There are several equations designed for pediatric use; the National Kidney Disease

Education Program (NKDEP) and the National Kidney Foundation recommend the

bedside isotope dilution mass spectroscopy (IDMS) Schwartz equation

53,54

:

where CLCr

is creatinine clearance (mL/minute/1.73 m2

), Ht is height (cm), and SCr

is

serum creatinine (mg/dL).

Using this method, H.G. has a calculated creatinine clearance of 116

mL/minute/1.73 m2

, indicating normal renal function. As with patients of any age, this

equation should be used only as an estimate of renal function. It should be interpreted

with caution in patients with little muscle mass or those who are dehydrated.

Pharmacokinetic Changes During Puberty

CASE 102-7

QUESTION 1: A.M. is a 16-year-old, 67-kg boy with osteosarcoma. He has received morphine for pain

throughout his numerous hospitalizations for surgery and chemotherapy during the past 2 years, requiring an

infusion rate as high as 0.5 mg/kg/hour. During this period, he has also progressed through puberty and is now a

mature adult male. During his last admission, it was noted that his pain was well controlled on an adult morphine

infusion rate of 10 mg/hour, equivalent to 0.15 mg/kg/hour. It was noted by the medical team that A.M.’s

morphine infusion requirements were actually lower than in earlier admissions, although his pain scores have

been unchanged. What might explain the change in A.M.’s response to morphine?

Although developmental pharmacology has traditionally focused on the differences

in neonatal pharmacokinetics, there is growing interest in the influence of puberty on

drug disposition.

55–57 Adolescence is not simply a link between childhood and

adulthood, but is a distinct period of significant physiologic change. Hormonal

fluctuations and sexual maturation can alter the efficacy or toxicity of many drugs

administered during this period. Drug distribution can be altered as a result of an

increase in body fat. Rapid increases in serum protein concentrations that occur

during puberty alter drug binding characteristics.

56 Renal function, as measured by

GFR, may exceed average adult values, resulting in rapid clearance of renally

eliminated drugs such as aminoglycosides and vancomycin. Metabolic activity

changes as well.

57 A study conducted in adolescents receiving morphine during a

sickle cell crisis revealed a reduction in drug clearance with advancing sexual

maturation.

58 Postpubertal adolescents, such as A.M., had weight-normalized

clearance values 30% lower than younger patients during early puberty, suggesting a

possible reduction in UGT2B7 activity. The titration of A.M.’s morphine must

encompass not only the changes in drug clearance resulting from growth and

development but also the progression of his

p. 2134

p. 2135

disease and his need for pain control. Assessment of pain, using frequent selfreport or a standardized pain scale, as well as heart rate, blood pressure, and

respiratory rate, is essential for appropriate adjustment of A.M.’s morphine infusion.

A second example comes from a recent study of lopinavir pharmacokinetics in

children who exhibited identified age- and sex-related differences in drug

clearance.

59 When normalized for weight, there was no significant difference in

clearance between prepubertal boys and girls. After the age of 12, boys had a mean

rate of lopinavir clearance 39% greater than girls. The area under the concentration–

time curve in boys was only half that of the girls. The authors suggest that this

difference may reflect a reduction in CYP3A4 in girls that becomes apparent only

with sexual maturation. Similar sex-related results have been reported in lopinavir

studies conducted in adults. Caffeine metabolism via CYP1A2 has also been found to

differ by sex in adolescents.

60 The rate of N-demethylation slows in both sexes after

puberty, but appears to decrease earlier in puberty for girls than for boys. Other

investigators have identified pharmacokinetic changes during adolescence with

acetaminophen, alprazolam, carbamazepine, digoxin, isoniazid, lamotrigine,

lorazepam, and theophylline.

56

PEDIATRIC PHARMACODYNAMIC

DIFFERENCES

Although not as well studied as pharmacokinetics, developmental changes in

pharmacodynamics during growth may have equally significant effects on response to

drug therapy in children.

CASE 102-8

QUESTION 1: S.L. is a 0.725-kg infant boy with an estimated gestational age of 24 weeks. He was brought

to the neonatal intensive care unit immediately after birth with severe hypotension. A dopamine infusion was

started at a rate of 10 mcg/kg/minute and quickly titrated to 20 mcg/kg/minute without significant benefit. What

might explain S.L.’s lack of response, and how should his hypotension be managed?

