1. Management of Nocturia: An Unmet Need in LUTS

2. Faculty
Matt T. Rosenberg, MD Director, Mid-Michigan Health Centers Jackson, MI 
David R. Staskin, MD
Associate Professor of Urology
Tufts University School of Medicine
Director, Center for Male and Female Pelvic Health
St. Elizabeth’s Medical Center
Boston, MA

3. Disclosures
Idiopathic Pulmonary Fibrosis: Ensuring an Accurate Diagnosis and Personalizing a Therapeutic Plan
Matt T. Rosenberg, MD serves as a consultant for Astellas, Avadel, OPKO, and Ferring. He also serves as a speaker for Astellas, Avadel and OPKO.
David R. Staskin, MD serves as an investigator for GTX and Urovant. Dr. Staskin also serves as a consultant for Ferring and a speaker, consultant, and investigator for Astellas Pharma.
NACE - Emerging Challenges in Primary Care: 2014

4. Learning Objectives
Describe the impact of nocturia on affected patients.
Evaluate symptoms of nocturia in affected patients.
Assess current pharmacologic and nonpharmacologic nocturia management strategies.
Differentiate the mechanisms of action and safety and efficacy profiles of available and emerging therapies for nocturia.

5. PRE-TEST QUESTIONS 5

6. Pre-test ARS Question 1
How confident are you in your ability to manage patients with nocturia?
Not at all confident         
Slightly confident                             
Moderately confident                   
Pretty much confident   
Very confident
Answer 2
LO #1

7. Pre-test ARS Question 2
In a patient with nocturia, which quality of life measure is not affected:
Sleep
Eating
Sex
Work
Answer 2
LO #1

8. Pre-test ARS Question 3
A 50 year-old patient with BPH and no other medical problems has persistent nocturia despite a greatly improved urine flow with an alpha blocker. Which of the following is a reasonable intervention?
Add an antimuscarinic
Add low dose desmopressin
Consider a TURP
Add a 5-alpha reductase inhibitor
Answer 2
LO #2,3

9. Pre-test ARS Question 4
Which of the following is a risk factor for developing hyponatremia in a patient treated with desmopressin?
Low sodium diet
Age
Gender
Low urine output at baseline
Answer 2
LO #3,4

10. Pre-test ARS Question 5
How often should you check sodium levels for a patient on low dose desmopressin?
At initiation and then every 3 months
At initiation and then every 1 month
Every 30 days
At initiation, day 7, day 30 and then periodically
Answer 4
LO #4

11. Clinically Meaningful
NOCTURIA is defined as waking at night to urinate, with each voiding episode preceded and followed by sleep ≥2
Clinically Meaningful
NOCTURNAL POLYURIA is defined as nighttime urine production >20% of the total urine output for younger adults and >33% for older adults
van Kerrebroeck P, et al. Neurourol Urodyn. 2002;21(2): Marshall SD, et al. Urology. 2015;85(6):

12. The Bottom Line
When the volume of urine made at night is greater than functional bladder capacity.
By understanding this, it helps us understand that we can either attempt to increase capacity, or decrease volume.

15. What Nocturia and Nocturnal Polyuria are Not
Merely a symptom of other urologic conditions (OAB, BPH)
Normal part of aging (or is it?)

16. Nocturia Prevalence by Gender and Age
Kupelian V, Fitzgerald M, Kaplan S, et al. Association of Nocturia and Mortality: Results From the Third National Health and Nutrition Examination Survey. J Urol :

17. Obstacles to Clinical Presentation Leads to Undertreatment
Patients may not recognize nocturia as a medical condition
60.7% of patients assumed it was part of aging process
Embarrassment and reluctance
66.4% with <3 nocturnal voids perceived it as a minor problem
Failure of medical professionals to acknowledge and treat
Of those who had consulted a doctor, 37.2% were not offered any treatment.
Delay in diagnosis
12 weeks to make a diagnosis
37 weeks until first prescribed treatment.
Time from the onset of symptoms to beginning treatment weeks
Oelke M, Anderson P, Wood R, et al. Nocturia is often inadequately assessed, diagnosed and treated by physician: results of an observation, real‐life practice dataset containing 8659 European and US‐American patients. Int J Clin Pract. 2016;70:940‐949. : Oelke M, De Wachter S, Drake MJ, et al. A practical approach to the management of nocturia. Int J Clin Pract Nov; 71(11)
*Population based study of 8659 patients, data reflects women

