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ARTICLE

Improving Pediatric Dosing Through Pediatric

Initiatives: What We Have Learned

William Rodriguez, MD, PhD, Arzu Selen, PhD, Debbie Avant, RPh, Chandra Chaurasia, PhD, Terrie Crescenzi, RPh, Gerlie Gieser, PhD, Jennifer Di Giacinto, PharmD, Shiew-Mei Huang, PhD, Peter Lee, PhD, Lisa Mathis, MD, Dianne Murphy, MD, Shirley Murphy, MD, Rosemary Roberts, MD, Hari Cheryl Sachs, MD, Sandra Suarez, PhD, Veneeta Tandon, PhD, Ramana S. Uppoor, PhD

Food and Drug Administration, Rockville, Maryland

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT

OBJECTIVE.The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling.

METHODS.We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing.

RESULTS.The first 108 drugs with new or revised pediatric labeling changes had dosing

changes or pharmacokinetic information (n⫽23), new safety information (n⫽34),

information concerning lack of efficacy (n⫽19), new pediatric formulations (n

12), and extended age limits (n⫽77). A product might have hadⱖ1 labeling change.

We selected specific examples (n ⫽ 16) that illustrate significant differences in

pediatric pharmacokinetics.

CONCLUSIONS.Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

E

FFORTS TO ENSUREthat drug therapies for the pediatric population are studied with the same level of scientific and clinical rigor as adult therapeutic agents have a long history. These efforts have advanced over the years through the com-mitment of many organizations, including the American Academy of Pediatrics, the

National Institutes of Health, and the Food and Drug Administration (FDA).1–5

Originally, pharmaceutical companies were reluctant to study drugs in children because of the complexity, difficulty, and expense of such trials. In addition, most physicians erroneously assumed that children with conditions or diseases similar to those of adults would consistently respond comparably to adults. This assumption perpetuated

empiric use of medications without evidence-based efficacy and safety studies in the relevant pediatric populations.6

Without appropriate safety and efficacy studies in children, pediatricians and other health professionals are often forced to treat children on a trial-and-error basis, through the off-label use of drugs. The outcomes of such off-label

treatment can range from beneficial to ineffective or harmful.6

Two legislative initiatives, the FDA Modernization Act in 1997 and the Best Pharmaceuticals for Children Act in 2002, authorized an incentive program for manufacturers who conducted pediatric clinical trials in response to an FDA written request. The Pediatric Research Equity Act in 2003 codified the authority of the FDA to require pediatric studies of certain drugs and biological agents. These 3 laws have resulted in improvements in pediatric information in drug labeling as a result of studies conducted to determine proper dosing and to identify the risks of therapies in pediatric patients.7–11

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1529

doi:10.1542/peds.2007-1529

The views expressed are those of the authors. No official support or endorsement by the US Food and Drug Administration is provided or should be inferred.

Key Words

pediatric dosing, safety, efficacy, labeling, exposure, bioavailability, pharmacology, pharmacokinetics, pharmacodynamics

Abbreviations

FDA—Food and Drug Administration BSA— body surface area ODT— orally disintegrating tablet ADHD—attention-deficit/hyperactivity disorder

Accepted for publication Aug 9, 2007 Dr Di Giacinto’s current affiliation is Salamandra LLC, Bethesda, MD. Dr Murphy is now retired.

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During pediatric development, physiologic and bio-chemical processes governing drug absorption, distribu-tion, metabolism, and excretion undergo significant

maturation.12 Although adjustment of drug

pharmaco-kinetic parameters according to body weight or body surface area (BSA) can occasionally explain the observed exposure differences between adult and pediatric pa-tients, the direction and extent of these differences across age groups, in general, are not predictable. Some drugs are eliminated more rapidly or more slowly in younger pediatric patients, compared with older pediat-ric patients. Therefore, weight-based methods for deter-mining pediatric doses, such as the rule of Clark and

Young,13 may not account accurately for all variables

related to the different stages of maturation and are unlikely to predict consistently the correct dose for each pediatric age group.

In 2003, we reported our experience with the first 33 drugs that received labeling changes as a result of the exclusivity incentive. Twelve of those drugs had dosing and/or safety information that was considered important

from a public health perspective.14This article provides

an update on dosing and safety information in drug labeling, with emphasis on significant aspects of phar-macokinetics such as clearance and pharmacodynamic findings, as well as the resulting labeling changes.

METHODS

General Procedures

We reviewed the pediatric studies for 108 products

(in-cluding the first 33 drugs, reported previously14)

submit-ted in response to a FDA written request for pediatric studies, as part of a new drug application or supplement, and the subsequent labeling changes through October 28, 2005. Approximately 92 000 pediatric patients

(in-cluding ⬃42 000 from a large safety study) were

en-rolled in the⬃250 studies conducted for these 108

prod-ucts. The studies included safety, clinical effectiveness or clinical outcome, and clinical pharmacology assess-ments. Although the sponsors were asked by the FDA to submit information on race and ethnicity, we chose not to include that information in this communication be-cause of the variability in interpretation of the informa-tion collected by the sponsors.

To assess the overall impact of pediatric efforts, we reviewed the data to determine trends and outcomes across studies that resulted in improved dosing recom-mendations and new labeling or labeling changes.

Pedi-atric studies were defined as representing ⱖ1 clinical

investigation, including pharmacokinetic studies, con-ducted in pediatric patients in the age groups in which

the drug is anticipated to be used.9 The numbers of

pediatric patients in the clinical pharmacology studies in this article are comparable to those in similar publica-tions. Patients’ ages ranged from those of the neonatal period through 17 years, depending on the individual study. Approximately 9500 patients participated in stud-ies of the 23 drugs with dosing changes or new pharma-cokinetic information. The numbers of participants in the pharmacokinetic and/or

pharmacokinetic/pharma-codynamic studies ranged from 22 to 357 patients per drug studied. The patient numbers were dependent on study design and data analysis considerations. A smaller number of patients participated in studies in which tra-ditional pharmacokinetic approaches were used, relative to the number of patients who participated in population pharmacokinetic and/or pharmacodynamic studies. In addition, demographic features of the target patient pop-ulation were taken into account for their adequate and appropriate representation in these clinical pharmacol-ogy studies, such that pharmacokinetic and/or pharma-codynamic studies were often conducted with a subset of the patients in the clinical outcome studies, to ensure that the demographic features of the target population were represented adequately and appropriately.

