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Effectiveness and tolerability of injectable testosterone undecanoate

Effectiveness and tolerability of injectable testosterone undecanoate: a post-marketing surveillance study

Wolf J, Keipert D, Motazedi H, Ernst M, Nettleship J, Gooren L. Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study. The Aging Male: the official journal of the International Society for the Study of the Aging Male. 2017;20(4):225-234.

Injectable testosterone esters are one of the most commonly used formulations for treatment of hypogonadism.1 Here we report results from an observational post-marketing surveillance study of injectable testosterone undecanoate, published in The Aging Male, with the aim to examine the effectiveness of testosterone undecanoate as a treatment of hypogonadism, and document adverse drug reactions, particularly regarding polycythemia (hematoctrit elevation) and prostate safety.2

Key Points

  • Long-acting injectable testosterone undecanoate is a treatment option for hypogonadism that only requires 4-5 injections per year to achieve therapeutic testosterone levels. Notably, injectable testosterone undecanoate prevents the roller-coaster fluctuations in testosterone levels that is seen with short-acting testosterone injectables.
  • Ratings of effectiveness and tolerability of testosterone undecanoate treatment increases over time in parallel with elevations in testosterone levels.
  • The most frequent reasons for choosing testosterone undecanoate were:
    • More comfort for the patient.
    • Steady drug levels
    • Better compliance
    • Prevention of mood changes
    • Less side effects
  • Most patients that were enrolled in the study wished to continue testosterone undecanoate after study completion.
  • Elevations in hematocrit and PSA are within the normal range in almost all patients.

What is known about injectable testosterone esters

The most commonly used testosterone esters are testosterone enanthate and testosterone undecanoate.1 Testosterone enanthate is a short-acting ester of testosterone causing peak testosterone levels 1–2 days after the injection, with waning levels over the subsequent 2 weeks.1,3 To increase testosterone levels into the therapeutic range i.m. injections of testosterone enanthate are required every 2 weeks. This leads to supraphysiological peaks shortly after administration, followed by a sharp fall in levels thereafter. Testosterone levels before the next injection are frequently in the hypogonadal range. 1,3 These marked fluctuations in testosterone levels can lead to adverse impacts on mood, energy, and sexual function, which can be bothersome or disruptive.4,5 Furthermore, the frequent injections are often reported as impractical and uncomfortable by many patients.6

To circumvent the inconvenience of short-acting testosterone esters, long-acting testosterone undecanoate was developed, which allows for achievement of desired benefits of testosterone therapy with stable testosterone levels and fewer required injections, with less risk of excessive hematocrit elevations beyond the normal range.7-13

In a head-to-head comparison study, trough levels of testosterone (the lowest point before next injection) were significantly higher in men receiving injections of testosterone undecanoate than in men receiving injections of testosterone enanthate (14.14 vs. 8.02 nmol/L, and 16.31 vs. 8.29 nmol/L, after 12 and 30 weeks of treatment, respectively). In the testosterone enanthate group, mean trough levels of testosterone were always less than 10 nmol/L before the next injection, whereas in the testosterone undecanoate group, mean trough levels of testosterone were 14.1 nmol/L after the first 2 doses (6-week interval) and 16.3 nmol/L after the 9-week interval at week 30.14

The following administration regimen is recommended for treatment of hypogonadism with testosterone undecanoate: After the first injection of 1000mg testosterone undecanoate, a second injection of 1000 mg testosterone undecanoate is to be administered 6 weeks after the first injection (loading dose) in order to quickly reach steady state, followed by injections every 12 weeks (maintaining dose).9 While this schedule is generally adequate, an individualization of testosterone undecanoate therapy, based on testosterone levels measured at the end of the interval or complaints of testosterone deficiency, may be desirable.15,16

What this study adds about testosterone undecanoate

The surveillance study gathered information to verify whether the recommended injection intervals do achieve therapeutic testosterone levels in the eugonadal range in routine clinical practice, and examine safety parameters related to hematocrit elevation, prostate safety and cardiovascular-related metabolic risk factors.17

870 patients who visited urology clinics six times between January 2005 and December 2006 were included. Effectiveness and tolerability of testosterone undecanoate treatment were assessed on a 4-point scale. Body weight, waist circumference, blood pressure, hemoglobin, hematocrit, PSA, and digital rectal prostate examination were assessed. Over 90% of subjects completed the observational duration of 53 weeks.

Assessment of effectiveness and tolerability

Figure 1 and 2 shows the ratings for effectiveness and tolerability. The percentage of “Very good” assessment increased during the course of the study from 42.4% at visit 1 to approximately 56% at visits 4 and 5. It is notable that the “very good” rating for efficacy increased over time along with rising testosterone levels from a baseline level of 8 nmol/L to 16.5 nmol/L (note that these are though levels recorded right before the next injection).

At all visits the tolerability was assessed as “Good” or “Very good” in approximately 90% of the patients. From visit 2 until the end of the observational period (visit 5), the percentage of “Very good” assessment was always higher than 60%.

Figure 1: Ratings of effectiveness at visit five.