18. Nocturia means poor sleep
Restorative or deep sleep happens in first hours
Awakenings during the first hours are most bothersome
Nocturia ≥ 2 correlates with disruption of deep sleep 18
Stanley N. The Underestimated Impact of Nocturia on Quality of Life. Eur Urol Suppl. 2005;4:17–19

19. Consequences of Nocturia and Poor Sleep?
Short-Term
Increased daytime sleepiness
Reduced daytime energy
Longer reaction time
Reduced psychomotor performance
Decreased concentration/ memory/cognitive function
Poor mood
Long-Term
Depression
Susceptibility to somatic disease
Risk of cardiovascular disease
Risk of car accidents 19
Abrams P. Eur Urol Suppl. 2005;3(6):1-7.

20. Impact of Nocturia on Bone Fracture and Mortality in Older Individuals20
Nakagawa H, Niu K, Hozawa A, et al. Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study. J Urol 2010; 184:

21. Increasing Nocturnal Voids Decreases Most HRQoL Dimensions21
Tikkinen K, Johnson T, Tammela T, et al. Nocturia Frequency, Both, and Quality of Life: How Often is Too Often? A Population-Based Study in Finland. Eur Uro 2010; 57:

22. Survival Probability with Nocturia
Kupelian V, Fitzgerald M, Kaplan S, et al. Association of Nocturia and Mortality: Results From the Third National Health and Nutrition Examination Survey. J Urol : 22

23. Risk Factors for Nocturia
Both genders
Men
Women
Age
Hispanic and Black ethnicity
Diabetes mellitus or insipidus
Arthritis
Asthma
High blood pressure
Anxiety
Depression
Childhood bed‐wetting
Prostatitis
Prostate cancer
High body mass index
Heart disease
Inflammatory bowel disease
Recurrent UTIs
Uterine prolapse
Hysterectomy
Postmenopausal
Oelke M, Wachter S, Drake M, et al. A practical approach to the management of nocturia. Int J Clin Pract Nov; 71(11). Wagg A, Kung Chen L, Johnson T, II, et al. In: Incontinence 6th Edition. Abrams P, Cardozo L, Wagg A, Wein A., editors. Tokyo: ICUD ICS; pp. 1373–1381 23

24. Cause of Nocturia is Multifactorial and Multidisciplinary
Intake
Urological
Cardiovascular
NOCTURIA
Nephrological
Sleep
Hormonal
Everaert K, Hervé F, Bower W, et al. How can we develop a more clinically useful and robust algorithm for diagnosing and treating nocturia? ICI-RS Neurourol Urodyn Jun;37(S4):S46-S59. 24

25. 25
Oelke M, Wachter S, Drake M, et al. A practical approach to the management of nocturia. Int J Clin Pract Nov; 71(11).

26. The Evaluation of Nocturia: History, Physical, and Labs are Essential
Medical and surgical history
Medications
Focused physical examination
Labs
Voiding diary or awareness of timing and amounts of voids (optional) 26
Wagg A, Kung Chen L, Johnson T, II, et al. In: Incontinence 6th Edition. Abrams P, Cardozo L, Wagg A, Wein A., editors. Tokyo: ICUD ICS; pp. 1373–1381.

