# Presentation: 316424

## 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**

## 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 (M****3****) 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**

- Pediatric Subcommittee 4/24/01

## 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**

- 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 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

## 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

## 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

## 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**

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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**

- 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**

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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**

- 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

## Slide 28

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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**

- 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