PERINATAL AND PEDIATRIC PHARMACOLOGY

1
PERINATAL AND PEDIATRIC PHARMACOLOGY

• Dr. Manuel E. Valdez
• Department of Pediatrics UPHRMC

2
Aspects of Drug Therapy During Pregnancy

• access of the drugs to the fetus
• pharmacodynamic aspects of drug action in the
  fetus
• Recent WHO survey showed that 89 of women take
  prescription drugs during pregnancy (avg 3
  prescription each) not including OTC preparation
  and alternative therapies

3
Access of the Drug to the Fetus

• Lipid solubility
• Molecular size
• Protein binding
• Placental and Fetal metabolism

4
Lipid solubility

• Lipid soluble drugs readily cross the placental
  barrier ionized drugs do not
• Example a) thiopental given as anesthetic for
  C/S. Readily crosses the placenta and can produce
  sedation and apnea in newborn
• b) salicylates ionized at blood
  PH. However, small amount that is not ionized
  crosses the placenta and can be trapped there

5
Molecular size

• Placenta excludes drugs of high MW
• MW 250-500 drugs are readily permeable
• MW 500-1000- greater difficulty in crossing the
  placenta
• MWgt1000- excluded or diffuse very poorly
• Exception-maternal antibody globulins cross
  placenta through poorly characterized carrier
  mechanism
• Therapeutic implications Most important clinical
  implication of this is that Heparin (large MW) is
  the anticoagulant of choice in pregnant women

6
Protein binding

• Plasma protein binding of a drug will inhibit
  placental transfer. Tighter binding inhibits more
  than weak binding
• Highly lipid soluble drugs may transfer anyway
  despite avid protein binding
• Plasma protein affinity may be different in fetal
  circulation vs. maternal . Thus free fetal plasma
  concentration may be higher than free maternal
  plasma concentration of drug at equilibrium
  (sulfonamides, barbiturates, phenytoin and local
  anesthetics)

7
Placental/Fetal drug metabolism

• Placenta important site of drug metabolism
  especially aromatic oxidation reactions
  (hydroxylation, N-dealkylation, demethylation)
  Ex. Phenobarbital oxidized by placenta
• Fetal drug metabolism 40-50 of umbilical
  venous blood enters fetal liver

8
Pharmacodynamic aspects of drug action on the
fetus

• Maternal drug action
• Therapeutic action on the fetus
• Toxic action on the fetus
• Teratogenic action of specific agents

9
Maternal drug action

• Mother may need to take drugs for conditions that
  arise during pregnancy. These drugs may affect
  the fetus or fetal drug metabolism
• Ex. Pregnancy induced heart failure (digitalis
  and diuretics) pregnancy induced diabetes
  (insulin)

10
Therapeutic action on the fetus

• Drugs are given for fetal condition in utero
• Ex. Corticosteroids-used to stimulate fetal lung
  maturation in expected premature birth
• Phenobarbital used to induce fetal hepatic
  enzymes which glucorunidate bilirubin

11
Toxic action on the fetus

• Ex. Opiates can cause dependency in newborn
  leading to neonatal withdrawal syndrome
• ACE inhibitors produce renal toxicity in the
  developing kidney

12
Teratogenic action of specific agents

• Teratogens result in characteristic malformation
  indicating selectivity of action of the drug
• Act predominantly at a defined stage of fetal
  development
• Dose dependency
• Lists of specific teratogens

13
Teratogenic drug effects

• Category Drug Teratogenic
  effect
• Antibiotics Amonoglycosides
  Deafness,vestibular damage
• Tetracyclines
  Anomalies of teeth bone
• Quinolones
  Arthropathies (Animal studies)
• Sulfonamides
  Hyperbilirubinemia/kernicterus
• Anticholinergics
  Meconium ileus
• Anticoagulants Warfarin
  Skeletal CNS defects (DWS)
• Anticovulsants Carbamazepine Neural tube
  defects
• Phenytoin
  Growth retardation,CNS defects
• Valproic acid
  Neural tube defects
• Trimethadione
  CNS and facial defects

14
Teratogenic drug effects

• Antidepressant Lithium
  Ebstein anomaly, hypotonia
• 
  reduced sucking,hyporeflexia
• Antihypertensives ACE inhibitors Renal
  failure, decreased skull
• 
  ossification, renal tubular
• 
  dysgenesis
• B-blockers
  Growth restriction, neonatal
• 
  bradycardia/hypoglycemia
• Antithyroid drugs PTU
  Fetal/neonatal goiter/hypo-
• 
  thyroidism
• Methimazole
  Aplasia cutis, fetal/neonatal
• 
  goiter/hypothyroidism