For ease of reference and for linkage to the relevant clinical pharmacology information in the product label-ing, we discuss several representative examples, to illus-trate the scope of observations related to drug clearance in pediatric patients and, as a result, the pediatric doses. The examples are taken from the approved product la-beling. Each label represents the data from the clinical trial and is the end product of a negotiation between the FDA and the owner of the label, the pharmaceutical company. We acknowledge that representation of infor-mation such as pharmacokinetic parameters and/or units varies in drug labels, as in literature publications, and is considered reflective of current practices. Because we chose to present the information as available in the individual labels, the units and parameters were not further standardized. Also, the available strengths and the range of safe and effective doses for rapidly growing children are taken into consideration when the doses according to weight range or age group are negotiated between the sponsor and the FDA.

Clearance as a Focus

Traditionally, choosing the correct pediatric dose has been empirical. However, as the number of pediatric studies increases, the necessity of basing dose selection on the appropriate drug exposure/dose and the clinical outcome becomes more evident. Because of this prom-inent relationship, this article focuses on drug clearance as 1 of the 2 key parameters (clearance and bioavailabil-ity) describing drug exposure. Because most of these studies were not designed to characterize drug bioavail-ability, clearance was determined to be most suitable for exploration of general trends and differences in drug exposure in the pediatric population. In addition to the general robustness of this parameter (because it is based on multiple measurements), drug clearance is influ-enced by the maturation processes. As evident in the specific examples in this article, the emerging pattern supports the observation that drug clearances in pediat-ric patients, unlike adults, reflect the parameters of growth and maturation in children.

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estimate of drug clearance and the fraction of the dose absorbed. In this article, clearance calculations are based on drug concentrations measured in plasma or serum. Because of the inverse relationship between clearance and elimination half-life, changes in clearance (in the absence of changes in distribution volume) are indicative of changes in drug elimination half-life (eg, a reduction in clearance would indicate a prolonged elimination half-life), which may necessitate an alteration in dose and/or dosing frequency.

To capture the emerging trends in these examples, observations of drug clearance (or apparent oral clear-ance, as applicable) are grouped as being lower or higher in younger patients, compared with older patients or adults, with “influencing” factors such as body weight or BSA as predictors of changes in clearance estimates. For ease of reading, observations related to clearance and apparent oral clearance are listed in the same sections. Unique to the pediatric population, drug clearance is occasionally reported with normalization according to body weight. This approach is used to address the wide body weight range observed in the pediatric patient pop-ulation.

RESULTS

Overall Findings

The 108 products with new pediatric labeling represent

⬃250 studies submitted by 42 sponsors in response to

108 FDA written requests. These 108 labeling changes included, among others, new or revised pediatric infor-mation such as new dosing, dosing changes, or

pharma-cokinetic information (n ⫽ 23) listed in Table 1, new

and/or enhanced safety data (n ⫽34), information on

lack of efficacy (n⫽19), new formulations (n⫽12), and

dosing instructions extending the age limits in the

pedi-atric populations (n ⫽ 77) (a product could have ⱖ1

pediatric labeling change). Seven of these applications were for new molecular entities.

Significant Pharmacokinetic and/or Pharmacodynamic Findings and Dosing Changes in Labeling

Pharmacokinetic findings yielded new dosing

recom-mendations in children for one fifth (n ⫽ 23) of the

products studied (see Table 1 for list and indications). Several examples are discussed in detail because they illustrate important pharmacokinetic findings and

dos-ing recommendations. A representative set of drugs (n

16) that highlight considerations pertinent to pediatric dosing is listed in Table 2, with a summary of the key pharmacokinetic findings.

Lower Drug Clearance (or Apparent Oral Clearance) in Younger Patients

Luvox (Fluvoxamine Maleate)

The multiple-dose pharmacokinetics of fluvoxamine (Luvox, Sandoz, Princeton, NJ) were determined in male

TABLE 1 Drugs Whose Labeling Has New Pediatric Pharmacokinetic and/or Dosing Information11

Drug (Brand Name; Date Labeled) Therapeutic Class Pediatric Indication in Labeling

Midazolam (Versed syrup; October 15, 1998) Sedative hypnotic agent Sedation, anxiolysis, amnesia Atovaquone/proguanil (Malarone; July 14, 2000) Antimalarial agent Prophylaxis and treatment of malaria

Etodolac (Lodine XL; August 11, 2000) Nonsteroidal antiinflammatory drug Relief of symptoms of juvenile rheumatoid arthritis Fluvoxamine (Luvox; September 28, 2000) Selective serotonin reuptake inhibitor Obsessive-compulsive disorder

Gabapentin (Neurontin; October 12, 2000) Second-generation anticonvulsant Adjunctive therapy in treatment of partial seizures Cromolyn (Nasalcrom; March 27, 2001) Mast cell stabilizer Allergic rhinitis

Lamivudine (Epivir; August 16, 2001) Antiviral agent Hepatitis B virus

Sotalol (Betapace; October 3, 2001) Antiarrhythmic agent Safety and effectiveness of Betapace AF in children have not been established

Stavudine (Zerit; March 29, 2002) Antiviral agent HIV

Famotidine (Pepcid; June 6, 2002) Histamine H2receptor antagonist Gastroesophageal reflux

Lamivudine (Epivir; October 8, 2002) Antiviral agent HIV

Fluoxetine (Prozac; January 3, 2003) Selective serotonin reuptake inhibitor Major depressive disorder and obsessive-compulsive disorder Benazepril (Lotensin; March 2, 2004) Angiotensin-converting enzyme inhibitor Hypertension

Leflunomide (Arava; March 5, 2004) Immunomodulatory agent None; safety and efficacy in pediatric patients with polyarticular juvenile rheumatoid arthritis have not been fully evaluated

Remifentanil (Ultiva; March 9, 2004) Analgesic/anesthetic agent Maintenance of anesthesia Nelfinavir (Viracept; March 19, 2004) Antiviral agent HIV-1

Methylphenidate (Concerta; October 21, 2004) Psychostimulant ADHD

Ondansetron (Zofran; March 25, 2005) Antiemetic agent Prevention of chemotherapy-induced and postoperative induced nausea and vomiting

Linezolid (Zyvox; December 19, 2002, and May 12, 2005) Antibacterial agent Infection

Levetiracetam (Keppra; June 21, 2005) Antiepileptic drug Adjunctive therapy in treatment of partial onset seizures Amphetamine mixed salts (Adderall XR; July 21, 2005) Central nervous system stimulant ADHD

Oxcarbazepine (Trileptal; October 28, 2005) Antiepileptic drug Use as monotherapy in treatment of partial seizures in childrenⱖ4 y of age and as adjunctive therapy in children

ⱖ2 y of age with epilepsy

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and female children (age: 6 –11 years) and adolescents (age: 12–17 years). After administration of a 100-mg

fluvoxamine dose, the apparent oral clearance (mean⫾

SD) of fluvoxamine normalized according to body

weight was 0.449⫾0.261 L/hour per kg in the younger

patients and 0.884⫾0.737 L/hour per kg in the

adoles-cents. The steady-state plasma fluvoxamine concentra-tions were approximately twofold higher in the younger patients than the adolescents. As in adults, fluvoxamine pharmacokinetics in younger patients and adolescents were nonlinear, that is, the systemic drug exposure in-creased disproportionately with dose.