27. Examples in the Patient’s History that may Cause or Worsen LUTS
Diabetes (new onset or poorly controlled)
Causing polyuria/polydipsia
Congestive heart failure
Nighttime fluid mobilization
Recent Surgery
Catheterization during surgery, immobilization, constipation from pain medications
A recent onset of the symptoms may provide a clue to the etiology 27

28. Examples of Medications Associated with Nocturia or Polyuria
Mechanism of Action
Calcium channel blockers
Direct blocking of proximal tubular sodium reabsorption or increased atrial natriuretic peptide levels; promote peripheral edema and/or pedal edema
Excessive vitamins A and D; thiazides
Reduced sodium and bicarbonate reabsorption in proximal tubule
NSAIDs; thiazolidinedione anti-diabetic agents, GABAnergic agents
Promote peripheral edema and/or dependent edema 28
Weiss J, Blaivas J, Blanker M, et al. The New England Research Institutes, Inc. (NERI) Nocturia Advisory Conference 2012: focus on outcomes of therapy. BJU Int 2013; 111:

29. Treatment Considerations29
Oelke M, De Wachter S, Drake MJ, et al. A practical approach to the management of nocturia. Int J Clin Pract Nov; 71(11)

30. Behavioral Intervention Considerations
Decreasing overall fluid intake and limiting nighttime fluids
Emptying bladder before going to bed
Reduction or avoidance of caffeine, alcohol, and salt
Altering the timing of diuretic medication administration
Use of compressive stockings
Leg elevation in the early evening
Treatment of OSA with continuous positive airway pressure
Barrier-free access to toilet or toilet chair
Weight loss and exercise 30
McVary KT, Roehrborn CG, Alvins AL. J Urol. 2011;185:1793– Cho SY, Lee SL, Kim IS. Neurourol Urodyn. 2012;31:64–68. Soda T, Masui K, Okuno H. J Urol. 2010;184:1000– Hashim H, Abrams P. BJU Int. 2008;102:62–66. Margel D, Shochat T, Getzler O. Urology. 2006;67:974–977.

31. Behavior Therapy is Beneficial Regardless of Etiology of Nocturia
Japanese study of 56 patients
Restriction of fluid intake
Refraining from excess hours in bed
Moderate daily exercise
Staying warm in bed
Benefits
Reduction of mean number of nocturnal voids from 3.6 – 2.7 (p<0.0001)
Reduction in mean nocturnal urine volume from 923 to 768 ml (p<0.0005)
Elimination of 1 or more voiding episodes per night in 53.1% of patients 31
Soda T, Masui K, Okumo H, et al. Efficacy of Nondrug Lifestyle Measures for the Treatment of Nocturia. J Urol. 2010;184(3):

32. Drug Therapies for OAB and BPH do Not Address Nocturia1-3
Symptoms Direct Therapy
Drug Therapies for OAB and BPH do Not Address Nocturia1-3
Nocturia due to nocturnal polyuria
Sleep Disorders
BPH
OAB
Speaker Notes
Dr. Newman to review content
Key Takeaway1-3
OAB and BPH therapies do not address all sources of nocturia
Additional Information
In patients with nocturia, the main contributing factor is usually too much nighttime urine production (ie, nocturnal polyuria)4
Even in patients with OAB or BPH, nocturnal polyuria is usually present and contributing to the nocturia5-7
OAB drugs work only on the bladder2
BPH drugs work only on the prostate1
References
Van Asseldonk B, Barkin J, Elterman DS. Medical therapy for benign prostatic hyperplasia: a review. Can J Urol. 2015;22(suppl 1):7-17.
Jayarajan J, Radomski SB. Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life. Res Rep Urol. 2013;6:1-16.
Fine ND, Weiss JP, Wein AJ. Nocturia: consequences, classification, and management. F1000Research. 2017;6:1-7.
Weiss JP, van Kerrebroeck PE, Klein BM, Norgaard JP. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol. 2011;186(4):
Brubaker L, FitzGerald MP. Nocturnal polyuria and nocturia relief in patients treated with solifenacin for overactive bladder symptoms. Int Urogynecol J. 2007;18(7):
Yoong HF, Sundaram MB, Aida Z. Prevalence of nocturnal polyuria in patients with benign prostatic hyperplasia. Med J Malaysia. 2005;60(3):
Koseoglu H, Aslan G, Ozdemir I, Esen A. Nocturnal polyuria in patients with lower urinary tract symptoms and response to alpha-blocker therapy. Urology. 2006;67(6):
Alpha Blockers
5 ARIs
PDE 5
Antimuscarinics
Beta 3
Sleep Clinic
Treat the cause 32

