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WARNING
SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS AND ANAPHYLAXIS
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.
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.
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 anaphylaxis among 3,556 patients treated with intramuscular testosterone undecanoate in 18 clinical trials were judged to have occurred.
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 [95% CI -0.7, 5.0] and 1.5 mm Hg [95% CI -0.1, 3.2], respectively [n=73]). In patients with no history of hypertension, the mean systolic and diastolic blood pressure increased by 3.3 mm Hg [95% CI 0.8, 5.8] and 2.5 mm Hg [95% CI 1.0, 4.0], respectively [n=65].
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%).
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 (7.9) 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/m2. 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 [95% CI: 0.78, 1.17]).
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.
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
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.
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.
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.
AVEED contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.
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.
Behaviors Associated with Addiction
Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:
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.
Included as part of the PRECAUTIONS section.
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.
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:
Further information is available at www.aveedrems.com or call 1-855-755-0494.
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.
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.
In the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Study, a randomized, double-blind, placebo-controlled, cardiovascular (CV) outcomes study, compared to placebo, topical testosterone gel was associated with a numerically higher incidence of VTE (1.7% vs 1.2%) which included DVT (0.6% vs 0.5%) and PE events (0.9% vs 0.5%) [see Adverse Reactions (6.1)].
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.
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)].
AVEED can increase blood pressure. In an ambulatory blood pressure monitoring (ABPM) study, AVEED increased the mean systolic/diastolic blood pressure by 3.1/2.0 mm Hg from baseline after 16 weeks of treatment. In patients with hypertension on antihypertensive therapy, AVEED increased the mean systolic/diastolic BP by 2.1/1.5 mm Hg from baseline. Blood pressure increases can increase cardiovascular (CV) risk over time.
The CV risk associated with topical testosterone gel was evaluated in TRAVERSE, a randomized, double-blind, placebo-controlled, CV outcomes study in men with a history of CV disease or multiple CV risk factors. In TRAVERSE, topical testosterone gel increased mean systolic blood pressure by 1.0 mm Hg from baseline to 36 months, whereas a mean decrease from baseline of 0.5 mm Hg was observed in the placebo group at this timepoint, for a mean between-group difference of 1.5 mm Hg. However, the incidences of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction [MI] and non-fatal stroke, were similar between treatment groups (7% for topical testosterone gel vs 7.3% for placebo) [See Adverse Reactions (6.1)].
Monitor blood pressure periodically in men using AVEED, especially men with hypertension. AVEED is not recommended for use in patients with uncontrolled hypertension.
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.
Due to lack of controlled evaluations in women and potential virilizing effects, AVEED is not indicated for use in women [see Contraindications (4) and Use in Specific Populations (8.1, 8.2)].
With large doses of exogenous androgens, including AVEED, spermatogenesis may be suppressed through feedback inhibition of pituitary FSH which could possibly lead to adverse effects on semen parameters including sperm count.
Prolonged use of high doses of orally active 17-alpha-alkyl androgens (eg, 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 (eg, jaundice). If these occur, promptly discontinue AVEED while the cause is evaluated.
Androgens, including AVEED, may promote retention of sodium and water. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.
Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism [see Adverse Reactions (6.1)].
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.
Changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of testosterone therapy, such as AVEED. Monitor the lipid profile periodically, particularly after starting testosterone therapy.
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.
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.
Carcinogenesis
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.
Mutagenesis
AVEED was negative in the in vitro Ames assays, the chromosomal aberration assay in human lymphocytes, and in the in vivo mouse micronucleus assay.
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.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients of the following:
Men with known or suspected prostate or breast cancer should not use AVEED [see Contraindications (4)].
Patients should be informed that treatment with androgens may lead to adverse reactions which include:
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.
AVEED should not be used in any of the following patients:
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 2 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).
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 to 42 days) then slowly decline (Figure 3). Steady-state serum testosterone concentration was achieved with the third injection of AVEED at 14 weeks.
Figure 3 shows the mean serum total testosterone concentration-time profile during the third injection interval (at steady state, 14 to 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 to 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 2 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 to testosterone 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 BMIs 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.
MEDICATION GUIDE AVEED®
(Uh-Veed)
(testosterone undecanoate)
injection
Read this Medication Guide before you receive AVEED and before each injection. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.
What is the most important information I should know about AVEED?
AVEED may cause serious side effects, including:
These reactions can happen after you receive your first dose of AVEED or may happen after receiving more than 1 dose.
You may need emergency treatment in a hospital, especially if these symptoms get worse over the 24 hours after your AVEED injection.
These side effects may happen during or right after each injection. To be sure that you are not having one of these reactions:
AVEED is only available through a restricted program called the AVEED Risk Evaluation and Mitigation Strategy (REMS) Program. For more information about the AVEED REMS Program go to www.AveedREMS.com or call 1-855-755-0494.
What is AVEED?
AVEED is a prescription medicine that contains testosterone. AVEED is used to treat adult males who have low or no testosterone due to certain medical conditions.
AVEED is only for adult males who need testosterone replacement therapy and when the benefit of receiving AVEED is more than the risk of POME and anaphylaxis.
Your healthcare provider will test your blood before you start and while you are taking AVEED.
It is not known if AVEED is safe or effective to treat men who have low testosterone due to aging.
It is not known if AVEED is safe and effective for use in children younger than 18 years old. Improper use of AVEED may affect bone growth in children.
AVEED is a controlled substance (CIII) because it contains testosterone that can be a target for people who abuse prescription medicines.
AVEED is not meant for use in women.
Who should not receive AVEED?
Do not receive AVEED if you:
Talk to your doctor before receiving this medicine if you have any of the above conditions.
What should I tell my doctor before receiving AVEED?
Before receiving AVEED, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Receiving AVEED with certain other medicines can affect each other. Especially tell your doctor if you take:
Ask your doctor or pharmacist for a list of these medicines, if you are not sure.
Know the medicines you take. Keep a list of your medicines and show them to your doctor and pharmacist when you get a new medicine.
How will I receive AVEED?
See “What is the most important information I should know about AVEED?”
Your doctor will inject AVEED deep into the muscle of your buttock. You will get 1 injection when you start, 1 injection 4 weeks later, and then 1 injection every 10 weeks.
Your doctor will test your blood before you receive and while you are receiving AVEED.
What are the possible side effects of AVEED?
AVEED can cause serious side effects including:
Call your doctor right away if you have any of the serious side effects listed above.
The most common side effects of AVEED include:
Other side effects include more erections than are normal for you or erections that last for a long time.
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects with AVEED. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about AVEED
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
This Medication Guide summarizes the most important information about AVEED. If you would like more information, talk with your doctor. You can ask your doctor or nurse for information about AVEED that is written for health professionals. For more information, go to www.AVEEDUSA.com or call 1-800-462-3636.
What are the ingredients in AVEED?
Active ingredient: testosterone undecanoate
Inactive ingredients: benzyl benzoate, refined castor oil
This Medication Guide has been approved by the U.S. Food and Drug Administration.