Although gender differences were not detected for adolescents, fluvoxamine mean body weight-normal-ized apparent oral clearance values for the 3 dose groups (25-mg, 50-mg, and 100-mg doses) in the younger fe-male pediatric patients were approximately one half the

values seen in male pediatric patients. Titration of dosing to the desired clinical effect, as recommended in the labeling, addresses these differences. Consequently, therapeutic effects in female patients may be achieved with a lower dose. The recommended starting dose for fluvoxamine tablets in pediatric populations (age: 8 –17 years) is 25 mg, administered as a single daily dose at bedtime. The dose should be increased in 25-mg incre-ments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. The maximum dose should not exceed 200 mg/day in patients up to 11 years

of age and 300 mg/day in adolescents.15

Pepcid (Famotidine)

In pharmacokinetic studies, famotidine clearance after intravenous administration of 0.5 mg/kg famotidine

doses in pediatric patients⬍1 year of age was lower than

TABLE 2 Examples Summarizing Changes in Drug Exposure and/or Clearance Seen in Pediatric Patients (Attributable to Age, Gender, Body Weight, BSA, and Other Factors)

Pharmacologic Findings Drug Name Findings According to Age, Gender, and/or Weight

Lower drug clearance (or apparent oral clearance) in younger patients

Fluvoxamine Lower apparent oral clearance in younger patients (age: 6–11 y); gender effect noted in clinical study (girls 8–11 y of age may benefit from lower doses)

Famotidine Lower clearance in younger patients based on intravenous dose; after oral suspension dose, 0–3-mo-old patients had apparent oral famotidine clearance 50% less than that for older children and adults

Lamivudine Substantially reduced oral clearance in patients⬍3 mo of age, particularly 1-wk-old neonates

Methylphenidate Apparent oral clearance reduced⬃40% in younger pediatric patients (age: 6–12 y), compared with adolescents

Amphetamine Apparent oral clearance of amphetamine lower in pediatric patients (age: 6–12 y), compared with adolescents and adults

Drug clearance (or apparent oral clearance) increases with increasing body weight (up to adult values)

Atovaquone/proguanil Lower atovaquone and proguanil apparent oral clearance values for patients weighing⬍40 kg; recommended dosing of Malarone fixed-dose tablets based on body weight in pediatric patients from 11 kg to 40 kg; table describing dosage for treatment provided in labeling Fluoxetine Differences in fluoxetine exposure between younger patients and

adolescents explained by differences in body weight Leflunomide Lower clearance of M1 metabolite in patients weighingⱕ40 kg Ondansetron Ondansetron elimination half-life of⬃7 h in 1- to 4-mo-old pediatric

patients, 3 h in 5-mo- to 12-y-old pediatric patients, and 5 h in adults Higher apparent oral clearance in younger patients Gabapentin Higher apparent oral clearance in children 1 mo to⬍5 y of age

Benazepril Higher apparent oral clearance in hypertensive pediatric patients (age: 6–12 y) and adolescents, compared with adults; terminal elimination half-life in children one third of that in adults

Oxcarbazepine Weight-adjusted clearance of active metabolite is higher in younger pediatric patients and decreases as age and body weight increase, approaching adult values; in pediatric patients 1 mo to 4 y of age, weighing⬃11 kg, weight-normalized clearance of metabolite was approximately 2 times adult value

Levetiracetam Body weight-normalized apparent oral clearance of levetiracetam in 6- to 12-y-old pediatric patients⬃40% higher than that in adults Apparent oral clearance and distribution volume

increase with increasing BSA

Sotalol Similar exposure after corrections for dose and BSA except for smallest patients (BSA:⬍0.33 m2), who had greater exposure and response;

additional monitoring and dose adjustment needed for those patients Othera Remifentanil Clearance and volume of distribution higher and larger, respectively, in

younger patients, compared with adolescents and adults; high variability in pharmacokinetics in neonatal patients, and individual dose titration recommended

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that in older pediatric patients (age: 1–15 years) and adults. After intravenous administration of a 0.5 mg/kg

dose, famotidine clearance (mean ⫾ SD) was 0.13 ⫾

0.06 L/hour per kg in infants 0 to 1 month of age and

0.21⫾0.06 L/hour per kg in those 0 to 3 months of age,

⬃25% and⬃50%, respectively, of the values seen in

1-to 15-year-old pediatric patients and adults. Famotidine

clearance was 0.54 ⫾ 0.34 L/hour per kg in pediatric

patients 1 to 11 years of age and 0.48⫾0.14 L/hour per

kg in 11- to 15-year-old patients. In adults, famotidine

clearance after a 20-mg intravenous dose was 0.39 ⫾

0.14 L/hour per kg.

Similar trends were observed in famotidine distribu-tion volume. In pediatric patients 0 to 1 month, 0 to 3

months, ⬎3 to 12 months, and 1 to 11 years of age,

famotidine distribution volume (mean⫾SD) was 1.4⫾

0.4 L/kg, 1.8⫾0.3 L/kg, 2.3⫾0.7 L/kg, and 2.07⫾1.49

L/kg, respectively. Famotidine distribution volumes were comparable in 11- to 15-year-old patients and

adults, with mean ⫾SD values of 1.5 ⫾0.4 L/kg and

1.3⫾0.2 L/kg, respectively.

Bioavailability of famotidine after administration of famotidine oral suspension (Pepcid, Merck and Co, Inc,

Whitehouse, NJ) was similar in pediatric patients ⬍1

year of age, compared with pediatric patients 1 to 15 years of age and adults. Therefore, on the basis of lower

famotidine clearance in pediatric patients⬍1 year of age,

lower famotidine doses are recommended. The recom-mended oral starting dose is 0.5 mg/kg once daily for

infants⬍3 months of age and 0.5 mg/kg twice daily for

children 3 months to⬍1 year of age.

