睾酮注射剂新药Aveed获FDA批准治疗男性性腺功能减退 2014年3月7日，睾酮注射剂药物Aveed获FDA批准，用于治疗成年男性性腺功能减退症（hypogonadism）。Aveed能够提高血清中睾酮水平并稳定维持10周，但此前曾因风险控制策略不足被FDA拒批3次。 男性性腺功能减退症（hypogonadism）的特点是睾丸分泌的睾酮水平低，而睾酮是维持肌肉的体积、骨骼生长和性功能的重要激素。睾酮水平低可导致性欲减退、抑郁、疲劳。 Aveed（testosterone undecanoate，十一酸睾酮）是一种长效处方药，含有十一酸睾酮和蓖麻油，作为一种睾酮替代疗法，用于治疗成年男性与激素分泌不足或缺失有关的性腺机能减退，包括原发性性腺功能减退症（先天性或后天性）、性腺功能减退症（先天性或后天性），该药旨在使血清睾酮水平维持在正常范围内。 FDA已对该制剂中所含篦麻油导致肺部血管堵塞及注射后相关并发症的风险表示担忧。去年5月，FDA拒绝批准Aveed，要求公司提供用药指南及其它一些额外的风险减轻战略措施，以确保Aveed的安全使用及避免与注射后反应有关的严重并发症。今年2月，一个消费者维权组织呼吁FDA推迟对Aveed的审查决定，称治疗睾酮水平低的药物应带心脏问题风险的强烈警告。 Aveed具有一个黑框警告，即严重肺部油微栓（pulmonary oil microembolism，POME）反应和过敏反应，该药应用于需要治疗且临床益处大于严重风险的患者群体。 当前的睾酮药物包括皮肤贴、短效注射剂和外用凝胶。目前，AbbVie公司的AndroGel是该市场的领导者，该药在2012年的销售额约12亿美元。 Endo公司称，预计于3月上旬将Aveed推向市场。EndoEndo公司从拜耳获得十一酸睾酮长效制剂的美国市场独占权，拜耳公司在美国以外市场以商品名Nebido上市该药物。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AVEED® safely and effectively.  See full prescribing information for AVEED®. AVEED® (testosterone undecanoate) injection, for intramuscular use CIII Initial U.S. Approval: 1953 WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS AND ANAPHYLAXIS See full prescribing information for complete boxed warning Serious POME reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of testosterone undecanoate injection.  These reactions can occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose (5.1).   Following each injection of Aveed, observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (5.1). Aveed is available only through a restricted program called the Aveed REMS Program (5.2). RECENT MAJOR CHANGES Warnings and Precautions (5.7)          10/2016 INDICATIONS AND USAGE Aveed (testosterone undecanoate) injection is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: o Primary hypogonadism (congenital or acquired) (1) o Hypogonadotropic hypogonadism (congenital or acquired) (1) Aveed should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis (1). Limitations of use: Safety and efficacy of Aveed in men with “age-related hypogonadism” have not been established (1). Safety and efficacy of Aveed in males less than 18 years old have not been established (1, 8.4). DOSAGE AND ADMINISTRATION Prior to initiating Aveed, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range (2). For intramuscular use only (2.1). 3 mL (750 mg) is to be injected intramuscularly at initiation, at 4 weeks, and every 10 weeks thereafter (2.1). Following each injection of Aveed, observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (2.3). Inject Aveed deeply into the gluteal muscle following the usual precautions for intramuscular administration of oily solutions (2.3). DOSAGE FORMS AND STRENGTHS 750 mg/3 mL (250 mg/mL) testosterone undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap (3). CONTRAINDICATIONS Men with carcinoma of the breast or known or suspected carcinoma of the prostate (4, 5.3). Pregnant or breastfeeding women.  Testosterone may cause fetal harm (4, 8.1, 8.3). Known hypersensitivity to Aveed or its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate) (4). WARNINGS AND PRECAUTIONS Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH (5.3). Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. (5.5) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. (5.6) Exogenous administration of androgens may lead to azoospermia (5.9). Edema with or without congestive heart failure may be a complication in patients with preexisting cardiac, renal, or hepatic disease (5.11). Sleep apnea may occur in those with risk factors (5.13). Monitor prostatic specific antigen (PSA), hemoglobin, hematocrit, and lipid concentrations periodically (5.3, 5.4, 5.14). ADVERSE REACTIONS The most commonly reported adverse reactions (≥2%) are acne, injection site pain, prostatic specific antigen (PSA) increased, estradiol increased, hypogonadism, fatigue, irritability, hemoglobin increased, insomnia, and mood swings (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Androgens may decrease blood glucose, and therefore may decrease insulin requirements in diabetic patients (7.1). Changes in anticoagulant activity may be seen with androgens.  More frequent monitoring of international normalized ratio (INR) and prothrombin time is recommended in patients taking warfarin (7.2). Use of testosterone with corticosteroids may result in increased fluid retention.  Use with caution, particularly in patients with cardiac, renal, or hepatic disease (7.3). USE IN SPECIFIC POPULATIONS Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer (8.5). