Desmopressin use in pediatric nocturnal enuresis patients: is there a sex difference in prescription patterns?

Desmopressin is a long-established treatment for nocturnal enuresis with clear guidelines regarding its usage. A sex difference in renal sensitivity has recently been reported in adults. The objective of this study was to investigate real-life desmopressin prescription in the Danish pediatric population, and prescription patterns which may reflect a sex difference in pediatric usage. Formulation, dose, treatment duration, and safety (hyponatremia) were investigated. 40,596 children received 214,220 desmopressin prescriptions between 2004 and 2011 in the Danish National Prescription Registry. Data were linked to hyponatremia diagnoses from the National Patient Registry. Although the lowest recommended dose of desmopressin oral lyophilisate is 120 µg, around a fifth of children were prescribed 60 µg for long-term use. A greater proportion of girls (22.6%) than boys (19.8%) received this low dose. Treatment duration was longer for boys than girls on oral lyophilisate (mean 489-524 vs. 414-462 days) and tablet (0.1 mg: 204 vs. 161 days). Prescribed daily dose was consistent with time between prescriptions, indicating no significant drug holidays. There were no admissions for hyponatremia during the observation period. CONCLUSION: Danish national prescription data on pediatric desmopressin dosage are consistent with a greater sensitivity to desmopressin in girls than boys. Further studies are required. What is Known: • Desmopressin has been used for pediatric nocturnal enuresis for decades • Recent evidence suggests a sex difference in desmopressin sensitivity in adults What is New: • For the first time, desmopressin prescription practices in nocturnal enuresis are documented for an entire country • A higher proportion of girls than boys received a low dose of desmopressin, consistent with the sex difference in sensitivity reported in adults.

National Surveillance of Central Diabetes Insipidus (CDI) in Denmark: results from 5 years registration of 9309 prescriptions of desmopressin to 1285 CDI patients.

CONTEXT: Epidemiological data for central diabetes insipidus (CDI) are sparse. OBJECTIVE: The purpose of this study was to provide accurate epidemiological data on CDI on a national level. DESIGN AND SETTING: This was a drug utilization and patient registry study during a 5-year period from 2007 to 2011. METHODS: We used the Danish National Prescription Registry data linked with the Danish National Patient Registry to study the epidemiology of CDI using waiting time distribution and other pharmacoepidemiological methods. PATIENTS: A total of 1285 patients with CDI were recorded in the observation period and given 9309 prescriptions for desmopressin in the nasal formulation, orodispersible tablet, or conventional tablet. RESULTS: The period prevalence rate of CDI in Denmark over the 5-year period investigated was 23 CDI patients per 100 000 inhabitants, with a higher prevalence in children and older adults (>80 years of age). The 1-year period prevalence rate of CDI decreased in Denmark over the 5 years from approximately 10 to 7 CDI patients per 100 000 inhabitants. The yearly incidence rate of new cases of CDI was found to be 3 to 4 patients per 100 000. The incidence of (presumable) congenital CDI was found to be 2 infants per 100 000 infants. Half of the patients with CDI prescribed as oral treatment were provided dosing instructions to only administer the drug before bedtime, and one third of the CDI patients either had no specific instructions or were instructed to use the drug as needed. Hospital admissions due to severe hyponatremia occurred in 0.9% of patients over a 5-year period, predominantly in females with an incidence ratio of women to men of 1.8:1. CONCLUSION: Half of the cases of CDI are acquired later in life. At least half of the patients with CDI are instructed to prevent nocturnal polyuria, but it is not clear whether their CDI remains uncontrolled during the daytime or, alternatively, whether they use desmopressin only as needed. Female patients with CDI had approximately twice the number of hospital admissions due to severe hyponatremia than male patients with CDI.

Long-term desmopressin response in primary nocturnal enuresis: open-label, multinational study.