For pediatric patients 1 to 16 years of age, famotidine dose varies depending on the indication, as described in the drug labeling (peptic ulcer: 0.5 mg/kg per day, orally, at bedtime or divided at twice per day, up to 40 mg/day; gastroesophageal reflux disease with or without esoph-agitis including erosions and ulcerations: 1.0 mg/kg per day, orally, divided at twice per day, up to 40 mg twice per day). As described in the drug label, treatment du-ration and dose should be individualized on the basis of clinical response and/or pH determination (gastric or esophageal) and endoscopic findings.

Epivir (Lamivudine)

Pharmacokinetic information from 36 neonates given lamivudine at up to 1 week of age demonstrated that the clearance of Epivir (lamivudine) (GlaxoSmithKline, Re-search Triangle Park, NC) was substantially reduced in

1-week-old neonates, compared with patients ⬎3

months of age. Although there was insufficient informa-tion to characterize the time course of changes in lami-vudine clearance between 1-week-old neonates and in-fants for the period up to 3 months of age, lamivudine clearance was higher in patients 4 months to 14 years of age than in younger infants, and the clearance in older children (adolescents) became comparable to adult val-ues. Unlike the observation in neonates, lamivudine clearance (normalized according to body weight) was approximately twofold higher in 1-year-old patients than in older pediatric patients. As illustrated in the drug

labeling, systemic clearance of lamivudine was ⬃0.75

L/hour per kg for 1-year-old patients and ⬃0.4 L/hour

per kg for 14-year-old patients in a pharmacokinetic study.

In pediatric patients (n⫽11) 4 months to 14 years of

age, 4 mg/kg twice-daily doses resulted in lamivudine exposures comparable to those in adults after a daily dose of 4 mg/kg per day. In combination with other antiretroviral agents, the recommended oral dose of lamivudine for HIV-infected pediatric patients 3 months up to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice per day), administered in combination with other antiretroviral agents. No dosing

recommendation is available in the label for infants⬍3

months of age.

Concerta (Methylphenidate HCl)

In a multiple-dose study, the apparent oral clearance of

methylphenidate (mean⫾SD) after administration of a

36-mg oral dose of methylphenidate extended-release tablets (Concerta, ALZA Corporation, Mountain View,

CA) was 372⫾137 L/hour in healthy adolescents with

attention-deficit/hyperactivity disorder (ADHD). This mean apparent oral clearance of methylphenidate in the

younger group (age: 6 –12 years) was ⬃40% lower in

comparison with adolescents and 50% lower in compar-ison with adults. Starting with methylphenidate HCl immediate-release tablets (Ritalin), the therapeutic dose

in pediatric patientsⱖ6 years of age is 5 mg twice daily,

whereas the average adult dose is considerably higher, 20 to 30 mg daily, administered in 2 or 3 divided doses. For adolescents naive to methylphenidate, higher max-imum methylphenidate doses are recommended, com-pared with children 6 to 12 years of age. Dose recom-mendations are based on current dosing regimens and clinical judgment. A dose-conversion table is provided in the Concerta labeling for switching to a single daily dose

of methylphenidate.16

Adderall XR (d-Amphetamine and l-Amphetamine Neutral Sulfate Salts, 3:1)

Systemic exposure to amphetamines is higher in younger pediatric patients (age: 6 –12 years) than ado-lescents or adults for a given dose of Adderall XR (Shire US Inc, Wayne, PA). Comparison of the

pharmacokinet-ics ofd- andl-amphetamine after oral administration of

Adderall XR to pediatric patients and adolescent and healthy adult volunteers indicated that body weight is the primary determinant of apparent differences in the

pharmacokinetics of d- andl-amphetamine. The d

-am-phetamine apparent oral clearance (mean⫾SD) after a

20-mg oral dose was 377⫾87.7 mL/min in adolescents

weighingⱕ75 kg (ⱕ165 lb) and 436⫾77.3 mL/min in

adolescents weighing⬎75 kg (⬎165 lb). Thel

-amphet-amine apparent oral clearance was 331⫾94.4 mL/min

in adolescents weighing ⱕ75 kg (ⱕ165 lb) and 389 ⫾

83.8 mL/min in adolescents weighing⬎75 kg (⬎165 lb).

The mean elimination half-life ford-amphetamine was 9

hours in pediatric patients (age: 6 –12 years), 11 hours in

adolescents weighingⱕ75 kg (ⱕ165 lb), and 10 hours in

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-amphet-amine was 11 hours in pediatric patients (age: 6 –12

years), 13 to 14 hours in adolescents weighing ⱕ75 kg

(ⱕ165 lb), and 13 hours in adults.

For pediatric patients (age: 6 –12 years) with ADHD, the starting dose is 10 mg of Adderall XR once daily in the morning for first-time patients or those switching from another medication. The daily dosage may be ad-justed in increments of 5 mg or 10 mg at weekly inter-vals. The maximum recommended dose for pediatric

patients (age: 6 –12 years) is 30 mg/day; doses of ⬎30

mg/day Adderall XR have not been studied in pediatric patients. In adolescents with ADHD, the recommended Adderall XR dose starts at 10 mg/day. The dose may be increased to 20 mg/day (a dose similar to adults) after 1 week if ADHD symptoms are not adequately controlled.

Increasing Drug Clearance (or Apparent Oral Clearance) With Increasing Body Weight (Up to Adult Values)

General Considerations

Drugs in this group are similar to those in the first group (lower drug clearance in the youngest or younger pa-tients) with a primary distinction that adjustments to accommodate differences in body weight are adequate to explain differences in drug clearances and exposures across all age groups. Optimal dosing recommendations for this group are influenced primarily by patient body weight.