Maturational changes in receptor conformation, density, and affinity, as well as

signal transduction, can result in clinically significant differences in response to

common therapies.

61 Although a dopamine infusion of 20 mcg/kg/minute will produce

an adequate increase in myocardial contractility and elevate systemic vascular

resistance in most children and adults, infants may not have a significant change in

cardiovascular response. Infants have long been suspected to be relatively resistant

to the effects of β-adrenergic agonists, including dopamine, dobutamine, and

epinephrine. Recent research suggests the lack of response is related to a relative

reduction in adrenergic receptor density or a downregulation of receptors within the

myocardium of premature and critically ill neonates.

62 A higher dopamine infusion

rate, up to 40 mcg/kg/minute, may be necessary to achieve an adequate blood

pressure for S.L. If the dopamine is increased, S.L.’s extremities must be closely

monitored for any signs of excessive peripheral vasoconstriction. Supplemental

therapy with hydrocortisone, at a dose of 0.7 mg (1 mg/kg) IV every 8 hours, may

also be used to manage his hypotension.

CASE 102-9

QUESTION 1: You will be counseling the parents of E.S., a 7-year-old girl with refractory seizures as a result

of Lennox-Gastaut syndrome, on the use of lamotrigine. While preparing for your discussion, you notice in the

manufacturer’s prescribing information a black box warning regarding the risk for serious skin rashes. The

incidence is listed as 0.8% in children 2 to 16 years of age, but only 0.3% in adults.

63 What might explain the

difference in the incidence of an adverse effect by age?

Differences in pharmacodynamics resulting from growth and development can

alter more than just therapeutic response. A drug’s adverse effect profile may be

distinctly different during childhood. A classic example of this phenomenon is the

higher incidence of serious dermatologic reactions, including toxic epidermal

necrolysis, in children taking lamotrigine compared with that of adults.

64–66 This was

first suspected during initial pediatric clinical trials and appeared to be associated

with rapid dose titration during the first several months of treatment, which had been

based on previous studies in adults.

65 The slower dose escalation, now recommended

for pediatric patients, is starting E.S.’s lamotrigine dose at 0.15 mg/kg/day and

increasing by 0.15- to 0.3-mg/kg/day increments every 2 weeks, and may reduce the

likelihood for these reactions.

CASE 102-9, QUESTION 2: What is the possible mechanism(s) for the increased risk for toxicity with

lamotrigine in children such as E.S.?

Research has led to several theories for the greater incidence of serious

dermatologic reactions in children. Some investigators have suggested that this is a

dose-related toxicity more evident in children who have a limited capacity to

metabolize lamotrigine through glucuronidation to its inactive metabolites.

65 This

theory, however, does not explain why other patient groups known to have higher

serum lamotrigine concentrations during treatment, such as the elderly, are not at

increased risk. Others have speculated that this represents an immune-mediated

hypersensitivity response, because many of the affected patients reported have had

previous reactions with other antiepileptic drugs.

66 Children with refractory seizures,

such as those with Lennox-Gastaut syndrome, who are often treated with multiple

agents beginning in the first years of life may be more likely to develop

hypersensitivity. Although the mechanism underlying the age-related difference in the

incidence of lamotrigine-associated rashes is not yet well understood, the importance

of patient counseling is clear. The caregivers of all children receiving lamotrigine

should be made aware of the risk and the need to seek medical care as soon as any

signs of rash or erythema are noted.

MEDICATION DOSING IN CHILDREN

CASE 102-10

QUESTION 1: A.K. is a 7-year-old, 20-kg boy recently diagnosed with ADHD. After developing insomnia

when treated with methylphenidate, he was switched to clonidine by his pediatrician. The recommended starting

dose for clonidine in children is 5 mcg/kg/day divided and given in two to four doses.

67 His prescription is for

clonidine 0.05 mg by mouth twice daily. Because A.K. does not yet swallow tablets easily, he will need a

solution made from the tablets. It will be prepared from a published extemporaneous formulation with a final

concentration of 0.1 mg/mL. What steps are necessary to ensure the accuracy of this prescription?

p. 2135

p. 2136

The differences in pharmacokinetics and pharmacodynamics observed in children

influence the choice of dose and dosing interval.

68 Because incorporating all of these

variables would result in dosing calculations too difficult for practical use, weight

has traditionally been chosen as the single best estimate of growth. Pediatric drug

references provide most doses in units per weight, such as mg/kg/day or

mcg/kg/dose. Among the exceptions to this are chemotherapeutic agents, which are

dosed by body surface area, incorporating height as an additional variable. Because

of the difficulty in accurately determining height (or length) in young children, it is

not commonly used for other drugs.

