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testosterone 1.62% 1.25 g pkt

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Uses

Testosterone is used for replacement or substitution of diminished or absent endogenous testicular hormone caused by certain medical conditions.

Diagnosis of hypogonadism must be confirmed by laboratory testing prior to initiation of testosterone therapy.(See Dosage and Administration.)

The safety and efficacy of testosterone replacement therapy in men with low testosterone concentrations related to aging have not been established.(See Late-onset Hypogonadism under Uses: Uses in Males.)

Uses in Males

Hypogonadism

In males, testosterone is used for the management of congenital or acquired primary hypogonadism such as that resulting from orchiectomy or from testicular failure caused by cryptorchidism, bilateral torsion, orchitis, or vanishing testis syndrome. Testosterone also is used in males for the management of congenital or acquired hypogonadotropic hypogonadism such as that resulting from idiopathic gonadotropin or gonadotropin-releasing hormone (luteinizing hormone releasing hormone) deficiency or from pituitary-hypothalamic injury caused by tumors, trauma, or radiation. If any of these conditions occur before puberty, androgen replacement therapy will be necessary during adolescence for the development of secondary sexual characteristics and prolonged therapy will be required to maintain these characteristics. Prolonged androgen therapy also is required to maintain sexual characteristics in other males who develop testosterone deficiency after puberty.

Manifestations

Hypogonadism in males may manifest with signs and symptoms of testosterone deficiency and/or infertility, with manifestations depending principally on the age of the patient at the time of development. Hypogonadism seldom is recognized before the age of puberty unless it is associated with growth retardation or other anatomic and/or endocrine abnormalities. When hypogonadism develops before puberty onset, manifestations include small testes, phallus, and prostate; minimal pubic and axillary hair; disproportionately long arms and legs (secondary to delayed epiphyseal closure); reduced male musculature; gynecomastia; and a persistently high-pitched voice. Postpubertal loss of testicular function results in slowly evolving subtle clinical manifestations, which may be difficult to appreciate in aging men because they often are attributed to growing old. Growth of body hair usually slows, while the voice and size of the phallus and prostate remain unchanged. Patients with postpubertal hypogonadism may manifest a progressive decrease in muscle mass, libido loss, impotence, oligospermia or azoospermia, and/or occasionally menopause-type hot flushes (with acute onset of hypogonadism). Hypogonadism also is associated with a risk of osteoporosis and resultant fractures. Many cases of postpubertal hypogonadism are initially detected during fertility evaluations.

Hypogonadism Associated with HIV Infection

Hypogonadism occurs commonly in human immunodeficiency virus (HIV)-infected men, particularly as their disease progresses to acquired immunodeficiency syndrome (AIDS). Hypogonadism has been reported in up to 50% of HIV-infected men, being most likely in those with AIDS; however, the incidence may now be lower as a result of highly active antiretroviral therapy (HAART) and resultant improved overall health in HIV-infected patients. Such patients generally exhibit low serum testosterone concentrations and usually low (indicating hypothalamic-pituitary involvement) or occasionally high (indicating testicular involvement) gonadotropin concentrations. In addition to typical manifestations of hypogonadism (e.g., impaired sexual mood and functioning, loss of body hair, gynecomastia, bone loss, impaired sense of well-being), hypogonadal HIV-infected men may exhibit a disproportionate loss of lean body mass and muscle wasting. The etiology of hypotestosteronism in HIV-infected men likely is multifactorial and may show interindividual variation and may include primary testicular problems, changes in the hypothalamic-pituitary-gonadal axis, and/or changes caused by chronic illness, poor nutrition, or medications; approximately 25% of hypogonadism cases in HIV-infected men are primary. Testosterone replacement therapy is considered the androgen of choice for the treatment of androgen deficiency (e.g., hypogonadism) and AIDS wasting in HIV-infected men.

Late-onset Hypogonadism

The safety and efficacy of testosterone replacement therapy for men with late-onset hypogonadism (i.e., low testosterone concentrations related to aging) have not been established. Although endogenous testosterone concentrations decline with aging and manifestations of hypogonadism such as decreased libido, impotence, decreased body hair growth, decreased muscle mass, increased risk of cardiovascular disease, and decreased bone mass and resultant osteoporosis may occur, it is unclear whether these symptoms are related to such decreased concentrations or to normal aging; therefore, the need to replace testosterone in aging men is unclear.

There currently is a paucity of information from well-designed studies on the use of testosterone in middle-aged or older men who do not meet the clinical diagnostic criteria for established hypogonadism but who may have testosterone levels in the low range for young adults and/or who show one or more manifestations common to both aging and hypogonadism. In addition, studies that have been conducted generally have been of short duration, involved small numbers of patients, and often lacked adequate controls. Therefore, assessments of risks and benefits have been limited to date, and uncertainties remain about the value of testosterone therapy in older men without a clinical diagnosis of hypogonadism. In most studies to date, it appears that older men were given testosterone dosages that increased testosterone levels to the normal physiologic range for young adult males. Because of the potential risks of testosterone therapy and the availability of other safe and effective intervention options for some of the diseases and conditions it is intended to prevent or treat (e.g., bisphosphonates for osteoporosis), testosterone should be considered a therapeutic rather than a preventative measure in aging men. Although endogenous testosterone levels clearly decline with aging, it currently is unclear whether such decreased levels affect health outcomes in older men. Much remains unknown about how physiologic pathways are affected by changes in endogenous testosterone concentrations or by the administration of exogenous testosterone in aging men.

Current limited evidence suggests that testosterone therapy in aging men may produce beneficial effects on body composition, strength, bone density, frailty, cognitive function, mood, sexual function, and quality of life. However, additional evidence from well-designed studies is needed to further elucidate the role of testosterone therapy in men with low testosterone concentrations related to aging.

Testosterone Replacement Therapy for Hypogonadism

Men with symptomatic hypogonadism and clearly low testosterone concentrations (free or total, considering SHBG) are potential candidates for testosterone replacement therapy; however, the potential prostatic risk must be considered. Serum total (bound and free) testosterone concentrations less than 300 ng/dL generally are considered indicative of hypogonadism in men, and the biochemical goal of hormone replacement therapy with testosterone generally is to increase serum total testosterone concentrations to within the normal physiologic range of 300-1200 ng/mL. The principal goals of testosterone replacement are to restore sexual function, libido, well-being, and behavior; to stimulate and maintain virilization (e.g., secondary sex characteristics such as muscle mass, body hair, phallus growth); to optimize bone density and prevent osteoporosis; to possibly normalize somatotropin (growth hormone) concentrations in geriatric men; to potentially improve cardiovascular risk; and to restore fertility in cases of hypogonadotropic hypogonadism. In HIV-infected men, additional goals include improvement in mood (e.g., depression), energy level (fatigue), quality of life, and lean body mass (wasting syndrome); however, clinical response to testosterone therapy in HIV-infected men is not necessarily correlated to baseline serum testosterone concentrations, and eugonadal HIV-infected men may benefit from such therapy.

Delayed Puberty

When the diagnosis is well established, testosterone may be used to stimulate puberty in carefully selected males with delayed puberty. These males usually have a family history of delayed puberty that is not caused by a pathologic disorder. Brief treatment with conservative doses of an androgen may occasionally be justified in these males if they do not respond to psychologic support. Because androgens may adversely affect bone maturation in these prepubertal males, this potential risk should be fully discussed with the patient and his parents prior to initiation of androgen therapy. (See Cautions: Pediatric Precautions.) If androgen therapy is initiated in these prepubertal males, radiographs of the hand and wrist should be obtained at 6-month intervals to determine the effect of therapy on the epiphyseal centers. Testosterone is designated an orphan drug by the FDA for use in this condition.

Corticosteroid-induced Hypogonadism and Osteoporosis

Patients receiving long-term corticosteroid therapy may develop hypogonadism secondary to inhibition of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary as well as secondary to direct effects on the testes and ovaries, and such hypogonadism may be associated with bone loss. Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present. Unlike experience with hormone replacement therapy (HRT, combined estrogen and progestin therapy) in postmenopausal women receiving chronic prednisone therapy, there currently is only limited information on the effect of androgen (e.g., testosterone) replacement therapy in men with hypogonadism secondary to long-term corticosteroid therapy. In a small study in men with corticosteroid-treated asthma and low serum testosterone concentrations, lumbar spine bone mass density (BMD) was increased nearly 4% after 12 months of monthly testosterone injections; lean body mass also was increased and fat mass was reduced. Therefore, men who develop low serum testosterone concentrations while receiving long-term corticosteroid therapy should be offered testosterone replacement therapy in an attempt to treat hypogonadism and possibly reduce the risk of corticosteroid-induced osteoporosis when contraindications to androgen therapy are not present. Some experts (e.g., the American College of Rheumatology) recommend that such men with serum testosterone concentrations below the physiologic range (i.e., less than 300 ng/mL) receive replacement therapy. The goal of testosterone replacement therapy in men receiving long-term corticosteroid therapy is to provide serum testosterone concentrations within the therapeutic range. It is important that the possibility of prostate cancer be ruled out in any man being considered for such replacement therapy.

Erectile Dysfunction

Although testosterone replacement therapy may restore sexual function in hypogonadal men (see Uses in Males: Hypogonadism, in Uses), the American Urological Association (AUA) states that the drug is not indicated for the treatment of erectile dysfunction in men with normal serum testosterone concentrations. Outcome measures in studies to date are inadequate to evaluate testosterone's efficacy in eugonadal men. In men with borderline testosterone concentrations, a clinical trial of replacement therapy may be warranted in the management of erectile dysfunction; however, the risks of hormone replacement must be weighed carefully.

