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  • CLASSES

    Androgens
    Compounding Kits, Hormonal Agents

    BOXED WARNING

    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 for accidental exposure; patients should be encourage 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. 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. Most branded products are not indicated for use in females due to lack of controlled evaluations and/or the potential for virilizing effects. 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.

    Pulmonary oil microembolism

    Administration of testosterone undecanoate 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 a 1000 mg 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 (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed, 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.

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Primary androgen in humans synthesized by testes, ovaries, and adrenal cortex; available in a variety of dosage forms
    Used primarily for androgen replacement in males with hypogonadism due to medical conditions
    FDA warns against use for low testosterone status exclusively due to aging due to potential cardiovascular risk

    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

    HOW SUPPLIED

    Androderm 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

    DOSAGE & INDICATIONS

    For the treatment of delayed puberty in males.
    Intramuscular dosage (testosterone suspension or testosterone propionate)
    Adolescent males

    Up to 100 mg IM per month for a limited period, usually between 4—6 months. Different dosage schedules have been employed dependent on patients chronological and skeletal age, and response.

    Intramuscular dosage (testosterone cypionate or testosterone enanthate)
    Adolescents males

    50—200 mg IM once every 2—4 weeks for a limited period. Or, 40—50 mg/m2/dose IM monthly for 6 months.

    Subcutaneous dosage (Testopel Pellets)
    Adolescent males

    Generally, 150—450 mg (2—6 pellets) is inserted subcutaneously by a health care professional every 3—6 months, although the lower end of the dosing range is typically sufficient. Treatment is usually only required for 4—6 months. The dosage is based on the minimal daily requirements of testosterone propionate determined by a gradual reduction of the amount administered parenterally. For every 25 mg/week of testosterone propionate, 150 mg (2 pellets) should be implanted every 3—6 months. Therapeutic effects of the pellets typically lasts for 3—4 months but sometimes as long as 6 months. If testosterone therapy needs to be discontinued (e.g., for severe adverse reactions), the pellets should be removed by a health care professional.

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

    50—100 mg IM three times a week.

    Intramuscular dosage (testosterone cypionate or testosterone enanthate)
    Adults

    200—400 mg IM once every 2—4 weeks.

    For the treatment of postpubertal cryptorchidism†.
    Intramuscular dosage (testosterone suspension or testosterone propionate)
    Adult males

    10—25 mg IM two or three times per week.

    For the treatment of microphallus†.
    Intramuscular dosage (testosterone enanthate)
    Children

    25—50 mg IM once a month for 3—6 months.

    Topical dosage (testosterone propionate)
    Children

    Apply a 5% ointment topically to the penis twice daily for three months.

    For the treatment of anemia† in patients with chronic renal failure.
    Intramuscular dosage (testosterone enanthate)
    Adults

    Initially, 400 mg IM daily for one week, then 400 mg IM once or twice a week. Maintenance dose is 200—400 mg IM once every 4 weeks.

    For female-to-male gender change (trans-sexualism†).
    Intramuscular dosage (testosterone cypionate or testosterone enanthate)
    Adults

    200 mg IM once every 2 weeks. Higher doses may be required for cessation of menses.

    For the treatment of lichen sclerosus†.
    Topical dosage (testosterone ointment)
    Adults

    Apply a 1% or 2% ointment topically to the vulva twice daily for six weeks or until itching is relieved. Decrease dosage to minimum effective dose.

    For the treatment of AIDS-associated wasting syndrome†.
    Intramuscular dosage
    Adults

    In a randomized double-blind, placebo-controlled study, 51 HIV-positive men with AIDS-associated wasting syndrome were randomly assigned to receive testosterone enanthate 300 mg IM or placebo every 3 weeks for 6 months. Compared to patients treated with placebo, testosterone-treated patients had significant increases in lean body mass and an overall improvement in quality of life. In another study, the effects of testosterone enanthate (200 mg/week IM) or placebo, each with or without progressive resistance training three times weekly, were compared. Testosterone administration significantly increased lean body mass, muscle area, and muscle strength. Resistance exercise, independent of testosterone administration, also increased lean body mass and muscle area but had no effect on muscle strength; the increase in lean body mass with exercise alone was equivalent to the effects seen with anabolic steroids and lower doses of testosterone.

    †Indicates off-label use

    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

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Testosterone enanthate is a clear, colorless to pale yellow solution. For testosterone cypionate, warming and shaking the vial should re-dissolve any crystals that may have formed during storage at temperatures lower than recommended.