Malarone (Atovaquone/Proguanil HCl)

The elimination half- life of atovaquone after admin-istration of atovaquone/proguanil is shorter in pedi-atric patients (1–2 days), compared with adults (2–3 days). The elimination half-life of proguanil is 12 to 21 hours in pediatric and adult patients. Although longer elimination half-lives in older patients or adults, com-pared with pediatric patients, may seem paradoxical with increasing clearance in older patients, compared with younger patients, this observation was found to be mostly attributable to differences in body weight. The clearance of each component increased with

in-creasing body weight for patients who weighed ⬍40

kg. Body weight was found to be the primary factor describing the differences in the apparent oral clear-ances of atovaquone and proguanil. Atovaquone

apparent oral clearance (mean ⫾ SD) was 1.34 ⫾

0.63 L/hour for patients weighing 11 to 20 kg, 1.87 ⫾

0.81 L/hour for patients weighing 21 to 30 kg, 2.76⫾2.07

L/hour for patients weighing 31 to 40 kg, and 6.61⫾3.92

L/hour for patients weighing⬎40 kg. For proguanil,

ap-parent oral clearance was 29.5 ⫾ 6.5 L/hour for

pa-tients weighing 11 to 20 kg, 40.0 ⫾ 7.5 L/hour for

patients weighing 21 to 30 kg, 49.5⫾8.30 L/hour for

patients weighing 31 to 40 kg, and 67.9⫾19.9 L/hour

for patients weighing⬎40 kg. As a result, atovaquone/

proguanil HCl daily doses, as fixed-dose Malarone (GlaxoSmithKline) tablets, are recommended accord-ing to a patient’s body weight (ie, higher doses with increasing body weight). For example, for pediatric patients with body weights within the 11- to 20-kg

range and for patients who weigh⬎40 kg, fixed-dose

Malarone (atovaquone/proguanil) tablets of 62.5 mg/25 mg and 250 mg/100 mg, respectively, are rec-ommended for prevention of malaria. Body weight-based dosing information for prevention and treat-ment of malaria in pediatric patients weighing 11 to 20 kg, 21 to 30 kg, and 31 to 40 kg is stated in the drug labeling. Adult doses are recommended for pediatric

patients who weigh ⬎40 kg.

Prozac (Fluoxetine HCl)

After daily 20-mg fluoxetine oral dosing, the average steady-state concentrations of Prozac (Fluoxetine HCl, Eli Lilly and Co, Indianapolis, IN) and its active

metab-olite norfluoxetine in pediatric patients (age: 6 to ⬍13

years) were 2- and 1.5-fold higher, respectively, than those in adolescents (age: 13–18 years) with major de-pressive disorder or obsessive-compulsive disorder. The mean steady-state fluoxetine concentrations in the

younger group (age: 6 to⬍13 years) and in adolescents

were 171 ng/mL and 86 ng/mL, respectively. Similarly, the mean norfluoxetine steady-state concentrations in the younger group and in adolescents were 195 ng/mL and 113 ng/mL, respectively. Because a fixed daily dose was administered to the younger group and the adoles-cents, exposure values corrected for body weight sug-gested that the observed differences in exposure among the 2 groups could be explained almost entirely by dif-ferences in body weight. As in adults, steady-state con-centrations were achieved within 3 to 4 weeks of daily dosing. In adults, after administration of 40 mg/day for 30 days, the plasma concentrations of fluoxetine and norfluoxetine ranged from 91 to 302 ng/mL for fluox-etine and from 72 to 258 ng/mL for norfluoxfluox-etine. Al-though concentration ranges were comparable between adult and pediatric patients, these concentrations were achieved at twofold higher fluoxetine doses in adults, compared with pediatric patients. A lower starting dose (10 mg daily, compared with 20 mg in adults) is recom-mended in the labeling for children, particularly for those with lower weight, compared with adults.

Arava (Leflunomide)

The safety and efficacy of Arava Leflunomide (Sanofi-Aventis US LLC, Bridgewater, NJ) in pediatric patients with polyarticular juvenile rheumatoid arthritis have not been fully evaluated. Leflunomide is metabolized to 1 primary active metabolite (metabolite 1) and several minor metabolites. The parent compound is rarely de-tectable in plasma. The mean clearance of metabolite 1

from orally administered leflunomide is⬃30% lower in

pediatric patients (age: 3–17 years) with polyarticular

course juvenile rheumatoid arthritis weighingⱕ40 kg,

compared with those weighing ⬎40 kg. In a 16-week

multicenter study in which the loading dose and main-tenance dose of Arava were based on 3 weight categories

(⬍20 kg, 20 to ⱕ40 kg, and ⬎40 kg), the clinical

re-sponse to Arava in pediatric patients weighing ⬍40 kg

was less robust than that in pediatric patients weighing

ⱖ40 kg. The reason for this outcome is unknown and

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pediatric patients and/or other clinical differences in re-sponses in this group of patients.

Zofran (Ondansetron HCl)

Zofran (GlaxoSmithKline) is approved for prevention of postoperative nausea and vomiting in adults and pedi-atric patients 1 month to 12 years of age (0.1 mg/kg dose) and for prevention of chemotherapy-induced nau-sea and vomiting in adults and pediatric patients 6 months to 18 years of age (0.15 mg/kg per dose every 4 hours up to 4 doses). In the studies conducted in re-sponse to the FDA written request, ondansetron was studied in younger pediatric patients (age: 1–24 months) for postoperative induced nausea and vomiting and in 6-to 48-month-old patients for chemotherapy-induced nausea and vomiting. When the drug was administered intravenously on a weight basis to pediatric surgical patients 1 to 24 months of age, the clearance of ondan-setron was lower and the half-life was longer in the 1- to 4-month-old patients, compared with the older pediatric patients (5 and 24 months of age). The mean half-life of ondansetron was 6.7 hours in patients 1 to 4 months of age and 2.9 hours in the older age groups (5–24 months and 3–12 years). In healthy adult volunteers given a single 24-mg tablet dose, the ondansetron half-life was

⬃5 hours. According to a population pharmacokinetic

analysis, ondansetron clearance and volume of distribu-tion were dependent on body weight and age. Because body weight and age are highly correlated in pediatric patients, ondansetron dosing was based on body weight. For prevention of postoperative induced nausea and vomiting, ondansetron dosing is a single 0.1 mg/kg dose

for patients weighingⱕ40 kg or a maximum single dose

of 4 mg for patients weighing⬎40 kg. For prevention of

chemotherapy-induced nausea and vomiting, based on similarity of exposures, the intravenous ondansetron dose is 0.15 mg/kg every 4 hours for 3 doses in pediatric patients with cancer 6 to 48 months of age, as well as older pediatric patients with cancer (age: 4 –18 years).

For prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy,

the Zofran oral dosage for pediatric patientsⱖ12 years

of age is the same as that for adults. The recommended adult oral dose is one 8-mg Zofran tablet, one 8-mg Zofran orally disintegrating tablet (ODT), or 10 mL (2 teaspoonfuls, equivalent to 8 mg of ondansetron) of Zofran oral solution given twice per day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. The second dose should be followed by one 8-mg Zofran tablet, one 8-mg Zofran ODT, or 10 mL of Zofran oral solution administered twice per day (every 12 hours) for 1 to 2 days after completion of chemotherapy.