BACKGROUND: Primary nocturnal enuresis (PNE) is a distressing condition, particularly in severe cases (> or = 3 wet nights/week). A prevalent pathophysiological mechanism, especially in monosymptomatic PNE (PMNE), is commonly believed to be an insufficient increase in night-time release of antidiuretic hormone. Desmopressin, a synthetic analogue of antidiuretic hormone, has been shown to reduce the number of wet nights experienced by PMNE patients in several controlled trials. AIM: This study was performed to evaluate desmopressin treatment in the real-life clinical setting and was a large-scale, 6-month investigation of efficacy and safety in patients with severe PNE. Predictive factors for desmopressin response were also evaluated. A total of 744 children aged 5 years and above from four countries were involved in the study. RESULTS: At baseline, patients had a median of 6 wet nights/week; at 6 months, 41% of patients had experienced > or = 50% reduction in the mean number of wet nights. Long-term desmopressin treatment was consistently well-tolerated across all ages, with 5% of patients experiencing any treatment-related adverse events. The strength of treatment response was associated with nocturnal diuresis (p < 0.0001) and age (p = 0.0167) in logistic regression analyses. Compliance and dosage were also associated with response and more patients experienced > or = 50% reduction in wet nights after 6 months' treatment than earlier in the study, suggesting the value of persistent treatment. CONCLUSION: This study shows that long-term desmopressin treatment in the clinical setting is effective and well-tolerated in PNE patients of 5 years and upwards. Early improvements in bedwetting of any appreciable magnitude may be rewarding, may facilitate compliance and enable good long-term response.

The comparative safety of oral versus intranasal desmopressin for the treatment of children with nocturnal enuresis.

PURPOSE: Desmopressin is a well established and effective therapy for nocturnal enuresis. Water intoxication leading to hyponatremia is an infrequent but serious adverse event associated with desmopressin. We assessed the safety of desmopressin in children 18 years or younger with nocturnal enuresis with a focus on the relative safety of the oral compared with the intranasal formulation. MATERIALS AND METHODS: Published data (MEDLINE) from December 1972 to August 2006 and post-marketing safety data from December 1972 to June 2005 were analyzed. RESULTS: A total of 21 clinical trials on desmopressin use in children with nocturnal enuresis were identified. There were no reports of hyponatremia. A total of 21 publications were identified that included 48 case reports of hyponatremia in children with nocturnal enuresis. In all case reports patients were treated with intranasal desmopressin. Post-marketing safety data included 151 cases of hyponatremia in children with nocturnal enuresis, of whom 145 were treated with intranasal desmopressin and 6 were treated with the tablet formulation. Prodromal symptoms of hyponatremia were identified as headache, nausea and vomiting. CONCLUSIONS: Data suggest that there is a decreased risk of hyponatremia with oral desmopressin compared with intranasal desmopressin. Identifiable and preventable risk factors for hyponatremia are inappropriately high fluid intake, administration of a larger than recommended dose, young age (less than 6 years) and concomitant administration of another medication. When desmopressin is prescribed, patients should be instructed to avoid high fluid intake when the medication is ingested, not ingest a higher than recommended dose and promptly discontinue the medication and seek assessment if headache, nausea or vomiting develops.

Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia.

AIMS: To explore the incidence, severity, time course, and risk factors of clinically significant hyponatremia in desmopressin treatment for nocturia. METHODS: Data from three multi-center phase III trials were pooled. Hyponatremia was categorised as borderline (134-130 mmol/L) or significant (<130 mmol/L). Risk factors were explored with logistic regression and subgroup analysis performed to explore threshold values for contra-indication. RESULTS: In total 632 patients (344 men, 288 women) were analyzed. During dose-titration, serum sodium concentration below normal range was recorded in 95 patients (15%) and 31 patients (4.9%) experienced significant hyponatremia. The risk increased with age, lower serum sodium concentration at baseline, higher basal 24-hr urine volume per bodyweight and weight gain at time of minimum serum sodium concentration. Age was the best single predictor. Elderly patients (>or=65 years of age) with a baseline serum sodium concentration below normal range were at high risk (75%). Limiting treatment in elderly with normal basal serum sodium concentration to those below 79 years and with a 24-hr urine output below 28 ml/kg would reduce the risk from 8.1% to 3.0% at the cost of 34% fulfilling the contra-indication. CONCLUSIONS: The majority of nocturia patients tolerate desmopressin treatment without clinically significant hyponatremia. However, the risk increases with increasing age and decreasing baseline serum sodium concentration. Treatment of nocturia in elderly patients with desmopressin should only be undertaken together with careful monitoring of the serum sodium concentration. Patients with a baseline serum sodium concentration below normal range should not be treated.