33. NocturNAl POLYURIA: Definition and etiologies
With Nocturnal Polyuria,
if Possible, Treat the Cause
NocturNAl POLYURIA: Definition and etiologies
OVERCONSUMPTION
Behavioral
Environmental
Dipsogenic diabetes insipidus
Diabetes mellitus
OVERDIURESIS
Third-space fluid resorption
Fluid shifts
Medications (eg, diuretics)
Sleep disorders or apnea
Congestive heart failure
Renal conditions
Diabetes mellitus
TOO LITTLE ANTIDIURESIS
Circadian defect in secretion or action of vasopressin
Renal conditions
Cerebrovascular damage
Central diabetes insipdious
Nephrogenic diabetes insipidous
Speaker Notes
Dr. Newman to review content
Key Takeaway
Nocturnal polyuria is defined by the ICS as nocturnal urine output >20% of the daily total in young adults and >33% in older people1; it may be caused by several different conditions2,3
References
van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):
Brubaker L, FitzGerald MP. Nocturnal polyuria and nocturia relief in patients treated with solifenacin for overactive bladder symptoms. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18(7):
Cornu JN, Abrams P, Chapple CR, et al. A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management--a systematic review and meta-analysis. Eur Urol. 2012;62(5): 33

34. How much does the Etiology Matter?
Regardless of the cause, voiding at night results from a production of nocturnal urine that exceeds the capacity of the urinary bladder to comfortably store it.
Therefore, treatment must be focused on decreasing fluid production, increasing bladder capacity, or improved emptying. 34

35. Urine Production Regulated by Arginine Vasopressin
AVP is produced in the hypo-thalamus and travels along nerve fibers to the posterior pituitary, where it is stored and released
AVP promotes reabsorption of water in the distal tubules and collecting duct of nephrons
As we age we either produce less AVP or it becomes less potent
Nephron
Proximal tubule
Collecting duct
Distal tubule
Loop of Henle 35
Oelke M, De Wachter S, Drake MJ, et al. A practical approach to the management of nocturia. Int J Clin Pract Nov; 71(11)

36. Pausing Urine Production
Desmopressin
A synthetic analog of AVP and a selective V2 receptor agonist
Increases water reabsorption in the distal tubule and collecting ducts
Concentrates the urine
Decreases urine production
Nephron
Proximal tubule
Collecting duct
Distal tubule
Loop of Henle 36
Oelke M, De Wachter S, Drake MJ, et al. A practical approach to the management of nocturia. Int J Clin Pract Nov; 71(11)

37. Available Formulations of Desmopressin
Indications
Nasal spray
Nocturia due to nocturnal polyuria
Sublingual melt
Tablet
Diabetes insipidus and primary nocturnal enuresis
Cohn JA, Kowalik CG, Reynolds WS, et al. Desmopressin acetate nasal spray for adults with nocturia. Expert Rev Clin Pharmacol. 2017;10(12): Chung E. Desmopressin and nocturnal voiding dysfunction: Clinical evidence and safety profile in the treatment of nocturia. Expert Opin Pharmacother. 2018;19(3): Desmopressin Tablets - FDA prescribing information, side effects and uses. Drugs.com. Accessed Sept 9, Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June DDAVP® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; December Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017. 37

