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1Institute of Pediatrics, Catholic University Medical School, Rome, Italy.
2Campus Bio-Medico University, Rome, Italy.
Corresponding Author E-mail: firstname.lastname@example.org
To review the safety of the recent oral lyophilisate formulation of desmopressin (MELT) in the pharmacological therapy for nocturnal enuresis (NE) and diabetes insipidus in pediatric patients. We searched for published reviews and references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 2000, until July 31, 2017 by using the terms MELT enuresis, MELT desmopressin, sublingual desmopressin, lyophilisate desmopressin. We evaluated all studies about side effects and effectiveness of MELT in pediatric patients. Twelve articles were analyzed with 1275 pediatric patients (<18 years old). The indication was enuresis in 1269 patients and central diabetes insipidus in 6 patients. In 11 studies desmopressin was administered alone while in 1 study in association with Tolterodina. In 3 studies were reported side effects in only 60 patients. The reported side effects in pediatric population were nausea, lethargy, lower limb weakness, headache, diarrhea, viral gastroenteritis, hyponatremia. Our review confirm that the MELT formulation of desmopressin guarantee the same response of other formulations with a lower doses and a lowest number of side effects. We believe according with the literature that this formulation is actually an effective and safe treatment for NE.
MELT; Enuresis; SafetyDownload this article as:
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Ferrara P, Ianniello F, Vescovo E. D, Sodero G, Gatto A, Ruggiero A. Safety of the Recent Oral Lyophilisate Formulation (MELT) in Pediatric Patients-A Review. Biomed Pharmacol J 2017;10(4).
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Ferrara P, Ianniello F, Vescovo E. D, Sodero G, Gatto A, Ruggiero A. Safety of the Recent Oral Lyophilisate Formulation (MELT) in Pediatric Patients-A Review. Biomed Pharmacol J 2017;10(4). Available from: http://biomedpharmajournal.org/?p=17814
Nocturnal enuresis (NE) is defined as a repeated and uncontrollable leakage of urine into the bed or clothes without other symptoms of low urinary tract.1
Decreased nocturnal antidiuretic hormone (ADH) excretion has been suggested to be a causative factor for NE in children affected.2 Moreover, NE may be present with several comorbidities such as sleep disorders, psychological problems, parasomnias, left-handedness, polythelia, language disorders and testicular pathology.3-5
The persistence of NE in teenagers causes feelings like anger, shame and low level of self-esteem. These considerations underline the need of an appropriate treatment during childhood. Desmopressin (dDAVP) is one of the most widely, well-tolerated, rapid acting prescribed medications for MNE (level 1, grade A, according to ICCS).
Pharmacokinetics and Pharmacodynamics
dDAVP is a well-known synthetic analogue of the antidiuretic hormone vasopressin.6 It was produced in 1966 by removing an amino group from the cysteine molecule in position 1 and replacing a residue of L-arginine with D-arginine in position 8. It led to a considerable increase in the anti-diuretic action and a longer plasmatic half-life.7
dDAVP has selectively effect on V2 receptors-agonist (vasopressor effect). These receptors are located on the cells of the distal renal tubules and collecting ducts: their activation determines the opening of water channels, acquaporin-2 type water channels, responsible for increased reabsorption of free water. Altered expression of aquaporins is detected in enuretic children.7,8
Vande Walle et al. suggested that the new oral lyophilisate formulation (MELT) is responsible for the decrease of urine output and an increase in mean urinary osmolality.8 Moreover, the clinical effects between MELT at lower doses and tablets are similar because the MELT formulation has a better bioavailability. 8,9
dDAVP intranasal solution is also available in children but has many unknowns regarding its bioavailability, especially when children are affected by upper respiratory infections, allergies and rhinitis.10
In Japan, intranasal desmopressin had been the only formulation for the treatment of central diabetes insipidus (CDI) until 2012 until Kataoka et al. demostrated that orally disintegrating tablet (ODT) is superior to intranasal desmopressin in controlling water balance. Nowadays the efficiency and safety of desmopressin ODT have been clear, and oral formulations are preferred for administration.11
Safety of dDAVP
dDAVP is a well established and effective therapy for NE. Hyponatremia is a possible adverse event associated with dDAVP. It is the most severe complication due to water intoxication, though it is infrequent.8,12,13 Risk factors for hyponatremia are identifiable and preventable: high fluid intake, increment of the recommended dose, young age (less than 6 years) and concomitant administration of another medication.12
In many clinical trials of PNE, changes in blood chemistry values (serum sodium, calcium and potassium, alanine aminotransferase and aspartate aminotransferase and osmolality), were not clinically significant.8 Moreover, there were no difference between the reported incidences of adverse events in treatment and control groups.