Uses in Females

Inoperable Carcinoma of the Breast

In females, testosterone has been used for the palliative treatment of androgen-responsive, advanced, inoperable, metastatic (skeletal) carcinoma of the breast in women who are 1-5 years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity include adrenalectomy, hypophysectomy, and/or antiestrogen therapy (e.g., tamoxifen). Androgen therapy also has been used in premenopausal women with carcinoma of the breast who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. The decision to use androgen therapy in women with carcinoma of the breast should be made by an oncologist with expertise in the treatment of this carcinoma.

Postpartum Breast Pain and Engorgement

Testosterone formerly was used for the prevention of postpartum breast pain and engorgement; however, the drug does not appear to prevent or suppress lactation. Testosterone esters also have been used in combination with estrogens for the prevention of postpartum breast pain and engorgement; however, the FDA has withdrawn approval of estrogen-containing drugs for this indication. Data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to analgesic or other supportive therapy.

Menopause

In females, testosterone esters also are used in combination with estrogens for the management of moderate to severe vasomotor symptoms associated with menopause in patients who do not respond adequately to estrogens alone. While estrogen/androgen combinations were found to be effective for the management of vasomotor symptoms associated with menopause under a determination made by the FDA in 1976, formal administrative proceedings were initiated by the FDA in April 2003 to examine the effectiveness of estrogen/androgen combinations for this indication. FDA is undertaking this action because the agency does not believe there is substantial evidence available to establish the contribution of androgens to the effectiveness of estrogen/androgen combinations for the management of vasomotor symptoms in menopausal women who do not respond to estrogens alone. The FDA will allow continued marketing of combination estrogen/androgen products while the matter is under study.

Misuse, Abuse, and Dependence

Because of their anabolic and androgenic effects on performance (ergogenic potential) and physique, androgens have been misused and abused by athletes, bodybuilders, weight lifters, and others, including high school- and college-aged individuals engaged in sports. The drugs also have been misused and abused for cosmetic purposes by noncompetitors attempting to achieve bodies with lean muscle mass. Although historically the drugs have been regarded as ineffective for anabolic and androgenic uses in athletes, limited evidence suggests that androgens may increase skeletal muscle mass and strength when used in conjunction with proper (e.g., high-protein, high calorie) diet and training but that their use is not associated with increased power or capacity for aerobic work. There continues to be a lack of evidence of long-term beneficial effects, and the drugs have been associated with substantial adverse health effects and toxicity. When used to improve athletic performance and physique, dosages employed often substantially (e.g., 10- to 1000-fold) exceed usual therapeutic dosages of the drugs. In addition, several androgens often are taken concomitantly (''stacking'') for extended periods. The extent of misuse and abuse of androgens has not been fully determined, but nonmedical use is believed to be widespread. Estimates for the rate of misuse and abuse by weight lifters and body builders have ranged up to 50-80%. However, in terms of actual numbers, it has been suggested that most misuse and abuse of androgens are by individuals who never compete in sports. Evidence from one study indicates that about 7% of male high school seniors use or have used the drugs. Although the likelihood of use was increased in males intending to participate in school-sponsored sports (particularly football and wrestling), 35% of users had no intention of participating in school-sponsored sports. About 40% of these high school students admitted initiating use of the drugs at 15 years of age or younger. In studies of college students, androgen use among athletes ranged up to about 20%.

Following review of data from published literature and case reports in October 2016, the FDA concluded that misuse and abuse of androgens are associated with serious adverse effects. Serious adverse effects including increased aggression, hostility, and antisocial behavior (''roid rage''); psychotic manifestations and affective disorders (e.g., manic episode, depression, paranoia, psychosis, delusions, hallucinations); changes in libido; cardiovascular events (e.g., cardiac arrest, myocardial infarction [MI], hypertrophic cardiomyopathy, congestive heart failure [CHF], cerebrovascular accident); and hepatotoxicity (e.g., abnormal liver function test results, liver tumors [hepatic adenomas, hepatocellular carcinoma], peliosis hepatis, jaundice) have been reported in individuals who misuse and abuse androgens. Other potential adverse effects of androgens in adolescents or younger children include premature bone maturation and epiphyseal closure with resultant irreversible short stature, precocious puberty, possible increased risk of ruptured tendons and ligaments and of tendinitis, and acne. Other potential adverse effects of androgens in males include transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, gynecomastia, hair loss, testicular atrophy and sperm abnormalities (oligospermia, decreased motility, abnormal morphology, azoospermia), impotence, subfertility, infertility, and prostatic enlargement with resultant difficulty in urinating. Other potential adverse effects in females include clitoral enlargement (which may be irreversible), menstrual irregularities, hirsutism, androgenetic alopecia, deepened voice, breast atrophy, and virilization. Manifestations of withdrawal (e.g., depressed mood, major depression, fatigue, cravings, restlessness, irritability, anorexia, insomnia, decreased libido, hypogonadotropic hypogonadism) may occur if androgens, such as testosterone, are discontinued abruptly or the dosage is substantially reduced in patients who are physically dependent or receiving supratherapeutic doses of the drug; withdrawal symptoms may persist for weeks or months.

Serum testosterone concentrations should be evaluated in patients who may be misusing or abusing androgens (e.g., patients experiencing serious adverse cardiovascular or psychiatric effects); however, serum testosterone concentrations may be below or within the normal range in patients abusing synthetic derivatives of testosterone. Because of the potential for serious adverse effects associated with misuse and abuse of androgens, preventive measures have been initiated, including educational programs, interdiction of black market supplies, drug screening of athletes with associated penalties for use, and other control measures. The prescription, dispensing, distribution, and use of most androgens currently are restricted as controlled substances. In addition, medical and sports experts, including the American College of Sports Medicine, American Medical Association, American Academy of Pediatrics, American College Health Association, National Strength and Conditioning Association, National Collegiate Athletic Association, National Football League, US Olympic Committee, and the International Olympic Committee, consider the use of androgens to enhance athletic performance or physique inappropriate and unacceptable because of known adverse effects, lack of data regarding long-term gains in size and strength, and potential long-term adverse sequelae and because their use by athletes is contrary to the rules and ethical principles of athletic competition.

Dosage and Administration

Diagnosis of hypogonadism must be confirmed by laboratory testing prior to initiation of testosterone therapy. To confirm this diagnosis, serum testosterone concentrations should be measured in the morning on at least 2 separate days and must be consistently below the normal range. Serum testosterone concentrations may be low later in the day in men with or without hypogonadism; therefore, measuring testosterone concentrations later in the day should be avoided.

Administration

Testosterone is administered by IM injection; percutaneously by topical application of a transdermal system, solution, or gel to the skin; intranasally; subcutaneously as a biodegradable implant; and intrabuccally (transmucosally) as a buccal tablet.

IM Injection

Testosterone cypionate (Depo-testosterone), testosterone enanthate (Delatestryl), and testosterone undecanoate (Aveed) are administered by deep IM injection into the gluteal muscle; the usual precautions for IM administration should be followed.

Because of the risk of serious pulmonary oil microembolism reactions and anaphylaxis following IM administration of testosterone undecanoate, patients should be observed for 30 minutes in a healthcare setting following each IM injection of the drug.

Restricted Distribution Program

Because of the potential for serious pulmonary oil microembolism reactions and anaphylaxis in patients receiving IM testosterone undecanoate (Aveed) (see Cautions: Sensitivity Reactions and also Other Adverse Effects), testosterone undecanoate must be obtained through a restricted distribution program, the Aveed Risk Evaluation and Mitigation Strategy (REMS) Program, designed to minimize the risk of pulmonary oil microembolism reactions and anaphylaxis. Clinicians and institutions that prescribe and/or dispense testosterone undecanoate must enroll in and comply with all requirements of the Aveed REMS Program. Institutions are required to have appropriate equipment for the treatment of serious pulmonary oil microembolism and anaphylactic reactions for immediate use in patients receiving the drug. For additional information or to enroll in the Aveed REMS program, clinicians may contact 855-755-0494 or visit www.AveedREMS.com.

Subcutaneous Administration

Testosterone pellets are administered as a biodegradable implant subcutaneously into the hip or other fatty area by a clinician; the usual precautions for subcutaneous implantation should be followed.

Transdermal Administration

Patients receiving transdermal testosterone therapy (Androderm) should be carefully instructed in the proper use and disposal of the transdermal system. To obtain optimum results, patients should be given a copy of the patient instructions provided by the manufacturer. To expose the adhesive surface of the system, the protective liner should be peeled and discarded prior to administration.

The transdermal system should then be applied topically to a clean, dry area of skin on the back, abdomen, upper arm, or thigh by firmly pressing the system with the adhesive side touching the skin; the system should not be applied to the scrotum. The system should be applied immediately after removal from its protective pouch and removal of the protective liner. The system should be pressed firmly in place, ensuring good contact, particularly around the edges. The application site should not be oily, damaged, or irritated. Application of transdermal systems over bony prominences or 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, the ischial tuberosity) should be avoided, because burn-like blisters may occur. If the transdermal system becomes loose, the system should be smoothed down by firmly rubbing around the edges. If the system should inadvertently come off before noon following application the previous evening, a new system may be applied until the next scheduled application that evening. If the transdermal system comes off later in the day, the system should not be replaced until the next scheduled application that evening. If a system comes off, it should not be reapplied with tape.

