1. Which patients need safety monitoring during desmopressin therapy?
Jeffrey P. Weiss, MD, FACS
Professor and Chair
Department of Urology
SUNY Downstate College of Medicine
Brooklyn, NY

2. What we need to know…

3. Overall Incidence of AE’s is ~5% in Clinical Trials of PNE1
Side effects reported were generally mild
Headache, abdominal pain, nausea, nasal congestion and epistaxis1,2,3,4
Few patients withdrew from treatment due to AE’s2
Long-term SWEET trial (intranasal formulation)3
2.5% of patients (6/242) withdrew from treatment due to AE’s
No significant differences between control and treatment arms plus no association between dose levels and AE’s4
There was no increase in incidence of AE’s due to extended treatment duration1
Only serious adverse reaction associated with desmopressin was hyponatremia (HN)5
~1% of patients in clinical trials reported to have developed HN without clinical symptoms
What is the SWEET trial? Was this in the pediatric population? Should have much less HN in kids than adults
The Swedish Enuresis Trial (SWEET) was conducted to evaluate the long-term safety and efficacy of intranasal desmopressin treatment in children with primary, monosymptomatic nocturnal enuresis (PMNE). The study had an open, multicentre design and comprised a 4-wk observation period, a 6-wk dose titration period (with μg desmopressin) and a 1-y, long-term treatment period. A treatment-free week was introduced every 3 mo to identify dry patients. In total, 399 children aged 6-12 y with PMNE were recruited. Of these, 245 patients (61%) experienced ≥ 50% reduction in the number of wet nights during the last 4 wk of dose titration compared with the observation period. These responders entered the long-term phase of the trial. The mean number of wet nights per wk decreased from a median of 5.3 (range ) during the observation period to a median of 0.8 (range ) during the last 3-mo period. Seventy-seven children became dry, 63 (83%) within 6 mo of treatment initiation. The % of children who became dry was similar in all age groups. Significantly fewer children in the lowest age group were defined as responders (52%; 95% CI 45, 59) among the 6-7-y-olds compared to 65% (56, 74) and 81% (72, 90) in the two older age groups. Desmopressin was well tolerated. No serious drug-related adverse events were recorded. Although 5 children reported low s-sodium levels at end of study, non had clinical symptoms of hyponatremia. AE’s were seen but non serious, and in only 3.5% of the total study population were they a reason for withdrawal. The SWEET trial has demonstrated that desmopressin is both safe and effective for the long-term treatment of PMNE, with a significant therapeutic effect also in children of 6–7 y of age.
1. Van Kerrebroeck PE. BJU Int. 2002;89(4): ; 2. Matthiesen TB et al. J Urol. 1994;151(2): ; 3. Tullus K et al. Acta Paediatr ;88(11): ; 4. Schulman SL et al. J Urol. 2001;166(6): ; 5. Robson et al. Eur J Pediatr .1996;155(11):

4. Hyponatremia: What Constitutes Clinical Relevance?
Hyponatremia (HN): a sodium concentration of <135 mmol/L
HN results from water retention caused by the drug’s antidiuretic effect and simultaneous excess intake of fluids
Risk could be reduced by restricting fluid intake and by not exceeding the recommended dose
Important: obtain an antidiuresis-free window of minimum of 8 hours
Hyponatremia
Serum Sodium Level
Asymptomatic borderline
< mmol/L
Symptomatic Class I
mmol/L
Symptomatic Class II
<125 mmol/L
1. Robson et al. Eur J Pediatr .1996;155(11):

5. Hyponatremia in PNE Treated with Intranasal dDAVP
Although treatment of PNE with dDAVP is associated with a low incidence of AE’s, seizures or altered level of consciousness due to water intoxication have been reported associated with use of nasal spray
Excess fluid intake was identified as a contributor factor in 6 of the 11 case reports1
Were there any deaths among these reports? No deaths reported from these seizures or altered level of consciousness due to water intoxication. Duration of follow-up was up to 7 months.
9/11 patients developed a seizure and 2 became disoriented but did not develop a seizure
6/11 patients had other symptoms preceding the seizure or disorientation episode
5/11 had headache, vomited and one had nausea
Previous studies report headaches as an AE in 0.4% to 1.3%; it is possible that the headache in these patients might have represented transient episodes of symptomatic water intoxication
2 of the patients with seizures or altered level of consciousness were also taking neurologically active meds at the time of the episode (imipramine and methylphenidate, respectively)
Four articles that did report specific data on serum sodium. Three reported asymptomatic hyponatremia. One reported hyponatremia as mmol/L. Another one reported a range of sodium between mmol/L. with a mean 138 mmol/L. Matthiesen reported 1 (3%) of 33 patients had a s-sodium of 128 mmol/L..
1. Robson et al. Eur J Pediatr .1996;155(11):

6. Due to safety superiority of desmopressin tablets for PNE treatment, intranasal spray is no longer recommended

7. NOCTUPUS Studies: The Tablet “High-Dose” Program
Overall Incidence of AE’s in Clinical Trials of Adults with Nocturia Associated with NP
NOCTUPUS Studies: The Tablet “High-Dose” Program