38. Key Differences of Approved Medications
Formulation
Study Population
Onset of action
Available doses
Dosing nuances
Nasal spray
Adult patients ≥50 years of age
Tmax was 15 minutes for 0.83 mcg and 45 minutes for 1.66 mcg
0.83 mcg and 1.66 mcg desmopressin acetate per 0.1 mL spray
Recommended to start at lower dose in patients ≥65 years of age or at risk for hyponatremia
Sublingual melt
Patients >18 years of age
30 minutes
27.7 μg for women and 55.3 μg for men
No titration Gender specific dosing
Cohn JA, Kowalik CG, Reynolds WS, et al. Desmopressin acetate nasal spray for adults with nocturia. Expert Rev Clin Pharmacol. 2017;10(12): Chung E. Desmopressin and nocturnal voiding dysfunction: Clinical evidence and safety profile in the treatment of nocturia. Expert Opin Pharmacother. 2018;19(3): Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017. 38

39. Typical Study Design in Assessing Nocturia
Patient characteristics were comparable across the placebo and desmopressin groups:
Mean age: 62.0 years
Gender: 55% men
Ethnicity: 80% Caucasian
BMI: kg/m2
Overall, 46% of patients experienced >3 voids per night
Nocturnal polyuria was present in 90.2% of patients
Approximately 20% of patients (143/799) received concomitant treatment for OAB, BPH or both conditions
BMI, body mass index; BPH, benign prostatic hyperplasia; OAB, overactive bladder
Weiss JP et al. Neurourol Urodyn 2012;31:441–447. Weiss JP & Klein BM. ICS, 29 September –3 October 2009, San Francisco, USA. Abstract 718 39

40. Sublingual Desmopressin Effects Nocturnal Volume
Women
Men **
10 µg
N= 137
50 µg
N= 138
100 µg
N= 135
Placebo
N= 140 *
* p<0.05
** p<0.01 desmopressin vs placebo
25 µg
N= 144
Change in Nocturnal Urine Void Volume (mL) 40
Weiss et al. Neurourol Urodyn 2012;31:441–447.

41. Decreases Nocturnal Urine Production
Nasal Desmopressin
Decreases Nocturnal Urine Production
Nocturnal Urine Void
Volume (mL) 41
Kaminetsky J, Fein S, Dmochowski R, et al. Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials. J Urol Apr 12. epub

42. Nasal Desmopressin: Mean Decrease in Nocturnal Voids
Placebo
(pooled data)
Nasal Desmopressin
0.83 mcg
(pooled data)
Nasal Desmopressin
1.66 mcg
(pooled data)
LS Mean Change in Nocturic Episodes/Night
P<.0001 42
Kaminetsky J, Fein S, Dmochowski R, et al. Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials. J Urol Apr 12. epub

43. Sublingual Desmopressin in Women: Mean Decrease in Nocturnal Voids
Sand P, Dmochowski R, Reddy J, et al. Efficacy and Safety of Low Dose Desmospressin Orally Disintegrating Tablets in Women with Nocturia: Results of a Multicenter, Randomized Double-Blind, Placebo Controlled, Parallel Group Study. J Urol 2013; 190: 43

44. Sublingual Desmopressin in Men: Mean Decrease in Nocturnal Voids
Weiss JP, Herschorn S, Albei CD, Meulen EA van der. 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;190(3): 44

45. Sublingual Desmopressin Efficacy is Maintained in the Long Term
Number of Nocturnal Voids
Placebo
25 µg
50 µg N
Mean (SD)
Baseline
156
3.3 (1.16)
152
3.3 (1.32)
147
3.4 (1.07)
Change from baseline to Week 12 81
-1.4 (1.25) 76
-1.5 (1.16)
Change from baseline to Week 52 91
-1.4 (1.22) 80
-1.8 (1.33) 45
Juul KV et al. Neurourol Urodyn. 2013;32:

46. Nasal Desmopressin Extends Time for Bladder Filling and Subsequent Emptying46
Kaminetsky J, Fein S, Dmochowski R, et al. Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials. J Urol Apr 12. epub

47. Sublingual Desmopressin Extends Time for Bladder Filling and Subsequent Emptying
o50 μg is the approved dose in men 47
Sand PK et al. J Urol 2013;190:958–964; Weiss JP et al. J Urol 2013;190:965–972