To minimize and/or prevent potential skin irritation, each testosterone transdermal system should be applied at a different site, with an interval of at least 1 week allowed between applications to a particular site. Mild skin irritation may be ameliorated by application of over-the-counter topical hydrocortisone cream after system removal; alternatively, a small amount of triamcinolone acetonide cream 0.1% may be applied to the skin under the drug reservoir to minimize irritation (ointment formulations should not be used because they may reduce testosterone absorption).

Testosterone transdermal systems are applied once daily; to produce serum testosterone concentrations that mimic endogenous profiles, the system should be applied at night (e.g., 10 p.m.). The system should be left in place for approximately 24 hours; after this period, the system should be removed and discarded and a new system applied.

The transdermal system does not need to be removed during sexual intercourse nor while showering or bathing; however, patients should avoid swimming, showering, or washing the administration site for at least 3 hours following application.

Topical Administration

Patients receiving testosterone topical gel (AndroGel, Fortesta, Testim, Vogelxo) or solution (Axiron) should be instructed on use of the gel or solution and given a copy of the patient instructions provided by the manufacturer.

AndroGel is commercially available as unit-dose packets or as a metered-dose pump. AndroGel should be applied topically once daily, preferably in the morning, to clean, dry, intact skin only; testosterone topical gel 1% (AndroGel 1%) should be applied on the shoulders, upper arms, and/or abdomen and testosterone topical gel 1.62% (AndroGel 1.62%) should be applied only on the shoulders and upper arms. The gel should not be applied to other parts of the body (e.g., genitals, chest, axillae, knees, back). To apply a dose from the unit-dose packet, the entire contents of the packet should be squeezed into the palm of the hand and immediately applied to the application site; alternatively, a portion of the contents should be squeezed into the palm of the hand and applied to the application site and the procedure repeated until the entire contents of the packet has been applied. Alternatively, the gel can be applied directly to the application site. Patients using the metered-dose pump should be instructed to prime the pump prior to initial use by depressing the pump 3 times; this gel should be discarded by rinsing down the sink or placing in household trash in a manner that avoids accidental exposure or ingestion by household members or pets. To apply a dose from the metered-dose pump, the gel may be collected in the palm of the hand by pressing the pump firmly and fully; the gel is applied to the application site. Patients should immediately wash their hands with soap and water following application of the gel. Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) to prevent transfer of testosterone to another individual. Following application of AndroGel 1 or 1.62%, patients should avoid swimming, showering, or washing the application site for at least 5 or 2 hours, respectively.

Testim is commercially available as unit-dose tubes. Testim should be applied topically once daily, preferably in the morning, to clean, dry, intact skin only on the shoulders and/or upper arms; the gel should not be applied to the abdomen or genitals. Upon opening the tube, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site. Patients should immediately wash their hands with soap and water following application of the gel. Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) to prevent transfer of testosterone to another individual. Patients should avoid swimming, showering, or washing the administration site for at least 2 hours following application.

Vogelxo is commercially available as unit-dose tubes or packets and as a metered-dose pump. Vogelxo should be applied topically once daily to clean, dry, intact skin only on the shoulders and/or upper arms; the gel should not be applied to the abdomen or genitals. To apply a dose from the unit-dose tube or packet, the entire contents of the tube or packet should be squeezed into the palm of the hand and immediately applied to the application site. Patients using the metered-dose pump should be instructed to prime the pump prior to initial use by pressing the pump 3 times; this gel should be discarded by rinsing down the sink to avoid accidental exposure or ingestion by others. To apply a dose from the metered-dose pump, the gel may be collected in the palm of the hand by pressing the pump firmly and fully; the gel is applied to the application site. Patients should immediately wash their hands with soap and water following application of the gel. Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) to prevent transfer of testosterone to another individual. Patients should avoid swimming, showering, or washing the application site for at least 2 hours following administration.

Fortesta is commercially available as a metered-dose pump. Fortesta should be applied topically once daily, in the morning, to clean, dry, intact skin only on the front and inner thighs; the gel should not be applied to the genitals or other parts of the body. Patients should be instructed to prime the pump prior to initial use by pressing the pump 8 times; this gel should be discarded by rinsing down the sink or placing in household trash in a manner that avoids accidental exposure or ingestion by others. To apply a dose from the metered-dose pump, the gel should be applied directly to the application site; the area of the thigh adjacent to the scrotum should be avoided. Patients should use one finger to gently and evenly rub the gel into the application site. Patients should immediately wash their hands with soap and water following application of the gel. Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., pants, shorts) to prevent transfer of testosterone to another individual. Patients should avoid swimming, showering, or washing the application site for at least 2 hours following administration.

Axiron is commercially available as a metered-dose pump. Axiron should be applied topically once daily to clean, dry, intact skin only on the axilla; the solution should not be applied to the genitals or other parts of the body (i.e., abdomen, shoulders, upper arms). Patients should be instructed to prime the pump prior to initial use by pressing the pump 3 times; this solution should be discarded by rinsing down a basin, sink, or toilet. To dispense a dose from the metered-dose pump, the solution should be dispensed into the applicator cup. To apply a dose from the applicator cup, the applicator cup should be held upright and placed onto the application site and then wiped steadily up and down. If the solution drips or runs, excess solution should be collected using the applicator cup; the solution should not be rubbed in with fingers or hands. Application sites should be allowed to dry completely prior to another application. Deodorants and antiperspirants should not affect the efficacy of Axiron; however, application of a deodorant or antiperspirant (stick or roll-on) should occur prior to application of Axiron to avoid contamination of the deodorant or antiperspirant product. Patients should immediately wash their hands with soap and water following application of the solution. Before dressing, the patient should allow the application site to dry; after the solution has dried, the application site should be covered with clothing (e.g., shirt) to prevent transfer of testosterone to another individual. Patients should avoid swimming, showering, or washing the application site for at least 2 hours following administration.

Prior to any situation in which skin-to-skin contact with other individuals at the site of testosterone gel or solution application is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue. If unwashed or unclothed skin at the site of testosterone gel or solution application comes in contact with the skin of another individual, the general area of contact should be washed with soap and water as soon as possible. Studies show that residual testosterone is removed from the skin surface by washing with soap and water. Signs of virilization in children (e.g., changes in genital size, libido, or development of pubic hair) and women (e.g., changes in body hair distribution, substantial increases in acne) and the possibility of secondary exposure to topical testosterone products (AndroGel, Axiron, Fortesta, Testim, Vogelxo) should be brought to the attention of a clinician.(See Cautions: Precautions and Contraindications.)

Buccal Administration

Patients receiving testosterone extended-release buccal (transmucosal) tablets (Striant) should be instructed on use of the buccal system and given a copy of the patient instructions provided by the manufacturer. Testosterone extended-release buccal (transmucosal) tablets are applied to the gum region twice daily, morning and evening (approximately 12 hours apart). Upon opening the packet, the rounded-side surface of the buccal tablet should be placed against the gum and held in place with a finger over the lip and against the buccal tablet for 30 seconds. The buccal tablet should be placed just above the incisor tooth; the application site should be alternated between the left and right upper incisors. The buccal tablet is designed to stay in place until removed. Care should be taken not to dislodge the buccal tablet; placement of the tablet should be verified after tooth brushing, use of mouthwash, and eating or drinking liquids. The buccal tablet should not be chewed or swallowed. If the buccal tablet fails to properly adhere to the gum or falls off, the buccal tablet should be removed and a new tablet applied. If the buccal tablet must be replaced within 8 hours after application, the new tablet can remain in place until the next regularly scheduled dose (i.e., the application schedule employed should be continued). If the tablet must be replaced more than 8 hours after application, the replacement tablet can remain in place for the remainder of the current dosing interval as well as the next full dosing interval. To remove the buccal tablet, the tablet should be slid downward from the gum toward the tooth.

Intranasal Administration

Testosterone nasal gel (Natesto) is administered intranasally using a metered-dose nasal pump. Patients should be instructed carefully in the use of the nasal pump. To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer. Testosterone nasal gel should be administered intranasally 3 times daily; the nasal gel should not be applied to other parts of the body. Patients should be instructed to prime the pump prior to initial use by depressing the pump 10 times; this gel should be discarded by rinsing down a sink with warm water. Prior to administration of testosterone nasal gel, patients should clear their nasal passages. Patients should place their right index finger on the pump of the actuator and slowly insert the actuator into the left nostril until the finger reaches the base of the nose. To ensure adequate application of the gel, the tip of the actuator should be in contact with the lateral wall of the nostril. To dispense a dose from the metered-dose pump, the pump should be slowly pressed until it stops and the tip of the actuator should be wiped along the inside of the lateral nostril wall upon removal from the nose. This procedure is then repeated using the patient's left index finger for administration to the right nostril. Patients should lightly massage the application site by pressing on the nostrils just below the nasal bridge. Patients should avoid blowing their nose or sniffing for 1 hour following application. If testosterone nasal gel gets on the hands, patients should wash their hands with soap and warm water.

Dosage

Dosage of testosterone is variable and should be individualized according to the condition being treated; the severity of symptoms; the patient's age, gender, and history of prior androgenic therapy; and the specific testosterone preparation being used.

