pediatric subcommittee presentation on pharmacologic control of drooling john v. kelsey, d.d.s. lisa...

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


Questions for the Pediatric Subcommittee

• Assessment of adverse events in this population

• Appropriate formulations• Development of useful dosing

information• Ethical and legal considerations



(DDDDP, HFD-540)


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


Agenda (cont’d)• Scott Stiefel, M.D.• Murray Goldstein, D.O.• Belinda Hurlburt• Open public hearing• Subcommittee discussion of

issues/questions


Autonomic Nervous System• Involuntary nervous system

• Innervates heart, blood vessels, visceral organs, smooth muscle, glands

• Sympathetic v. parasympathetic systems

• Acetylcholine

• Muscarinic receptors


Innervation of Salivary Glands

• Both sympathetic and parasympathetic stimulate

• Acetylcholine is neurotransmitter for both

• Muscarinic (M3) receptors


Reasons Drooling Requires Intervention

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


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


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


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 Presentation on

Pharmacologic Control of Drooling

John V. Kelsey, D.D.S.Lisa Mathis M.D.


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


Drooling• Significant problem in children with

cerebral palsy and other neurologic conditions

• Not a result a hypersalivation• Impaired motor function results in

difficulty swallowing


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


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



• 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



• May compromise education

• May affect placement


Methods Used to Control Drooling

• Behavioral– Oromotor therapy

– Behavioral modification

• Pharmacologic

• Surgical– Irreversible

– Many risks associated with surgery


Pharmacologic Control• Antimuscarinics Used to Inhibit

Salivation– Benztropine– Glycopyrrolate– Scopolamine– Trihexyphenidyl– Others


Antimuscarinics• Not approved for chronic use in

children– Acute use in pre-anesthesia

• No pediatric formulation• Limited efficacy, safety, dosing

information from clinical studies


Antimuscarinic Effects• Neurologic

– Headache– Irritability, nervousness– Confusion, disorientation– Depression

• Special Senses– Blurred vision– Loss of taste


Antimuscarinic Effects• Gastrointestinal

– Nausea– Vomiting – Paralytic ileus– Constipation

• Cardiovascular– Tachycardia– Palpitations


Antimuscarinic Effects

• Urogenital

– Urinary retention

– Dysuria

• Other

– Hyperthermia

– Xerostomia


Clinical Trials Necessary to Evaluate New Formulations

• Increase safety and consistency in administration

• Appropriate concentration would allow caregivers to titrate dose in small increments


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


Effects of Atropine in Relation to Dose

0.5 1 2 5 10

Dose

Eff

ects


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


Challenges of Conducting Clinical Trials in Children with

Special Needs:

• Patient selection

• Consent/assent/communication

• Efficacy and safety evaluation


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


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?


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


Safety Assessment

• Adverse events can be serious

• Pain Scales have been developed

–Checklists of behavioral and/or physiologic characteristics

• Who will administer tools?


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 presentation on pharmacologic control of drooling john v. kelsey, d.d.s. lisa...

Documents

sweating slide

dangerous slide

placement slide

drooling significant

division of dermatologic

lisa mathis

products dose

dental drug products