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 10/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE Aveed is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter"s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Aveed should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis. Limitations of use: Safety and efficacy of Aveed in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established. Safety and efficacy of Aveed in males less than 18 years old have not been established [see Use in Specific Populations (8.4)]. 2 DOSAGE AND ADMINISTRATION Prior to initiating Aveed, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range. 2.1  Dosage Aveed is for intramuscular use only.  Dosage titration is not necessary. Inject Aveed deeply into the gluteal muscle following the usual precautions for intramuscular administration; care must be taken to avoid intravascular injection [see Dosage and Administration (2.3)]. Intravascular injection of Aveed may lead to pulmonary oil microembolism [see Warnings and Precautions (5.1)]. The recommended dose of Aveed  is 3 mL (750 mg) injected intramuscularly, followed by 3 mL (750 mg) injected after 4 weeks, then 3 mL (750 mg) injected every 10 weeks thereafter. 2.2  Preparation Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Carefully remove the gray plastic cap from the top of the vial by lifting it up from the edges with your fingers or by pushing the bottom edge of the cap upward using the top of your thumb.  Remove only the gray plastic cap while leaving the aluminum metal ring and crimp seal around the gray rubber stopper in place. To facilitate the removal of medication from the vial, you can draw 3 mL of air into the syringe and inject it through the gray rubber stopper into the vial to create positive pressure within the vial chamber. Withdraw 3 mL (750 mg) of Aveed solution from the vial.  Expel excess air bubbles from the syringe.  Replace the syringe needle used to draw up the solution from the vial with a new intramuscular needle and inject.  Discard any unused portion in the vial. 2.3  Administration Instructions The site for injection for Aveed is the gluteus medius muscle site located in the upper outer quadrant of the buttock.  Care must be taken to avoid the needle hitting the superior gluteal arteries and sciatic nerve.  Between consecutive injections, alternate the injection site between left and right buttock. Figure 1:  Identifying the injection site Following antiseptic skin preparation, enter the muscle and maintain the syringe at a 90° angle with the needle in its deeply imbedded position.  Grasp the barrel of the syringe firmly with one hand.  With the other hand, pull back on the plunger and aspirate for several seconds to ensure that no blood appears.  If any blood is drawn into the syringe, immediately withdraw and discard the syringe and prepare another dose.    If no blood is aspirated, reinforce the current needle position to avoid any movement of the needle and slowly (over 60 to 90 seconds) depress the plunger carefully and at a constant rate, until all the medication has been delivered.  Be sure to depress the plunger completely with sufficient controlled force.  Withdraw the needle.  Immediately upon removal of the needle from the muscle, apply gentle pressure with a sterile pad to the injection site.  If there is bleeding at the site of injection, apply a bandage. Following each injection of Aveed, observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (5.1). 3 DOSAGE FORMS AND STRENGTHS 750 mg/3 mL (250 mg/mL) testosterone undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap. 4 CONTRAINDICATIONS Aveed should not be used in any of the following patients: Men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.3)]. Women who are or may become pregnant, or who are breastfeeding.  Testosterone can cause fetal harm when administered to a pregnant woman.  Aveed may cause serious adverse reactions in nursing infants.  Exposure of a female fetus or nursing infant to androgens may result in varying degrees of virilization [see Use in Specific Populations (8.1, 8.3)].  Men with known hypersensitivity to Aveed or any of its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate). 5 WARNINGS AND PRECAUTIONS 5.1  Serious Pulmonary Oil Microembolism (POME) Reactions and Anaphylaxis Serious POME reactions, involving cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular testosterone undecanoate 1000 mg (4 mL).  