Various dosage regimens have been used to induce pubertal changes in hypogonadal males. Some clinicians recommend that lower dosages be used initially, followed by gradual increases in dosage as puberty progresses; subsequently, the dosage may be decreased to maintenance levels. Other clinicians state that higher dosages are required initially to induce pubertal changes and lower dosages can then be used for maintenance therapy after puberty. The chronologic and skeletal ages of the patient must be considered when determining the initial dosage and subsequent dosage adjustment.

IM Dosage

Male Hypogonadism

For replacement of endogenous testicular hormone in androgen-deficient males, the usual IM dosage of testosterone cypionate or testosterone enanthate is 50-400 mg every 2-4 weeks. The recommended initial dosage of testosterone undecanoate is 750 mg every 4 weeks for the first 2 doses, then 750 mg every 10 weeks thereafter. In general, testosterone therapy is initiated with full therapeutic doses; subsequent dosage adjustment should be made according to the patient's tolerance and therapeutic response.

Alternatively, some clinicians state that complete androgen replacement in hypogonadal men generally can be achieved with 50-100 mg of testosterone cypionate or testosterone enanthate administered IM every 7-10 days. This regimen generally will achieve relatively physiologic testosterone concentrations throughout the time interval between doses. Longer time intervals between IM doses are more convenient but are associated with greater fluctuations in testosterone concentrations. Higher dosages produce longer-term effects but higher peak concentrations and wider swings between peak and nadir testosterone concentrations and resultant symptom fluctuation in many patients. If less frequent injection is desired, 100-150 mg IM every 2 weeks may be considered. While 300 mg IM every 3 weeks also may be considered for convenience, such dosing is associated with wider testosterone fluctuations and generally is inadequate to ensure a consistent clinical response. For men who develop pronounced symptoms in the week prior to the next dose with such prolonged dosing intervals, a smaller dose at a shorter dosing interval should be tried; in general, serum total testosterone concentrations should exceed 250-300 ng/dL just before the next dose.

If full androgen replacement is not required, lower testosterone dosages are used. For example, in adult males with prepubertal onset of hypogonadism who are going through puberty for the first time with IM testosterone replacement, testosterone therapy may be initiated at 50 mg every 3-4 weeks, gradually increasing the dose in subsequent months as tolerated up to full replacement within 1 year.

Attainment of full virilization in men with hypogonadism may require up to 3-4 years of IM testosterone replacement. Patients generally should be monitored at 4-6 months to assess clinical progress, review compliance, and determine whether any complications or psychologic adjustment problems are present.

For delayed puberty, the usual IM dosage of testosterone enanthate is 50-200 mg every 2-4 weeks for a limited period of time (e.g., 4-6 months).

Inoperable Carcinoma of the Breast

For the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in women, the usual IM dosage of testosterone enanthate is 200-400 mg every 2-4 weeks.

Subcutaneous Dosage

For replacement of endogenous testicular hormone in androgen-deficient males, the usual dosage of testosterone pellets is 150-450 mg implanted subcutaneously every 3-6 months. Dosage adjustment should be made according to the patient's tolerance and therapeutic response.

For delayed puberty, the dosage of testosterone pellets is generally less than the dosage used for male hypogonadism and for a limited period of time (e.g., 4-6 months).

Transdermal Dosage

Transdermal testosterone (Androderm) is commercially available as a system delivering 2 mg/24 hours or 4 mg/24 hours. Dosage should be adjusted according to determinations of serum testosterone concentrations.

When Androderm is used for the treatment of male hypogonadism, the usual initial transdermal dosage is 4 mg once daily administered nightly as one system delivering 4 mg/24 hours. Dosage should be adjusted according to morning serum testosterone concentrations approximately 2 weeks following initiation of therapy. Depending on requirements, dosage can be increased to 6 mg once daily administered nightly as one system delivering 4 mg/24 hours plus one delivering 2 mg/24 hours or can be decreased to 2 mg once daily administered nightly as one system delivering 2 mg/24 hours.

Patients currently maintained on a transdermal dosage of 2.5 mg once daily may be switched to one system delivering 2 mg/24 hours at the next scheduled dose. Patients currently maintained on a transdermal dosage of 5 mg once daily may be switched to one system delivering 4 mg/24 hours at the next scheduled dose. Patients currently maintained on a transdermal dosage of 7.5 mg once daily may be switched to 6 mg once daily with one system delivering 4 mg/24 hours plus one delivering 2 mg/24 hours.

Approximately 2 weeks after switching therapy, the early morning serum testosterone concentrations should be measured in patients following system application the previous evening to ensure proper dosing.

Topical Gel Dosage

Topical testosterone is commercially available as a 1% gel in unit-dose packets containing a 25-mg dose of testosterone (2.5 g of gel) (AndroGel) or a 50-mg dose of testosterone (5 g of gel) (AndroGel, Vogelxo); as a 1.62% gel in unit-dose packets (AndroGel) containing a 20.25- or 40.5-mg dose of testosterone (1.25 or 2.5 g of gel, respectively); as a nonaerosol metered-dose pump (AndroGel [each actuation of the pump delivers 1.25 g of gel containing 20.25 mg of testosterone after priming], Fortesta [each actuation of the pump delivers 0.5 g of gel containing 10 mg of testosterone after priming], Vogelxo [each actuation of the pump delivers 1.25 g of gel containing 12.5 mg of testosterone after priming]); or in unit-dose tubes (Testim, Vogelxo) containing a 50-mg dose (5 g of gel).

For the treatment of male hypogonadism, the usual initial dosage of testosterone gel 1% (AndroGel 1%, Testim, Vogelxo) is the entire contents of a packet or tube containing 50 mg of testosterone, the entire contents of 2 packets containing 25 mg of testosterone, or 4 actuations of the pump (5 g of gel) applied topically once daily, preferably in the morning; this dose delivers about 5 mg of testosterone systemically. The usual initial dosage of testosterone gel 1.62% (AndroGel 1.62%) is the entire contents of a packet containing 40.5 mg of testosterone or 2 actuations of the pump (2.5 g of gel) applied topically once daily in the morning. The usual initial dosage of Fortesta is 40 mg of testosterone or 4 actuations of the pump (2 g of gel) applied topically once daily in the morning. Dosage should be adjusted according to serum testosterone concentrations obtained at regular intervals following initiation of AndroGel 1% therapy, approximately 14 days after initiating daily application of Testim or Vogelxo, approximately 14 and 28 days after initiating daily application or dosage adjustment of AndroGel 1.62%, and approximately 14 and 35 days after initiating daily application or dosage adjustment of Fortesta.

If serum testosterone concentrations are below the normal range in a patient receiving AndroGel 1%, the dosage can be increased initially to 75 mg of testosterone (7.5 g of gel) and, if necessary, subsequently to 100 mg of testosterone (10 g of gel). If serum testosterone concentrations exceed the normal range in a patient receiving AndroGel 1% therapy, the daily dosage may be decreased. AndroGel 1% should be discontinued if the serum testosterone concentrations consistently exceed the normal range at a daily dosage of 50 mg of testosterone (5 g of gel).

If serum testosterone concentrations are below the normal range in a patient receiving Testim or Vogelxo, the dosage can be increased to 100 mg of testosterone (10 g of gel, 8 actuations of the pump).

If serum testosterone concentrations exceed 750 ng/dL in a patient receiving AndroGel 1.62%, the dosage should be decreased to 20.25 mg of testosterone (1.25 g of gel, 1 actuation of the pump). If serum testosterone concentrations are below 350 ng/dL in a patient receiving AndroGel 1.62%, the dosage should be increased initially to 60.75 mg of testosterone (3.75 g of gel, 3 actuations of the pump) and, if necessary, subsequently to 81 mg of testosterone (5 g of gel, 4 actuations of the pump).

In patients receiving Fortesta, the dosage should be decreased by 20 mg of testosterone (2 actuations of the pump) if serum testosterone concentrations reach or exceed 2500 ng/dL or by 10 mg of testosterone (1 actuation of the pump) if serum testosterone concentrations are 1250 ng/dL or greater, but less than 2500 ng/dL; however, if a 10-mg dosage of testosterone requires further reduction, Fortesta should be discontinued. If serum testosterone concentrations are below 500 ng/dL in a patient receiving Fortesta, the dosage of testosterone can be adjusted in 10-mg increments (1 actuation of the pump); however, the daily dosage should not exceed 70 mg of testosterone (7 actuations of the pump).

Topical Solution Dosage

Topical testosterone is commercially available as a solution in a metered-dose pump (Axiron; each actuation of the pump delivers 1.5 mL of solution containing 30 mg of testosterone after priming). For the treatment of male hypogonadism, the recommended initial dosage of testosterone solution is 60 mg (2 actuations of the pump) applied topically once daily. Dosage should be adjusted according to serum testosterone concentrations obtained following initiation of therapy and at least 14 days after initiating daily application or dosage adjustment of testosterone solution. If serum testosterone concentrations exceed 1050 ng/dL in a patient receiving testosterone topical solution, the dosage should be decreased from 60 mg (2 actuations of the pump) to 30 mg (1 actuation of the pump); however, if a 30-mg dosage of testosterone requires further reduction, testosterone topical solution should be discontinued. If serum testosterone concentrations are below 300 ng/dL in a patient receiving testosterone topical solution, the dosage of testosterone can be adjusted in 30-mg increments (1 actuation of the pump); however, the daily dosage should not exceed 120 mg of testosterone (4 actuations of the pump).

