Pediatric Dosing of OTC Medicines:

Application to Cough and Cold Medicines

Introduction• The purpose of this presentation is to

encourage the NDAC to:– Endorse (once again) the use of a dosing

schedule based on the more finely divided age breaks, with inclusion of and emphasis on the addition of a proposed weight schedule

– Endorse the placing of dosing information on the consumer label for all age ranges in which the product will be used

A Brief History of Proposals for a New Standardized Pediatric Dosing Schedule

[1] • 1976: Proposed rule for CCABA selects dosing

schedules for children using only 2 broad age ranges (2-5, 6-11);no weight schedule proposed.

• 1979: Done, Yaffe, and Clayton propose that a revised dosing schedule be used for pediatric aspirin. Their revised schedule provided for shorter age ranges for a given dose: 2-3, 4-5, 6-8, 9-10, and 11 years of age were the age ranges, each receiving an increased number of 81mg aspirin tablets.1

• 1982: Pediatric dosing schedule for acetaminophen was revised using the same age breaks. This included a proposed weight-based schedule.2

1.Done AK, Yaffe SJ, Clayton JM, “Aspirin dosage for infants and children”, J. Pediatrics 1979; 95:617-625.2.Temple AR, “Pediatric dosing of acetaminophen”, Pediatric Pharmacology 1983; 3:321-327.

A Brief History of Proposals for a New Standardized Pediatric Dosing Schedule

[2] • 1983: ANPR issues for antitussives. McN response proposes a

new pediatric dosing schedule for antitussives using same age breaks as analgesics and a weight schedule.

• 1985: ANPRs issue for antihistamines and nasal decongestants with wide age range pediatric dosing

• 1985(Feb 25): McN meeting with FDA staff to review dosing and labeling proposal. At that time a full and complete discussion of dosing principles and schedules was provided to FDA.

• 1985: McN submissions propose the new pediatric dosing schedule for antihistamines and decongestants, with consumer labeling on all products for children 2 and older and professional dosing for children under age 2yrs

• 1988: FDA publishes a request for information about pediatric dosing schedules on OTC medication. McN response once again proposes the new consumer and professional dosing schedules.

A Brief History of Proposals for a New Standardized Pediatric Dosing Schedule

[3]

• 1992: Antihistamine FM issued: decision about pediatric dosing deferred

• 1994: Nasal decongestant FM issued: decision about pediatric dosing deferred

• 1995: NDAC meeting held to discuss pediatric dosing of OTC medicines; Presentation given: “A rational approach to the dosing of nonprescription medications in the pediatric patient”; NDAC committee voted unanimously in favor of the improved dosing schedule where it could be applied.

• Since then:

What is FDA’s Current Approach to Pediatric Dosing

for OTCs?

• Adults and Children 12 years of age and older: “Approved Adult Dose”

• Children 6 through 11 years: 1/2 the Adult Dose

• Children 2 through 5 years: 1/4 the Adult Dose

• Children Under 2 years: Physician decision

Impact of the overly wide dosing age ranges Comparisons for weights for children at various

points in the current dosing schedule ranges

Age (years) Percentile for Age

Weight (kg) Ratio

6 50 20.1 0.5211.5 50 38.4

6 10 17.2 0.3411.5 90 51.3

2 50 12.1 0.635.5 50 19.1

2 10 10.6 0.475.5 90 22.7

Impact of the overly wide dosing age ranges

So, if the dose for an average (50th percentile) 6 year old is

0.50mg/kg

Then, the dose for an average (50th percentile) 11.5 year old is

0.26mg/kg

And the dose for a very large (90th percentile) 11.5 year old is

0.20mg/kg

So, is the pediatric dosing approach currently being used for

most OTC oral medicines an adequate method?

• Not really– No significant safety risks when given in the

recommended doses, BUT– Will not provide as consistent dosing (mg/kg)

as a schedule with narrower age breaks– May not provide an effective dose for some

children (lower mg/kg doses)

• The preferred schedule would be one with narrower age-breaks, with an added comparable weight schedule

Dosing based on the concept of a standardized pediatric dosing

unit(SPDU)

Standard Pediatric Dosing Units and Corresponding Ages

and WeightsSPDUs

Age Ranges

Weight Ranges Fraction of Adult Doselbs kg

1 4-11m 12-17 5.5-7.9 1/ 8

1.5 12-23m 18-23 8-10 3/16

2 2-3y 24-35 11-15 1/ 4

3 4-5y 36-47 16-21 3/ 8

4 6-8y 48-59 22-26 1/ 2

5 9-10y 60-71 27-32 5/ 8

6 11y 72-95 33-43 3/ 4

8 12+y 96+ 44+ 1Temple AR, Pediatric Pharmacology 1983; 3:321-327.

