Aveed

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 POME 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 )]. 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: Primary hypogonadism (congenital or acquired) ( 1 ) 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 ).

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 2 separate days and that these serum testosterone concentrations are below the normal range. 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 ). Three (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 ). 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 POME [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, attach an 18-gauge needle and draw 3 mL of air into the syringe. Hold the needle at a 45° angle to the stopper with the bevel in the up orientation. Inject 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 pati…

5 WARNINGS AND PRECAUTIONS Venous thromboembolism (VTE): 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 ( 5.4 ). Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer: Monitor patients with BPH for worsening of signs and symptoms of BPH ( 5.5 ). Blood Pressure Increases: Testosterone can increase blood pressure, which can increase cardiovascular risk over time. Measure blood pressure periodically. Not recommended for use in men with uncontrolled hypertension ( 5.6 ) Abuse of Testosterone: Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids ( 5.7 ). Potential for Adverse Effects on Spermatogenesis: Exogenous administration of androgens may lead to azoospermia ( 5.9 ). Edema: Edema with or without congestive heart failure may be a complication in patients with preexisting cardiac, renal, or hepatic disease ( 5.11 ). Sleep apnea: Sleep apnea may occur in those with risk factors ( 5.13 ). Monitor prostatic specific antigen (PSA), hemoglobin, hematocrit, and lipid concentrations periodically ( 5.3 , 5.5 , 5.14 ). 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 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 incre…

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 ( 5.5 )]. Women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman [see Use in Specific Populations ( 8.1 , 8.2 )] . Men with known hypersensitivity to AVEED or any of its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate). Men with carcinoma of the breast or known or suspected carcinoma of the prostate ( 4 , 5.5 ). Women who are pregnant. Testosterone may cause fetal harm ( 4 , 5.8 , 8.1 , 8.2 ). Known hypersensitivity to Aveed or its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate) ( 4 ).

7 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 ). 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.

8.1 Pregnancy Risk Summary AVEED is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm based on data from animal studies and its mechanism of action [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.1 )] . Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal development studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies. Data Animal Data In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased anogenital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes. Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant female rats and their offspring exposed to doses approximately twice those used for testosterone replacement therapy.

8.3 Females and Males of Reproductive Potential Infertility During treatment with large doses of exogenous androgens, including AVEED, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis [see Warnings and Precautions ( 5.9 )] , possibly leading to adverse effects on semen parameters including sperm count. Reduced fertility is observed in some men taking testosterone replacement therapy. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence ( 9.2 )] . With either type of use, the impact on fertility may be irreversible.

6 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 at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 (14) 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 (eg, 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 POME 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 an…