# Presentation: 192508

## Drug Formulationin Pediatrics:If it tastes bad it must be good for you

- Jeffrey Blumer, Ph.D., M.D.Professor of Pediatrics and PharmacologyCase Western Reserve University
- Chief, Pediatric Pharmacology and Critical CareRainbow Babies and Children’s HospitalCleveland, Ohio

## Slide 2

## Slide 3

## Slide 4

## Drug Treatmentfor Infants and Children–  The Challenge  –

- Pediatric Patients are dynamic with respect to drug disposition
- Developmental changes in body composition
- Developmental changes in drug metabolism
- Developmental changes in organ function

## Drug Treatmentfor Infants and Children–  The Challenge  –

- Pediatric patients are different with respect to drug action
- Ontogeny of receptor expression and function
- Greater regenerative and recuperative potential
- Unique disease processes
- Patients with chronic diseases will undergo growth and developmental changes during therapy

## Practical Issuesin Pediatric Drug Dosing

- Traditionally pediatric dosing is weight based (mg/kg)
- Drug dose will often require change as the child grows
- Parenteral dosage forms often require significant dilution prior to administration
- Children are often unable to swallow pills or capsules until they are 6 (or 7 or 12 or never) years of age

## Practical Issuesin Pediatric Drug Dosing

- Complex solid dosage forms (e.g. sustained release preparations) are not engineered with consideration of pediatric GI physiology
- Palatability is the major determinant of compliance with treatment with oral liquids and chewable/dissolving dosage forms
- Dosing of young children generally depends on parent/guardian

## Formulations Availablefor Treating Infants and Children

- Intravenous
- Solutions
- Emulsions
- Oral
- Solutions
- Suspensions
- Elixirs
- Syrups
- Granules
- Tablets
- Effervescent tablets
- Chewable tablets
- Drops

- Rectal
- Solutions
- Foams
- Cutaneous
- Creams
- Ointments
- Percutaneous
- Patches

## Slide 10

| Potent Medications with Potential for “Dilution Intoxication” Due to Concentration Available in Pharmaceutical Preparations |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  | Calculated Individual Dose |  |  |  |  |
| 
  Drug | Available Concentration |  | Volume(ml) | Amount | Dose Delivered with Flush | Delivered Dose 
(% Calculated) |  |
| Atropine | 0.4 mg/ml |  | 0.0025 | 0.01 mg | 0.016 mg | 160 |  |
| Diazepam | 5 mg/ml |  | 0.05 | 0.1 mg | 0.18 mg | 180 |  |
| Digoxin | 100 μg/ml |  | 0.05 | 5 μg | 6.5 μg | 130 |  |
| Epinephrine | 1:10,000 |  | 0.10 | 10 μg | 11.5 μg | 115 |  |
| Hydralazine | 20 mg/ml |  | 0.05 | 1 mg | 1.3 mg | 130 |  |
| Insulin | 100 U/ml |  | 0.001 | 0.1 U | 0.115 U | 115 |  |
| Morphine | 8 mg/ml |  | 0.013 | 0.1 mg | 0.22 mg | 220 |  |
| Phenytoin | 50 mg/ml |  | 0.08 | 4 mg | 4.75 mg | 120 |  |

## Pediatric Formulation Methods

- Bona fide pediatric formulations (e.g., drops, suspensions, chewable tablets or syrups)
- Extemporaneous pediatric formulations made with “standardized” extemporaneous vehicles (e.g., NF, USP, or marketed vehicles)
- Extemporaneous pediatric formulations made with food (e.g., sprinkles on applesauce or yogurt)

## Determinants of the Typeof Formulation for Children

- Age
- Ability to handle solid dosage forms
- Disease / Disorder being treated

## Recommended Drug Formulations for Infantsand Children

- Oral solutions
- Oral suspensions
- Rapidly dissolving tablets
- Sprinkles/sachets
- Transcutaneous delivery systems
- Implantable reservoirs

## The Pediatric Holy Grail

- AnOralLiquidPreparation

## Statement of thePediatric Pharmacy Advocacy Grouphttp://www.ppag.org/

- For every new chemical entity and currently marketed drug still under patent, *with or without* safety and effectiveness data in children, where *no oral liquid dosage form is available*, the manufacturer should be required to provide a formulation that effectively converts an oral solid or intravenous dosage form to an oral solution or suspension dosage form.

## Is This What We ReallyWant / Need?

## Pediatric Formulation Approaches

- Proprietary – Liquids, suspensions, chewable tablets
- Extemporaneous preparations
- Compounded with known vehicles
- Crushed solid dosage forms

## Oral Formulations for Children–  The Down Side  –

- Solutions often contain potentially toxic excipients
- Suspensions often result in unequal drug delivery over time due to nonuniform dispersal
- Suspensions often have palatability problems due to _**both**_ taste and texture
- Sprinkles/sachets often have erratic absorption
- Transcutaneous delivery systems depend on uniform nature of integument

## Issues Affecting Extemporaneous Preparations

- Stability
- Bioavailability
- Nonuniform composition
- Variable effect of food

## The Food Myth

- Generally accepted that food may affect bioavailability
- “Not all applesauce is created equal”	S. Hirschfeld M.D., Ph.D.
- Generally little impact
- No studies dealing with foods children actually eat

## Results to Date

**Bona fide**
- Many antivirals
- Atovaquone/proguanil
- Ibuprofen/     pseudoephedrine
- Gabapentin
- Midazolam

**Extemporaneous “standardized”**
- Enalapril
- Sotalol

**Sprinkles**
- Topiramate
- Montelukast

## “Bona Fide” Applications – Pediatric Antivirals

- Zidovudine	Oral Solution
- Didanosine	Powder (reconstitute with antacid)
- Lamivudine	Oral Solution
- Abacavir	Oral Solution
- Nevirapine	Suspension
- Efavirenz	Capsules (50 mg for 7 kg patient)
- Ritonavir	Solution
- Nelfinavir mesylate	Oral Powder (mix with foods)
- Amprenavir	Oral Solution (propylene glycol)
- Lopinavir/Ritonavir	Oral Solution
- Acyclovir	Oral Suspension
- Ribavirin	Powder for Inhalation Solution
- Oseltamavir phosphate	Suspension