Age can be an important variable, especially for premature infants, in whom it can

be used to account for differences in volume of distribution and elimination half-life.

For example, neonatal gentamicin dosing is often based on a rubric of gestational or

postconceptional age, postnatal age, and weight.

17 A recent study of clonidine

clearance in the early postnatal period suggests that both age and weight should be

used to optimize clonidine doses in newborns being treated for neonatal abstinence

syndrome.

69

In the future, pediatric dosing recommendations for many drugs may be

based on more than just weight to incorporate new pharmacokinetic data.

70

Medication orders or prescriptions with doses outside of the dosing range listed in

a pediatric drug reference should always be questioned for appropriateness. Older

children and adolescents should transition to adult dosing whenever the calculated

weight-based dose exceeds the usual adult dose. When evaluating a pediatric

prescription or medication order, determining whether the dose is appropriate for the

patient’s weight is not the only step undertaken by the pharmacist. As with all

patients, allergies, underlying diseases, and concomitant therapy must be taken into

account as well.

A.K.’s clonidine dose of 0.05 mg twice daily is equivalent to 5 mcg/kg/day, the

appropriate starting dose for a child. Using a 0.1-mg/mL extemporaneous solution,

his dose will be 0.5 mL twice daily. The label on A.K.’s clonidine bottle should

include the concentration of the formulation, as well as the dose in both mg and mL.

Before the start of treatment, A.K.’s parents should be counseled about the drug, the

dose, and potential adverse effects. They should be given or have access to an oral

dosing syringe or spoon to accurately measure the dose.

PREVENTING MEDICATION ERRORS IN

CHILDREN

CASE 102-10, QUESTION 2: After 2 days of therapy, A.K. returns to his pediatrician’s office with his

parents. He is lethargic and feels dizzy when getting out of bed. His blood pressure is 90/54 mm Hg (normal for

age and weight is 99/59 mm Hg), suggesting a possible clonidine overdose. As you begin to investigate the

potential cause of A.K.’s symptoms, what factors may have led to an error in A.K.’s case?

Medication errors pose a significant risk for infants and children.

71–75 Whereas the

rate of medication errors reported in studies of adults is approximately 5%, rates in

many pediatric studies have ranged from 10% to 15%.

71–73 The need to calculate

weight-based doses can lead to mathematic errors. In A.K.’s case, the dose must be

multiplied by the patient’s weight, divided into individual doses, and converted from

micrograms to milligrams. Unit conversions and decimal point errors are particularly

dangerous in pediatrics, because a 10-fold overdose of a drug with a narrow dosing

range such as clonidine, digoxin, morphine, or fentanyl can be fatal.

76

In addition to

prescribing errors, dosage formulation manipulation, such as the preparation of an

extemporaneous liquid in this case, increases the risk for drug preparation errors.

Oral liquid medications also present a risk for administration errors. Healthcare

providers and caregivers in the home must be aware of the potential for errors and

the need for precise dose measurement. A.K.’s medical history must include

information on how the clonidine had been prepared by the pharmacy as well as how

his parents were preparing and administering his doses.

CASE 102-10, QUESTION 3: What steps could have been taken to prevent the medication error that

occurred with A.K.?

There are a number of methods to reduce the potential for medication errors,

including recommendations from the Joint Commission, the American Academy of

Pediatrics, and a recent Cochrane review (Table 102-3).

74,75,77–82 Use of standard

concentrations for IV products and oral liquids, smart-pump technology, bar coding,

and electronic prescribing with clinical decision support tools have been found to

significantly reduce errors in pediatric hospitals. In the outpatient setting, medication

errors can be reduced by the inclusion of patient-specific information on

prescriptions, including diagnosis and patient weight.

83 The product label, whether it

is a prescription or over-the-counter medication, should include all the information

needed to correctly prepare and administer the dose. Caregivers should have access

to the appropriate tools for measuring liquid medications, such as oral dosing spoons

or syringes, and the opportunity to practice preparing a dose under the supervision of

a healthcare provider to ensure that they are able to prepare the dose correctly.

