Pediatric Subcommittee Presentation onPharmacologic Control of Drooling John V. Kelsey, D.D.S. Lisa Mathis M.D. Division of Dermatologic and Dental Drug Products 24 April 2001
Issues for the Pediatric Subcommittee • Drooling is a problem in children with neurological impairments • Currently no approved pharmacologic therapies • Special considerations for studying drugs in this patient population Pediatric Subcommittee 4/24/01
Questions for the Pediatric Subcommittee • Assessment of adverse events in this population • Appropriate formulations • Development of useful dosing information • Ethical and legal considerations Pediatric Subcommittee 4/24/01
Division of Dermatologic and Dental Drug Products(DDDDP, HFD-540) Pediatric Subcommittee 4/24/01
Agenda • John V. Kelsey, D.D.S. • Lisa Mathis, M.D. • Benjamin Wilfond, M.D. • Maria Pena, M.D. • Ross Hays, M.D. Pediatric Subcommittee 4/24/01
Agenda (cont’d) • Scott Stiefel, M.D. • Murray Goldstein, D.O. • Belinda Hurlburt • Open public hearing • Subcommittee discussion of issues/questions Pediatric Subcommittee 4/24/01
Autonomic Nervous System • Involuntary nervous system • Innervates heart, blood vessels, visceral organs, smooth muscle, glands • Sympathetic v. parasympathetic systems • Acetylcholine • Muscarinic receptors Pediatric Subcommittee 4/24/01
Innervation of Salivary Glands • Both sympathetic and parasympathetic stimulate • Acetylcholine is neurotransmitter for both • Muscarinic (M3) receptors Pediatric Subcommittee 4/24/01
Reasons Drooling Requires Intervention • May lead to aspiration • Can lead to maceration of skin • Predisposes to secondary infection • May compromise education • May affect placement Pediatric Subcommittee 4/24/01
Other Cholinergic Effects • Dilation of pupils • Increased heart rate • Decreased gut motility • Urinary retention • Reduced sweating Pediatric Subcommittee 4/24/01
Summary • Pharmacologic target for controlling drooling is the muscarinic receptors • Antimuscarinic drugs are currently used off-label • Antimuscarinics are not selective and extrasalivary antimuscarinic effects can be unpleasant and dangerous Pediatric Subcommittee 4/24/01
Summary (cont’d) • Studies are needed to safely and properly dose these products • Dose-ranging and assessment of adverse events is problematic in CP patients Pediatric Subcommittee 4/24/01
Pediatric Subcommittee Presentation onPharmacologic Control of Drooling John V. Kelsey, D.D.S. Lisa Mathis M.D. Division of Dermatologic and Dental Drug Products 24 April 2001 Pediatric Subcommittee 4/24/01
Issues for the Pediatric Subcommittee • Drooling is a problem in children with neurological impairments • Currently no approved pharmacologic therapies • Special considerations for studying drugs in this patient population Pediatric Subcommittee 4/24/01
Drooling • Significant problem in children with cerebral palsy and other neurologic conditions • Not a result a hypersalivation • Impaired motor function results in difficulty swallowing Pediatric Subcommittee 4/24/01
Prevalenceof Cerebral Palsy1 • 1.5 to 2.5 per 1000 live births • Approximately 400,000 - 800,000 children • Approximately 400,000 adults • Nolan J, Chalkiadis G.A.,Low J., et al, Anesthesia and pain management in cerebral palsy, Anesthesia,2000; 55:32-41 Pediatric Subcommittee 4/24/01
Prevalence of Drooling4 • 25-35% of patients with CP have some degree of drooling • Approximately 10% require intervention • Several other conditions with drooling • Down’s Syndrome, CVAs, hemiparesis, Rett’s Syndrome Camp-Bruno J, Winsberg B, Green Parsons A, Abrams J, Efficacy of Benztropine Therapy for Drooling, Dev Med Child Neuro, 1989; 40: 340-343 Pediatric Subcommittee 4/24/01
Reasons Drooling Requires Intervention • May lead to aspiration • Can be life threatening, leads to secondary pneumonia, pulmonary inflammation (RAD) • Can lead to maceration of skin • Breakdown of skin can be very painful, similar to a burn • Predisposes to secondary infection Pediatric Subcommittee 4/24/01