The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization. To minimize the risk of intravascular injection of Aveed, care should be taken to inject the preparation deeply into the gluteal muscle, being sure to follow the recommended procedure for intramuscular administration [see Dosage and Administration (2.2, 2.3) and Adverse Reactions (6.2)]. In addition to serious POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular testosterone undecanoate. Both serious POME reactions and anaphylaxis can occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose.  Patients with suspected hypersensitivity reactions to Aveed should not be re-treated with Aveed.   Following each injection of Aveed, observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions and anaphylaxis. 5.2   Aveed Risk Evaluation and Mitigation Strategy (REMS) Program Aveed is available only through a restricted program called the Aveed REMS Program because of the risk of serious POME and anaphylaxis. Notable requirements of the Aveed REMS Program include the following: Healthcare providers who prescribe Aveed must be certified with the REMS Program before ordering or dispensing Aveed. Healthcare settings must be certified with the REMS Program and have healthcare providers who are certified before ordering or dispensing Aveed. Healthcare settings must have on-site access to equipment and personnel trained to manage serious POME and anaphylaxis. Further information is available at www.AveedREMS.com or call 1-855-755-0494. 5.3  Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer Patients with BPH treated with androgens are at an increased risk of worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms. Patients treated with androgens may be at an increased risk for prostate cancer.  Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications (4)].   5.4 Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require discontinuation of testosterone. Check hematocrit prior to initiating testosterone treatment.  It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting testosterone treatment, and then annually.  If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.5 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as Aveed. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with Aveed and initiate appropriate workup and management. 5.6  Cardiovascular Risk Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Aveed. 5.7 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids.  Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions [see Drug Abuse and Dependence (9)]. If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events. 5.8  Use in Women Due to lack of controlled evaluations in women and potential virilizing effects, Aveed is not indicated for use in women. 5.9  Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including Aveed, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle- stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count. 5.10  Hepatic Adverse Effects Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice).  Peliosis hepatis can be a life-threatening or fatal complication.  Long-term therapy with intramuscular testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas.  Aveed is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice).  If these occur, promptly discontinue Aveed while the cause is evaluated. 5.11  Edema Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism [see Adverse Reactions (6.1)]. 5.13  Sleep Apnea The 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. 5.14  Lipids Changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of testosterone therapy. 5.15  Hypercalcemia Androgens, including Aveed, 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. 5.16  Decreased Thyroxine-binding Globulin Androgens, including Aveed, may decrease concentrations of thyroxine-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4.  Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. 6 ADVERSE REACTIONS 6.1  Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Aveed was evaluated in an 84-week clinical study using a dose regimen of 750 mg (3 mL) at initiation, at 4 weeks, and every 10 weeks thereafter in 153 hypogonadal men.   The most commonly reported adverse reactions (>2%) were: acne (5.2%), injection site pain (4.6%), prostate specific antigen increased (4.6%), hypogonadism (2.6%)  and estradiol increased (2.6%). Table 1 presents adverse reactions reported by ≥1% of patients in the 84-week clinical study. Table 1 Adverse Reactions Reported in at Least 1% of Patients in the 84-Week Clinical Study of Aveed MedDRA Preferred term Number of patients (%) Aveed 750 mg (N=153) Acne 8 (5.2%) Injection site pain 7 (4.6%) Prostatic specific antigen increased* 7 (4.6%) Estradiol increased 4 (2.6%) Hypogonadism 4 (2.6%) Fatigue 3 (2%) Irritability 3 (2%) Hemoglobin increased 3 (2%) Insomnia 3 (2%) Mood swings 3 (2%) Aggression 2 (1.3%) Ejaculation disorder 2 (1.3%) Injection site erythema 2 (1.3%) Hematocrit increased 2 (1.3%) Hyperhidrosis 2 (1.3%) Prostate Cancer 2 (1.3%) Prostate induration 2 (1.3%) Weight increased 2 (1.3%) Prostate specific antigen increased defined as a serum PSA concentration >4 ng/mL. In the 84-week clinical trial, 7 patients (4.6%) discontinued treatment because of adverse reactions.  