84

Table 102-3

Methods for Reducing Pediatric Medication Errors

Improve Ordering and Preparation

Perform careful medication histories, including assessment of oral liquid concentrations

Provide access to current pediatric medication information

Include patient weight (in kg) on all medication orders and prescriptions

Include dosage calculations on orders and prescriptions

Limit the number of concentrations available for high-risk medications

Use accurate measuring devices, in both the hospital and home settings

Implement Appropriate Technology

Adopt weight-based electronic prescribing or dose-checking software

Employ barcode technology to reduce patient identification and medication administration errors

Use smart-pump technology (programmable IV pumps with weight-based dosing limits)

Use Staff Expertise

Provide pediatric-specific continuing education for allstaff on a routine basis

Develop pediatric-specific medication orders and protocols to guide care

Assign staff with pediatric expertise to all committees involved in medication management

Involve Families and Other Caregivers

Encourage all caregivers to ask questions about their child’s medications

Recommend that all caregivers know the names and doses of their children’s medications or carry information

about their medications

Remind caregivers to include nutritionalsupplements, herbal or complementary therapies, and over-the-counter

medications when giving a medication history

Ensure that caregivers can accurately prepare the medication dose

IV, intravenous.

p. 2136

p. 2137

One of the most effective methods to prevent medication errors has been to include

pharmacists in the medication ordering and review process.

83,85 The value of

pharmacists in reducing pediatric medication errors was demonstrated by Folli et

al.

85

In this landmark study, clinical pharmacists performed prospective evaluations

of medication orders at two children’s hospitals for a 6-month period. The overall

rate of medication errors detected by the pharmacists averaged 4.7 per 1,000

medication orders. Of these, 5.6% were considered potentially lethal. The majority

of the errors (64.3%) occurred in children younger than 2 years of age. The most

common type of error identified by the pharmacists was incorrect dosage. The

authors concluded that pharmacy intervention had a significant effect on medication

error prevention, a finding that resulted in the expansion of pediatric clinical

pharmacy services in many institutions. Pharmacists in the community provide the

same benefit when reviewing pediatric prescriptions and play a significant role in

caregiver medication education.

INCREASING AVAILABILITY OF PEDIATRIC

MEDICATION INFORMATION

CASE 102-10, QUESTION 4: Although the dose of clonidine for the treatment of ADHD is available in

most pediatric dosing references, it is not found in the manufacturer’s prescribing information (package insert)

for the drug because the treatment of ADHD is not currently an FDA-approved indication. What is being done

to increase the availability of pediatric drug information?

Although the availability of pediatric drug information has been limited in the past,

several recent initiatives from the FDA are increasing the number of clinical trials

being conducted in infants and children. The Pediatric Exclusivity Program, part of

the FDA Modernization Act of 1997, was developed to address the lack of pediatric

study data, including medication prescribing information.

8,86–88 The Exclusivity

Program provides pharmaceutical manufacturers with incentives to study their

products in children, including a 6-month extension at the end of a drug’s patent life if

a pediatric study is conducted. The 1998 Pediatric Rule and the Research Equity Act

of 2003 authorized the FDA to require that manufacturers conduct clinical trials of

drugs that would be used in a significant number of patients. The Best

Pharmaceuticals for Children Act supplements the previous incentives by the creation

of a mechanism for funding studies of older, off-patent medications that are often

used in children.

These programs have been successful in adding pediatric dosing and adverse

effect information to the prescribing information of many drugs routinely used in

children. As of June 2017, the FDA had issued 430 written requests for pediatric

studies, and 241 drugs had been granted a patent extension under the Exclusivity

Program.

86 An assessment of the first 7 years of the program found that 50% of the

studies conducted resulted in the new information supporting the use of the drug in

children.

87

In spite of this success, much work remains to be done. Modifications in

clinical trial design to incorporate pharmacogenomic studies and the use of combined

pharmacokinetic–pharmacodynamic analyses have been recommended to further

refine our knowledge of drug disposition in children.

87,88 The emphasis on the needs

of pediatric patients has not been limited to just the United States; similar programs

are in place in the European Union and throughout Asia. With the growing interest in

developmental pharmacology and pharmacogenomics, as well as the increased

funding and support for pediatric clinical trials worldwide, our understanding of the

unique differences in how children respond to drug therapy continues to improve.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Kearns GL et al. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N

EnglJ Med. 2003;349:1157. (7)

Leeder JS et al. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development

and regulatory science. J Clin Pharmacol. 2010;50:1377. (24)

Maaskant JM et al. Interventions for reducing medication errors in children in hospital. Cochrane Database Syst

Rev. 2015;3:CD006208.