8. NOCTUPUS Studies Treatment-Related Adverse Events
NOCTUPUS 2A1
Males aged ≥18 years with symptoms of nocturia
N = 151 patients (86 randomized to desmopressin; 65 to placebo)
Mean of ≥2 voids/night, with nocturia index scores of >1
Treatment-related AE’s
107 of 224 (48%) patients in safety population reported AEs
Mild, moderate, and severe: 67%, 27%, and 6%, respectively
Serious AEs: 5 patients (1 [thrombocytopenia] was deemed related to study medication)
Hyponatremia
49 (22%) patients had ≥1 episodes of s-sodium level below normal range
10 (4%) had levels <130 mmol/L (all occurred during dose-titration; 3 cases led to withdrawal)
Patients at highest risk were ≥65 years
1. Mattiasson A et al. BJU Int. 2002;89:855–862.

9. NOCTUPUS Studies Treatment-Related Adverse Events
NOCTUPUS 3A1
Females aged ≥18 years with symptoms of nocturia
N = 144 patients (72 randomized to desmopressin; 72 to placebo)
Mean of ≥2 nocturnal voids during screening
Nocturia index score >1
Treatment-related AE’s
158 of 224 (71%) patients in the safety population reported AE’s
Mild, moderate, and severe: 53%, 37%, 10%, respectively
Serious AEs: 5 (2%) patients (4 during dose-titration period [2 fatalities and 2 patients with hyponatremia]; 1 during double-blind period in a placebo-treated patient)
Fatalities not deemed desmopressin related
Hyponatremia: 14 (6%) patients reported as AE; 27 (12%) had sodium levels below normal
1. Lose G et al. Am J Obstet Gynecol. 2003;189:1106–1113.

10. NOCTUPUS Studies Treatment-Related Adverse Events
Males and Females aged ≥18 years with symptoms of nocturia
N = 127 patients (61 randomized to desmopressin; 66 to placebo)
Treatment-related AE’s
93 of 184 (51%) patients in the safety population reported AEs
Majority were mild (67%); 9 serious events were recorded in 5 patients (3%; none were considered related to study medication)
Hyponatremia (<130 mmol/L)
6 cases in 6 patients (all occurred during the dose titration period; 5 cases related to patients aged >72 years; the sixth case was in a 58-yr-old patient
1. van Kerrebroek P et al. Eur Urol. 2007;52:221–229.

11. NOCTUPUS Studies: Pooled Data
Classification of Patients Based on Severity of HN in Dose Titration and Frequency of Symptomatic and Reported HN
Severity of HN
ALL
Lose et al, 2003:1
Mattiasson et al, 2002:2
Van Kerrebroeck et al, 2007:3 n %
Exposed patients
632
100
224
184
Non-hyponatremic
537 85
198 88
181 81
158 86
Hyponatremic (mmol/L)
Borderline (134 – 130)
Significant (<130)
Significant (<125) 95 15 26 12 43 19 14 64 10 13 6 34 17 9 31 3 5 2 8 4 1
<1
Symptomatic HN 27 11
Adverse event
SAE 29
1. Lose G et al. Am J Obstet Gynecol. 2003;189:1106–1113; 2. Mattiasson A et al. BJU Int. 2002;89:855–862; 3. van Kerrebroek P et al. Eur Urol. 2007;52:221–229.

12. Significantly Hyponatremic
NOCTUPUS Studies: Characteristics of Patients With and Without Significant HN1
Patients with Significant HN were on Average: Older, Smaller, Had Lower CrCl, Higher Total and NUV, and Lower Basal S-sodium
Non-hyponatremic
Significantly Hyponatremic n
Mean (SD)
Demographics
Age (years)
601
61 (12) 31
75 (8)
Weight (kg)
80 (15)
71 (13)
BMI (kg/m2)
27 (5) 30
25 (5)
Baseline values
Nocturnal voids
3.0 (1.0)
3.2 (1.1)
24-hr urine vol.BW (ml/kg)
599
24 (8)
29 (7)
NUV (ml)
790 (311)
940 (302)
Largest voided volume (ml)
406 (144)
465 (196)
Serum sodium (mmol/L)
598
140 (2.2)
138 (3.3)
Creatinine Clearance (ml/min)
597
86 (26)
60 (15)
On-treatment changes
Wt gain at min s-sodium (kg)
567
0.5 (1.9)
1.9 (2.1)
1. Rembratt A et al. Neurourol Urodyn. 2006;25:

13. 95% Wald confidence limits
NOCTUPUS Studies: Pooled Data Subgroups Based on Age and Basal S-sodium
Risk of HN Increased with: Age, Increasing Baseline 24-hr Urine Volume Per Bodyweight, Decreased Baseline Serum Sodium, and Weight Gain at Time of Minimum Serum Sodium Concentration
Odds ratio
95% Wald confidence limits
P value
Age (years)
1.16
1.09
1.25
<0.0001
BL 24-urine volume/BW (mL/kg)
1.04
0.0016
BL s-sodium (mmol/L)
0.76
0.64
0.91
0.0025
Weight gain at time of minimum s-sodium (%)
1.31
1.07
1.61
0.016
N=594
1. Rembratt A et al. Neurourol Urodyn. 2006;25:

14. No of patients with significant hyponatremia
NOCTUPUS Studies: Pooled Data Subgroups Based on Age and Basal S-sodium
In an open-label extension study, long-term treatment with desmopressin tablet was safe and well tolerated1
Age
Basal s-sodium n
No of patients with significant hyponatremia
Risk
<65
Normal
336 3
<1%
Low 5 a
≥65
260 22 8% 8 6
75%
aRisk not assessed due to insufficient data.
1. Rembratt A et al. Neurourol Urodyn. 2006;25:

15. Desmopressin “High-Dose” Tablet: Overall Safety
HN appears to be the only significant AE of desmopressin therapy in patients with nocturia
HN is a well-known undesired effect of desmopressin, when water intake is not 
5% of all patients develop HN (defined as serum sodium <130 mmol/L)
The minimum level ranged from 129 to 116 mmol/L
Half were symptomatic
No new cases occurred on extended treatment
Subjects with HN were older, smaller, moderately more polyuric and had slightly lower basal serum sodium level and moderately lower creatinine clearance rate
Nearly all patients who developed HN were ≥65 years old
Desmopressin lower dosages were tested hoping to maintain efficacy (CS29 study) to address issue of HN
AE, adverse event; HN, hyponatremia.
Data on file. Ferring, Inc.

16. Serum sodium data in Clinical Trials of Adults with Nocturia using desmopressin ODT (melt)
CS29 & CS31 Studies
(“Low-Dose” Program of orally disintegrating tablet (melt) containing desmopressin)

17. CS29 Trial of Desmopressin MELT Serum Sodium Levels <130 mmol/L1
(all ≥65 yr)
n = 4 (2 ≥65 yr)
Reductions in serum sodium concentration tended to occur early in treatment (usually during the first week), and at similar rates to placebo in lower dose groups (≤25 μg), but with increased rates at ≥50-μg doses1
Reductions in serum sodium to <125 mmol/L were seen in 6 women and 2 men on active treatment and all occurred within a week of treatment initiation
4 women aged 52, 56, 76, and 77 years in 50-μg dose group (unpublished detail)
2 women aged 70 and 75 years in 100-μg dose group (unpublished detail)
2 men aged 67 and 82 years in 100-μg dose group
These reductions were most frequently seen in patients ≥65 years
No reductions in serum sodium to <125 mmol/L were seen in women receiving 25 μg desmopressin or in men under the age of 65 years
1. Weiss JP et al. ICS 23–27 August 2010, Toronto, Canada. Abstr 198.
Serum sodium <130 mmol/L but ≥125 mmol/L (considered a clinically relevant cutoff)
Was dose related ≥50 µg
Was age related (28/34 were ≥65 years)
Serum sodium <125 mmol/L not observed at 25-µg dose
1. Weiss JP et al. Neurourol Urodyn. 2012;31(4):
1/Weiss/IC S/Slide10

18. CS31 Trial of Desmopressin MELT Extension Study Safety
Adverse Event (AE) and Hyponatremia Rates
Part II and Extension
Incidence (%)
10 µg n=135
25 µg n=135
50 µg n=132
100 µg
n=127
Any AE 76 74 82 83
Serious AE 7 3 8
AE withdrawal 4 6
Hyponatremia* 2
<1
Desmopressin was generally well tolerated following long-term use
No episode of serum sodium reductions was reported as a serious AE
Early monitoring of changes in serum sodium and oral fluid intake reduction are essential to avoid the sequelae of serum sodium reductions especially in the elderly
Weiss et al. ICS/IUGA, 23–27 August 2010, Toronto, Canada. Abstract 198
Severe hyponatremia (<125mmol/L) was not reported during extension study
*listed as ‘hyponatremia’ or ‘blood sodium decrease’ or ‘serum sodium <130 mmol/L’)
Weiss et al. ICS 23–27 August 2010, Toronto, Canada. Abstract198.

19. CS29 Trial of Desmopressin MELT Conclusions
Safety data are generally consistent with the desmopressin tablet and support previous findings that hyponatremia is the only safety issue associated with desmopressin
Gender difference allowed for establishing a low-dose efficacy program with significant improvement in safety profile (post hoc analysis)
As expected, the only ADRs differentiating active treatment from placebo were those related to hyponatremia
Serum sodium <130 mmol/L was age- and dose-related
No serum sodium <125 mmol/L at 25 µg dose
1 year data raised no new concerns
These data have been confirmed in prospective RCT CS40 and CS41 trials

20. So which patients need sodium monitoring on desmopressin?
All patients >65 years of age
Women receiving >25 mcg and men receiving >50 mcg desmopressin nightly
Data supports no need to monitor women at low dose >65

21. What studies are needed?
Need “real world” experience to confirm safety of gender specific low dose desmopressin ODT
Long term studies are necessary to determine whether there is indeed enhanced safety for patients with:
Normal baseline serum sodium (>138 baseline best safety?)
GFR >50 ml/min at baseline (>60 even better?)
Increased body mass
Higher NPi at baseline
Lower weight gain especially early during therapy

22. Discussion