    Intramuscular Administration

    Aspirate before IM injection to avoid injection into a blood vessel. Inject deep into the gluteal muscle.
    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.
    While preparing for testosterone undecanoate injection, carefully remove the gray plastic cap from the top of the vial while leaving the aluminum metal ring and crimp seal around the gray rubber stopper in place. Inject testosterone undecanoate slowly (over 60—90 seconds) and deeply into the gluteus medius muscle. For subsequent injections, alternate injection site between the right and left buttocks. 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.

    Subcutaneous Administration

    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 subcutaneous 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

    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.
     
    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—6 hours after applying AndroGel 1% and for 2 hours after applying Adrogel 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. 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. In clinical studies, vigorous contact with a female partner for 15 minutes resulted in serum female testosterone levels > 2 times normal values. 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 topical gels are typically flammable; therefore, fire, flame, and smoking should be avoided during use.

    Transdermal Patch Formulations

    NOTE: 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.
     
    Androderm Transdermal System:
    NOTE: See Dosage to determine when it is appropriate to apply more than 1 patch to achieve a given daily dose.
    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. 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).
    Rotate sites daily and do not reuse a site for 7 days.
    Do not apply to an area that is oily, damaged, or irritated.
    Washing, showering, and swimming should be avoided for a minimum of 3 hours after application.
    Removal of the Androderm patch before undergoing magnetic resonance imaging (MRI) is recommended because the patch contains aluminum.

    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:
    NOTE: The extemporaneous compounded testosterone ointment is not approved by the FDA for topical administration.
    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.

    Other Administration Route(s)

    Buccal Administration
    Striant Buccal System:
    Wash hands before and after application.
    Take care not to 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.
     
    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 (one 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 at controlled room temperature (between 68 and 77 degrees F)
    AndroGel:
    - Store at controlled room temperature (between 68 and 77 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 controlled room temperature (between 68 and 77 degrees F)
    - Store upright
    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)
    - Store in carton until contents are used
    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 between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    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:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Testopel:
    - 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)
    - Store in carton until contents are used
    Vogelxo:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Benzoic acid hypersensitivity, benzyl alcohol hypersensitivity, polyoxyethylated castor oil hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis, soya lecithin 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. 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.

    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.

    Intramuscular administration, intravenous administration

    Testosterone injections are administered intramuscularly. Do not inject via intravenous administration. Respiratory adverse events have been reported immediately after intramuscular administration of testosterone enanthate and testosterone undecanoate. Care should be taken to ensure slow and deep gluteal muscle injection of testosterone.

    Breast cancer, geriatric, prostate cancer, prostatic hypertrophy

    Testosterone can stimulate the growth of cancerous tissue and is contraindicated in male patients with prostate cancer or breast cancer. Patients 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. Elderly patients and other 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. Testosterone replacement is not indicated in geriatric patients who have age-related hypogonadism only or andropause because there is insufficient safety and efficacy information to support such use. Additionally, the efficacy and long-term safety of testosterone topical solution in patients over 65 years of age has not been determined due to an insufficient number of geriatric patients involved in controlled trials. 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.

    Cardiac disease, coronary artery disease, heart failure, hepatic disease, myocardial infarction, renal disease, stroke

    Because of reduced drug clearance and an increased risk of drug accumulation, patients with hepatic disease or hepatic dysfunction should be prescribed testosterone with caution. In addition, edema secondary to water and sodium retention may occur during treatment with androgens. Use testosterone with caution in patients with hepatic disease; renal disease, including nephritis and nephrosis; preexisting edema; or cardiac disease, including heart failure, coronary artery disease, and myocardial infarction (MI), as fluid retention may aggravate these conditions. Long term clinical safety trials 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 use of testosterone replacement therapy in men. An observational study in the U.S. Veteran Affairs health system included adult male patients of an average age of 60 years. Patients (n = 8709) undergoing coronary angiography with a recorded low serum testosterone concentration of < 300 ng/dl were included in the retrospective analysis. Within the larger cohort, testosterone therapy was initiated in 1223 males after a median of 531 days following coronary angiography; 7486 males did not receive testosterone therapy. Three years after coronary angiography, 25.7% of patients receiving testosterone therapy compared to 19.9% of patients not receiving therapy suffered a severe and/or fatal cardiovascular event (MI, stroke, death). A second observational study, investigated the incidence of acute non-fatal MI following an initial testosterone prescription in both younger (<= 55 years) and older (>= 65 years) 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 one 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 cardiac 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 cardiac disease. Due to these findings, the FDA has alerted clinicians and the public of a possible increased cardiovascular risk associated with approved and unapproved uses of testosterone products. 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. Prior to initiating testosterone, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two 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.

    Obesity, pulmonary disease

    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. In addition, the safety and efficacy of testosterone topical solution and intranasal gel in obese males with BMI > 35 kg/m2 has not been established.

    Polycythemia

    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.

