Aveed Drug Information

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 . Intravascular injection of AVEED may lead to POME. 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.

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.

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. Figure1

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 (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 anaphylaxis among 3,556 patients treated with intramuscular testosterone undecanoate in 18 clinical trials were judged to have occurred.

Blood Pressure Increases In a 4-month clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted on 222 patients. ABPM was conducted at baseline and at Week 16 of AVEED therapy. A total of 139 patients had acceptable ABPM recordings at both baseline and Week 16 and were at least 85% compliant with study drug.

In that group, the mean change in 24-hour systolic blood pressure (BP) and diastolic BP from baseline to end-of-treatment at Week 16 (n=139) was 3.1 mm Hg (95% CI 1.2, 4.9) and 2.0 mm Hg (95% CI 0.9, 3.1), respectively. In patients with a history of hypertension who were receiving antihypertensive therapy, the mean ABPM systolic and diastolic BP increased by 2.1 mm Hg and 1.5 mm Hg, respectively ). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 3.3 mm Hg and 2.5 mm Hg, respectively. 2 patients (1.4%) on AVEED, both of whom were receiving antihypertensive medications at baseline, either started new antihypertensive medications (n=2) or had their antihypertensive medication regimen adjusted (n=0) during the ABPM study. Of the 222 patients in the ABPM study who used AVEED, 8 patients (3.6%) were reported to have either an adverse reaction of hypertension (7 patients, 3.2%) or increased blood pressure (1 patient, 0.4%). Cardiovascular Outcomes TRAVERSE was a randomized, double-blind, cardiovascular outcomes study to assess the cardiovascular (CV) safety of topical testosterone gel compared to placebo in 5198 hypogonadal men aged 45 to 80 years with a history of CV disease or with multiple CV risk factors.

The primary outcome was the incidence of the composite endpoint of major adverse cardiovascular events (MACE), consisting of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. The mean duration of therapy was approximately 22 months. The mean duration of follow-up was 33 months.

Approximately 61% of all patients discontinued topical testosterone gel or placebo therapy. The mean patient age (±SD) was 63.3 years, with 2452 patients aged 65 years or more (47%); 2847 (about 55%) patients had pre-existing cardiovascular disease, whereas 2357 patients (about 45%) had an elevated cardiovascular risk at baseline, and mean BMI was 35 kg/m 2. Approximately 80% of patients were White, 17% were Black, and 3% were of other races or ethnic groups. Approximately 69%, 84%, and 93% had diabetes mellitus, hyperlipidemia, and hypertension, respectively.

The mean serum testosterone concentration at baseline in patients receiving topical testosterone gel was 220.4 ng/dL (n=2596). The mean serum testosterone concentrations at 12 months, 24 months, 36 months, and 48 months in patients receiving topical testosterone gel were 440.5 ng/dL (n=1683), 420.9 ng/dl (n=1125), 428.7 ng/dL (n=731), and 365.2 ng/dL (n=220), respectively. For patients treated with topical testosterone gel, the incidence of MACE was 7.0% (n=182 events) and for those receiving placebo, the incidence of MACE was 7.3% (n=190 events). The study demonstrated non-inferiority of topical testosterone gel versus placebo because the upper bound of 95% CI was less than the pre-specified risk margin, of 1.5 for MACE (Hazard Ratio 0.96 ). Additional Adverse Reactions Reported in TRAVERSE Additional adverse reactions reported in TRAVERSE at an incidence rate >2% in either treatment group and greater in topical testosterone gel versus placebo included: nonfatal arrythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and bone fracture (3.5% vs 2.5%). For the adverse reaction of bone fracture, each event was adjudicated by clinical review.

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 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 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 : azoospermia, 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

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.

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.

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.

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 . 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.

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.

should not be used in any of the following patients: Men with carcinoma of the breast or known or suspected carcinoma of the prostate. Women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman . 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.

Women who are pregnant. Testosterone may cause fetal harm. Known hypersensitivity to Aveed or its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate).

There have been no reports of overdosage in the AVEED clinical trials. There is 1 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.