Antidiuresis: a new concept in managing female daytime urinary incontinence.

OBJECTIVE: To investigate the efficacy of desmopressin nasal spray on daytime urinary incontinence in women. PATIENTS AND METHODS: A multicentre, multinational, randomized, double-blind, placebo-controlled, cross-over exploratory study of women (aged 18-80 years) complaining of severe daytime urinary incontinence was conducted in three centres (King's College Hospital; Boras County Hospital and Skejby Hospital). Seventy-five patients were screened of whom 64 were randomized. In all, 60 women received study medication (safety population) and 57 completed the study. The intention-to-treat population comprised 59 patients and there were 41 in the per protocol analysis. The primary efficacy endpoint was the number of periods with no leakage for 4 h after dosing. Women were instructed to take the drug at a time of their choosing, but >/= 4 h before bedtime. Secondary efficacy variables included the time to first void or incontinence episode, volume leaked per incontinence episode, total volume voided and number of periods with no leakage. All measurements were made over 7 days on desmopressin and 3 days on placebo. RESULTS: There was a higher mean (sd) incidence of periods with no leakage in the first 4 h on desmopressin, at 62 (35)%, than on placebo, at 48 (40)%, and during the first 8 h, at 55 (37)% vs 40 (41)%. There was also a higher frequency of dry days on desmopressin than on placebo; 36% of patients had no leakage on virtually all treatment days (6 or 7) for 4 h after dosing. At 4-8 h the incidence of periods with no leakage on desmopressin was 68 (35)% vs 63 (41)% on placebo, and thereafter the incidence was similar. The time from dosing to first incontinence episode was longer on desmopressin, at 6.3 (2.5) h, vs 5.2 (3.3) h, whilst the volume leaked per incontinence episode was lower on desmopressin than placebo. The total volume voided was consistently lower on desmopressin, at 1180 (58) mL vs 1375 (57) mL, over the 24-h period after administration. There were no serious or severe adverse events reported. Seven women (11%) withdrew from the study, of whom five did not attend for the final visit and two (3%) because of mild adverse events. CONCLUSIONS: The results of this exploratory study suggest that desmopressin is an effective and safe treatment in women with daytime urinary incontinence, and allows them to choose when they need treatment, thus improving motivation, which may aid compliance with therapy.

Nocturia and associated morbidity in a community-dwelling elderly population.

OBJECTIVE: To investigate the association between nocturia and selected concomitant diseases and medications in a community-dwelling elderly population. SUBJECTS AND METHODS: Data were obtained with a validated questionnaire mailed to all inhabitants aged >or= 65 years in Tierp, Sweden. Descriptive statistics on age, gender, concomitant diseases and medications were calculated for non-nocturics (subjects reporting a mean of < 1 void/night), intermediate (reporting a mean of 1-2 voids/night) and nocturics (reporting a mean of >or= 2 voids/night). Correlations between the number of nocturnal voids/week and concomitant diseases/medications were investigated with logistic regression, controlling for age and gender. RESULTS: Of the 4264 questionnaires sent, 67% (2866) were returned, of which 73% (2081) were fully evaluable on nocturia and incorporated in the analysis. Of these, 62% reported >or= 1 void/night and 29%>or= 2 voids/night. The median (range) age of the respondents was 74 (65-99) years. The prevalence of nocturia increased with age and men reported more nocturia than women. The nocturic group had the highest percentage of reported disease and medication on each question. In the logistic regression, controlling for age and gender, there was no significant correlation between the number of nocturnal voids and hypertension, angina pectoris or diabetes mellitus, nor with treatment of these diseases. Neither was there any correlation for congestive heart failure, snoring, use of diuretics or hypnotics. There were highly statistically significant correlations (P < 0.001) between the increase in number of nocturnal voids and incontinence, daytime urge and nocturnal thirst. The increase in number of nocturnal voids was negatively correlated with good sleep and with feeling in good health (P < 0.001). CONCLUSION: There was no correlation between the number of nocturnal voids and a known and treated hypertension, angina pectoris, congestive heart failure or diabetes mellitus. The number of nocturnal voids was highly correlated with urge and incontinence.

Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns.

OBJECTIVE: To investigate the short-term safety of desmopressin in elderly patients with nocturia, with special focus on the risk of hyponatraemia, and to assess the short-term effects on urine output, sleep and voiding patterns. PATIENTS AND METHODS: Patients (72) were recruited from a study using frequency-volume charts, which in turn was preceded by a questionnaire study. Each patient took one 0.2 mg desmopressin tablet at bedtime for three consecutive nights and kept a frequency-volume chart. Serum sodium was assessed in the morning after the first and the third dose. Patients with a mean serum sodium level during treatment deviating more than five units from baseline were considered sensitive to change in serum sodium. Potential predictors for sodium sensitivity and response were investigated with logistic and multiple regression. RESULTS: All 72 enrolled patients completed the trial; no serious adverse events occurred and no adverse events of severe intensity were recorded. Six patients were sensitive to change in serum sodium. The risk (odds ratio, 95% confidence interval) increased with increasing age (1.3, 1.1-1.6), concomitant cardiac disease (10.0, 0.9-105.8) and increasing baseline 24-h urine output (1.2, 1.0-1.5). Patients sensitive to change in serum sodium were pharmacological responders and desmopressin had a greater effect on their 24-h diuresis, indicating that the drug effect was not limited to the night only. CONCLUSION: Desmopressin was well tolerated in elderly patients with nocturia, but the results suggest that serum sodium should be measured before and after a few days of treatment.

Differences between nocturics and non-nocturics in voiding patterns: an analysis of frequency-volume charts from community-dwelling elderly.

OBJECTIVE: To evaluate differences between elderly people with and without nocturia (waking up in the night to void) in terms of voiding habits, urine production and voided volumes. SUBJECTS AND METHODS: Nocturics or= two voids/night) and non-nocturics (< one void/night) were recruited from a questionnaire survey. Subjects were asked to complete a 3-day frequency-volume chart, including time and volume of each void, and their bedtime and waking time. Diaries from 108 non-nocturics and 116 nocturics were analysed. The number of voids, urine production, largest and average voided volumes were analysed using repeated-measures analysis of variance models, controlling for variables such as age, gender, body weight and gender-diagnosis interaction. RESULTS: Nocturnal urine volume was higher in nocturics than in non-nocturics. The difference between the groups was larger among the men (estimated difference 384 mL) than among the women (227 mL), but highly statistically significant (P < 0.001) in both genders. Among the men the diurnal urine and 24-h urine volumes were significantly higher in nocturics (difference, diurnal 131 mL, 24-h 462 mL, both P < 0.001). In the women the diurnal urine volume was lower in nocturics than in non-nocturics (difference 147 mL P = 0.0022) with no difference detected in 24-h urine volume. The largest voided volume was significantly less in nocturics than in non-nocturics; the difference was larger in women (128 mL, P < 0.001) than in men (42 mL, P = 0.0027). The average voided volume was 85 mL less (P < 0.001) in nocturics. The overlap between the groups in nocturnal urine and voided volumes was substantial and several significant covariates identified. The ratio between nocturnal urine volume and largest voided volume was the most statistically significant predictor of the number of nocturnal voids. CONCLUSION: Elderly nocturics had a higher nocturnal urine production and lower volume per void than non-nocturics. Differences between nocturics and non-nocturics in urine production and largest voided volume did not follow the same pattern in men and women. Nocturia was a result of a mismatch between nocturnal urine volume and largest voided volume, rather than abnormal values in either. The treatment of nocturia should be directed at one or both of these factors, depending on the findings from the 3-day frequency-volume chart of the individual.

Renal concentrating capacity test using desmopressin at bedtime.