MacLeod S. Therapeutic drug monitoring in pediatrics: how do children differ? Ther Drug Monit. 2010;32:253. (88)

Schwartz GJ et al. New equations to estimate GFT in children with CKD. J Am Soc Nephrol. 2009;20:629. (54)

Taketomo CK et al. Pediatric Dosage Handbook. 21st ed. Hudson, OH: Lexi-Comp; 2014. (17)

Key Websites

American Academy of Pediatrics. Ages and Stages. http://www.healthychildren.org.

The Joint Commission. Sentinel event alert: preventing pediatric medication errors.

http://www.jointcommission.org/assets/1/18/SEA_39.PDF. (74)

U.S. Department of Health and Human Services, Food and Drug Administration. Pediatric Drug Development.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm.

(86)

COMPLETE REFERENCES CHAPTER 102 PEDIATRIC

PHARMACOTHERAPY

U.S. Census Bureau. Profile of general population and housing characteristics: 2010 demographic profile.

http://factfinder.census.gov/faces/tableservices /jsf/pages/productview.xhtml?

pid=ACS_13_5YR_DP05&src=pt. Accessed July 12, 2017.

Vernacchio L et al. Medication use among children <12 years of age in the United States: results from the Slone

Survey. Pediatrics. 2009;124:446.

American Academy of Pediatrics. Periodic survey of fellows, #44; executive summary. Division of Health

Policy/Research. 2009 November. https://www.aap.org/en-us/professionalresources/Research/pediatrician-surveys/Pages/ps1-exe-summary.aspx. Accessed July 12, 2017.

Frattarelli DA et al.; American Academy of Pediatrics Committee on Drugs. Off-label use of drugs in children.

Pediatrics. 2014;133:563.

Young L et al. Access to prescribing information for paediatric medicines in the USA: post-modernization. Br J

Clin Pharmacol. 2009;67:341.

Bazzano AT et al. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9:81.

Kearns GL et al. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N

EnglJ Med. 2003;349:1157.

Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther.

2014;19:262.

Drozdowski LA et al. Ontogeny, growth and development of the small intestine: understanding pediatric

gastroenterology. World J Gastroenterol. 2010;16:787.

Anderson BJ et al. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled

population analysis. Anesthesiology. 2002;96:1336.

Johnson TN et al. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and

children. Clin Pharmacokinet. 2006;45:931.

Boucher FD et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human

immunodeficiency virus. J Pediatr. 1993; 122:137.

Loughnan PM, McDougall PN. Does intramuscular vitamin K1 act as an unintended depot preparation? J

Paediatr Child Health. 1996;32:251.

Thaker VV et al. Iodine-induced hypothyroidism in full-term infants with congenital heart disease: more common

than currently appreciated? J Clin Endocrinol Metab. 2014;99:3521.

Lehr VT et al. Lidocaine 4% cream compared with lidocaine 2.5% and prilocaine 2.5% or dorsal penile block for

circumcision. Am J Perinatol. 2005;22:231.

Holsti M et al. Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric

patients with epilepsy. Arch Pediatr Adolesc Med. 2010;164:747.

Taketomo CK et al. Gentamicin. In: Taketomo CK, ed. Pediatric Dosage Handbook. 21st ed. Hudson, OH: LexiComp, Inc; 2014:962.

Harskamp-van Ginkel MW et al. Drugs dosing and pharmacokinetics in children with obesity: a systematic

review. JAMA Pediatr. 2015;169(7):678–685. doi: 10.101/jamapediatrics.2015.132.

Miller JL et al. Evaluation of inpatient admissions and potential antimicrobial and analgesic dosing errors in

overweight children. Ann Pharmacother. 2010;44:35.

Ahlfors CE. Unbound bilirubin associated with kernicterus: a historical approach. J Pediatr. 2000;137:540.

Ueshima S et al. Poor applicability of estimation methods for adults to calculate unbound serum concentrations

of valproic acid in epileptic neonates and infants. J Clin Pharm Ther. 2009;34:415.

de Wildt SN. Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and

children. Expert Opin Drug Metab Toxicol. 2011;7:935.

Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther.

2008;118:250.

Leeder JS et al. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development

and regulatory science. J Clin Pharmacol. 2010;50:1377.

