PharmacotherapyNew drug reviewGlycopyrrolate for Chronic Drooling in Children
Introduction
Sialorrhea, or drooling, is seen in the pediatric population and is defined as saliva that unintentionally goes beyond the lip margin.1 Drooling is normal in infants and decreases as they develop oral motor skills, usually at ∼18 months of age. However, the occurrence of continual drooling after 4 years of age should be evaluated.1 Sialorrhea is most commonly seen in patients with cerebral palsy (10%–25%) and other neurodevelopmental disabilities.1
Saliva is primary produced by the submandibular and sublingual glands during normal body activity. Its role is to maintain the oral pH; aid in bacterial growth, dental health, and lubrication; and assist with the digestion of food.1 When the parotid gland is stimulated secondary to eating, it releases a large amount of saliva. Patients who have excess production of saliva or the inability to swallow large amounts tend to exhibit drooling. Although it is not a life-threatening condition, drooling is associated with physical, social, and psychological issues.
Speech or physical therapy with oromotor or behavioral exercises may be beneficial for some patients with neurodevelopmental disabilities and is generally used first.1 Medications that decrease the volume of saliva are usually the subsequent treatment option, with surgical intervention as a last-line resort. Anticholinergic agents are primarily the drugs of choice; however, adverse effect profiles have limited options due to the inability to restrict the antimuscarinic activity to specific sites. Glycopyrrolate is a synthetic quaternary ammonium similar to atropine that inhibits acetylcholine at parasympathetic sites such as secretory glands.2, 3, 4 It has been used off-label for excessive drooling because it reduces the volume of saliva and has fewer adverse effects due to its inability to cross the blood–brain barrier.3, 4 General dose recommendations for controlling drooling with glycopyrrolate include the following: oral doses, 40 to 100 μg/kg per dose administered TID to 4 times daily without regard to food; intramuscular/intravenous injection, 4 to 10 μg/kg per dose administered TID to 4 times daily.4 Glycopyrrolate is available in brand⁎ and generic tablet and injectable solution formulations. However, the injectable product contains benzyl alcohol, which has been associated with a “gasping syndrome” in neonates and should be used with caution.4 Because an oral liquid was not available, product formulation availability may have restricted the use of glycopyrrolate in patients. To circumvent this issue, tablets could be crushed and administered or the injectable formulation could be used in enteral therapy in an inpatient setting. Recipes for making an extemporaneous suspension have been available but had a shorter shelf life. A newly published stability study of a compounded suspension (0.5 mg/mL) determined 90-day stability at room temperature for this formulation.5
However, in June of 2010, an oral solution† (1 mg/5 mL) was approved by the US Food and Drug Administration for use in children ages 3 to 16 years with neurologic disorders for chronic severe drooling.6 This is the first approval of a glycopyrrolate product for excessive drooling. The manufacturer recommends an initial dose of 0.02 mg/kg per dose administered orally TID. Doses may be increased by 0.02 mg/kg every 5 to 7 days to a maximum of 0.1 mg/kg per dose TID or 1.5 to 3 mg per dose. A detailed dose titration table is provided in the package insert from the manufacturer.6 It is formulated as a clear, cherry-flavored solution and should be stored at room temperature. The drug was made available for use in April 2011. However, for a patient to receive the solution, the physician must order the medication through a specialty pharmacy (Diplomat Specialty Pharmacy, Flint, Michigan), and it is then shipped directly to the patient or to the physician's office.7
This article provides an overview of the pharmacology, clinical efficacy, and tolerability of glycopyrrolate when used for sialorrhea in children.
Section snippets
Methods
Relevant reports pertaining to the use of glycopyrrolate for drooling or sialorrhea in children were identified through a MEDLINE database (1966–February 25, 2012) and International Pharmaceutical Abstracts search. Searches were conducted using the terms glycopyrrolate, sialorrhea, drooling, secretion, and pediatrics. The terms drug-induced and Parkinson disease–associated sialorrhea were excluded from the search. References in review articles identified were also screened for additional
Clinical Pharmacology
Oral bioavailability of glycopyrrolate varies widely. One study in 6 healthy children (median age, 10 years) found a range of 1.3% to 13.3%, with a median oral bioavailability of 3.3%.8 The manufacturer recommends that the oral solution be administered at least 1 hour before or 2 hours after a meal.6 A high-fat meal will reduce the bioavailability of glycopyrrolate oral solution if taken shortly within meal time. This finding was based on an evaluation in healthy adults. Mean Cmax in children
Discussion
Only small trials have evaluated the use of glycopyrrolate in children. However, it would be difficult to conduct a large prospective study because the patient population comprises children with neurodevelopmental disabilities. Caregivers of these children may not subject their child to a clinical study. Of the available trials, only 2 are prospective and placebo controlled. The others are retrospective or open-label. Despite these weaknesses, the studies did show positive benefit of
Conclusions
Glycopyrrolate was effective in decreasing sialorrhea in children with cerebral palsy or other neurodevelopmental disabilities in these small studies. Adverse effects such as constipation, dry mouth, and behavioral changes occurred in ∼30% of patients in older studies and were seen more frequently at higher doses. All patients who were evaluated for efficacy with the commercially available oral solution experienced adverse effects. Adverse effects should be monitored after dose initiation and
Conflicts of Interest
The author has indicated that he has no conflicts of interest regarding the content of this article.
Acknowledgments
The author was solely responsible for authorship of this paper including literature search and evaluation, writing, review, and revision.
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2019, Toxicology and Applied PharmacologyCitation Excerpt :Discontinuation due to side effects was reported in over 20% of the subjects in three out of the four studies. ( Evatt, 2011) An overview article on oral glycopyrrolate for chronic drooling in children reported that rates of adverse events identified in the studies ranged from 9% to 41% for dry mouth, from 9% to 39% for constipation and from 18% to 36% for behavioral changes (Eiland, 2012). Two further publications report on data from randomized phase III studies (glycopyrrolate vs placebo) regarding the safety of oral glycopyrrolate solution for pediatric patients with pathological drooling (Zeller et al., 2012a; Zeller et al., 2012b).
Dihydroergotoxine mesylate for the treatment of sialorrhea in Parkinson's disease
2019, Parkinsonism and Related DisordersCitation Excerpt :Both pharmaceutical and non-pharmaceutical treatments have been used to manage sialorrhea in PD patients. Non-pharmacological approaches include gum chewing, behavioral modification, radiotherapy, and surgical intervention [11–14]. Gum chewing and behavioral modifications could improve motor control of the masticatory and tongue muscles, along with improving the stooped posture of the lips, but there have been limited studies to support the efficacy of these interventions [11,13].