"The US Food and Drug Administration (FDA) has approved class-wide labeling changes for all prescription testosterone products, the agency announced today.
New safety information from published literature and case reports on the risks "...
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).
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
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.
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.
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.
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 concentration < 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 predetermined 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
|Aveed 750 mg
|Cavs (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.
Last reviewed on RxList: 11/7/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Aveed Information
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