Hyponatremia can be classified as ‘asymptomatic borderline’ (serum sodium of 130-134 mmol/l), ‘symptomatic class I’ (serum sodium 125-129 mmol/l), or ‘symptomatic class II’ (serum sodium <125 mmol/l). The onset of hyponatremia was found to be more frequent in younger patients and during the first administration of therapy and two trials of oral dDAVP in MNE, reported asymptomatic reductions in serum sodium levels.8
Many papers underline that the risk for this severe adverse reaction can be reduced by following some advertisements. The most important are: adhere to the indications and dosing recommendations when prescribing dDAVP and restrict inappropriately fluid intake, especially during the evening.8,9,12-15
It is important to underline that 14% of reported cases of this type of side effect were arisen in patients treated with dDAVP without an adequate indication for therapy (e.g. secondary NE, global polyuria) or in patients with definite contradictions to desmopressin use (polydipsia, dipsogenic diabetes insipidus).16 Moreover, none of the reported cases occurred in patients using an oral formulation of dDAVP.
Many studies underline that dDAVP side effects are deeply correlated with age. dDAVP can be also administrated in adult with nocturia, but elderly patients (> 65 years-old) with low serum sodium, are at high risk (>75%) of hyponatremia.17,18
There is only one report that highlights the potentially life-threatening side effects associated with the administration of non-steroidal anti-inflammatory drugs (NSAIDs) during dDAVP replacement therapy for CDI.19
Van Herzeele et al. in the “DRIP” study (desmopressin response in PNE), evaluates the safety profile of the oral dDAVP tablet in children with MNE. dDAVP tablet treatment resulted well tolerated in children with MNE, regardless of patient gender or age.20
Overall, 222 (30%) patients experienced 404 treatment-emergent adverse events. Although most of these treatment-emergent adverse events were considered unrelated to the study drug. They were experienced mostly as gastrointestinal disorders; infections and infestations; respiratory, thoracic and mediastinal disorders.
The MELT formulation retains similar levels of efficacy and safety at lower dosing levels, and requires no intake of water compared to the tablets.21,22 Moreover, taking tablets can be inconvenient and may be difficult for children to swallow.22 Significantly, MELT was well accepted by all ages and facilitates the early initiation of treatment in children with MNE.22
Another advantage of MELT compared to tablets can be observed in food interaction. The dDAVP tablet and oral lyophilisate should be administered 60 min before bedtime and at least 2 h after the evening meal, which may be impractical in school-aged children.23 The oral lyophilisate reduce difficulties posed by this short interval. Furthermore, oral lyophilisate it is less affected by intestinal motility because it is believed to be absorbed by oral and/or oesophageal mucosa.23
dDAVP is also used in severe and inherited bleeding disorders. Stoof et al. included 108 patients, median age 30 years, affected by Von Willebrand disease type 1 (76%).24 No patients presented severe hyponatremia. Some adverse events emerged after dDAVP infusion (hypotension and tachycardia), but none of them sustained at 24h. In conclusion, this study supports dDAVP use as a safe treatment option in patients with various bleeding disorders.24
Ferrara et al. reported that dDAVP was effective and safety in reducing bedwetting during treatment, compared with placebo and with homotoxicology.25
Post marketing safety data analysis, revealed 151 cases of hyponatremia in children with NE: 145 with intranasal formulations and 6 with tablets.12 The difficult administration of a spray formula, can be a possible cause of overdose in patients treated with intranasal dDAVP. In conclusion, there is a decreased risk of hyponatremia with oral compared with intranasal dDAVP.12,22,26
Table 1: Summary Data From Published Reports on oral lyophilisate formulation of desmopressin (MELT) and side effects.