For pediatric patients 4 through 11 years of age, the dosage is one 4-mg Zofran tablet, one 4-mg Zofran ODT, or 5 mL (1 teaspoonful, equivalent to 4 mg of ondanse-tron) of Zofran oral solution given 3 times per day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. Then one 4-mg

Zofran tablet, one 4-mg Zofran ODT, or 5 mL of Zofran oral solution should be administered 3 times per day (every 8 hours) for 1 to 2 days after completion of chemotherapy.

Higher Apparent Oral Drug Clearance in Younger Patients (ie, Pediatric and Adult Clearance Values Become Comparable After a Certain Age Range)

Neurontin (Gabapentin)

The experience with the anticonvulsant Neurontin (Parke Davis Pharmaceuticals, Vega Baja, PR) oral solu-tion provides another important example of age-related differences in drug clearance. The pharmacokinetics of gabapentin were characterized in 48 pediatric patients who were 1 month to 12 years of age, after

administra-tion of a ⬃10 mg/kg dose. The apparent oral clearance

normalized according to body weight was higher in

younger children (age: 1 month to ⬍5 years) and

re-sulted in⬃30% lower gabapentin exposure (area under

the drug concentration-time curve) than that observed

in older children (ⱖ5 years). The body

weight-normal-ized apparent oral clearance values in pediatric patients

ⱖ5 years of age were similar to values observed in adults

(⬃225 mL/min). Therefore, higher doses are required in

the younger pediatric age group. Patients 3 to 4 year of age should be given 40 mg/kg per day gabapentin in 3 divided doses, whereas patients 5 to 12 years of age should receive 25 to 35 mg/kg per day administered in 3 divided doses. For the entire age span of 3 to 12 years, gabapentin should be administered starting at a dose of 10 to 15 mg/kg per day in 3 divided doses, reaching the effective dose through upward titration over a period of

⬃3 days.

Lotensin (Benazepril HCl)

With repeated multiple daily oral doses of Lotensin (Benazepril HCl, Novartis Pharmaceuticals Corporation, Suffern, NY) ranging from 0.1 to 0.5 mg/kg, the clear-ance of benazeprilat, the active metabolite, was 0.35 L/hour per kg in 6- to 12 year-old, hypertensive, pedi-atric patients and 0.17 L/hour per kg in hypertensive

adolescent patients, ⬃50% and 27% higher,

respec-tively, than the values seen in healthy adults (0.13 L/hour per kg) receiving a single dose of 10 mg. The terminal elimination half- life of benazeprilat in pediatric

patients is ⬃5 hours, approximately one third of that

observed in adults. In pediatric patients, the recom-mended starting dose of benazepril is 0.2 mg/kg once per

day as monotherapy. Doses of⬎0.6 mg/kg (or⬎40 mg

daily) have not been studied in pediatric patients (age: 6 –16 years). Benazepril is not recommended for

chil-dren⬍6 years of age or pediatric patients with

glomer-ular filtration rates of ⬍30 mL/min, because there are

insufficient data available to support a dosing recom-mendation for those groups.

Trileptal (Oxcarbazepine)

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metabolite clearance is higher in younger pediatric pa-tients, compared with older pediatric patients and adults, and, with increasing age and body weight, approaches

adult values for patientsⱖ13 years of age. After a single

dose of 5 or 15 mg/kg Trileptal (Oxcarbazepine, Novartis Pharmaceuticals Corporation), the dose-adjusted area under the concentration-time curve values for the 10-monohydroxy metabolite were 30% to 40% lower in

children ⬍8 years of age, compared with children ⬎8

years of age. Children ⬎8 years of age had clearance

values similar to adult values of 0.043 L/hour per kg. Although the population pharmacokinetic model iden-tified BSA as a predictor of clearance, the clinical studies were conducted on the basis of weight-adjusted dose. Given the relationship between BSA and body weight, as well as for practical purposes and ease of calculation, ox-carbazepine dosing recommendations are based on body weight.

Patients first are exposed to oxcarbazepine as adjunc-tive therapy and then are converted to monotherapy. Specifically, as adjunctive therapy (for patients 2–16 years of age), oxcarbazepine treatment should be initi-ated at a daily dose of 8 to 10 mg/kg generally, not to exceed 600 mg/day, given in a twice-daily regimen. Detailed instructions for adjunctive therapy and conver-sion to monotherapy from adjunctive therapy and the doses according to body weight (20 –70 kg) are described in the Trileptal labeling.

Keppra (Levetiracetam)

The pharmacokinetics of single-dose Keppra (Levetirac-etam, UCB Inc, Smyrna, GA) (20 mg/kg) were evaluated in 24 pediatric patients (age: 6 –12 years). The body weight-adjusted apparent oral clearance of levetiracetam

was ⬃40% higher than that in adults (mean clearance

in adults: 0.96 mL/minute per kg). The half-life of

leve-tiracetam was⬃5 hours in pediatric patients (age: 4 –12

years) and 7 hours in adults.

In population pharmacokinetic analyses, body weight was shown to have a significant effect on both apparent oral clearance and apparent oral distribution volume of levetiracetam. Body weight-based dosing

recommenda-tions are made for pediatric patients weighing⬍40 kg. In

4- to 16-year-old pediatric patients, levetiracetam treat-ment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg, 2 times per day). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg, 2 times per day). Patients with body weights

ofⱕ20 kg should be treated with oral solution, whereas

patients with body weights of ⬎20 kg can be treated

with either tablets or oral solution. Keppra labeling pro-vides detailed dosing information for pediatric patients weighing between 20.1 and 40 kg and for those who

weighed⬎40 kg (ie, up to the adult dose of 60 mg/kg per

day 2 times per day, or 3000 mg/day).17

In adults, treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg, 2 times per day). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg.

BSA and Response Relationship

The study of Betapace (sotalol HCl) in pediatric patients demonstrated that BSA was the most important covari-ate and was more relevant than age in describing the exposure-response relationship for sotalol. Smaller

chil-dren (BSA: ⬍0.33 m2) showed a tendency for a larger

change in QTc and an increased frequency of

prolonga-tion of the QTc interval, as well as greater ␤

-receptor-blocking effects. Therefore, the best approach is individ-ualized dosing based on BSA and close monitoring of the patients, particularly pediatric patients whose BSA

val-ues areⱕ0.33 m2.