    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 for accidental exposure; patients should be encourage 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. 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. Most branded products are not indicated for use in females due to lack of controlled evaluations and/or the potential for virilizing effects. 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.

    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 as well. Testosterone distribution into breast milk has not been determined; it is unclear if exposure would increase above levels normally found in human milk. Significant exposure to this androgen 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. Historically, testosterone/androgens have been used adjunctively for lactation suppression. Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy.

    Diabetes mellitus

    Androgen therapy, such as testosterone, can result in loss of diabetic control and should be used with caution in patients with diabetes mellitus. 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.

    Pulmonary oil microembolism

    Administration of testosterone undecanoate 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 a 1000 mg 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 (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed, 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.

    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—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.

    Children, infants, neonates

    The safety and efficacy of testosterone topical products Androgel, Axiron, Fortesta, and Testim as well as Striant buccal tablets, Natesto intranasal gel, and Aveed injectable testosterone undecenoate have not been established in neonates, infants, children, and adolescents < 18 years old. In addition, the safety and efficacy Depo-Testosterone injection has not be established in children < 12 years , and Androdem patches have not been evaluated in pediatric patients < 15 years. Generally, the use of testosterone in children should be undertaken with caution. 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.

    Substance abuse

    Testosterone is a controlled substance that 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.

    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.

    ADVERSE REACTIONS

    Severe

    prostatic hypertrophy / Delayed / 1.0-5.0
    GI bleeding / Delayed / 2.0-2.0
    feminization / Delayed / Incidence not known
    epididymitis / Delayed / Incidence not known
    virilization / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    epiphyseal closure / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    erythrocytosis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    apnea / Delayed / Incidence not known

    Moderate

    erythema / Early / 0-7.0
    contact dermatitis / Delayed / 1.6-4.0
    hematuria / Delayed / 0-3.0
    prostatitis / Delayed / 0-3.0
    hypertension / Early / 1.0-3.0
    depression / Delayed / 1.0-3.0
    edema / Delayed / 0-1.0
    bullous rash / Early / 0-1.0
    stomatitis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    hostility / Early / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    hot flashes / Early / 1.0-1.0
    confusion / Early / 0-1.0
    impotence (erectile dysfunction) / Delayed / Incidence not known
    priapism / Early / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    dysuria / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    peliosis hepatis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    polycythemia / Delayed / Incidence not known
    furunculosis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 1.9-37.0
    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
    diarrhea / 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 / 1.0-3.0
    polyuria / Early / 0-3.0
    emotional lability / Early / 1.0-3.0
    asthenia / Delayed / 0-3.0
    rash (unspecified) / Early / 0-2.0
    hyperhidrosis / Delayed / 1.3-1.3
    alopecia / Delayed / 0-1.0
    diaphoresis / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    folliculitis / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    hair discoloration / Delayed / 0-1.0
    dental pain / Delayed / 0-1.0
    gingivitis / Delayed / 0-1.0
    xerostomia / Early / 0-1.0
    flushing / Rapid / 1.0-1.0
    malaise / Early / 0-1.0
    appetite stimulation / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    lacrimation / Early / 0-1.0
    insomnia / Early / 1.0-1.0
    musculoskeletal pain / Early / 0-1.0
    nausea / Early / 0-1.0
    dizziness / Early / 0-1.0
    pelvic pain / Delayed / 0-1.0
    anxiety / Delayed / 1.0
    pharyngitis / Delayed / 1.0
    spermatogenesis inhibition / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    urinary urgency / Early / Incidence not known
    nocturia / Early / Incidence not known
    oligomenorrhea / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    cough / Delayed / Incidence not known
    syncope / Early / 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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Afatinib: (Major) If the concomitant use of testosterone and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of testosterone. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and testosterone is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Alogliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alogliptin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alogliptin; Pioglitazone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Alpha-glucosidase Inhibitors: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Azithromycin: (Minor) Both testosterone and azithromycin are P-glycoprotein (PGP) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together.
    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.
    Cabazitaxel: (Minor) Cabazitaxel is a substrate for P-glycoprotein (Pgp). No formal drug interaction studies have been conducted with Pgp inhibitors, such as testosterone. Use caution when cabazitaxel is administered concomitantly with Pgp inhibitors.
    Cabozantinib: (Moderate) Monitor for an increase in testosterone-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of testosterone may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and testosterone is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Testosterone is a P-gp inhibitor/substrate. Theoretically, concentrations of canagliflozin may be increased. Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Testosterone is a P-gp inhibitor/substrate. Theoretically, concentrations of canagliflozin may be increased. Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Dapagliflozin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Dapagliflozin; Saxagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. Also, saxagliptin is primarily metabolized by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as danazol. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    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.
    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.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Empagliflozin; Linagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Empagliflozin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Glyburide; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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) Gonadotropin releasing hormone (GnRH) agonists (i.e.,histrelin) inhibit steroidogenesis, therefore the concomitant use of these agents with androgens may counteract this therapeutic effect. Avoid concurrent use of androgens with GnRH agonists.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Insulins: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and testosterone concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as testosterone, can increase testosterone exposure leading to increased or prolonged therapeutic effects and adverse events.
    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.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Linagliptin; Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and testosterone concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as testosterone, can increase testosterone exposure leading to increased or prolonged therapeutic effects and adverse events.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Pioglitazone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Repaglinide: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Rosiglitazone: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Saxagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. Also, saxagliptin is primarily metabolized by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as danazol. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Metformin; Sitagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Nintedanib: (Moderate) Testosterone is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of testosterone and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. Topical preparations of testosterone are unlikely to interact. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with testosterone is necessary, as the systemic exposure of testosterone may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and testosterone is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with testosterone is necessary, as the systemic exposure of testosterone may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and testosterone is a CYP3A4 substrate.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary. Also, saxagliptin is primarily metabolized by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as danazol.
    Simvastatin; Sitagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    Sitagliptin: (Moderate) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia.However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with testosterone is necessary, and monitor for an increase in temsirolimus- and testosterone-related adverse reactions; topical testosterone products are not expected to have this interaction. Temsirolimus is a P-glycoprotein (P-gp) substrate/inhibitor in vitro, while testosterone is also a P-gp substrate/inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both testosterone and temsirolimus (and active metabolite, sirolimus) is likely to 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) Exogenously administered androgens have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance, and may worsen hyperglycemia. However, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. Some patients may experience hypoglycemia. Other patients receiving androgen replacement may not have significant changes in blood glucose. Moniitor blood glucose and HbA1C in patients receiving antidiabetic agents and androgens. In some cases, dosage adjustments of the antidiabetic agent may be necessary.
    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.
    Topotecan: (Major) Avoid the concomitant use of testosterone, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. Topical preparations of testosterone are not expected to have this effect. If coadministration of testosterone and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    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.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as testosterone may increase testosterone concentrations. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with testosterone is necessary, due to a possible increase in testosterone-related adverse reactions. Testosterone is a partial substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of another P-gp substrate by 29% and 23%, respectively. This interaction is not expected for topical preparations of testosterone.
    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.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and testosterone. Venetoclax is a substrate of P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; testosterone is a substrate and an inhibitor of P-gp. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering testosterone at least 6 hours before venetoclax. If testosterone is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    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.
    Vinorelbine: (Moderate) Caution is warranted when testosterone is administered with vinorelbine as there is a potential for elevated vinorelbine concentrations. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression. Vinorelbine is a substrate of P-glycoprotein (P-gp) and testosterone is an inhibitor of P-gp.
    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 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.