Adverse reactions leading to discontinuation included:  hematocrit increased, estradiol increased, prostatic specific antigen increased, prostate cancer, mood swings, prostatic dysplasia, acne, and deep vein thrombosis.  During the 84-week clinical trial, the average serum PSA increased from 1.0 ± 0.8 ng/mL at baseline to 1.5 ±1.3 ng/mL at the end of study.  Fourteen patients (10.9%) in whom the baseline PSA was < 4 ng/mL had a post-baseline serum PSA of > 4 ng/mL during the 84-week treatment period. A total of 725 hypogonadal men received intramuscular testosterone undecanoate in a total of 7 controlled clinical trials.  In these clinical trials, the dose and dose frequency of intramuscular testosterone undecanoate varied from 750 mg to 1000 mg, and from every 9 weeks to every 14 weeks.  Several of these clinical trials incorporated additional doses upon initiation of therapy (e.g., loading doses).  In addition to those adverse reactions noted in Table 1, the following adverse events were reported by at least 3% of patients in these trials, irrespective of the investigator’s assessment of relationship to study medication: sinusitis, prostatitis, arthralgia, nasopharyngitis, upper respiratory tract infection, bronchitis, back pain, hypertension, diarrhea and headache. Pulmonary Oil Microembolism (POME) and Anaphylaxis in Controlled Clinical Studies Adverse events attributable to pulmonary oil microembolism and anaphylaxis were reported in a small number of patients in controlled clinical trials.  In the 84-week clinical trial of Aveed, 1 patient experienced a mild coughing fit lasting 10 minutes after his third injection, which was retrospectively attributed to POME. In another clinical trial of intramuscular testosterone undecanoate (1000 mg), a hypogonadal male patient experienced the urge to cough and respiratory distress at 1 minute after his tenth injection, which was also retrospectively attributed to POME. During a review that involved adjudication of all cases meeting specific criteria, 9 POME events in 8 patients and 2 events of anaphylaxis among 3,556 patients treated with intramuscular testosterone undecanoate in 18 clinical trials were judged to have occurred. 6.2  Postmarketing Experience The following adverse reactions have been identified during post-approval use of Aveed.  Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pulmonary Oil Microembolism (POME) and Anaphylaxis Serious pulmonary oil microembolism (POME) reactions, involving cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular testosterone undecanoate 1000 mg (4 mL) in post-approval use outside the United States.  The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization. In addition to serious POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular testosterone undecanoate in post-approval use outside of the United States.   Both serious POME reactions and anaphylaxis have been reported to occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose.     Other Events The following treatment emergent adverse events or adverse reactions have been identified during post-marketing clinical trials and during post-approval use outside the United States of intramuscular testosterone undecanoate.  In most cases, the dose being used was 1000 mg.  Blood and Lymphatic System Disorders:  polycythemia, thrombocytopenia Cardiac Disorders:  angina pectoris, cardiac arrest, cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, tachycardia Ear and Labyrinth Disorders:  sudden hearing loss, tinnitus Endocrine Disorders:  hyperparathyroidism, hypoglycemia Gastrointestinal Disorders:  abdominal pain upper, diarrhea, vomiting General Disorders and Administrative Site Conditions:  chest pain, edema peripheral, injection site discomfort, injection site hematoma, injection site irritation, injection site pain, injection site reaction, malaise, paresthesia, procedural pain Immune System Disorders:  anaphylactic reaction, anaphylactic shock, asthma, dermatitis allergic, hypersensitivity, leukocytoclastic vasculitis Infections and