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Which patients need safety monitoring during desmopressin therapy?

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. What we need to know…. Overall Incidence of AE’s is ~5% in Clinical Trials of PNE 1.

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Which patients need safety monitoring during desmopressin therapy?

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  1. Which patients need safety monitoring during desmopressintherapy? 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 1. Van Kerrebroeck PE. BJU Int. 2002;89(4):420-425; 2. Matthiesen TB et al. J Urol. 1994;151(2):460-463; 3. Tullus K et al. ActaPaediatr. 1999;88(11):1274-1278; 4. Schulman SL et al. J Urol. 2001;166(6):2427-2431; 5. Robson et al. Eur J Pediatr .1996;155(11):959-962.

  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 1. Robson et al. Eur J Pediatr .1996;155(11):959-962.

  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 1. Robson et al. Eur J Pediatr .1996;155(11):959-962.

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

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

  8. NOCTUPUS StudiesTreatment-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. MattiassonA et al. BJU Int.2002;89:855–862.

  9. NOCTUPUS StudiesTreatment-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 • Nocturiaindex 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 desmopressinrelated • 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 StudiesTreatment-Related Adverse Events • NOCTUPUS 41 • 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 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. EurUrol. 2007;52:221–229.

  12. 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 1. Rembratt A et al. NeurourolUrodyn. 2006;25:105-109.

  13. NOCTUPUS Studies: Pooled DataSubgroups 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 • N=594 1. Rembratt A et al. NeurourolUrodyn. 2006;25:105-109.

  14. NOCTUPUS Studies: Pooled DataSubgroups Based on Age and Basal S-sodium • In an open-label extension study, long-term treatment with desmopressin tablet was safe and well tolerated1 • aRisk not assessed due to insufficient data. • 1. Rembratt A et al.NeurourolUrodyn. 2006;25:105-109.

  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 MELTSerum Sodium Levels <130 mmol/L1 Serum Sodium n = 4 (all ≥65 yr) • 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 n = 4 (2 ≥65 yr) 1. Weiss JP et al. NeurourolUrodyn. 2012;31(4):441-447.

  18. CS31 Trial of Desmopressin MELTExtension Study Safety • Severe hyponatremia (<125mmol/L) was not reported during extension study Adverse Event (AE) and Hyponatremia Rates Part II and Extension *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 MELTConclusions • 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

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