Reasons Drooling Requires Intervention • May compromise education • May affect placement Pediatric Subcommittee 4/24/01
Methods Used to Control Drooling • Behavioral • Oromotor therapy • Behavioral modification • Pharmacologic • Surgical • Irreversible • Many risks associated with surgery Pediatric Subcommittee 4/24/01
Pharmacologic Control • Antimuscarinics Used to Inhibit Salivation • Benztropine • Glycopyrrolate • Scopolamine • Trihexyphenidyl • Others Pediatric Subcommittee 4/24/01
Antimuscarinics • Not approved for chronic use in children • Acute use in pre-anesthesia • No pediatric formulation • Limited efficacy, safety, dosing information from clinical studies Pediatric Subcommittee 4/24/01
Antimuscarinic Effects • Neurologic • Headache • Irritability, nervousness • Confusion, disorientation • Depression • Special Senses • Blurred vision • Loss of taste Pediatric Subcommittee 4/24/01
Antimuscarinic Effects • Gastrointestinal • Nausea • Vomiting • Paralytic ileus • Constipation • Cardiovascular • Tachycardia • Palpitations Pediatric Subcommittee 4/24/01
Antimuscarinic Effects • Urogenital • Urinary retention • Dysuria • Other • Hyperthermia • Xerostomia Pediatric Subcommittee 4/24/01
Clinical Trials Necessary to Evaluate New Formulations • Increase safety and consistency in administration • Appropriate concentration would allow caregivers to titrate dose in small increments Pediatric Subcommittee 4/24/01
Clinical Studies Necessary to Determine Pediatric Dosing • In indications other than drooling, optimal dose must be individualized • Response is variable • Degree of drooling at baseline poor predictor of response • Small dose adjustments must be made until benefit is achieved or side effects occur Pediatric Subcommittee 4/24/01
Pediatric Subcommittee 4/24/01
Effects of Atropine in Relation to Dose • 0.5 mg - Slight cardiac slowing, some dryness of mouth, inhibition of sweating • 1.0 mg - Tachycardia, definite dryness of mouth, dilatation of pupil • 2.0 mg - Tachycardia, palpitations, marked dryness of mouth, blurring of near vision • 5.0 mg - All above symptoms marked, restlessness, fatigue, headache, decreased urination, reduced intestinal peristalsis Pediatric Subcommittee 4/24/01
Challenges of Conducting Clinical Trials in Children with Special Needs: • Patient selection • Consent/assent/communication • Efficacy and safety evaluation Pediatric Subcommittee 4/24/01
Efficacy Assessment • What dose provides balance between control of drooling and adverse events? • Efficacy is predictable, but absolute xerostomia is not in the best interest of the patient Pediatric Subcommittee 4/24/01
Efficacy Assessment • Drooling can vary from hour to hour, assessments must be multiple • What objective tools can be used to measure efficacy? • Teacher’s Drooling Scale • Who will administer tools? Pediatric Subcommittee 4/24/01
Safety Assessment • Assessment of pain and discomfort can be difficult in target population • Self reporting of pain and discomfort is “gold standard” • Patients with cognitive disability or inability to communicate cannot self report • Failure to recognize side effects could lead to patient suffering, morbitity Pediatric Subcommittee 4/24/01
Safety Assessment • Adverse events can be serious • Pain Scales have been developed • Checklists of behavioral and/or physiologic characteristics • Who will administer tools? Pediatric Subcommittee 4/24/01
Conclusions • Drooling can be a serious problem • Pharmacologic control appears effective • There is a need for well-designed studies to provide information on dose-related safety and efficacy • Studies must be conducted in a manner that respects the rights of the patients and results in beneficial clinical information Pediatric Subcommittee 4/24/01
