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Are lower dosages of desmopressin of real benefit in clinical practice?
By Philip van Kerrebroeck
In several European countries, low dose formulations of desmopressin (Nocdurna 25 μg for females and Nocdurna 50 μg for males) are registered for the specific indication of nocturia due to nocturnal polyuria. This registration is based on the earlier registration of the higher dose melt formulations of desmopressin (Minrin melt 60 μg, 120 μg and 240 μg) for the same indication and two pivotal US trials with lower, gender-specific dosages.
In the initial US trial (1), the primary objective was to investigate the efficacy of desmopressin orally disintegrating tablet versus placebo in patients with nocturia. The results are based on a 4-week, randomised, double-blind study comparing 10, 25, 50, or 100 µg desmopressin versus placebo in adults with defined nocturia. The intent-to-treat population comprised 757 patients experiencing ≥3 voids/night due to nocturnal polyuria. Increasing dosages of desmopressin were associated with decreasing numbers of nocturnal voids and voided volume, greater proportions of subjects with >33% reduction in nocturnal voids, and increased duration of first sleep period. Improvements were clinically meaningful, so that patients actually had fewer nightly voids. Post hoc analyses by gender suggested that the minimum effective dose was lower for women. The therapy with lower dosages of desmopressin was generally well tolerated. Reductions in serum sodium to <125 mmol/L were registered in 6 women (taking >25 µg desmopressin) and 2 men (aged 67 and 82) taking 100 µg desmopressin.
In an additional trial (2), the efficacy and safety of 50 and 75 μg desmopressin orally disintegrating tablets were evaluated in men with nocturia (≥2 nocturnal voids). This was a 3-month, randomised, double-blind, parallel study comparing 50 and 75 μg desmopressin with placebo. The full analysis set comprised 385 men (age range 20 to 87 years). The 50 and 75 μg doses significantly reduced the number of nocturnal voids (-0.37, p <0.0001 and -0.41, p = 0.0003, respectively) and increased the odds of a 33% or greater response (OR 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively) compared with placebo during 3 months. Desmopressin 50 and 75 μg increased the time to first void from baseline by approximately 40 minutes compared to placebo (p = 0.006 and p = 0.003, respectively). The response to desmopressin was seen after 1 week of treatment and was sustained. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated, as only 2 subjects (age 74 and 79 years) on 50 μg had a serum sodium level of less than 130 mmol/L (vs. 9 subjects on 75 μg). On the basis of these results, specific starting dosages were selected at 25 μg for females and 50 μg for males.
The results of these trials indicate that, in clinical practice, a greater percentage of patients with nocturia due to nocturnal polyuria could potentially be treated with desmopressin, as there is a good balance between effect and side effects (especially hyponatraemia). The dosage could still be increased where necessary in individuals who are not at risk of developing hyponatremia. The lower dosage would be particularly important for the large group of elderly (>65 y) individuals, for whom the incidence of bothersome nocturia is greater than in younger patients and who are also more vulnerable and prone to hyponatremia. In several countries, the indication for the higher dosages has been limited to individuals under 65 y with nocturia. This restriction is now eliminated with the lower dosages.
But what are the results in clinical practice? We all know that patients included in studies are carefully selected on the basis of in- and exclusion criteria, and drugs may behave differently in the ‘real world’ of regular clinical practice. In our practice in the Netherlands, we have been using the lower dosages of desmopressin for about 2 years. As a secondary and tertiary referral centre for functional urological problems, we see a large number of patients, females and males, with more complex LUTS, e.g. with OAB symptoms combined with a significant number of nocturia episodes. In a significant proportion of these patients, the nocturia is mainly due to nocturnal polyuria. As most of these patients are older and many of them even frail, we have been reluctant to propose desmopressin treatment with the higher dosage, although we have had some spectacular results in specific individuals who were highly motivated to try this therapy. As the lower dosages of desmopressin are now available, we tend to propose antidiuretic therapy in any patient with nocturia and proven nocturnal polyuria. Several of these patients had tried a higher dosage before but developed hyponatraemia and had to stop the treatment, even though they had symptomatic relief. With the lower dosages, and in our 74 patients, we had no single incident of hyponatraemia and a significant reduction in nocturia episodes or even complete abolishment of night time voiding. Overall patients are very grateful for these results, as nocturia significantly impacted their quality of sleep and even overall quality of life. For these reasons, my answer to the initial question ”Are lower dosages of desmopressin a real benefit in clinical practice?” is definitely: YES THEY ARE!
- Weiss JP, Zinner NR, Klein BM, Nørgaard JP. Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial. Neurourol Urodyn. 2012 Apr;31(4):441-7. doi: 10.1002/nau.22243. Epub 2012 Mar 22
- Weiss JP, Herschorn S, Albei CD, van der Meulen EA. Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol. 2013 Sep;190(3):965-72. doi: 10.1016/j.juro.2012.12.112. Epub 2013 Feb 20