|Number of patients||Dose||Indication||Side effects|
|120 μg Minirin Melt
240 μg Minirin Melt
120-240 μg desmopressin Melt
120-240 μg desmopressin Melt + 1-2 g Tolterodina
|PMNE||At dose of 240 μg 10 patients nausea, lethargy and lower limb weakness|
|10.5||157||120 μg Minirin Melt||PMNE||No|
|8.7||73||120 – 240 µg desmopressin lyophilisate||PMNE||No|
|De Waele K
|60 μg Minirin Melt||Central Diabetes Insipidus||No|
|8.64||81||120 μg desmopressin Melt||MNE||No|
|Newborns||4||5 µg pro kg oral desmopressin lyophilisate||Central diabetes insipidus||No|
|11.5||32||120 μg desmopressin Melt||MNE||No|
|120 μg desmopressin Melt
+ 0,2 mg desmopressin tablets
240 μg desmopressin Melt +
0,4 mg desmopressin tablets
|120 μg desmopressin Melt
240 μg desmopressin Melt
|9.6||221||120 – 240 µg desmopressin Melt||PNE||35 patients
(headache 6 pts 2,7% nasopharingitis 4 pts 1,8% diarrhea 3 pts 1,4%
viral gastroenteritis 3 pts 1,4%)
|Vande Walle JG
|30 μg desmopressin Melt
60 μg desmopressin Melt
120 μg desmopressin Melt
240 μg desmopressin Melt
360 μg desmopressin Melt
480 μg desmopressin Melt
23 pts at the dose of 480μg
1 at the dose of 240μg
We performed a MEDLINE literature search (January 2000-July 2017) using the search terms MELT enuresis, MELT desmopressin, sublingual desmopressin and lyophilisate desmopressin, to review the safety of MELT and its effectiveness in the treatment of NE and CDI in pediatric patients. Additional references were identified from a review of literature citations. All english-language observational studies and case reports about side effects and effective of MELT in pediatric patients were evaluated.
Twelve articles were analyzed with 1275 pediatric patients (<18 years old). The indication was NE in 1269 patients and CDI in 6 patients. In 11 studies dDAVP was administered alone while in 1 study in association with Tolterodina.
In 3 studies were reported side effects in only 60 patients. The reported side effects in pediatric population were nausea, lethargy, lower limb weakness, headache, diarrhea, viral gastroenteritis, hyponatremia.
Our review confirms that the MELT formulation of dDAVP guarantee the same response of other formulations with a lower doses and a lowest number of side effects. We believe, according with the literature, that this formulation is actually the first line and safety treatment for NE in pediatric patients. 27,28
Finally we can resume that it is necessary to educate patients to avoid an inappropriately high fluid intake when dDAVP is prescribed, not ingest a higher than recommended dose and promptly discontinue the medication at the onset of signs like headache, nausea or vomiting, prodroms of hyponatremia, especially during the first 2 weeks following treatment initiation when hyponatremia is most likely.21,23 Fluid restriction is important both for the safety and efficacy of dDAVP therapy.23 According to ICCS recommendations, an evening fluid intake of ≤200 ml and then no drinking until morning is a safe guideline to minimize risk of hyponatremia; in general practice, it is commonly advised that patients should stop drinking 2 h before bedtime, with dDAVP administration up to 1 h before bedtime.23
- Austin PF, Bauer SB, Bower W et al. The standardization of terminology of lower urinary tract function in children and adolescents: update report from the Standardization Committee of the International Children’s Continence Society. J Urol. 2014;191:1863-1865.
- Pomeranz A, Abu-Kheat G, Korzets Z, Wolach B. Night-time polyuria and urine hypo-osmolality in enuretics identified by nocturnal sequential urine sampling–do they represent a subset of relative ADH-deficient subjects? Scand J Urol Nephrol. 2000;34:199-202.
- Ferrara P, Dell’Aquila L, Perrone G, et al. A Possible Pathogenic Linkage Among Headache, Migraine, and Nocturnal Enuresis in Children. Int Neurourol J. 2016;20:311-315.
- Ferrara P, De Angelis MC, Caporale O, et al. Possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study. Urol J. 2014;11:1777-1782.
- Ferrara P, Ianniello F, Romani L, Fabrizio GC, Gatto A, Chiaretti A. Five years of experience in nocturnal enuresis and urinary incontinence in children: where we are and where we are going. Urol Int. 2014;92:223-229.
- Berkenwald A, Pires J, Ellsworth P. Evaluating use of higher dose oxybutynin in combination with desmopressin for refractory nocturnal enuresis. J Pediatr Urol. 2016;12:220.
- Del Gado R, Del Gaizo D, Cennamo M, Auriemma R, Del Gado G, Vernì M. Desmopressin is a safe drug for the treatment of enuresis. Scand J Urol Nephrol. 2005;39:308-312.
- Vande Walle J, Stockner M, Raes A, Nørgaard JP. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf. 2007;2:232-238.