Figure 1: Ratings of effectiveness at visit five.
vergrößern Data from Wolf J, Keipert D, Motazedi H, Ernst M, Nettleship J, Gooren L. Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study. The Aging Male: the official journal of the International Society for the Study of the Aging Male. 2017;20(4):225-234.

Figure 2: Ratings of tolerability at visit five.

Figure 2: Ratings of tolerability at visit five.
vergrößern Data from Wolf J, Keipert D, Motazedi H, Ernst M, Nettleship J, Gooren L. Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study. The Aging Male: the official journal of the International Society for the Study of the Aging Male. 2017;20(4):225-234.

Reasons for switching to testosterone undecanoate

The most frequent reasons for choosing testosterone undecanoate were “more comfort for the patient” (51.3%) and “steady drug levels” (49.2%). “Better compliance” (29.5%), “prevention of mood changes” (16.4%), and “less side effects” (8.0%) were also cited reasons (several reasons were commonly cited).

Treatment regimen

For the interval between the first administration of testosterone undecanoate (study start) and the second administration at visit 1, the mean injection interval was 6.2 weeks, thus very close to the initial 6 weeks as recommended for testosterone undecanoate.9 An interval of 5-7 weeks between the first and second injection was followed in 685 subjects (78.7%). The subsequent mean intervals of 11.4, 12.6, 12.7 and 12.3 weeks were also within the recommended injection range of 10-14 weeks. At each visit, more than 70% of the subjects were in compliance with the product recommendations.

Effects on waist circumference, body weight, BMI

There was no significant change in overall mean body weight. However, a notable finding was that testosterone treatment had a normalizing effect on body weight; underweight and normal men experienced slight weight increase while overweight men lost 0.6 kg and obese men lost 2 kg. The changes in BMI paralleled the body weight changes.

Mean waist circumference was 102 cm at study start and 100 cm at the end of the observational period.

Blood pressure

There were only minimal effects on blood pressure. As for body weight, a normalization effect on blood pressure was found; men with low blood pressure showed an increase while men with elevated blood pressure had a decrease in blood pressure.

Safety

No adverse effects on indicators of cardiovascular risk were observed.

Hematocrit (normal range is 42–52%): Overall, mean hematocrit levels were 44.4% at baseline and slightly increased during the treatment period up to 45.3%.

Prostate-specific antigen (PSA; normal range <4 ng/mL): Overall, mean PSA levels were 1.4 ng/mL at baseline and slightly increased during the treatment period up to 1.7 ng/mL.

Supranormal hematocrit elevation only occurred in one subject (out of 870 patients). Four subjects developed supranormal PSA levels. Prostate carcinoma was found in one subject, one subject had recurrence of a previously surgically treated prostate carcinoma, and the other two showed no indication of malignancy.

It was concluded that injectable testosterone undecanoate is safe, effective, and well-tolerated in clinical practice and provides a good treatment option for hypogonadism.

Commentary

The present study confirmed that the recommended injection intervals result in good effectiveness and tolerability of intramuscular testosterone undecanoate.2 Poor effectiveness was very rarely documented. Considering that poor effectiveness is in most cases due to lack of achievement of therapeutic testosterone levels, shortening the injection interval of 12 weeks to 10 weeks can be tried.

The low drop-out rate during the 1-year treatment period - 90% of all subjects completed the study and the same percentage wished to continue testosterone undecanoate after study completion - supports the conclusion injectable testosterone undecanoate is well tolerated and that this treatment option facilitates long-term adherence in real-life clinical practice. This is of critical importance as it takes a number of years for several testosterone effects to manifest, such as reduction in body fat mass and gains in lean body mass, muscle strength and bone mineral density.18 Similar results were found in the IPASS study of 1438 hypogonadal men in 23 countries, in which each subject received up to five injections over a 9- to 12-month period and reported a marked improvement in psychosexual parameters (libido, vigour, overall mood, and ability to concentrate).19 The percentage of patients with “low” or “very low” levels of sexual desire/libido decreased from 64% at baseline to 10% whilst moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%. Overall, 89% of patients stated they were “satisfied” or “very satisfied” with testosterone undecanoate treatment.19

It is notable that during treatment in the study reported here, the mean trough testosterone levels ranged between 15.0 (visit 3) and 16.5 nmol/L (visit 5).2 This is similar to what has been reported previously in a pharmacokinetic study 14, and confirms the lack of “roller coaster” effect seen with other injectable testosterone preparations, all of which are short-acting and require bi-monthly injections.10

Safety analyses showed adverse reactions that were consistent with the product information in terms of type and frequency of the side effects. The most common side effect was an increase in hematocrit and PSA, however the elevations were still within normal range and are actually a physiological response to testosterone treatment. Only 1 patient (0.1%) developed hematocrit elevation above 52% and only 4 patients (4.6%) developed PSA above 4 ng/mL. These results are in line with a previous randomized controlled trial which reported that treatment with testosterone undecanoate injections for 48 weeks is well tolerated, and that treatment-induced elevations in PSA, hemoglobin and hematocrit were all within clinically safe limits.20 There was no significant adverse reaction that led to the cessation of treatment.20

Of the three serious events, only two (prostate cancer) were deemed to be causally related to testosterone undecanoate treatment and therefore classified as serious adverse drug reaction. Although concerns about prostate cancer with testosterone therapy are still highly prevalent 6, the verdict for the relationship between testosterone treatment and prostate cancer is still outstanding. The prevalence of prostate cancer in men undergoing testosterone treatment is not above that of the general male population; recently it has actually been suggested that testosterone treatment may even be protective against high-grade prostate cancer.21 For more information on testosterone and prostate cancer, see our previous reports:

Is there a protective role of testosterone against high-grade prostate cancer?