Other Significant Pharmacokinetic and/or Pharmacodynamic Findings

Ultiva (Remifentanil HCl)

In pediatric patients (age: 5 days to 17 years), the clear-ance of Ultiva (Remifentanil HCl, Abbott Park, IL) was higher in the younger patients and approached adult

values as the patients grew older. In patients⬍2 months

of age, the remifentanil clearance (mean ⫾ SD) was

⬃90.5 ⫾ 36.8 mL/minute per kg; in adolescents (age:

13–16 years), the value was 57.2⫾21.1 mL/minute per

kg. The volume of distribution of remifentanil was

greater in patients ⬍2 months of age and approached

adult values in adolescents, with steady-state

distribu-tion volume values (mean ⫾SD) of 452 ⫾144 mL/kg

and 223⫾30.6 mL/kg, respectively. The differences in

distribution volume in patients ⬍2 months of age are

most likely attributable to the higher fat content in that population and the greater lipid solubility of the drug, The adult remifentanil clearance and distribution vol-ume estimates are 40 mL/minute per kg and 350 mL/kg, respectively. The half-life of remifentanil was similar in neonates and in adolescents. The clearance of remifen-tanil was highly variable in neonates and approximately twice that observed in healthy young adults. Because of high variability in neonatal pharmacokinetics, starting

with a fixed remifentanil infusion rate of 0.4␮g/kg per

minute may be appropriate for some neonates but a higher infusion rate may be necessary for others to maintain adequate surgical anesthesia, and additional bolus doses may be required. Careful titration of indi-vidual doses for each patient is recommended.

Viracept (Nelfinavir Mesylate)

Although pharmacokinetic information for Viracept (Nelfinavir Mesylate, Agouron Pharmaceuticals, Inc, La Jolla, CA) is available for pediatric patients from birth through 13 years, the highly variable drug exposure and responses represent a significant problem in the dosing

of pediatric patients, especially those⬍2 years of age. In

adult clinical pharmacology studies, food high in fat and/or energy content increases nelfinavir exposure and reduces the variability in its exposure; as a result, taking nelfinavir with food is recommended. In pediatric pa-tients, however, food seems to increase the variability in nelfinavir exposure. This difference may be attributable to eating habits and inconsistent food intake in pediatric

(9)

of age (because of different food exposures such as for-mula and pureed foods, frequency of eating, and gastric motility). A reliable effective dose could not be

estab-lished for those ⬍2 years of age because of the large

variability in nelfinavir exposure and response.

Detrol (Tolterodine)

The approval of the muscarinic antagonist for adults was based on the improvement in clinical and urodynamic parameters. When Detrol (Tolterodine, Pfizer Pharma-ceuticals, Inc, New York, NY) was studied in pediatric patients to determine pediatric doses for treatment of urinary urge incontinence, urgency, and frequency in a pediatric population, the pharmacokinetic/pharmacody-namic and efficacy/safety trials did not show efficacy at the selected dose estimated from the adult studies. Al-though study resulted in invaluable pediatric safety in-formation for labeling, the trial also highlighted the im-portance of dose selection and the need to consider possible differences in drug pharmacokinetics and phar-macodynamics in pediatric and adult patients. Therefore, it is important to note that, in some instances, when the dose selection is based on assumptions of similar expo-sure-response relationships in pediatric patients and adults (ie, similar drug concentrations), the selected dose may not be efficacious.

DISCUSSION

Recent legislation and the efforts of the FDA, as well as those of many investigators, willing parents and pediat-ric patients, and the pharmaceutical industry, have re-sulted in a significant increase in the number of pediatric studies conducted to evaluate the safe and effective use of drugs in pediatric patients. These efforts have resulted in significant changes in drug labeling for pediatric pa-tients and have shown that unique pediatric dosing, reflecting growth and maturation stages, is often neces-sary. Before these initiatives, most therapies given to children were “off-label” (ie, studies of safety and effi-cacy had not been conducted and the drug labels did not include dosing, efficacy, or safety information for pedi-atric use). The pedipedi-atric trial designs are being modified as we continue to gain knowledge from the submitted studies regarding pharmacologic intervention in pediat-ric diseases and as our assumptions (such as similarity in responses) are being confirmed or challenged.

Depending on the drug therapeutic index, differences in drug exposure may result in modified dosing recom-mendations in drug labeling for various age groups. All pharmacokinetic studies may not result in dose or dosing adjustments; they may confirm the selected dose or serve to identify areas that deserve additional attention. The examples presented above highlight differences in drug pharmacokinetics in pediatric patients and the fac-tors that are important for pediatric dosing. Changes in drug clearance in pediatric patients cannot always be explained by changes in body weight and should not simply lead to body weight-adjusted dosing. Increasing body weight, particularly for younger patients, correlates strongly with growth and maturation, as reflected in traditional growth charts.

In the examples provided, drug clearance was lower in younger patients than in older pediatric patients and/or adults for some drugs, necessitating dose reduc-tions for fluvoxamine, famotidine, lamivudine,

methyl-phenidate, andd- andl-amphetamine. In contrast, drug

clearance was higher in younger patients for gabapentin, benazepril, oxcarbazepine, and levetiracetam, leading to recommendations for higher doses in those patients, compared with older patients. Body weight-related dif-ferences can account for difdif-ferences in drug exposure in pediatric patients for some therapies, with dosing rec-ommendations incorporating adjustments for body weight. This situation has been observed particularly when fixed doses (due to dosage forms) are administered to children and adolescents. Examples include atova-quone/proguanil, fluoxetine, and leflunomide. For other drugs, adjustment based on BSA leads to desired expo-sure, and BSA is the primary factor accounting for the differences in exposure and the subsequent response (eg, sotalol). Some of the significant findings (in indica-tions, drug safety, and efficacy) that have been

incorpo-rated into the drug labeling are available.11Overall, these

differences in drug pharmacokinetics in pediatric pa-tients may be explained by differences in maturation of drug-metabolizing enzymes and/or organs of elimina-tion and changes in body composielimina-tion, leading to changes in the distribution volumes of drugs. Because of the complexity of the factors involved, the magnitude and the direction of the differences are not always readily predictable. Furthermore, interpatient variability in pharmacokinetic and pharmacodynamic studies seems to be greater in pediatric patients, compared with adults. The volume of distribution also changes with age in many instances (the remifentanil labeling provides an example of this). This greater variability may be partly attributable to inherent differences, including variability in doses, which may be associated with difficulties re-lated to age-appropriate formulations.