Infestations:  injection site abscess, prostate infection Investigations:  alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood glucose increased, blood pressure increased, blood prolactin increased, blood testosterone decreased, blood testosterone increased, blood triglycerides increased, gamma-glutamyltransferase increased, hematocrit increased, intraocular pressure increased, liver function test abnormal, prostate examination abnormal, prostatic specific antigen increased, transaminases increased Metabolism and Nutrition Disorders:  diabetes mellitus, fluid retention, hyperlipidemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders:  musculoskeletal chest pain, musculoskeletal pain, myalgia, osteopenia, osteoporosis, systemic lupus erythematosus Neoplasms Benign, Malignant and Unspecified (including cysts and polyps):  prostate cancer, prostatic intraepithelial neoplasia Nervous System Disorders:  stroke, cerebrovascular insufficiency, reversible ischemic neurological deficiency, transient ischemic attack Psychiatric Disorders:  aggression, anxiety, depression, insomnia, irritability, Korsakoff’s psychosis non-alcoholic, male orgasmic disorder, nervousness, restlessness, sleep disorder Renal and Urinary Disorders:  calculus urinary, dysuria, hematuria, nephrolithiasis, pollakiuria, renal colic, renal pain, urinary tract disorder Reproductive System and Breast Disorders:  benign prostatic hyperplasia, breast induration, breast pain, erectile dysfunction, gynecomastia, libido decreased, libido increased, prostate induration, prostatitis, spermatocele, testicular pain Respiratory, Thoracic and Mediastinal Disorders:  asthma, chronic obstructive pulmonary disease, cough, dysphonia, dyspnea, hyperventilation, obstructive airway disorder, pharyngeal edema, pharyngolaryngeal pain, pulmonary microemboli, pulmonary embolism, respiratory distress, rhinitis, sleep apnea syndrome, snoring Skin and Subcutaneous Tissue Disorders:  acne, alopecia, angioedema, angioneurotic edema, dermatitis allergic, erythema, hyperhidrosis, pruritus, rash Vascular Disorders:  cerebral infarction, cerebrovascular accident, circulatory collapse, deep venous thrombosis, hot flush, hypertension, syncope, thromboembolism, thrombosis, venous insufficiency. 7 DRUG INTERACTIONS 7.1  Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens.  In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may necessitate a decrease in the dose of anti-diabetic medication. 7.2  Oral Anticoagulants Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy. 7.3  Corticosteroids The concurrent use of testosterone with corticosteroids may result in increased fluid retention and requires careful monitoring, particularly in patients with cardiac, renal or hepatic disease. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X:  Aveed is contraindicated in pregnant women or in women who may become pregnant.  Testosterone is teratogenic and may cause fetal harm.  Exposure of a fetus to androgens, such as testosterone, may result in varying degrees of virilizations. If this drug is used in pregnancy or if the patient becomes pregnant while taking this drug, the patient should be made aware of the potential hazard to the fetus. 8.3 Nursing Mothers Although it is not known how much testosterone transfers into human milk, Aveed is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.  8.4 Pediatric Use Safety and effectiveness of Aveed in pediatric patients less than 18 years old have not been established.  Improper use may result in acceleration of bone age and premature closure of epiphyses. 8.5 Geriatric Use There have not been sufficient numbers of geriatric patients in controlled clinical studies with AVEED to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. Of the153 patients enrolled in the pivotal clinical study utilizing Aveed, 26 (17.0%) were over 65 years of age. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potentially increased risk of cardiovascular disease and prostate cancer. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH [see Warnings and Precautions (5.3)]. 8.6  Renal Impairment No studies were conducted in patients with renal impairment. 8.7  Hepatic Impairment No studies were conducted in patients with hepatic impairment. 9 DRUG ABUSE AND DEPENDENCE 9.1  Controlled Substance Aveed contains testosterone, a Schedule III controlled substance in the Controlled Substances Act. 9.2  Abuse Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents.  Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse of men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice. Abuse-Related Adverse Reactions Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids, and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression. The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility. The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities. The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty. Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 9.3  Dependence Behaviors Associated with Addiction Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors: Taking greater dosages than prescribed Continued drug use despite medical and social problems due to drug use Spending significant time to obtain the drug when supplies of the drug are interrupted Giving a higher priority to drug use than other obligations Having difficulty in discontinuing the drug despite desires and attempts to do so Experiencing withdrawal symptoms upon abrupt discontinuation of use Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism. Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented. 10 OVERDOSAGE There have been no reports of overdosage in the Aveed clinical trials. There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident.  Treatment of overdosage would consist of discontinuation of Aveed together with appropriate symptomatic and supportive care. 11 DESCRIPTION Aveed (testosterone undecanoate) injection contains testosterone undecanoate (17β-undecanoyloxy-4-androsten-3-one) which is an ester of the androgen, testosterone. Testosterone is formed by cleavage of the ester side chain of testosterone undecanoate.  Testosterone undecanoate is a white to off-white crystalline substance. The empirical formula of testosterone undecanoate is C30H48O3 and a molecular weight of 456.7.  The structural formula is: FIGURE 2: Testosterone Undecanoate C30H48O3          MW:  456.7 Aveed is a clear, yellowish, sterile oily solution containing testosterone undecanoate, a testosterone ester, for intramuscular injection.  Each single use vial contains 3 mL of 250 mg/mL testosterone undecanoate solution in a mixture of 1500 mg of benzyl benzoate and 885 mg of refined castor oil.    12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endogenous androgens, including testosterone and dihydrotestosterone (DHT) are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics.  These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution.  Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies.  Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). 12.3 Pharmacokinetics Absorption Aveed 750 mg delivers physiologic amounts of testosterone, producing circulation testosterone concentrations that approximate normal concentrations (300-1000 ng/dL) seen in healthy men. Testosterone esters in oil injected intramuscularly are absorbed from the lipid phase.  Cleavage of the undecanoic acid side chain of Aveed by tissue esterases releases testosterone. Following intramuscular injection of 750 mg of Aveed, serum testosterone concentrations reach a maximum after a median of 7 days (range 4-42 days) then slowly decline (Figure 3).  Steady state serum testosterone concentration was achieved with the 3rd injection of Aveed at 14 weeks.  Figure 3 shows the mean serum total testosterone concentration-time profile during the 3rd injection interval (at steady state, 14-24 weeks) for hypogonadal men (less than 300 ng/dL) given 750 mg Aveed at initiation, at 4 weeks, and every 10 weeks thereafter.  Intramuscular injection of 750 mg of Aveed generates mean steady state serum total testosterone concentrations in the normal range for 10 weeks. FIGURE 3:   Mean (SD) Serum Total Testosterone Concentrations (ng/dL) at 14-24 Weeks Distribution Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.  Metabolism Testosterone undecanoate is metabolized to testosterone via ester cleavage of the undecanoate group. The mean (SD) maximum concentration of testosterone undecanoate was 90.9 (68.8) ng/dL on Day 4 following injection of Aveed. Testosterone undecanoate was nearly undetectable 42 days following injection of Aveed. Testosterone is metabolized to various 17-keto steroids through two different pathways.  The major active metabolites of testosterone are estradiol and DHT.  DHT concentrations increased in parallel with testosterone concentrations during Aveed treatment.  Average DHT concentrations during a dosing interval ranged from 244 to 451 ng/dL. The mean DHT:T ratios ranged from 0.05 to 0.07. Excretion There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. About 90% of a testosterone dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of testosterone or as metabolites.  