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Pediatric Subcommittee Presentation on Pharmacologic Control of Drooling

Pediatric Subcommittee Presentation on Pharmacologic Control of Drooling

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Pediatric Subcommittee Presentation on Pharmacologic Control of Drooling

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Presentation Transcript

  1. 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

  2. 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

  3. 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

  4. Division of Dermatologic and Dental Drug Products(DDDDP, HFD-540) Pediatric Subcommittee 4/24/01

  5. 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

  6. 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

  7. 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

  8. Innervation of Salivary Glands • Both sympathetic and parasympathetic stimulate • Acetylcholine is neurotransmitter for both • Muscarinic (M3) receptors Pediatric Subcommittee 4/24/01

  9. 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

  10. Other Cholinergic Effects • Dilation of pupils • Increased heart rate • Decreased gut motility • Urinary retention • Reduced sweating Pediatric Subcommittee 4/24/01

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. Reasons Drooling Requires Intervention • May compromise education • May affect placement Pediatric Subcommittee 4/24/01

  20. Methods Used to Control Drooling • Behavioral • Oromotor therapy • Behavioral modification • Pharmacologic • Surgical • Irreversible • Many risks associated with surgery Pediatric Subcommittee 4/24/01

  21. Pharmacologic Control • Antimuscarinics Used to Inhibit Salivation • Benztropine • Glycopyrrolate • Scopolamine • Trihexyphenidyl • Others Pediatric Subcommittee 4/24/01

  22. 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

  23. Antimuscarinic Effects • Neurologic • Headache • Irritability, nervousness • Confusion, disorientation • Depression • Special Senses • Blurred vision • Loss of taste Pediatric Subcommittee 4/24/01

  24. Antimuscarinic Effects • Gastrointestinal • Nausea • Vomiting • Paralytic ileus • Constipation • Cardiovascular • Tachycardia • Palpitations Pediatric Subcommittee 4/24/01

  25. Antimuscarinic Effects • Urogenital • Urinary retention • Dysuria • Other • Hyperthermia • Xerostomia Pediatric Subcommittee 4/24/01

  26. 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

  27. 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

  28. Pediatric Subcommittee 4/24/01

  29. 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

  30. Challenges of Conducting Clinical Trials in Children with Special Needs: • Patient selection • Consent/assent/communication • Efficacy and safety evaluation Pediatric Subcommittee 4/24/01

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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