28 February 2013 Subscribe to our news feed

Long-acting testosterone undecanoate is well tolerated in men with hypogonadism in daily clinical practice

IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. Zitzmann M, Mattern A, Hanisch J, et al. J Sex Med 2013;10(2):579–588.

This prospective, observational, post-authorization surveillance study investigated the safety and efficacy of intramuscular injections of testosterone undecanoate (TU) in men with testosterone deficiency syndrome (hypogonadism) in a clinical practice setting1. The study, conducted in 23 countries throughout Europe, Asia, Latin America and Australia, enrolled 1493 men (mean age 49.2 ± 13.9 years) with a diagnosis of primary or secondary testosterone deficiency syndrome (serum total testosterone 8–12 nmol/L for newly diagnosed treatment-naïve patients). The men received up to five injections of TU during an observation period of 9–12 months. Between the first and second injections of the agent there was an interval of 6–10 weeks, and subsequent injections were given at intervals of 12 ± 2 weeks.

An analysis of this study was reported in the Research News on this website on 26 October 2012 and focused on the therapeutic effectiveness of TU in a large global cohort of patients. This present analysis focuses on the primary aim of the International Post-Authorization Surveillance Study (IPASS), which was to confirm the established safety profile of TU in male patients with testosterone deficiency syndrome who received TU under ‘real-life’ conditions. Tolerability was assessed using patient ratings of treatment satisfaction at the end of the treatment period. Digital rectal examinations as well as laboratory measurements of prostate-specific antigen (PSA), hemoglobin and hematocrit were also used to establish the safety of TU, and were assessed at each study visit.

Of the 1493 men enrolled, 72.5% were Caucasian, followed by 19.7% and 7.5% of Asian and Latin American descent, respectively. A total of 1438 and 1140 men were evaluable at baseline and at the time of the fifth injection, respectively. At baseline, mean body weight was 86.8 kg, and 54% of those enrolled had previously received androgen therapy. Mean serum testosterone (T) was 9.6 ± 7.5 nmol/L, and comorbidities included erectile dysfunction (ED), hypertension and dyslipidemia.

Key Points1

  • TU was well tolerated in men with hypogonadism. Adverse drug reactions (ADRs) related to TU therapy were rare (5.8%), and only 1 (0.1%) was considered serious (prostate enlargement and urinary retention)

    • The most common ADRs were increased hematocrit, increased PSA levels and injection site pain, all of which occurred in < 1% of patients
    • No unexpected ADRs were reported
  • The majority of patients rated the tolerability of TU as “very good” or “good”, and at the final observation, 89% of those surveyed were “satisfied” or “very satisfied” with their treatment
  • The number of men who discontinued from the study was relatively low, with 17.5% of patients prematurely discontinuing TU

    • The majority of the men who discontinued therapy did so due to reasons unrelated to ADRs, such as “patient lost to follow-up” and “withdrawal of consent” (n=136)
    • Overall, ADRs were associated with treatment discontinuation in 31 patients, and less than a quarter of the men who discontinued therapy did so due to discomfort at injection sites
  • Mean PSA levels increased from 1.1 ± 0.9 to 1.3 ± 1.2 ng/mL from baseline after the first injection of TU and remained stable afterwards (p < 0.0001)

    • Patients who received androgen therapy (testosterone) before the initiation of this study appeared to have less variation in PSA levels over the trial period (Figure 1)
  • In 11 men, PSA levels exceeded 4 ng/mL, and in four of these patients there were clinical reasons to perform a prostate biopsy; however, no cases of prostate cancer were observed
  • Hematocrit levels increased slightly from a baseline level of 42.8 ± 6.6% to 44.5 ± 6.1% after the last TU injection (Visit 5; p < 0.0001) but remained below 50%, the recommended limit for testosterone treatment in men with androgen deficiency2
  • Adverse cardiac events were reported in 7 patients, all of whom had pre-existing cardiovascular impairment

