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
|Injection site pain||7 (4.6%)|
|Prostatic specific antigen increased*||7 (4.6%)|
|Estradiol increased||4 (2.6%)|
|Hemoglobin increased||3 (2%)|
|Mood swings||3 (2%)|
|Ejaculation disorder||2 (1.3%)|
|Injection site erythema||2 (1.3%)|
|Hematocrit increased||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.
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.
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: 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.