48. Special Populations: Nocturia Plus OAB or BPH
Low‐dose desmopressin plus tamsulosin in men with BPH*
Reduction of the nocturnal frequency of voids by 64.3% (combo) vs 44.6% (mono) in patients with or without nocturnal polyuria.
Combination therapy improved the quality of sleep.
Comparable overall tolerability with monotherapy.
Combination of desmopressin and the antimuscarinic tolterodine in women with OAB and nocturnal polyuria*
Decrease in nocturnal void volume (P = .034) with combination therapy.
Increase in time to first nocturnal void (P = .045) over tolterodine monotherapy.
*Sublingual Desmopressin used in this study
Ahmed AF, Maarouf A, Shalaby E, et al. The impact of adding low‐dose oral desmopressin therapy to tamsulosin therapy for treatment of nocturia owing to benign prostatic hyperplasia. World J Urol. 2015;33:649‐657. Rovner ES, Raymond K, Andruczyk E, et al. Low‐dose desmopressin and tolterodine combination therapy for treating nocturia in women with overactive bladder: a double‐blind, randomized, controlled study. Low Urin Tract Symptoms. 2017 48

49. Comparable Package Inserts
Sublingual Desmopressin
Nasal Desmopressin
Drug interactions
Concomitant use of medication and loop diuretics or systemic or inhaled glucocorticoids is contraindicated because of the risk of severe hyponatremia. Medication can be started or resumed 3 days or 5 half-lives after the glucocorticoid is discontinued, whichever is longer
Drugs such as tricyclic antidepressants, SSRIs, chlorpromazine, opiate analgesics, thiazide diuretics, carbamazepine, lamotrigine, sulfonylureas (particularly chlorpropamide), and NSAIDs may increase the risk of hyponatremia. Monitor serum sodium more frequently in patients taking medication concomitantly with these drugs and when doses of these drugs are increased
Concomitant use of medication and loop diuretics or systemic or inhaled glucocorticoids is contraindicated because of the risk of severe hyponatremia. Medication can be started or resumed 3 days or 5 half-lives after the glucocorticoid is discontinued, whichever is longer
Monitor serum sodium more frequently in patients taking medication concomitantly with medications that may cause water retention and increase the risk for hyponatremia (eg, tricyclic antidepressants, SSRIs, chlorpromazine, opioid analgesics, NSAIDs, lamotrigine, and carbamazepine)
The drug interaction potential between medication and other intranasally administered drugs has not been studied. Medication is not recommended for use in patients who require treatment with other drugs via the nasal route 49
Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

50. Sublingual Desmopressin Nasal Desmopressin
Contraindications
Hyponatremia or a history of hyponatremia
Polydipsia
Concomitant use with loop diuretics
Concomitant use with systemic or inhaled glucocorticoids
Renal impairment with eGFR below 50 mL/min/1.73 m2
Known or suspected SIADH
During illnesses that can cause fluid or electrolyte imbalance, such as gastroenteritis, salt-wasting nephropathies, or systemic infection
Heart failure
Uncontrolled hypertension
Primary nocturnal enuresis
Congestive heart failure (NYHA Class II–IV) 50
Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

51. Sublingual Desmopressin Nasal Desmopressin
Adverse reactions
Common adverse reactions (reported by >2% of medication- treated patients and at a higher incidence with either dose than with placebo) in patients with nocturia due to NP (in studies 1, 2, and 3) included dry mouth, hyponatremia, headache, and dizziness
Common adverse reactions (reported by ≥2% of medication- treated patients and at a higher incidence with the 1.66 mcg dose than with placebo) in 2 double-blind, placebo-controlled clinical trials in patients with nocturia due to NP included nasal discomfort, nasopharyngitis, nasal congestion, sneezing, hypertension, back pain, epistaxis, bronchitis, and dizziness 51
Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