About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.  Effect of Body Weight and Body Mass Index (BMI) Analysis of serum testosterone concentrations from 117 hypogonadal men in the 84-week clinical study of Aveed indicated that serum testosterone concentrations achieved were inversely correlated with the patient’s body weight.  In 60 patients with pretreatment body weight of ≥100 kg, the mean (±SD) serum testosterone average concentration was 426 ± 104 ng/dL.  A higher serum testosterone average concentration (568 ± 139 ng/dL) was observed in 57 patients weighing 65 to 100 kg.  A similar trend was also observed for maximum serum testosterone concentrations. In 70 patients with pretreatment body mass index of >30 kg/m2, the mean (±SD) serum testosterone average concentration was 445 ± 116 ng/dL.  Higher serum testosterone average concentrations (579 ± 101 ng/dL and 567± 155ng/dL) were observed in patients with BMIs <26 kg/m2 and 26 to 30 kg/m2,respectively.  A similar trend was also observed for maximum serum testosterone concentrations. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility Carcinogenicity Testosterone has been tested by subcutaneous injection and implantation in mice and rats.  In mice, the implant induced cervical-uterine tumors, which metastasized in some cases.  There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Mutagenicity Mutagenic effects of testosterone undecanoate were not detected in a battery of in vitro tests including bacterial mutation assays (Ames test) and chromosomal aberration tests in human lymphocytes. Testosterone undecanoate was also negative in an in vivo bone marrow micronucleus assay in mice. Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. Impairment of Fertility The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment. 14 CLINICAL STUDIES 14.1 Testosterone Replacement Therapy Aveed was evaluated for efficacy in an 84-week, single-arm, open-label, multicenter study of 130 hypogonadal men.  Eligible patients weighed at least 65 kg, were 18 years of age and older (mean age 54.2 years), and had a morning serum total testosterone concentrations <300 ng/dL (mean screening testosterone concentration 215 ng/dL).  Patients were Caucasian (74.6%), Black (12.3%), Hispanic (10.8%) and of Other ethnicities (2.3%).  The mean body mass index was 32 kg/m2.  All patients received injections of Aveed 750 mg at baseline, at 4 weeks, and then every 10 weeks thereafter. The primary endpoint was the percentage of patients with average serum total testosterone concentration (Cavg) within the normal range (300-1000 ng/dL) after the third injection, at steady state. The secondary endpoint was the percentage of patients with maximum total testosterone concentration (Cmax) above three pre-determined limits: greater than 1500 ng/dL, between 1800 and 2499 ng/dL, and greater than 2500 ng/dL. A total of 117 out of 130 hypogonadal men completed study procedures through Week 24 and were included in the evaluation of testosterone pharmacokinetics after the third Aveed injection.  Ninety-four percent (94%) of patients maintained a Cavg within the normal range (300 to 1000 ng/dL).  The percentages of patients with Cavg below the normal range (less than 300 ng/dL) and above the normal range (greater than 1000 ng/dL) were 5.1% and 0.9%, respectively. Table 2 summarizes the mean (SD) serum total testosterone pharmacokinetic parameters at steady state for these 117 patients. TABLE 2 Mean (SD) Serum Total Testosterone Concentrations at Steady State Pharmacokinetics at Steady State Aveed 750 mg (N=117) Cavg (0 to 10 weeks) (ng/dL) 495 (142) Cmax (ng/dL) 891 (345) Cmin (ng/dL) 324 (99) Cavg=average concentration; Cmax = maximum concentration; Cmin = minimum concentration The percentage of patients with Cmax >1500 ng/dL was 7.7%.  No patient had a Cmax >1800 ng/dL. 16 HOW SUPPLIED/STORAGE AND HANDLING Aveed, NDC 67979-511-43: 750 mg/3 mL (250 mg/mL) testosterone undecanoate sterile injectable solution is provided in an amber glass vial with silver-colored crimp seal and gray plastic cap.  Each vial is individually packaged in a carton box. Store at controlled room temperature 25 ºC (77 ºF); excursions permitted to 15 - 30 ºC (59 - 86 ºF) [See USP controlled room temperature] in its original carton until the date indicated. Before use, each vial should be visually inspected.  Only vials free from particles should be used.  Single Use Vial.  Discard unused portion. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f80f025b-17d8-40af-8739-20ce07902045