    MECHANISM OF ACTION

    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 (IM), to the skin as a topical gel, solution, ointment 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-gp
    Testosterone is a substrate for CYP3A4 and is also both transported by and an inhibitor of P-glycoprotein (P-gp) transport.

    Oral Route

    Testosterone is absorbed from the GI tract, but because of extensive first-pass metabolism, oral bioavailability is poor.

    Intramuscular Route

    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—4 weeks following IM administration. The esters are hydrolyzed to free testosterone, which is inactivated in the liver.

    Subcutaneous Route

    The duration of action of testosterone subcutaneous implantable pellets (Testopel) is usually 3—4 months, but may last as long as 6 months.

    Topical Route

    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.
     
    There are multiple brands of testosterone transdermal patches available.
    -Testoderm: Testoderm patches are applied to the scrotum and serum concentrations of testosterone rise to a maximum after 2—4 hours, returning to baseline two hours after patch removal. Serum concentrations of testosterone approach those of normal males, and reach a plateau after 3—4 weeks. The scrotal skin is about five times more permeable than normal skin and Testoderm will not achieve desired serum concentrations if applied to other skin sites.
    -Testoderm TTS: Testoderm TTS patches achieve adequate serum concentrations when applied to the arm, back, or upper buttocks; serum testosterone concentrations peak at 2—4 hours and return towards baseline within roughly 2 hours of patch removal.
    -Androderm: Androderm 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 at 10 PM 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 Androderm, hypogonadal status returns within 24 hours. Baseline serum testosterone concentrations may be reduced because endogenous secretion of testosterone may be suppressed by Androderm. 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 (Cavg) 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)

    Buccal Route
    Following application to the buccal mucosa, the buccal mucoadhesive system (Striant) 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—12 hours of application of the system.
     
    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—100 minutes is observed following intranasal application.