Elsevier

Clinical Therapeutics

Volume 34, Issue 4, April 2012, Pages 735-742
Clinical Therapeutics

Pharmacotherapy
New drug review
Glycopyrrolate for Chronic Drooling in Children

https://doi.org/10.1016/j.clinthera.2012.02.026Get rights and content

Abstract

Background

Sialorrhea, or drooling, is seen in the pediatric population, especially in patients with cerebral palsy and other neurodevelopmental disabilities. If medication use is warranted, anticholinergic agents are the drug of choice; however, adverse effects limit their use. Glycopyrrolate, a synthetic anticholinergic that acts at peripheral muscarinic receptors, has been used off-label for excessive drooling in children with neurodevelopmental disabilities for years. Product formulations restricted the use of glycopyrrolate. However, an oral solution was approved by the US Food and Drug Administration for children ages 3 to 16 years with neurologic disorders for chronic severe drooling in 2010; it became available for use in 2011.

Objective

This article provides an overview of the pharmacology, clinical efficacy, and tolerability of glycopyrrolate when used for sialorrhea in children.

Methods

To evaluate the efficacy and safety profile of glycopyrrolate for the treatment of sialorrhea in children, a comprehensive search was performed of the MEDLINE database (1966–February 25, 2012) and International Pharmaceutical Abstracts as well as references from additional review articles identified. 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. The pharmaceutical manufacturer of the oral solution was contacted for medical and study information.

Results

Oral bioavailability of glycopyrrolate varies widely, with a median of 3.3%. Mean Cmax in children was determined to be 0.37 μg/mL, and mean Tmax was 3.1 hours. The clearance in children ranges from 0.6 to 1.43 L/kg/h. The t½ ranges from 22 to 130 minutes and 19 to 99 minutes in infants and children, respectively. Six studies describing the use of glycopyrrolate for drooling in children were identified. A double-blind, crossover trial of 27 patients (age range, 4–19 years) demonstrated a reduced mean drooling score (modified Teacher's Drooling Scale [1 = never drools to 9 = clothing, hands, and objects frequently become wet]) for glycopyrrolate (mean highest tolerated dose, 0.11 mg/kg) compared with placebo of 1.85 versus 6.33 (P < 0.001). In a parallel study of 36 patients (age range, 3–16 years), 14 of 20 patients randomized to receive glycopyrrolate solution showed improvement in the mean modified Teacher's Drooling Scale score compared with only 3 patients receiving placebo (−3.5 vs −0.1, respectively). Glycopyrrolate was initiated at 0.02 mg/kg per dose orally TID (Max dose: 3 mg) and titrated over a 4-week period. Adverse effects identified in studies include dry mouth (9%–41%), constipation (9%–39%), and behavioral changes (18%–36%).

Conclusions

Glycopyrrolate is effective in decreasing sialorrhea in children with cerebral palsy or other neurodevelopmental disabilities. Adverse effects did occur, more frequently at higher doses, and should be monitored.

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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