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Pediatric Subcommittee Presentation on
Pharmacologic 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 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 on
Pharmacologic 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
Prevalence of 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
Effects of Atropine in Relation to Dose
0.5 1 2 5 10
Dose
Eff
ects
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