Buccal (Transmucosal) Dosage

When testosterone buccal (transmucosal) tablets (Striant) are used for the treatment of male hypogonadism, the usual dosage is 30 mg (one extended-release tablet) twice daily, morning and evening (about 12 hours apart). Serum testosterone concentrations should be obtained just prior to the morning dose 4-12 weeks after initiation of therapy with testosterone buccal tablets. If total serum testosterone concentrations are consistently outside of the normal range, testosterone buccal tablets should be discontinued.

Intranasal Dosage

Intranasal testosterone is commercially available as a gel in a metered-dose nasal pump (Natesto; each actuation of the pump delivers 0.122 g of gel containing 5.5 mg of testosterone after priming). For the treatment of male hypogonadism, the recommended initial dosage of testosterone nasal gel is 1 actuation of the pump per nostril for a total dosage of 11 mg 3 times daily. Dosage should be adjusted according to serum testosterone concentrations obtained at least 1 month after initiating therapy and periodically thereafter. If serum testosterone concentrations consistently exceed 1050 ng/dL, testosterone nasal gel should be discontinued. If serum testosterone concentrations are consistently below 300 ng/dL, testosterone nasal gel should be discontinued and alternative therapy considered. If severe rhinitis occurs, testosterone nasal gel should be temporarily interrupted until resolution of symptoms; however, if severe rhinitis persists, testosterone nasal gel should be discontinued and alternative therapy considered.

Dosage in Renal and Hepatic Impairment

The manufacturers of testosterone enanthate injection, testosterone undecanoate injection, and testosterone transdermal system, topical gel, topical solution, nasal gel, and buccal tablets state that clinical studies involving patients with renal or hepatic impairment have not been conducted. Therefore, there are no special population dosage recommendations at this time.

Cautions

Adverse effects associated with testosterone are similar to those of other synthetic or natural androgens and include acne, flushing of the skin, gynecomastia, increased or decreased libido, habituation, and edema. In addition, gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism.

Cardiovascular Effects

Long-term clinical safety studies have not been conducted to date to determine the cardiovascular effects of testosterone replacement therapy in men. Epidemiologic data and results from randomized, controlled clinical trials have been inconclusive for determining the risk of serious adverse cardiovascular events (i.e., nonfatal myocardial infarction [MI], nonfatal stroke, death) with testosterone use compared with nonuse.

In 2 observational studies, the risk of serious adverse cardiovascular events was increased in patients receiving testosterone replacement therapy compared with those not receiving such therapy; however, 2 other observational studies found a mortality benefit with use of testosterone replacement therapy and one observational study was inconclusive. In addition, findings from 2 meta-analyses of data from published, randomized, controlled clinical trials show conflicting results. Because the current evidence regarding the cardiovascular risk associated with testosterone replacement therapy is weak because of the limited scope, quality, design, and size of the clinical trials, the FDA has requested additional evidence from well-designed studies to further elucidate the cardiovascular risk associated with testosterone use.

Following review of the data from several observational studies and meta-analyses in March 2015, the FDA concluded that use of testosterone is associated with a possible increased risk of serious adverse cardiovascular events. Clinicians should inform patients of this potential increased risk when deciding whether to use or continue to use testosterone replacement therapy. Although the FDA Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) concluded that there was insufficient evidence to suggest that the potential cardiovascular risk was confined to a certain subset of patients, some experts state that testosterone replacement therapy should be used with caution in patients at high risk for cardiovascular disease, such as older men or those with diabetes mellitus or obesity.

Local Effects

IM administration of anabolic steroids has been associated with urticaria and inflammation at the injection site, postinjection induration, and furunculosis.

Pellet extrusion at or near the implantation site, generally during the first month following subcutaneous implantation of testosterone pellets (Testopel), has been reported in postmarketing surveillance; infection also may occur at the implantation site. Infection and/or extrusion at the implantation site may be manifested with induration, inflammation, fibrosis, bleeding, contusions, wound drainage, pain, and pruritus.

The most common adverse effect associated with transdermal testosterone is local irritation at the site of application. In clinical studies with Androderm transdermal systems, most patients developed mild to moderate erythema at the site of application at some time during therapy; 37% of patients receiving this preparation experienced pruritus at the application site, 12% experienced burn-like blisters (manifesting with bullae, epidermal necrosis, or ulceration) on the skin immediately under the system, and 6, 3, and 3% developed vesicles, burning, and induration, respectively, at the application site. In patients who developed burn-like blisters, most such lesions were associated with application of the system over bony prominences or on body parts that may have been subject to prolonged pressure during sleep or sitting (e.g., over the deltoid region of the upper arm, the greater trochanter of the femur, or the ischial tuberosity), and such administration should be avoided; the more severe lesions healed over several weeks with occasional scarring, and such lesions should be treated as burns. Application site reactions occurring in less than 3% of patients receiving Androderm include bullae, mechanical irritation, and contamination.

In one comparative study, the incidence of application site reactions was substantially less with Testoderm TTS (no longer commercially available in the US) than with Androderm, possibly because of the lower amount of delivered alcohol (a permeation-enhancer excipient in the transdermal systems) per unit area of skin with Testoderm TTS. The possibility exists that excipients other than alcohol also may play a role in application site reactions. Mild skin irritation may be ameliorated with topical application of over-the-counter hydrocortisone cream; alternatively, application of triamcinolone acetonide 0.1% cream under the central drug reservoir of the transdermal system may decrease the incidence and severity of application site reactions.

Application site reactions were reported in 5, 3, or 4% of patients who received 50, 75, or 100 mg, respectively, of testosterone gel 1% (as AndroGel 1%) topically for up to 6 months in a clinical trial, but none of these patients required treatment or discontinued the drug because of these reactions. Application site reactions were reported in 2.14% of patients who received testosterone gel 1.62% (as AndroGel 1.62%), but none of these patients discontinued the drug because of these reactions. In a long-term (up to 3 years) follow-up study, application site reactions were reported in 5.6% of patients. Application site reactions were reported in 2 or 4% of patients receiving 50- or 100-mg doses, respectively, of another testosterone gel formulation (Testim, Vogelxo) compared with placebo (3%). Application site reactions were reported in 16.1% of patients receiving another testosterone gel formulation (Fortesta). AndroGel 1% appears to have minimal potential for inducing phototoxic reactions. Other application site reactions reported with AndroGel 1% during postmarketing surveillance include pruritus, dry skin, erythema, rash, discolored hair, and paresthesia. The possibility that testosterone transfer to another individual (including women and children) could occur when skin-to-skin contact is made with the application site should be considered.(See Cautions: Precautions and Contraindications.) In vitro studies have shown that 96% of residual testosterone is removed from the skin by washing with soap and water.

In clinical studies with a testosterone topical solution (Axiron), irritation (5-7% of patients) or erythema (7-8% of patients) developed at the application site following 120 or 180 days of therapy, respectively.

The most common adverse effects associated with testosterone nasal gel are nasal discomfort, nasal scabbing, rhinorrhea, epistaxis, nasopharyngitis, bronchitis, upper respiratory tract infection, and sinusitis. In a clinical study with Natesto nasal gel, most patients developed mild to moderate adverse effects; however, long-term effects of testosterone nasal gel are unknown because of limited data.

Gum or mouth irritation, bitter taste, and gum pain or tenderness have been reported in 9.2, 4.1, and 3.1%, respectively, of patients receiving testosterone buccal tablets (Striant) in one controlled study. Gum edema or taste perversion occurred in 2% of patients receiving the drug in this study. Most gum-related adverse effects were transient; gum irritation generally resolved in 1-8 days and tenderness resolved in 1-14 days.

Genitourinary Effects

Oligospermia and decreased ejaculatory volume may occur in males receiving excessive dosage or prolonged administration of testosterone. Priapism or excessive sexual stimulation in males, especially geriatric patients, may also occur. If priapism or excessive sexual stimulation develops during testosterone therapy, the drug should be discontinued temporarily, since these are signs of excessive dosage; if therapy with testosterone is reinstituted, a lower dosage should be used. Male pattern of baldness may also occur.

Amenorrhea and other menstrual irregularities and inhibition of gonadotropin secretion occur commonly in females.

Gynecomastia can occur in males receiving testosterone replacement therapy as a result of aromatization of testosterone to estradiol and changes in sex hormone binding globulin (SHBG). Surgery can be considered for such patients.

Testosterone, especially its active metabolite dihydrotestosterone (DHT), stimulates growth of the prostate and seminal vesicles. In hypogonadal men receiving testosterone replacement, such growth did not exceed the volumes expected in normal men. Testosterone therapy was associated with an overall mean increase in serum prostate-specific antigen (PSA) concentrations of 0.11-0.14, 0.13, 0.1-0.2, or 0.5 ng/mL in studies evaluating the effect of topical testosterone gel (AndroGel), topical testosterone solution (Axiron), testosterone nasal gel (Natesto), or testosterone undecanoate injection (Aveed), respectively, on serum PSA concentrations in men with hypogonadism. In one study, PSA was reduced in 21%, unchanged in 22%, and increased in 57% of patients receiving testosterone replacement therapy for 1 year. Increased serum PSA concentrations also were observed in 18% of hypogonadal men receiving AndroGel 1% for up to 42 months; most of these increases occurred within the first year of therapy. No clear relationship between testosterone replacement therapy and prostate cancer has been established to date, although anecdotal reports have been published; additional long-term studies are needed to clarify the potential risk.(See Cautions: Mutagenicity and Carcinogenicity.)