52. Sublingual Desmopressin Nasal Desmopressin
Boxed
Warning
Medication can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death
Medication is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids
Ensure the serum sodium concentration is normal before starting or resuming medication. Measure serum sodium within 7 days, approximately 1 month after initiating therapy, and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia
If hyponatremia occurs, medication may need to be temporarily or permanently discontinued
Medication can cause hyponatremia. Severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death
Medication is contraindicated in patients at increased risk of severe hyponatremia, such as patients with excessive fluid intake, illnesses that can cause fluid or electrolyte imbalances, and in those using loop diuretics or systemic or inhaled glucocorticoids
Ensure the serum sodium concentration is normal before starting or resuming medication. Measure serum sodium within 7 days and approximately 1 month after initiating therapy or increasing the dose and periodically during treatment. More frequently monitor serum sodium in patients 65 years of age and older and in patients at increased risk of hyponatremia
If hyponatremia occurs, medication may need to be temporarily or permanently discontinued 52
Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

53. Sublingual Desmopressin Nasal Desmopressin
Warning
And
Precautions
Hyponatremia:
Limit fluid intake to a minimum from 1 hour before administration until 8 hours after administration. Use of medication without concomitant reduction of fluid intake may lead to fluid retention and hyponatremia. Advise patients to avoid drinks containing caffeine or alcohol before bedtime
Women are more sensitive to the effects of medication compared to men. The recommended dose for women is lower than for men because women have a higher risk of hyponatremia with the 55.3 mcg dose in clinical trials
Fluid Retention:
Medication can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Medication is not recommended in patients at risk for increased intracranial pressure or those with a history of urinary retention
When medicaton is administered, fluid intake in the evening and night-time hours should be moderated to decrease the risk of hyponatremia
Medication can cause fluid retention, which can worsen underlying conditions that are susceptible to volume status. Medication is not recommended for patients at risk for increased intracranial pressure or those with a history of urinary retention and should be used with caution (eg, monitoring of volume status) in patients with NYHA Class I CHF
Concurrent Nasal Conditions:
Discontinue medication in patients with concurrent nasal conditions that may increase systemic absorption of medication (eg, atrophy of nasal mucosa and acute or chronic rhinitis), because the increased absorption may increase the risk of hyponatremia. Medication can be resumed when these conditions resolve 53
Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

54. HYPONATREMIA 54

55. Duration of Action in Key to Safety
Yamaguchi O, Nishizawa O, Juul KV, Nørgaard JP. Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial. BJU Int Mar;111(3): 55

56. Hyponatremia in Combined Studies with Nasal Desmopressin OVERALL
Serum Sodium Concentration (mmol/L)
Placebo
N=349
Nasal Desmopressin 0.83 mcg
N=354
Nasal Desmopressin
1.66 mcg
N=341
, n (%)
18 (5.2)
33 (9.3)
42 (12.3)
, n (%)
8 (2.3)
7 (2.1)
≤125, n (%)
1 (0.3)
5 (1.5) 56
Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

57. Hyponatremia in Combined Studies with Nasal Desmopressin BY AGE
<65 YEARS
≥65 YEARS
Serum Sodium Concentration (mmol/L)
Placebo
N=144
Nasal Desmopressin 0.83 mcg
N=148
Nasal Desmopressin
1.66 mcg
N=146
N=205
Nasal DesmopressIn 0.83 mcg
N=206
N=195
, n (%)
7 (4.9)
8 (5.4)
14 (9.6)
11 (5.4)
25 (12.1)
28 (14.4)
, n (%)
2(1.4)
6 (2.9)
7 (3.6)
≤125, n (%)
1 (0.5)
5 (2.6) 57
Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

58. Hyponatremia in Combined Trials with Sublingual Desmopressin58
Juul KV, Anders Malmberg A, Meulen E, et al. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatremia in patients treated for nocturia. BJUI 2016

59. Hyponatremia in Combined Trials with Sublingual Desmopressin59
Juul KV, Anders Malmberg A, Meulen E, et al. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatremia in patients treated for nocturia. BJUI 2016