Strougo A et al. Predicting the “first dose in children” of CYP3A-metabolized drugs: evaluation of scaling

approaches and insights into the CYP3A7-CYP3A4 switch at young ages. J Clin Pharmacol. 2014;54:1006.

Ince I et al. Developmental changes in the expression and function of cytochrome P450 3A isoforms: evidence

from in vitro and in vivo investigations. Clin Pharmacokinet. 2013;52:333.

Chen YT et al. Ontogenic expression of hyman carboxylesterase-2 and cytochrome P450 3A4 in liver and

duodenum: postnatalsurge and organ-dependent regulation. Toxicology. 2015;330:55.

Blake MJ et al. Ontogeny of dextromethorphan Oand Ndemethylation in the first year of life. Clin Pharmacol

Ther. 2007;81:510.

Michelson D et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am

Acad Child Adolesc Psychiatry. 2007;46:242.

Koukouritaki SB et al. Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp

Ther. 2004;308:965.

Bourgeois BF, Dodson WE. Phenytoin elimination in newborns. Neurology. 1983;33:173.

Ward RM et al. Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and

preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD). Eur J Clin Pharmacol.

2010;66:555.

Johnsrud EK et al. Human hepatic CYP2E1 expression during development [published correction appears in J

Pharmacol Exp Ther. 2004;309:439]. J Pharmacol Exp Ther. 2003;307:402.

Taketomo CK et al. Caffeine. In: Taketomo CK, ed. Pediatric Dosage Handbook. 21st ed. Hudson, OH: LexiComp, Inc; 2014:338.

Aranda JV et al. Maturation of caffeine elimination in infancy. Arch Dis Child. 1979;54:946.

Charles BG et al. Caffeine citrate treatment for extremely premature infants with apnea: population

pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit.

2008;30:709.

Gershanik J et al. The gasping syndrome and benzyl alcohol poisoning. N EnglJ Med. 1982;307:1384.

Brown WI et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet. 1982;1:1250.39.

Lovejoy FH. Fatal benzyl alcohol poisoning in neonatal intensive care units. Anew concern for pediatricians. Am J

Dis Child. 1982;136:974.

Shehab N et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill

neonates. Pediatr Crit Care Med. 2009;10:256.

de Wildt SN et al. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet.

1999;36:439.

Miyagi SJ, Collier AC. Pediatric development of glucuronidation: the ontogeny of hepatic UGT1A4. Drug Metab

Dispos. 2007;35:1587.

Strassburg CP et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults.

Gut. 2002;50:259.

Allegaert K et al. In vivo glucuronidation activity of drugs in neonates: extensive interindividual variability despite

their young age. Ther Drug Monit. 2009;31:411.

Allegaert K et al. Intra-and interindividual variability of glucuronidation of paracetamol during repeated

administration of propacetamol in neonates. Acta Paediatr. 2005;94:1273.

Weiss CF et al. Chloramphenicol in the newborn infant. A physiologic explanation of its toxicity when given in

excessive doses. N EnglJ Med. 1960;262:787.

Anand KJ et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary

results from the NEOPAIN trial. Br J Anaesth. 2008;101:680.

Knibbe CA et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin

Pharmacokinet. 2009;48:371.

Duanmu Z et al. Developmental expression of aryl, estrogen, and hydroxysteroid sulfotransferases in pre-and

postnatal human liver. J Pharmacol Exp Ther. 2006;316:1310.

Anderson BJ et al. Population clinical pharmacology of children: modelling covariate effects. Eur J Pediatr.

2006;165:819.

Vieux R et al. Glomerular filtration rate reference values in very preterm infants. Pediatrics. 2010;125:e1186.

Taketomo CK et al. Digoxin. In: Taketomo CK, ed. Pediatric Dosage Handbook. 21st ed. Hudson, OH: LexiComp; 2014:658.

National Kidney Disease Education Program. GFR calculator for children. http://nkdep.nih.gov/labevaluation/gfr-calculators/children-conventional-unit.asp#guidelines-for-labs. Accessed July 12, 2017.

Schwartz GJ et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629.

Kearns GL, Spaulding-Barclay M. Adolescent pharmacology: a pertinent issue of medicine as opposed to

medicines. Clin Pharmacol Ther. 2008;84:639.

Carr RR, Ensom MH. Drug disposition and therapy in adolescence: the effects of puberty. J Pediatr Pharmacol

Ther. 2003;8:86.