- Vande Walle J, Rittig S, Bauer S, Eggert P, Marschall-Kehrel D, Tekgul S; American Academy of Pediatrics.; European Society for Paediatric Urology.; European Society for Paediatric Nephrology.; International Children’s Continence Society. Practical consensus guidelines for the management of enuresis. Eur J Pediatr. 2012;171:971-983.
- Vande Walle JG, Bogaert GA, Mattsson S, et al. Desmopressin Oral Lyophilisate PD/PK Study Group. A new fast-melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis. BJU Int. 2006;97:603-609.
- Kataoka Y, Nishida S, Hirakawa A, Oiso Y, Arima H. Comparison of incidence of hyponatremia between intranasal and oral desmopressin in patients with central diabetes insipidus. Endocr J. 2015;62:195-200.
- Robson WL, Leung AK, Norgaard JP. The comparative safety of oral versus intranasal desmopressin for the treatment of children with nocturnal enuresis. J Urol. 2007;178:24-30.
- Lucchini B, Simonetti GD, Ceschi A, Lava SA, Faré PB, Bianchetti MG. Severe signs of hyponatremia secondary to desmopressin treatment for enuresis: a systematic review. J Pediatr Urol. 2013;9:1049-1053.
- Ferrara P, Del Volgo V, Romano V, Scarpelli V, De Gara L, Miggiano GA. Combined dietary recommendations, desmopressin, and behavioral interventions may be effective first-line treatment in resolution of enuresis. Urol J. 2015;12:2228-2232.
- Ferrara P, Romano V, Cortina I, Ianniello F, Fabrizio GC, Chiaretti A. Oral desmopressin lyophilisate (MELT) for monosymptomatic enuresis: structured versus abrupt withdrawal. J Pediatr Urol. 2014;10:52-55.
- Thumfart J, Roehr CC, Kapelari K, Querfeld U, Eggert P, Müller D. Desmopressin associated symptomatic hyponatremic hypervolemia in children. Are there predictive factors? J Urol. 2005;174:294-298.
- ten Doesschate T, Reichert LJ, Claassen JA. Desmopressin for nocturia in the old: an inappropriate treatment due to the high risk of side-effects? Tijdschr Gerontol Geriatr. 2010;41:256-261.
- Rembratt A, Riis A, Norgaard JP. Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia. Neurourol Urodyn. 2006;25:105-10
- Verrua E, Mantovani G, Ferrante E, et al. Severe water intoxication secondary to the concomitant intake of non-steroidal anti-inflammatory drugs and desmopressin: a case report and review of the literature. Hormones (Athens). 2013;12:135-141.
- Van Herzeele C, De Bruyne P, Evans J, et al. Safety profile of desmopressin tablet for enuresis in a prospective study. Adv Ther. 2014;31:1306-1316.
- Ferrara P, Vena F, Basile MC, Ianniello F, Gatto A. Focus on desmopressin and enuresis: a review of literature. Minerva Urol Nefrol. 2016;68:14-19.
- Lottmann H, Froeling F, Alloussi S, et al. A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresis. Int J Clin Pract. 2007;61:1454-1460.
- Kamperis K, Van Herzeele C, Rittig S, Vande Walle J. Optimizing response to desmopressin in patients with monosymptomatic nocturnal enuresis. Pediatr Nephrol. 2017;32:217-226.
- Stoof SC, Cnossen MH, de Maat MP, Leebeek FW, Kruip MJ. Side effects of desmopressin in patients with bleeding disorders. 2016;22:39-45.
- Ferrara P, Marrone G, Emmanuele V, et al. Homotoxicological remedies versus desmopressin versus placebo in the treatment of enuresis: a randomised, double-blind, controlled trial. Pediatr Nephrol. 2008;23:269-274.
- Van de Walle J, Van Herzeele C, Raes A. Is there still a role for desmopressin in children with primary monosymptomatic nocturnal enuresis?: a focus on safety issues. Drug Saf. 2010 Apr 1;33(4):261-271.
- Schulz-Jürgensen S, Feldmann B, Eggert P. Desmopressin in the Treatment of Enuresis: Is Lyophilisate Superior to Tablets? Aktuelle Urol. 2016 Dec;47(6):480-486.
- Jain S, Bhatt GC. Advances in the management of primary monosymptomatic nocturnal enuresis in children. Paediatr Int Child Health. 2016 Feb;36(1):7-14.
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