Pediatric Subcommittee Presentation on Pharmacologic Control of Drooling

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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

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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

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Questions for the Pediatric Subcommittee

• Assessment of adverse events in this population
• Appropriate formulations
• Development of useful dosing information
• Ethical and legal considerations

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Division of Dermatologic and Dental Drug
Products(DDDDP, HFD-540)
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Agenda

• John V. Kelsey, D.D.S.
• Lisa Mathis, M.D.
• Benjamin Wilfond, M.D.
• Maria Pena, M.D.
• Ross Hays, M.D.

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Agenda (contd)

• Scott Stiefel, M.D.
• Murray Goldstein, D.O.
• Belinda Hurlburt
• Open public hearing
• Subcommittee discussion of issues/questions

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Autonomic Nervous System

• Involuntary nervous system
• Innervates heart, blood vessels, visceral organs,
  smooth muscle, glands
• Sympathetic v. parasympathetic systems
• Acetylcholine
• Muscarinic receptors

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Innervation of Salivary Glands

• Both sympathetic and parasympathetic stimulate
• Acetylcholine is neurotransmitter for both
• Muscarinic (M3) receptors

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Reasons Drooling Requires Intervention

• May lead to aspiration
• Can lead to maceration of skin
• Predisposes to secondary infection
• May compromise education
• May affect placement

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Other Cholinergic Effects

• Dilation of pupils
• Increased heart rate
• Decreased gut motility
• Urinary retention
• Reduced sweating

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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

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Summary (contd)

• Studies are needed to safely and properly dose
  these products
• Dose-ranging and assessment of adverse events is
  problematic in CP patients

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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
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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

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Drooling

• Significant problem in children with cerebral
  palsy and other neurologic conditions
• Not a result a hypersalivation
• Impaired motor function results in difficulty
  swallowing

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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 5532-41

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Prevalence of Drooling4

• 25-35 of patients with CP have some degree of
  drooling
• Approximately 10 require intervention
• Several other conditions with drooling
• Downs Syndrome, CVAs, hemiparesis, Retts
  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

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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

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Reasons Drooling Requires Intervention

• May compromise education
• May affect placement

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Methods Used to Control Drooling

• Behavioral
• Oromotor therapy
• Behavioral modification
• Pharmacologic
• Surgical
• Irreversible
• Many risks associated with surgery

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Pharmacologic Control

• Antimuscarinics Used to Inhibit Salivation
• Benztropine
• Glycopyrrolate
• Scopolamine
• Trihexyphenidyl
• Others

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Antimuscarinics

• Not approved for chronic use in children
• Acute use in pre-anesthesia
• No pediatric formulation
• Limited efficacy, safety, dosing information from
  clinical studies

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Antimuscarinic Effects

• Neurologic
• Headache
• Irritability, nervousness
• Confusion, disorientation
• Depression
• Special Senses
• Blurred vision
• Loss of taste

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Antimuscarinic Effects

• Gastrointestinal
• Nausea
• Vomiting
• Paralytic ileus
• Constipation
• Cardiovascular
• Tachycardia
• Palpitations

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Antimuscarinic Effects

• Urogenital
• Urinary retention
• Dysuria
• Other
• Hyperthermia
• Xerostomia

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Clinical Trials Necessary to Evaluate New
Formulations

• Increase safety and consistency in administration
• Appropriate concentration would allow caregivers
  to titrate dose in small increments

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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

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(No Transcript)
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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

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Challenges of Conducting Clinical Trials in
Children with Special Needs

• Patient selection
• Consent/assent/communication
• Efficacy and safety evaluation

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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

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Efficacy Assessment

• Drooling can vary from hour to hour, assessments
  must be multiple
• What objective tools can be used to measure
  efficacy?
• Teachers Drooling Scale
• Who will administer tools?

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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

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Safety Assessment

• Adverse events can be serious
• Pain Scales have been developed
• Checklists of behavioral and/or physiologic
  characteristics
• Who will administer tools?

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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