60. Incidence of Hyponatremia in Women and Men Long-term (Up to 3 Years)
Question: What effect does applying the proposed serum sodium monitoring have on the rate of hyponatremia seen in your clinical trials CS29/CS31?
Responder: Joe Verbalis
Direct Answer/Takeaway Message: This table will allow you to see the number and the severity of hyponatremia cases that occurred over a period of up to 3 years. However it will not allow you to appreciate the individual serum sodium profiles over time like the line plots. Over a period of over 3 years of treatment on the proposed doses, there was only one case of severe hyponatremia in the 50 ug arm. The most common cases were mild (18-31%) to moderate (4-10%) hyponatremia in both 25 and 50ug. VIEW IN PLOTS
Full Answer:
Bridge to key message:
Follow-up question:
Weiss JP1, Zinner NR, Klein BM, Nørgaard JP. Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial.Neurourol Urodyn Apr;31(4): Weiss JP et al. ICS/IUGA, 23–27 August 2010, Toronto, Canada. Abstract 198 60

61. Risk Factors for Hyponatremia
Age (single best predictor)
Lower serum sodium at baseline
Higher basal 24-hour urine at baseline per body weight
Weight gain at time of serum sodium concentration
Higher dose
Decreased GFR 61
Juul Kristian Vinter, Malmberg Anders, Meulen Egbert, Walle Johan Vande, Nørgaard Jens Peter. Low‐dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. BJU Int. 2016;119(5): Rembratt A, Riis A, Norgaard JP. Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia. Neurourol Urodyn. 2006;25(2):

62. Monitoring Sodium FDA Recommendations Expert Opinion
Prior to initiation
7 days
30 days
Periodically thereafter
Prior to initiation
7 days
30 days
60 days
90 days
Every 3 months 62
Nocdurna® [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc; June Noctiva™ [prescribing information]. Milford, PA: Serenity Pharmaceuticals, LLC; March 2017.

63. A PERFECT OPPORTUNITY FOR SHARED CARE63

64. Urologists and Primary Care Must Work Together on This
Must be able to effectively evaluate and differentiate other diseases.
Must be able to safely treat and monitor. 64

65. Conclusions
Nocturia may have a complicated etiology but simply results from a production of nocturnal urine that exceeds the functional bladder capacity
The prevalence is significant
Behavioral therapy and treating underlying medical conditions is essential but may fall short
Short acting versions of desmopressin reduce nocturia by decreasing urine production during sleeping hours
Attention to contraindications and monitoring recommendations regarding serum sodium are critical 65

66. POST-TEST QUESTIONS 66

67. Post-test ARS Question 1
After completing this activity, how confident are you now in your ability to manage patients with nocturia?
Not at all confident         
Slightly confident                             
Moderately confident                   
Pretty much confident   
Very confident
Answer 2
LO #1

68. Post-test ARS Question 2
In a patient with nocturia, which quality of life measure is not affected:
Sleep
Eating
Sex
Work
Answer 2
LO #1

69. Post-test ARS Question 3
A 50 year old patient with BPH and no other medical problems has persistent nocturia despite a greatly improved urine flow with an alpha blocker. Which of the following is a reasonable intervention?
Add an antimuscarinic
Add low dose desmopressin
Consider a TURP
Add a 5-alpha reductase inhibitor
Answer 2
LO #2,3

70. Post-test ARS Question 4
Which of the following is a risk factor for developing hyponatremia in a patient treated with desmopressin?
Low sodium diet
Age
Gender
Low urine output at baseline
Answer 2
LO #3,4

71. Post-test ARS Question 5
How often should you check sodium levels for a patient on low dose desmopressin?
At initiation and then every 3 months
At initiation and then every 1 month
Every 30 days
At initiation, day 7, day 30 and then periodically
Answer 4
LO #4

72. Post-test ARS Question 6
Approximately how many patients with complaints of nocturia do you see on a weekly basis:
0-1
1-5
6-10
11-15
16-20
>20
Patient Reach

73. Questions