Current dosing intervalsProposed dosing

intervals

Some proposed Standard Pediatric Dosing Units for some common OTC

ingredients

DRUG SPDU(mg)

Acetaminophen 80

Chlorpheniramine 0.5

Brompheniramine 0.5

Diphenhydramine 3.0*

Dextromethorphan 2.5

Pseudoephedrine 7.5

Phenylephrine 1.25

16mg/kg

9mg/kg

Dosing Ranges Provided by Current OTC Formulations

Use of PK/Clinical Trial Data

• PK data show potential for extrapolation for children ages 2-11 in pseudoephedrine and ages 6-11 in chlorpheniramine

• Clinical data that contains dose ranging in the pediatric population are rare, but some data do support the proposed dosing concept, e.g. dextromethorphan

1mg/kg

0.5mg/kg

Dosing Ranges Provided by Current OTC Formulations

0.75mg/kg

1.5mg/kg

Dosing Ranges Provided by Current OTC Formulations

Dosing of Dextromethorphan

• In 1985, in response to the antitussive proposed rule, using available adult data, a recommendation for a standard pediatric dosing unit and schedule that would consistently produce a dose of ~0.5mg/kg was made. Subsequently, little additional data has become available.

• In 2004, Paul et al, studying children ages 2-11 yrs using current OTC (wide age-ranges) doses reported that subjects who received doses of 0.35 to<0.45mg/kg were less likely to have symptom control (N.S.) than those receiving doses of 0.45 to<0.60mg/kg, or doses above 0.60mg/kg. *– [Although no analysis was done to stratify the doses achieved

in the study group by age, it would be more than likely that the oldest and heaviest children were getting doses in the low range.]

*Paul IM et al, Dose-response relationship with increasing doses of dextromethorphan for children with cough, Clinical Therapeutics 2004;26:1508-1514

Dosing of Dextromethorphan

Paul IM et al, “Dose-response relationship with increasing doses of dextromethorphan for children with cough”, Clinical Therapeutics 2004;26:1508-1514

0.5mg/kg

0.25mg/kg

Dosing Ranges Provided by Current OTC Formulations

What is the most practical basis for determining and labeling pediatric OTC

medicines?

Body Surface Area

ImpracticalWeight schedules approximate

Height (Length) Not very practicalNo advantage over weight

Age Good

Weight Better

Age and Weight

Ideal

Why use the standard pediatric dosing unit based schedule for individual OTC ingredients or specific OTC classes of drugs?• The “standard pediatric dosing unit”

schedule can be applied to analgesic/antipyretic, antihistamine, antitussive, and oral nasal decongestant products

• Having a common schedule would allow – each ingredient to be given in a more consistent

mg/kg dose and, – when given in combination with any of the others

ingredients that have such a schedule, would allow all of the ingredients to be properly dosed

A Reasoned Approach to Labeling

• The SPDU approach, using more narrow age ranges, provides a more consistent dose– None of the new age ranges provide a dose higher than

the current peak dose (highest mg/kg--at 6 years of age) for either the old or the new schedule

– Each of the new age ranges provide higher trough levels (lowest mg/kg dose) than the old schedule

• Weight schedule provides doses even more consistently in range

• Age-appropriate use should be determined for each individual OTC Cold and Cough ingredient and not “as a group”

Appropriate labeling should reflect accurate dosing

information

“Appropriate labeling should reflect . . . accurate dosing information so that children’s health care providers can make an informed decision as to whether or not to recommend use of these products and counsel parents appropriately should they choose to do so.” (letter to FDA from AAP dated September 6, 2007)

Root Cause Analysis of Misuse Leading to Overdose Suggests Lack

of Dosing on the Label is Major Contributing Factor

• Vast majority of non-accidental ingestions by exploratory children occurred in the Under 2 yrs age range

• None of the products produced for ease of administration to small children have been allowed to have the dosing on the label

• Health care professionals have not been able or available to give dosing instructions

A Reasoned Approach to Labeling

• The consumer label should contain dosing information for children for each and every specific age group--if the drug is to be used in that age group– Must not let the concern about the

likelihood of use without consulting a health professional override the risk of misuse if consumer dosing information is not provided

Conclusions• The NDAC should:

– Endorse (once again) the use of a dosing schedule based on the more finely divided age breaks, with inclusion of and emphasis on the addition of a proposed weight schedule

• The current OTC ingredients should remain on the market

• New PK and efficacy data should be obtained to refine doses

• And the new dosing schedules be adopted while new scientific studies are undertaken

Conclusions• The NDAC should:

– Endorse the placing of dosing information on the consumer label for all age ranges in which the product will be used

• Do not use the excuse that since you want the consumer to call their doctor you would not give them access to correct dosing information

• The Dose should be on the Label!