 and a substrate/inhibitor of P-glycoprotein (PGP).Testosterone is a substrate of CYP3A4 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
    Vinblastine: (Minor) Testosterone is an inhibitor of the efflux transporter P-glycoprotein. Vinblastine is a P-glycoprotein substrate. Increased concentrations of vinblastine are likely if it is coadministered with testosterone; exercise caution.
    Vincristine Liposomal: (Major) Testosterone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Major) Testosterone inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Voriconazole: (Minor) Limited data suggest that testosterone concentrations increase during fluconazole administration. Although data are not available, a similar reaction may occur with voriconazole. Also, voriconazole is an inhibitor of CYP3A4, the hepatic microsomal isoenzyme responsible for metabolism of testosterone.
    Warfarin: (Moderate) Testosterone can increase the anticoagulant action of warfarin. Serious bleeding has been reported in some patients with this drug-drug interaction. Although the mechanism is unclear, testosterone may reduce procoagulant factors. Reduction of warfarin dosage may be necessary if testosterone therapy is coadministered. More frequent monitoring of INR and prothrombin time in patients taking such oral anticoagulants is recommneded, especially at the initiation and termination of androgen therapy. It is unclear if testosterone can augment the anticoagulant response to heparin therapy or if testosterone alters the effect of other non-coumarin oral anticoagulants in a similar manner.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and testosterone is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Testosterone topical solution, transdermal patches, and gels are contraindicated in lactating women who are breast-feeding. It is recommended that other testosterone formulations be avoided during breast-feeding.  Testosterone distribution into breast milk has not been determined; it is unclear if exposure would exceed levels of the hormone normally found in human milk. Significant exposure to testosterone via breast-feeding may have adverse androgenic effects on the infant and the drug may also interfere with proper establishment of lactation in the mother. Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy.

    MECHANISM OF ACTION

    Endogenous testosterone is responsible for sexual maturation at all stages of development throughout life. Synthetically, it is prepared from cholesterol. The function of androgens in male development begins in the fetus, is crucial during puberty, and continues to play an important role in the adult male. Women also secrete small amounts of testosterone from the ovaries. The secretion of androgens from the adrenal cortex is insufficient to maintain male sexuality.
     
    Increased androgen plasma concentrations suppress gonadotropin-releasing hormone (reducing endogenous testosterone), luteinizing hormone, and follicle-stimulating hormone by a negative-feedback mechanism. Testosterone also affects the formation of erythropoietin, the balance of calcium, and blood glucose. Androgens have a high lipid solubility, enabling them to rapidly enter cells of target tissues. Within the cells, testosterone undergoes enzymatic conversion to 5-alpha-dihydrotestosterone and forms a loosely bound complex with cystolic receptors. Androgen action arises from the initiation of transcription and cellular changes in the nucleus brought about by this steroid-receptor complex.
     
    Normally, endogenous androgens stimulate RNA polymerase, resulting in an increased protein production.These proteins are responsible for normal male sexual development, including the growth and maturation of the prostate, seminal vesicle, penis, and scrotum. During puberty, androgens cause a sudden increase in growth and development of muscle, with redistribution of body fat. Changes also take place in the larynx and vocal cords, deepening the voice. Puberty is completed with beard development and growth of body hair. Fusion of the epiphyses and termination of growth is also governed by the androgens, as is the maintenance of spermatogenesis. When endogenous androgens are unavailable, use of exogenous androgens are necessary for normal male growth and development.