Other adverse genitourinary effects of testosterone include epididymitis and bladder irritability. Impaired urination, prostatic enlargement, prostate cancer, testicular atrophy, oligospermia, priapism, gynecomastia, and mastodynia have been reported during postmarketing experience with topical testosterone gel (AndroGel 1%).

Endocrine and Metabolic Effects

Virilization, including deepening of the voice, hirsutism, and clitoral enlargement, occur commonly in females; these changes may not be reversible following discontinuance of the drug.

Secondary exposure to testosterone resulting in virilization of children has been reported with use of topical testosterone gel during postmarketing surveillance.(See Cautions: Precautions and Contraindications.) The FDA has fully reviewed 8 reports of secondary exposure to testosterone from testosterone gel products in children 9 months to 5 years of age. Additional cases in children have been reported and currently are under FDA review. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms resolved with removal of the testosterone exposure. However, in a few cases, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronologic age. In some of these children, invasive diagnostic procedures were performed as a result of the delay in recognizing the underlying cause of the signs and symptoms. Direct contact of the child with application sites on the skin of men using testosterone gel was reported in most of the cases. The possibility of secondary exposure from contact with items such as shirts and bed linens of men receiving testosterone gel also may be considered.

Because of the aromatization of testosterone to estradiol, lipid abnormalities usually do not develop secondary to testosterone replacement, and the ratio of HDL to total cholesterol generally remains constant. However, the possibility that lipid abnormalities may develop should be considered.(See Cautions: Precautions and Contraindications.) Anabolic steroids that do not undergo aromatization increase LDL-cholesterol and lower HDL-cholesterol, which could increase cardiovascular risk.

Hypercalcemia resulting from osteolysis, especially in immobile patients and those with metastatic carcinoma of the breast, has been reported in patients receiving testosterone. (See Cautions: Precautions and Contraindications.) The drug should be discontinued if hypercalcemia occurs in patients with cancer, since this may indicate progression of metastases to the bone. Retention of water, sodium, chloride, potassium, and inorganic phosphates has also occurred in patients receiving the drug. If edema is present before or develops during therapy, administration of diuretics may be required.

Nervous System Effects

Sleep apnea has occurred occasionally in men receiving testosterone replacement. Although the mechanism of testosterone-induced apnea remains to be elucidated, a relationship between sex hormones and sleep apnea has been suggested since untreated males are more likely than females to develop this disorder and disordered breathing during sleep is more common among healthy males than among premenopausal women. In addition, loud snoring is more common in untreated men than in women, and physiologic mechanisms for snoring and obstructive sleep apnea are similar. Therefore, it has been postulated that abnormal relaxation of pharyngeal muscles seen in both snoring and obstructive sleep apnea is affected by circulating concentrations of hormones, including testosterone. If manifestations of sleep apnea occur or worsen in testosterone-treated patients, sleep studies should be performed and testosterone replacement dosage should be decreased or the drug discontinued if sleep apnea is confirmed. In addition, patients receiving testosterone replacement should be advised to report any sleep-associated changes such as snoring, daytime somnolence, and emotional disturbances.

Sleeplessness, headache, anxiety, mental depression, and generalized paresthesia also have occurred in patients receiving testosterone. Headache, dizziness, sleep apnea, insomnia, depression, emotional lability, nervousness, hostility, amnesia, and anxiety have been reported during postmarketing experience with topical testosterone (AndroGel 1%).

Sensitivity Reactions

Hypersensitivity reactions, including skin manifestations and anaphylactoid reactions, have occurred rarely with testosterone. Allergic contact dermatitis has been reported with topical administration (e.g., as transdermal systems) of testosterone.(See Cautions: Local Effects.)

Hematologic Effects

Supraphysiologic concentrations of testosterone can stimulate erythropoiesis. Increased hemoglobin and hematocrit and possibly adverse effects secondary to hyperviscosity may result. In addition, leukopenia, polycythemia, and suppression of clotting factors II, V, VII, and X also have occurred in patients receiving testosterone.

Hepatic Effects

Cholestatic hepatitis, peliosis hepatis, hepatic neoplasms, jaundice and abnormal liver function test results have occurred in patients receiving androgens, principally 17-α-alkylandrogens such as fluoxymesterone or methyltestosterone. and in Multiple hepatic adenomas have been reported with long-term use of testosterone enanthate injection. Abnormal liver function tests (e.g., ALT, AST, gamma-glutamyltranspeptidase [GGTP], bilirubin) also have been reported during postmarketing surveillance with topical testosterone (AndroGel 1%).

Other Adverse Effects

Other adverse effects associated with testosterone therapy include nausea, chills, and excitation. Nausea, asthenia, edema, malaise, dyspnea, acne, alopecia, sweating, weight gain, hypertension, and vasodilation (hot flushes) have been reported during postmarketing experience with topical testosterone (AndroGel 1%).

Serious pulmonary oil microembolism reactions, including cough, urge to cough, dyspnea, hyperhidrosis, throat tightness, angina, dizziness, and syncope, have occurred rarely with IM testosterone undecanoate. In clinical trials, pulmonary oil microembolism reactions have occurred during or immediately following IM administration of 750 mg or 1 g of testosterone undecanoate; these reactions have been reported following administration of the third and tenth injection of the drug. Although these reactions generally lasted a few minutes and resolved following initiation of supportive measures, some reactions persisted for several hours and required emergency care and/or hospitalization.(See Dosage and Administration: Administration.)

Precautions and Contraindications

Testosterone shares the toxic potentials of other androgens, and the usual precautions of androgen therapy should be observed. When testosterone esters are used in combination with estrogens, the usual precautions associated with estrogen therapy should also be observed. Clinicians prescribing estrogens should be aware of the risks associated with use of these drugs and the manufacturers' labeling should be consulted for further discussion of these risks and associated precautions.

Patients receiving testosterone replacement therapy should be monitored periodically for response and tolerance. Some clinicians recommend that patients be monitored every 3-4 months during the first year of testosterone replacement, and periodically thereafter. Patients with benign prostatic hyperplasia (BPH) receiving androgen therapy are at increased risk for worsening of signs and symptoms of BPH. Patients treated with androgens also may be at increased risk for development of BPH and/or prostate cancer.(See Cautions: Mutagenicity and Carcinogenicity.) The manufacturers of testosterone transdermal system, nasal gel, and topical solution state that evaluation of patients for prostate cancer is appropriate prior to initiation of therapy, 3-6 months after initiation of therapy, and then in accordance with current standards of care. The manufacturers of testosterone topical gel, testosterone buccal tablets, and testosterone undecanoate injection state that evaluation of patients for prostate cancer is appropriate prior to initiating and during androgen therapy. Some clinicians recommend that rectal prostate examination be performed routinely along with assessment of prostate-related symptoms every 6-12 months. Additionally, determination of PSA should be performed annually in older men.

Increases in hematocrit may occur during testosterone therapy as a manifestation of increased red blood cell (RBC) mass, and may require dosage reduction or discontinuance of testosterone. Increased RBC mass also may increase the risk for a thromboembolic event. Annual determination of hematocrit is recommended by some clinicians during testosterone replacement therapy because of the hormone's erythropoietic potential. Determination of hematocrit should occur prior to initiation of therapy, and is appropriate 3-6 months after initiation of therapy, and then annually thereafter. Patients receiving high dosages of testosterone should have periodic hemoglobin and hematocrit determinations, since polycythemia may occur. Some clinicians state that hyperviscosity states are relative contraindications to testosterone therapy.

Changes in serum lipid profiles may require dosage adjustment or discontinuance of testosterone therapy. Some clinicians recommend that patients receiving testosterone replacement have a lipid profile performed at baseline, 6-12 months after initiation of therapy, and then annually thereafter. Androgen therapy should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

Cardiovascular events, including MI or stroke, have been reported during postmarketing experience with testosterone preparations. Testosterone should be used with caution in patients at high risk for cardiovascular disease (e.g., older men, those with diabetes mellitus or obesity). Patients should be advised to immediately report symptoms suggestive of MI or stroke (e.g., chest pain, shortness of breath, unilateral weakness, difficulty talking) to their clinician.

Venous thromboembolic events, including deep-vein thrombosis (DVT) and pulmonary embolism (PE), have been reported during postmarketing experience with testosterone preparations. Patients reporting symptoms of pain, edema, warmth, and erythema in a lower extremity or presenting with acute shortness of breath should be evaluated for possible DVT or PE, respectively. If venous thromboembolism is suspected, testosterone therapy should be discontinued and appropriate evaluation and management should be initiated.

Testosterone should be used with caution in patients with cardiac, renal, and/or hepatic dysfunction since edema may occur as a result of sodium and water retention. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, and/or hepatic disease. If edema occurs during testosterone therapy and it is considered a serious complication, the drug should be discontinued; diuretic therapy may also be necessary. Testosterone cypionate (Depo-testosterone) is contraindicated in patients with serious cardiac, hepatic, or renal disease.

Females should be carefully monitored for signs of virilization (e.g., deepening of the voice, hirsutism, clitoromegaly, menstrual irregularities) during testosterone therapy. The drug should generally be discontinued when mild virilization is evident, since some adverse androgenic effects (e.g., voice changes) may not subside following discontinuance of the drug. The woman and physician may decide that some virilization is acceptable during treatment for carcinoma of the breast.