A crossover trial was undertaken to evaluate the bedtime administration of desmopressin (Minirin) as a renal concentrating capacity test (RCCT). Medication was given intranasally as a single 20-microgram dose to 58 children ranging from 3 to 15 years of age with suspected or known renal impairment. The night-time test was shown to be a simple and effective means of assessing renal concentrating capacity. Comparison with the standard daytime test resulted in a 60 mosmol/kg higher mean osmolality in the night-time test. The results were reproducible, with a 95% confidence interval of -26 to 43 mosmol/kg. The procedure was easy to perform, with 51 of 52 patients (or their parents) preferring the night-time regimen compared with the daytime test. Night-time desmopressin therefore offers the potential of a user-friendly RCCT in patients with suspected impairment of renal tubular function.

Water intoxication in a patient with the Prader-Willi syndrome treated with desmopressin for nocturnal enuresis.

PURPOSE: We report on a girl with the Prader-Willi syndrome who received desmopressin for nocturnal enuresis, and water intoxication developed after she ingested a large amount of fluid. MATERIALS AND METHODS: The patient received 10 mg. desmopressin at bedtime for enuresis. She was hospitalized when a major motor seizure and coma (Glasgow coma scale 8) occurred after ingesting 48 ounces of fluid. Treatment included 3% saline, followed by 5% dextrose in water and sodium chloride given intravenously. RESULTS: Serum sodium increased to 128 mEq./l. and serum glucose remained normal. Computerized tomography and magnetic resonance imaging of the head were normal and revealed no evidence of cerebral pontine myelinosis. Patient consciousness returned to normal by day 5 after the seizure. CONCLUSIONS: In patients treated with desmopressin the risk of a seizure or altered level of consciousness can be minimized by not ingesting large quantities of fluid. We recommend that patients drink no more than 8 ounces of fluid on any evening that desmopressin is administered.

What is an acceptable treatment outcome?

Nocturnal enuresis is a multifactorial condition and, as such, is accessible to a variety of treatment modalities. In order to evaluate and compare the efficacies of different treatments in patients with specific pathophysiologies, studies should describe fully the patient population under investigation. In addition, many of the studies conducted to date have applied different outcome measures, making comparisons difficult. Therefore, it is necessary to define standard outcome measures that should be used universally. These may relate to the effect of the treatment on the number of wet nights per week, the effect on the family economy of a reduction in the number of episodes of enuresis and the effect on the child's self esteem and/or quality of life.

Hyponatremia in patients with nocturnal enuresis treated with DDAVP.

UNLABELLED: Treatment of nocturnal enuresis with DDAVP is associated with a low incidence of adverse effects. The only reported serious adverse effect is seizure or altered level of consciousness due to water intoxication. We reviewed 14 articles that reported data on serum sodium in patients treated with DDAVP for nocturnal enuresis and 11 articles that reported patients who developed a seizure or altered level of consciousness during treatment with DDAVP for nocturnal enuresis. Excess fluid intake was identified as a contributing factor in 6 of the 11 case reports. CONCLUSION: Hyponatremia is a potential adverse effect in patients with nocturnal enuresis who are treated with DDAVP. To prevent this adverse effect we recommend that the patients prescribed DDAVP for nocturnal enuresis should be counseled not to ingest more than 240 ml (8 ounces) of fluid on any night that DDAVP is administered.

Nocturnal polyuria and natriuresis in male patients with nocturia and lower urinary tract symptoms.

PURPOSE: We investigated the circadian variation in urine output, plasma angiotensin II, aldosterone, atrial natriuretic peptide, arginine vasopressin and blood pressure. MATERIALS AND METHODS: We studied 17 elderly men with nocturia and lower urinary tract symptoms, and 10 age matched controls without nocturia. RESULTS: Of the 17 patients studied 11 had a lack of diurnal variation in urine output and increased nocturnal urine production associated with increased nocturnal sodium excretion, and 6 had a diurnal variation in urine output comparable to controls. CONCLUSIONS: Nocturia in a large proportion of elderly men with lower urinary tract symptoms is caused by nocturnal polyuria and natriuresis.