    PHARMACOKINETICS

    Testosterone is administered intramuscularly, subcutaneously, and applied to the skin as a topical gel, solution, or transdermal systems for transdermal absorption, by implantation of long-acting pellets, or via buccal systems. In serum, testosterone is bound to protein. It has a high affinity for sex hormone binding globulin (SHBG) and a low affinity for albumin. The albumin-bound portion freely dissociates. The affinity for SHBG changes throughout life. It is high during prepuberty, declines during adolescence and adult life, then rises again in old age. The active metabolite DHT has a greater affinity for SHBG than testosterone. Elimination half-life is 10-100 minutes and is dependent on the amount of free testosterone in the plasma. Testosterone is metabolized primarily in the liver to various 17-keto steroids. It is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme. Estradiol and dihydrotestosterone (DHT) are the major active metabolites, and DHT undergoes further metabolism. Testosterone activity appears to depend on formation of DHT, which binds to cytosol receptor proteins. Further metabolism of DHT takes place in reproductive tissues. About 90% of an intramuscular testosterone dose is excreted in the urine as conjugates of glucuronic and sulfuric acids. About 6% is excreted in the feces, largely unconjugated. There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
    Testosterone is a substrate for CYP3A4. Testosterone is also a substrate and inhibitor of P-gp transport.

    Oral Route

    Oral Route
    Testosterone is absorbed from the GI tract, but because of extensive first-pass metabolism, oral bioavailability is poor. Thus, the drug is not administered by the oral route.
     
    Buccal Route
    Following application to the buccal mucosa, the buccal mucoadhesive system slowly releases testosterone where it is absorbed through gum and cheek surfaces that are in contact with the buccal system. Venous drainage from the mouth is to the superior vena cava, therefore transbuccal delivery of testosterone circumvents first-pass metabolism. Maximum testosterone concentrations are achieved within 10 to 12 hours of application of the system.

    Intramuscular Route

    Intramuscular parenteral testosterone formulations have been developed that reduce the rate of testosterone secretion, with esters being less polar and slowly absorbed from intramuscular sites. Esters have a duration of action of 2 to 4 weeks following IM administration. The esters are hydrolyzed to free testosterone, which is inactivated in the liver.

    Subcutaneous Route

    Subcutaneous Injection Route
    -Xyosted: Following weekly subcutaneous injection for 12 weeks, serum testosterone concentrations reached a maximum after a median of 11.9 hours post-dose (5.8 to 168.7 hours) then slowly declined. Steady state testosterone concentration was achieved by week 6. At week 12, the mean Cmax was 215 ng/dL, with a mean Tmax of 11.9 hours. The mean AUC (0 to 168 hour) was 21,385 ng/hour/dL.
     
    Subcutaneous Implant Route
    -Testopel: The duration of action of testosterone subcutaneous implantable pellets (Testopel) is usually 3 to 4 months, but may last as long as 6 months.

    Topical Route

    -Topical solution or gel: Roughly 10% of an applied topical dosage of testosterone skin gel or ointment is systemically absorbed with once daily dosing; absorption of the gel and solution from the skin occurs continually over the 24 hour dosing interval, which indicates that the skin acts as a reservoir for sustained-release. Application of testosterone solution or gel delivers physiologic circulating testosterone that resembles normal concentration range seen in healthy men. Steady-state concentrations are achieved after approximately 14 days of solution application; when the solution is stopped, pre-treatment testosterone concentrations are achieved in approximately 7 to 10 days.
     
    -Transdermal patches: Patches can be applied to any healthy skin site other than on the scrotum or bony areas. Daily application of two Androderm 2.5 mg skin patches in the late evening results in serum testosterone concentrations that approach those of healthy young men and follow normal circadian variation. The first day of dosing results in morning serum testosterone concentrations within the normal range. There is no testosterone accumulation with continued use. Following removal of the patch, hypogonadal status returns within 24 hours. Baseline serum testosterone concentrations may be reduced because endogenous secretion of testosterone may be suppressed by testosterone transdermal. The pharmacokinetic effects of showering after a single application of Androderm 4 mg/day were assessed in 16 hypogonadal males. Showering 3 hours after application increased the average concentration by 0.5% and decreased the Cmax by 0.4% respectively, as compared to not showering. The systemic exposure (AUC) was similar following applications with or without showering 3 hours after application.

    Other Route(s)

    Intranasal Route
    Following intranasal administration, maximum testosterone concentration is achieved within approximately 40 minutes. The average daily testosterone concentration produced by intranasal testosterone administration (33 mg total daily dose) and assessed on Day 90 of treatment was 421 (+/- 116) ng/dL. A half-life ranging from 10 to 100 minutes is observed following intranasal application.