Kennedy M. Hormonal regulation of hepatic drug metabolizing enzyme activity during adolescence. Clin

Pharmacol Ther. 2008;84:662.

Robieux IC et al. Analgesia in children with sickle cell crisis: comparison of intermittent opioids vs. continuous

intravenous infusion of morphine and placebo-controlled study of oxygen inhalation. Pediatr Hematol Oncol.

1992;9:317.

Jullien V et al. Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of

lopinavir in children from birth to 18 years. Antimicrob Agents Chemother. 2006;50:3548.

Lambert GH et al. The effect of age, gender, and sexual maturation on the caffeine breath test. Dev Pharmacol

Ther. 1986;9:375.

Mulla H. Understanding developmental pharmacodynamics: importance for drug development and clinical

practice. Paediatr Drugs. 2010;12:223.

Noori S et al. Hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated

preterm and term neonates. Pediatrics. 2006;118:1456.

Lamictal (lamotrigine) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; May 2015.

Iannetti P et al. Lamotrigine hypersensitivity in childhood epilepsy. Epilepsia. 1998;39:502.

Hirsch LJ et al. Predictors of lamotrigine-associated rash. Epilepsia. 2006;47:318.

Aurich-Barrera B et al. Paediatric postmarketing pharmacovigilance using prescription-event monitoring:

comparison of the adverse event profiles of lamotrigine prescribed to children and adults in England. Drug Saf.

2010;33:751.

Taketomo CK et al. Clonidine. In: Taketomo CK, ed. Pediatric Dosage Handbook. 21st ed. Hudson, OH: LexiComp, Inc; 2014:516.

Barbour AM et al. Practical considerations for dose selection in pediatric patients to ensure target exposure

requirements. AAPS J. 2014;16:749.

Xie H et al. Clonidine clearance matures rapidly during the early postnatal period: a population pharmacokinetic

analysis in newborns with neonatal abstinence syndrome. J Clin Pharmacol. 2011;51:502.

Holford N. Dosing in children. Clin Pharmacol Ther. 2010;87:367.

Conroy S et al. Interventions to reduce dosing errors in children: a systematic review of the literature. Drug Saf.

2007;30:1111.

Ghaleb MA et al. The incidence and nature of prescribing and medication administration errors in paediatric

patients. Arch Dis Child. 2010;95:113.

Chua SS et al. Drug administration errors in paediatric wards: a direct observation approach. Eur J Pediatr.

2010;169:603.

The Joint Commission. Sentinel event alert: preventing pediatric medication errors (Issue 39). April 11,2008.

http://www.jointcommission.org/sentinel_event_alert_issue_39_preventing_pediatric_medication_errors/

Accessed July 12, 2017.

Aaskant JM et al. Interventions for reducing medication errors in children in hospital. Cochrane Database Syst

Rev. 2015;3:CD006208.

Crouch BI et al. Tenfold therapeutic dosing errors in young children reported to U.S. poison control centers. Am J

Health Syst Pharm. 2009;66;1292.

Stucky ER et al. Prevention of medication errors in the pediatric inpatient setting. Pediatrics. 2003;112:431.

Larsen GY et al. Standard drug concentrations and smart pump technology reduce continuous-medication-infusion

errors in pediatric patients. Pediatrics. 2005;116:e21.

Morriss FH Jr et al. Effectiveness of a barcode medication administration system in reducing preventable

adverse drug events in a neonatal intensive care unit: a prospective cohort study. J Pediatr. 2009;154:363.

Sethuraman U et al. Prescription errors before and after introduction of electronic medication alert system in a

pediatric emergency department. Acad Emerg Med. 2015;22:714.

van Rosse F et al. The effect of computerized physician order entry on medication prescription errors and clinical

outcome in pediatric and intensive care: a systematic review. Pediatrics. 2009;123:1184.

Ginzburg R et al. Effect of a weight-based prescribing method within an electronic health record on prescribing

errors. Am J Health Syst Pharm. 2009;66:2037.

Condren M et al. Influence of a systems-based approach to prescribing errors in a pediatric resident clinic. Acad

Pediatr. 2014;14:485.

Shah R et al. Communicating doses of pediatric liquid medicines to parents/caregivers: a comparison of written

dosing directions on prescriptions with labels applied by dispensed pharmacy. J Pediatr. 2014;164:596.

Folli HL et al. Medication error prevention by clinical pharmacists in two children’s hospitals. Pediatrics.

1987;79:718.