Testosterone Therapy in Men with Prostate Cancer - new research

Dispelling the myth of testosterone treatment and prostate cancer

Incidence of Prostate Cancer after Testosterone Therapy for up to 17 years

Testosterone and Prostate Cancer - a paradigm shift

Regarding cardiovascular safety, we previously reported the results of a study showing that long-term testosterone therapy for 8 years in obese men with testosterone deficiency reduces deaths and non-fatal heart attacks and strokes, compared to men not receiving testosterone therapy.22 For more information, see “Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease: Real-Life Results

It should be noted that injectable testosterone undecanoate should not be confused with oral testosterone undecanoate. A head-to-head comparison study of oral testosterone undecanoate (2 capsules of 40 mg/twice per day at breakfast and dinner, a total dose of 160 mg/day) and injectable testosterone undecanoate (1000 mg/12 weeks).23 It was found that injectable testosterone undecanoate resulted in more therapeutic testosterone levels (>17.3 nmol/L or > 500ng/dL) and greater reductions in insulin resistance (HOMA-index), waist circumference and fat mass, and improvements in the International Index of Erectile Function-5 and Aging Males' Symptoms scores.23

References:

1. Behre HM, Nieschlag E. Testosterone preparations for clinical use in males Testosterone: Action, Deficiency, Substitution. 4 ed: Cambridge University Press; 2014:309-335.
2. Wolf J, Keipert D, Motazedi H, Ernst M, Nettleship J, Gooren L. Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study. The Aging Male: the official journal of the International Society for the Study of the Aging Male. 2017;20(4):225-234.
3. Nakazawa R, Baba K, Nakano M, et al. Hormone profiles after intramuscular injection of testosterone enanthate in patients with hypogonadism. Endocr J. 2006;53(3):305-310.
4. Jockenhovel F, Minnemann T, Schubert M, et al. Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men. Eur J Endocrinol. 2009;160(5):815-819.
5. Thirumalai A, Berkseth KE, Amory JK. Treatment of Hypogonadism: Current and Future Therapies. F1000Research. 2017;6:68.
6. Gooren L. Diagnosing hypogonadism and treating decisions in different parts of the world: shifts in patterns between 2006 and 2015. The aging male : the official journal of the International Society for the Study of the Aging Male. 2016;19(1):46-53.
7. Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men. J Androl. 1998;19(6):761-768.
8. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert opinion on pharmacotherapy. 2005;6(10):1751-1759.
9. Saad F, Kamischke A, Yassin A, et al. More than eight years' hands-on experience with the novel long-acting parenteral testosterone undecanoate. Asian journal of andrology. 2007;9(3):291-297.
10. Yassin AA, Haffejee M. Testosterone depot injection in male hypogonadism: a critical appraisal. Clinical interventions in aging. 2007;2(4):577-590.
11. Minnemann T, Schubert M, Freude S, et al. Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism. J Endocrinol Invest. 2008;31(8):718-723.
12. Wang C, Harnett M, Dobs AS, Swerdloff RS. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. J Androl. 2010;31(5):457-465.
13. Edelstein D, Basaria S. Testosterone undecanoate in the treatment of male hypogonadism. Expert opinion on pharmacotherapy. 2010;11(12):2095-2106.
14. Schubert M, Minnemann T, Hubler D, et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab. 2004;89(11):5429-5434.
15. Moisey R, Swinburne J, Orme S. Serum testosterone and bioavailable testosterone correlate with age and body size in hypogonadal men treated with testosterone undecanoate (1000 mg IM--Nebido). Clin Endocrinol (Oxf). 2008;69(4):642-647.
16. Bang AK, Jorgensen N, Rajpert-De Meyts E, Juul A. UGT2B17 Genotype and the Pharmacokinetic Serum Profile of Testosterone during Substitution Therapy with Testosterone Undecanoate. A Retrospective Experience from 207 Men with Hypogonadism. Frontiers in endocrinology. 2013;4:94.
17. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91(11):4335-4343.
18. Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675-685.
19. Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. 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. The journal of sexual medicine. 2013;10(2):579-588.
20. Tan WS, Low WY, Ng CJ, et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU Int. 2013;111(7):1130-1140.
21. Yassin A, Salman M, Talib RA, Yassin DJ. Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients who underwent prostate biopsy: a prospective data register. The aging male : the official journal of the International Society for the Study of the Aging Male. 2017:1-9.
22. Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433.
23. Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest. 2010;33(11):776-783.

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Last updated: 2018
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