The findings from these pediatric trials support the need to continue studying drugs in this population. The dosing, efficacy, and safety information incorporated into pediatric labeling provides practicing pediatricians and generalists with the data that support a pragmatic safe approach to prescribing drugs for this vulnerable patient population. The translation of this information into improved prescribing therapies for children is criti-cal to ensure the safety and efficacy of therapy.

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meta-anal-ysis of studies), whereas innovative methods could in-corporate unique growth and maturation characteristics of the pediatric patients and include pharmacogenomic and biomarker information. All of these efforts com-bined could facilitate efficient pediatric drug develop-ment and bring advancedevelop-ment in this field. A long-term commitment, starting in early drug development, to gaining and optimizing knowledge for pediatric patients is of utmost importance for developing therapies for this unique and vulnerable patient population.

ACKNOWLEDGMENT

We thank Jim Angel for his technical assistance through-out the various phases of development of this communi-cation.

REFERENCES

1. Shirkey H. Therapeutic orphans.J Pediatr.1968;72(1):119 –128 2. American Academy of Pediatrics, Committee on Drugs. Guide-lines for the ethical conduct of studies to evaluate drugs in pediatric populations.Pediatrics.1977;60(1):91–101

3. Food and Drug Administration. Labeling and prescription drug advertising: content and format for labeling for human pre-scription drugs.Fed Regist.1979;44:37434 –37467

4. Food and Drug Administration. Specific requirements on con-tent and format of labeling of human prescription drugs: revi-sion of “pediatric use” subsection in the labeling. Fed Regist.

1994;59:64240 – 64250

5. Food and Drug Administration. Regulation requiring manufac-turers to assess the safety and effectiveness of new drugs and biological products in pediatric patients: final rule.Fed Regist.

1998;63;66631– 66672

6. Rodriguez W, Roberts R, Murphy D. Adverse drug events in children: the US Food and Drug Administration perspective.

Curr Ther Res.2001;62(10):711–723

7. Food and Drug Administration. Modernization Act of 1997. Pub L 105 No. 107-109, 111 Stat 2296 (1997)

8. Food and Drug Administration.US Food and Drug Administration Guidance for Industry: Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act. Rockville, MD: Food and Drug Administration; 1999. Available at: www.fda.gov/cder/guidance/2891fnl.htm. Accessed Novem-ber 20, 2006

9. Best Pharmaceuticals for Children Act. Pub L no. 107-109, 115 Stat 1408 (2002). Available at: http://frwebgate.access.gpo.gov/ cgi-bin/useftp.cgi?IPaddress162.140.64.21&filenamepubl109. pdf&directory⫽/diskc/wais/data/107㛭cong㛭public㛭laws. Accessed November 20, 2006

10. Pediatric Research Equity Act of 2003, S 650, 108th Congress. Available at: http://frwebgate.access.gpo.gov/cgi-bin/ getdoc.cgi?dbname108congbills&docidf:s650enr.txt. Ac-cessed November 20, 2006

11. Food and Drug Administration. Pediatric exclusivity labeling changes (as of July 14, 2006). Available at: www.fda.gov/cder/ pediatric/labelchange.htm. Accessed November 20, 2006 12. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Drug

therapy: developmental pharmacology: drug disposition, ac-tion, and therapy in infants and children.N Engl J Med.2003; 349(12):1157–1167

13. Munzenberger PJ, McKercher P. Pediatric dosing: the pharma-cist dilemma.Contemp Pharm Pract.1980;3(1):11–14

14. Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric drug labeling: improving the safety and efficacy of pediatric thera-pies.JAMA.2003;290(7):905–911

15. Fluvoxamine prescription information. In:Physicians’ Desk Ref-erence. Oradell, NJ: Medical Economics; 2002:3256 –3264 16. Concerta prescribing information. In:Physicians’ Desk Reference.

Montvale, NJ: Thompson PDR; 2006:1828 –1832

17. Keppra prescribing information. In:Physicians’ Desk Reference. Montvale, NJ: Thompson PDR; 2006:3307–3312

BRITAIN: COOKING LESSONS FOR ALL CHILDREN

“Cooking lessons will be made compulsory for youths at British schools starting in September as a way to counter obesity, the government an-nounced. Boys and girls ages 11 and 14 will have to attend the classes and will learn to cook eight classic healthful British favorites, including roast chicken and shepherd’s pie. Education Secretary Ed Balls, who made the announce-ment, has asked the public to suggest other dishes students could be taught to cook. According to a government-commissioned study last year, in 25 years half of all Britons will be obese if current eating trends are not halted.”

(11)

DOI: 10.1542/peds.2007-1529

2008;121;530

Pediatrics

Suarez, Veneeta Tandon and Ramana S. Uppoor

Dianne Murphy, Shirley Murphy, Rosemary Roberts, Hari Cheryl Sachs, Sandra

Gerlie Gieser, Jennifer Di Giacinto, Shiew-Mei Huang, Peter Lee, Lisa Mathis,

William Rodriguez, Arzu Selen, Debbie Avant, Chandra Chaurasia, Terrie Crescenzi,

Learned

Improving Pediatric Dosing Through Pediatric Initiatives: What We Have

Services

Updated Information &

http://pediatrics.aappublications.org/content/121/3/530 including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/121/3/530#BIBL This article cites 9 articles, 1 of which you can access for free at:

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http://www.aappublications.org/cgi/collection/safety_sub Safety

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following collection(s):

This article, along with others on similar topics, appears in the

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DOI: 10.1542/peds.2007-1529

2008;121;530

Pediatrics

Suarez, Veneeta Tandon and Ramana S. Uppoor

Dianne Murphy, Shirley Murphy, Rosemary Roberts, Hari Cheryl Sachs, Sandra

Gerlie Gieser, Jennifer Di Giacinto, Shiew-Mei Huang, Peter Lee, Lisa Mathis,

William Rodriguez, Arzu Selen, Debbie Avant, Chandra Chaurasia, Terrie Crescenzi,

Learned

Improving Pediatric Dosing Through Pediatric Initiatives: What We Have

http://pediatrics.aappublications.org/content/121/3/530

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1Drugs Whose Labeling Has New Pediatric Pharmacokinetic and/or Dosing Information11
TABLE 2Examples Summarizing Changes in Drug Exposure and/or Clearance Seen in Pediatric Patients (Attributable to Age, Gender, BodyWeight, BSA, and Other Factors)

References

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