Males should be carefully monitored for the development of priapism or excessive sexual stimulation since these are signs of excessive dosage. Males, especially geriatric patients, may become overly stimulated. Stimulation to the point of increasing the nervous, mental, and physical activities beyond the patient's cardiovascular capacity should be avoided when testosterone is used to treat decreased testosterone concentrations related to aging. Geriatric males may be at increased risk of developing prostatic hypertrophy and carcinoma during androgen therapy.

Adult or adolescent males should be advised to report too frequent or persistent penile erections to their physician. Females should be advised to report hoarseness, acne, menstrual changes, or the growth of facial hair to their physician. All patients should be advised to report nausea, vomiting, changes in skin color, or ankle swelling to their physician.

Treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases. Some clinicians also state that a history of sleep apnea is a relative contraindication to testosterone therapy.(See Cautions: Systemic Effects.)

Testosterone topical gels and topical solution contain a flammable vehicle (alcohol), and should not be exposed to an open flame or ignited materials (e.g., a lighted cigarette). The topical gel or topical solution is no longer flammable once the gel or solution has dried.

Virilization in children and women can occur following secondary exposure to testosterone in topical testosterone preparations, including gels or solution. Cases of secondary exposure resulting in virilization of children have been reported during postmarketing surveillance of topical testosterone preparations.(See Cautions: Endocrine and Metabolic Effects.) Signs and symptoms of virilization in children have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the testosterone exposure. However, in a few cases, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronologic age.

The risk of testosterone transfer in some of these reported cases was increased by lack of adherence to precautions for the appropriate use of the topical testosterone preparations. Men using topical testosterone gel or solution should strictly adhere to the recommended instructions for use and appropriate precautions from the manufacturers to minimize the potential for secondary exposure to testosterone in other individuals.(See Dosage and Administration: Administration.) Children and women should avoid contact with application sites on the skin of men using topical testosterone products.

Inappropriate changes in genital size or development of pubic hair or libido in children, changes in body hair distribution, substantial increase in acne, or other signs of virilization in adult women, and the possibility of secondary exposure to testosterone topical gel should be brought to the attention of a clinician. Testosterone topical gel should be promptly discontinued at least until the cause of virilization in such children and women has been identified.

Testosterone transdermal system (Androderm) should be removed before undergoing magnetic resonance imaging (MRI), since the transdermal system contains aluminum and may cause skin burns at the application site.

Serious pulmonary oil microembolism reactions and anaphylaxis have been reported following IM administration of testosterone undecanoate. Patients should be monitored for 30 minutes following each dose of IM testosterone undecanoate.

Adverse nasal reactions have been reported with testosterone nasal gel. Because of limited data in patients with a history of nasal disorders (e.g., nasal or sinus surgery, nasal fracture within the previous 6 months, nasal fracture resulting in a deviated anterior nasal septum), mucosal inflammatory disorders (e.g., Sjogren's syndrome), and/or sinus disease, testosterone nasal gel is not recommended in such patients. Patients should be advised to report nasal symptoms to their clinician to determine if further evaluation by an ear, nose, and throat (ENT) specialist or discontinuance of testosterone nasal gel is necessary.

Testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed) are not indicated for use in women, have not been evaluated in women, and should not be used in women.

Testosterone is contraindicated in males with carcinoma of the breast or known or suspected carcinoma of the prostate. Testosterone also is contraindicated in women who are or may become pregnant or who are breastfeeding.(See Cautions: Pregnancy, Fertility, and Lactation.) Testosterone cypionate injection, testosterone enanthate injection, and testosterone undecanoate injection are contraindicated in patients with known hypersensitivity to the drug or any ingredient in the respective formulation. Because of the potential risk of serious adverse health effects, testosterone should not be used for enhancement of athletic performance or physique.(See Uses: Misuse, Abuse, and Dependence.) Patients should be informed of the serious adverse effects associated with misuse and abuse of androgens.

Pediatric Precautions

Androgens should be used with extreme caution in children and only by specialists who are aware of the adverse effects of these drugs on bone maturation. Testosterone should be used cautiously to stimulate puberty, and only in carefully selected males with delayed puberty. (See Uses: Uses in Males.) In children, testosterone may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child, the greater the risk of testosterone compromising final mature stature. If testosterone is administered to prepubertal children (e.g., to stimulate puberty in males), the drug should be used with extreme caution, and radiographic examination of the hand and wrist should be performed every 6 months to determine the rate of bone maturation and to assess the effect of treatment on the epiphyseal centers. If testosterone is to be used to stimulate puberty in a male with delayed puberty, the potential risk of therapy should be fully discussed with the patient and his parents prior to initiation of the drug.

Safety and efficacy of testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed) in pediatric patients younger than 18 years of age have not been established. Safety and efficacy of testosterone cypionate injection (Depo-testosterone) in pediatric patients younger than 12 years of age have not been established. Secondary exposure to testosterone in children can occur with the use of topical testosterone preparations, including gels or solution, in other individuals.(See Cautions: Precautions and Contraindications.)

Geriatric Precautions

Clinical studies evaluating testosterone enanthate injection (Delatestryl), testosterone undecanoate injection (Aveed), and testosterone topical gel (AndroGel, Fortesta), topical solution, nasal gel, and transdermal system have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. There also are insufficient long-term safety data with testosterone enanthate injection, testosterone undecanoate injection, and testosterone topical gel (AndroGel, Fortesta, Testim, Vogelxo). topical solution, nasal gel, and transdermal system to determine the potential risks of cardiovascular disease, prostate cancer, and prostatic hyperplasia in geriatric adults. The manufacturer of testosterone buccal tablets (Striant) states that no substantial differences in safety and efficacy were observed in clinical studies in patients 65 years of age or older relative to younger adults. Differences in pharmacokinetics were observed between geriatric and younger adults in studies with Striant, but it is not known whether these differences are clinically important.

Mutagenicity and Carcinogenicity

Hepatocellular carcinoma has reportedly occurred in patients receiving long-term therapy with high dosages of androgens. Regression of the tumor does not always occur following discontinuance of androgen therapy. Geriatric patients may be at increased risk of developing prostatic hypertrophy and carcinoma during androgen therapy, although the manufacturers state that conclusive evidence to support this risk is lacking. Testosterone replacement is contraindicated in men with known or suspected prostate cancer or male breast cancer since the drug can stimulate tumor growth in androgen-dependent neoplasms. The prostate and breasts should be examined carefully prior to initiating testosterone therapy in men and at follow-up visits. Baseline and follow-up determinations of PSA also should be performed in older men (e.g., older than 50 years of age) at increased risk for prostate cancer.

Following implantation of testosterone in mice, cervical-uterine tumors developed which occasionally metastasized. There is some evidence to suggest that injection of testosterone into some strains of female mice increases their susceptibility to hepatomas. Testosterone has also been shown to increase the number of tumors and decrease the degree of differentiation of chemically induced tumors in rats. It is not known whether androgens, including testosterone, are mutagenic.

Pregnancy, Fertility, and Lactation

Pregnancy

Testosterone may cause fetal harm when administered to pregnant women due to the potential for virilization of a female fetus. Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given androgens during pregnancy. The degree of masculinization is related to the amount of drug given to the woman and the age of the fetus; masculinization is most likely to occur in a female fetus when exposure to androgens occurs during the first trimester. Since the risks clearly outweigh the possible benefits in women who are or may become pregnant, testosterone is contraindicated in such women. Women who become pregnant while receiving the drug should be informed of the potential hazard to the fetus.

Pregnant women or those who may become pregnant should be aware of the possibility that testosterone could be transferred from patients treated with topical preparations of the drug such as their sexual partners or other individuals in close physical contact.(See Cautions: Precautions and Contraindications.) Testosterone transdermal system (Androderm) has an occlusive backing that prevents the partner from coming in contact with active ingredient in the system. Transdermal systems that inadvertently are transferred to a sexual partner should be removed immediately and the contacted skin washed. Pregnant women should avoid skin contact with testosterone topical gel application sites in men.(See Cautions: Precautions and Contraindications.) If unwashed or unclothed skin to which testosterone topical gel has been applied comes in direct contact with the skin of a pregnant woman, the general area of contact by the woman should be washed with soap and water immediately. In vitro studies show that residual testosterone is removed by such washing.

Fertility

Although the effect of testosterone on fertility in humans has not been conclusively determined, the drug produces oligospermia and decreased ejaculatory volume in males. With high dosages of androgen therapy, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone possibly leading to adverse effects on semen parameters including sperm count. Priapism and excessive sexual stimulation also have occurred in males receiving the drug. (See Cautions: Precautions and Contraindications.) Increased or decreased libido also has been reported.

Lactation

It is not known whether testosterone is distributed into milk. The manufacturers of testosterone enanthate injection (Delatestryl) and testosterone pellets (Testopel) state that because of the potential for serious adverse reactions to androgens in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. The manufacturer of testosterone cypionate injection (Depo-testosterone) states that use in nursing women is not recommended. Testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed) are not indicated for use in women. Testosterone topical gel, topical solution, nasal gel, and buccal tablets and testosterone undecanoate injection also are contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants. Exposure of a female nursing infant to androgens may result in varying degrees of virilization. Testosterone and other androgens also may adversely affect lactation.

Drug Interactions

Testosterone may potentiate the action of oral anticoagulants, causing bleeding in some patients. When testosterone therapy is initiated in patients receiving oral anticoagulants, dosage reduction of the anticoagulant may be required to prevent an excessive hypoprothrombinemic response. In patients receiving concomitant therapy with testosterone and anticoagulants, more frequent monitoring of INR and prothrombin time is recommended, especially during initiation or discontinuance of therapy.