    • The cardiac adverse events reported included atrial fibrillation, myocardial infarction, bradycardia and palpitations
    • No cases of heart failure or edema associated with heart failure were reported
    • No de novo cardiac adverse events were recorded

What is known

Hypogonadism, which can be defined as serum total testosterone ≤ 12 nmol/L and a positive score suggestive of androgen deficiency on the Aging Male Symptoms (AMS) scale, is increasingly recognized as a significant health problem in aging men3-9. Androgen replacement therapy is the principal treatment for testosterone deficiency syndrome, and involves the administration of T at doses which aim to reproduce normal blood T levels, in order to improve exposure of androgen-dependent tissues and organs to T. In general, the better the improvement in T levels after androgen replacement therapy, the better the clinical outcomes1. TU is an intramuscularly administered, long-acting formulation of T used as an androgen replacement therapy for men affected by testosterone deficiency syndrome. Previous studies have established the safety profile of TU10, 11, however, as few large-scale post-marketing surveillance studies of TU have been conducted, and no large trials evaluating the agent in Asian and South American populations have been conducted at all, this present trial aimed to confirm the safety profile of TU in men with testosterone deficiency syndrome, and to evaluate the agent in a ‘real world’ clinical setting throughout Europe, Asia, Latin America and Australia.

What this study adds

This international, multicenter, one-arm, non-interventional, prospective post-authorization surveillance study demonstrated that TU is well tolerated in daily clinical practice and confirmed the established safety profile of TU in the largest worldwide sample of men with testosterone deficiency1.

TU was well tolerated, with the majority of patients rating the tolerability as “very good” or “good”. Few reports of ADRs occurred and no unexpected ADRs were observed. Furthermore, the number of men who discontinued from the study was relatively low, with 17.5% of patients prematurely discontinuing TU (of which only 31 discontinued treatment due to ADRs). The most commonly reported ADRs were increased hematocrit, increased PSA levels and injection site pain, all of which occurred in < 1% of patients. However, abnormal increases in hematocrit and PSA were rarely observed and no cases of prostate cancer were detected. Finally, cardiac adverse events were reported in 7 patients, all of whom had pre-existing cardiovascular impairment. These results support previous studies investigating the cardiovascular safety of TU and other T preparations12-15, and further demonstrate the ‘real world’ safety of TU.

Figure 1: Mean change in prostate-specific antigen levels from baseline (Visit 1) to the fifth injection (Visit 5) of long-acting testosterone
Figure 1: Mean change in prostate-specific antigen levels from baseline (Visit 1) to the fifth injection (Visit 5) of long-acting testosterone

References

1. Zitzmann M, Mattern A, Hanisch J, et al. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med 2013;10(2):579–588.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
3. Ullah MI, Washington T, Kazi M, et al. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res 2011;43(3):153-164.
4. Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care 2011;34(7):1669-1675.
5. Bassil N, Morley JE. Late-life onset hypogonadism: a review. Clin Geriatr Med 2010;26(2):197-222.
6. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130.
7. Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am J Med 2007;120(10):835-840.
8. Traish AM, Miner MM, Morgentaler A, et al. Testosterone deficiency. Am J Med 2011;124(7):578-587.
9. Saad F, Aversa A, Isidori AM, et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol 2011;165(5):675-685.
10. Saad F, Kamischke A, Yassin A, et al. More than eight years’ hands-on experience with the novel long-acting parenteral testosterone undecanoate. Asian J Androl 2007;9(3):291-297.
11. Haider A, Gooren LJ, Padungtod P, et al. A safety study of administration of parenteral testosterone undecanoate to elderly men over minimally 24 months. Andrologia 2010;42(6):349-355.
12. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: A double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 2009;54(10):919-927.
13. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: A randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010;95(2):639-650.
14. Kenny AM, Kleppinger A, Annis K, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc 2010;58(6):1134-1143.
15. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363(2):109-122.

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