Increased serum oxyphenbutazone concentrations have reportedly occurred in patients receiving androgens concurrently with oxyphenbutazone.

Changes in insulin sensitivity or glycemic control may occur in patients receiving androgen therapy. The metabolic effects of androgens may decrease blood glucose concentrations and insulin requirements in patients with diabetes.

Concomitant administration of testosterone with ACTH or corticosteroids may result in increased fluid retention and edema formation. Therefore, testosterone should be administered with caution in patients with cardiac, renal, and/or hepatic disease. Patients should be monitored for fluid retention and edema formation.

Administration of IM testosterone cypionate resulted in increased clearance of propranolol in one study. It is not known whether there is a potential for this interaction with topically administered testosterone gel.

Topical administration of 0.1% triamcinolone cream prior to application of a testosterone transdermal system did not alter absorption of testosterone; however, pretreatment with topical administration of triamcinolone ointment substantially reduced absorption of testosterone.

Administration of intranasal oxymetazoline, a sympathomimetic nasal decongestant, prior to administration of testosterone nasal gel (Natesto) did not alter absorption of testosterone. Concomitant administration of testosterone nasal gel with other drugs administered intranasally has not been studied. The manufacturer does not recommend concomitant use with such drugs.

Pharmacokinetics

For information on the pharmacokinetics of endogenous testosterone, see Pharmacology.

Absorption

Following oral administration of testosterone, only small amounts of the drug reach systemic circulation unchanged. The low bioavailability of orally administered testosterone results from metabolism of the drug in the GI mucosa during absorption and on first pass through the liver. The synthetic androgens (i.e., fluoxymesterone, methyltestosterone) are less extensively metabolized following oral administration.

Esterification of testosterone generally results in less polar compounds. The enanthate ester of testosterone is absorbed slowly from the lipid tissue phase at the IM injection site, achieving peak serum concentrations about 72 hours after IM injection; thus, this preparation has a prolonged duration of action (i.e., up to 2-4 weeks) following IM administration. Because IM injection of testosterone esters causes local irritation, the rate of absorption may be erratic.

Testosterone is absorbed systemically through the skin following topical application as a gel, solution, or transdermal system. Following topical application of a hydroalcoholic gel formulation of testosterone (AndroGel, Testim, Vogelxo) to the skin, the gel quickly dries on the skin surface, which serves as a reservoir for sustained release of the hormone into systemic circulation. Approximately 10% of a testosterone dose applied topically to the skin as a 1% gel is absorbed percutaneously into systemic circulation.

The manufacturer of AndroGel states that increases in serum testosterone concentrations were apparent within 30 minutes of topical application of a 100-mg testosterone dose of the 1% gel, with physiologic concentrations being achieved in most patients within 4 hours (pretreatment concentrations were not described); percutaneous absorption continues for the entire 24-hour dosing interval. Serum testosterone concentrations approximate steady-state levels by the end of the initial 24 hours and are at steady state by the second or third day of dosing of the 1% gel. With daily topical application of the 1% gel (AndroGel), serum testosterone concentrations 30, 90, and 180 days after initiating treatment generally are maintained in the eugonadal range. Administration of 10 or 5 g of the 1% gel (AndroGel) daily results in average daily serum testosterone concentrations of 792 or 566 ng/dL, respectively, at day 30. Following discontinuance of such topical therapy, serum testosterone concentrations remain within the normal range for 24-48 hours but return to pretreatment levels by the fifth day after the last application. The manufacturer states that mean concentrations of the active metabolite dihydrotestosterone (DHT) were within or about 7% above the normal range 180 days after initiating daily topical application of 50 or 100 mg, respectively, of testosterone as the gel. Increases in DHT concentrations appeared to parallel those of testosterone, and the mean steady-state ratio of DHT to testosterone was maintained in the normal range during the 180-day treatment period.

Following administration of testosterone gel (Testim), physiologic concentrations of testosterone are achieved within 24 hours; percutaneous absorption continues for the entire 24-hour dosing interval. Administration of 10 or 5 g of Testim daily results in average daily serum testosterone concentrations of 612 or 365 ng/dL, respectively, at day 30. DHT concentrations increase in parallel with testosterone concentrations; DHT concentrations have remained within the normal range during a 90-day treatment period.

Following topical application of testosterone solution (Axiron) to the skin, ethanol and isopropyl alcohol evaporate leaving testosterone on the skin surface, which serves as a reservoir for sustained release of the hormone into systemic circulation. Following topical application of testosterone solution daily, serum testosterone concentrations reach steady-state levels by approximately 14 days. Following discontinuance of such topical therapy, serum testosterone concentrations return to pretreatment levels by 7-10 days after the last application. DHT concentrations increase in parallel with testosterone concentrations; mean steady-state ratios of testosterone to DHT have remained within the normal range during a 120-day treatment period.

Following topical application of transdermal systems of testosterone, the hormone is absorbed percutaneously into systemic circulation. Although interindividual variation in percutaneous testosterone absorption occurs, serum testosterone concentrations achieved with recommended dosages of transdermal systems of the drug generally reach the normal range during the first day of dosing and are maintained during continuous dosing without accumulation. Average daily serum testosterone concentrations in patients receiving Androderm reportedly are 498 ng/dL at steady state. Mean ratios of testosterone to DHT are within the normal range.

With topical application of a transdermal preparation, the extent of percutaneous testosterone absorption varies according to the site of application, possibly secondary to regional differences in skin permeability, cutaneous blood flow, and/or degree of adhesion between the transdermal system and skin. In one study in which transdermal systems were applied to the abdomen, back, chest, shin, thigh, or upper arm, serum hormone profiles were qualitatively similar with each site, but steady-state serum concentrations showed significant differences, decreasing in order with the back, thigh, upper arm, abdomen, chest, and shin. Application of Androderm transdermal systems to the abdomen, back, thighs, or upper arms results in achievement of similar serum testosterone concentration profiles, and these sites are recommended as optimal for rotation of application sites during chronic therapy. Daily nighttime (at approximately 10 p.m.) application of Androderm transdermal system results in a serum testosterone concentration profile that mimics the endogenous diurnal pattern in healthy young men. In one study, showering 3 hours after application of Androderm decreased peak plasma concentrations of testosterone by 0.4% compared with not showering 3 hours after application of the transdermal system. In addition, showering 3 hours after transdermal system application did not substantially alter the systemic exposure of testosterone.

Following intranasal administration of testosterone nasal gel (Natesto), peak plasma concentrations occur approximately 40 minutes after administration. Average daily serum testosterone concentration in patients receiving 11 mg of the nasal gel 3 times daily is 421 ng/dL. DHT concentrations increase in parallel with testosterone concentrations; mean steady-state ratios of testosterone to DHT have remained within the normal range during a 90-day treatment period.

Following buccal (transmucosal) administration of testosterone (Striant), the drug is absorbed transmucosally from the buccal mucosa; testosterone that is absorbed systemically via the oral mucosa bypasses first-pass metabolism. Following administration of testosterone buccal tablets every 12 hours, steady-state concentrations of testosterone are achieved after the second dose. Testosterone concentrations decrease to concentrations below the normal range about 2-4 hours after removal of the buccal tablet. Average daily serum testosterone concentrations in patients receiving the buccal tablet are 520-550 ng/dL at steady state. Increases in DHT concentrations appear to parallel those of testosterone, and mean steady-state ratios of testosterone to DHT are within the normal range.

Following IM administration of testosterone undecanoate (Aveed), the drug is slowly absorbed from the lipid phase and hydrolyzed to testosterone. Following IM administration of testosterone undecanoate 750 mg, peak plasma concentrations of testosterone occur after a median of 7 days and steady-state concentrations are achieved after the third injection (14 weeks). Increases in DHT concentrations appear to parallel those of testosterone, and mean ratios of testosterone to DHT are within the normal range.

Distribution

Circulating testosterone is chiefly bound in the serum to sex steroid binding globulin (sex hormone binding globulin, SHBG; testosterone-estradiol-binding globulin, TEBG) and albumin. Because testosterone easily dissociates from albumin, the albumin-bound drug is presumed to be pharmacologically active. The SHBG-bound portion is not considered to be pharmacologically active.

In serum, testosterone is bound with high affinity to SHBG and with low affinity to albumin. The amount of SHBG in serum and the total testosterone concentration determine the distribution of pharmacologically active and non-active forms of the androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life. Approximately 30-40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is bound to albumin and other proteins.

Elimination

The plasma half-life of testosterone reportedly ranges from 10-100 minutes. The plasma half-life of testosterone cypionate after IM injection is approximately 8 days. Following removal of an Androderm transdermal system, plasma testosterone concentrations decline with an apparent half-life of approximately 70 minutes and hypogonadal concentrations are reached within 24 hours.

Testosterone is metabolized principally in the liver to various 17-ketosteroids via 2 different pathways. The major active metabolites of testosterone are estradiol and DHT. In many tissues, the activity of testosterone appears to depend on reduction to DHT, which binds to SHBG with greater affinity than does testosterone. Testosterone and its metabolites are excreted in urine and feces. Approximately 90% of an IM dose of testosterone is excreted in urine as glucuronic and sulfuric acid conjugates of the drug and its metabolites; approximately 6% of a dose is excreted in feces, principally as unconjugated drug.

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