15
Teratogenic drug effects

• Cytotoxic drugs Amonopterin/
  CNS/limb malformations
• methotrexate
• Cyclophosphamide
  CNS malformations,
• 
  secondary cancer
• Diuretics Furosemide
  ? uterine blood flow,
• 
  hyperbilirubinemia
• Thiazides
  Neonatal
• 
  thrombocytopenia
• Hypoglycemics Chlorpropamide,
  Neonatal hypoglycemia
• glibenciamide

16
Teratogenic drug effects

• NSAIDS Indomethacin Premature
  closure of PDA, NEC,
• 
  neonatal PHN
• Salicylates
  Hemorrhage
• PG analogues Misoprostol Moebius
  sequence
• Recreational Ethanol
  Fetal alcohol syndrome
• drugs Cocaine
  Growth retardation
• Sex hormones DES
  Genitourinary defects in male/
• 
  female offspring
• Danazol
  Masculinization of female fetus

17
Teratogenic drug effects

• Sedatives Thalidomide Limb
  shortening(phocomelia)
• 
  hearing defect
• Psychoactive drugs Barbiturates Neonatal
  withdrawal syndromes
• benzodiazepines
• opioids
• Phenothiazines
  Neonatal effects of impaired
• 
  thermoregulation, extra-
• 
  pyramidal effects
• Miscellaneous Vit.A
  Congenital anomalies, cleft
• 
  palate,eye damage,syndactyly
• Vit K
  Hyperbilirubinemia/kernicterus

18
Effect of drug administration to lactating mother

• Drugs affecting lactation
• Drug concentration in breastmilk
• Pharmacodynamics of drug ingested in breastmilk

19
Drugs affecting lactation

• Bromocriptine,ergotamine,cabergoline,lisuride,terg
  uride, and metergoline- inhibit prolactin
• OCP -risk of ?milk supply, N2 protein content
  of milk
• estrogen-antagonizes the milk producing effect of
  prolactin and inhibit lactation
• clonidine- inhibit milk ejection ?maternal
  prolactin levels
• Thiazides- suppress lactation

20
Drug concentration in breastmilk

• Most drugs are excreted into breastmilk by
  passive diffusion making the drug concentration
  in milk directly proportional to maternal plasma
  concentration
• Human milk is more acidic than plasma, drugs that
  pass into milk are weak bases,water soluble,
  lipid soluble and poorly bound to proteins
• Milkplasma (MP) ratio serves as an index of
  extent of drug excretion in the milk

21
Drug excretion in human breastmilk

• DRUG
• Amoxicillin
• Atenolol
• Carbamazepine
• Cefotoxime
• Diazepam
• Digoxin
• Lithium
• Penicillin
• Phenytoin
• Propranolol
• Theophylline
• Warfarin

• MP RATIO
• 0.014-0.043
• 1.5-6.8
• 0.6-0.7
• 0.029-0.16
• 0.08-0.13
• 0.6-0.8
• 0.25-0.77
• 0.02-0.2
• 0.12-0.24
• 0.5
• 0.57
• lt0.01

22
Principles that can guide management of cases of
drug exposure in a breastfed infant

• Human milk drug concentration usually do not
  exceed the maternal plasma concentration
• Even when the MP ratio for a given drug
  approaches or exceeds 1.0, the amount of drug
  ingested by the infant rarely is sufficient to
  attain therapeutic concentration
• Short exposure to a drug is usually of less
  concern than given for long period of time
• Amount of drug ingested can be minimized by
  feeding the infant just before or at the time of
  maternal administration

23
Drug concentration in breastmilk

• Drug concentration in breastmilk difficult to
  predict and usually measured empirically. However
  effect on infant is usually lower than in mother
  since dose comes from free plasma concentration
  of the mother
• If nursing mother must take drugs, optimal
  time is 30-60 minutes after feeding and 3-4 hrs
  before next feeding or before the next dose is
  due, when the concentration of drug in milk is
  low.

24
Pharmacodynamics of drug ingested in breast milk

• Drugs that eventually reach the infants systemic
  circulation in any appreciable amount (gt10)
  should be avoided.

25
Pharmacodynamics of drugs ingested in breastmilk
Examples

• Tetracyclines-70 of maternal serum
  concentration-- permanent tooth staining in
  infants
• Diazepam( many other sedative hypnotics)--
  sedation in infants and can accumulate in infant
  due to long half life
• Cancer chemotherapy- immunosuppresion/neutropenia
  
• I tracers - thyroid cancer in infant
• Lithium(same concentration in breastmilk as in
  plasma)- tremor and involuntary movements
• Amiodarone- thyroid disturbance because of high
  Iodine content
• ASA- Reye syndrome

26
Pharmacodynamics of drug ingested in
breastmilk-Examples

• Chloramphenicol- grey baby syndrome
• Sulphonamides- jaundice because of competition
  for bilirubin for binding to albumin
• Quinolones- adverse effect on cartilage
  development
• Tinidazole- risk of carcinogenicity and
  mutagenicity
• Laxatives containing phenolpthalein- risk of
  carcinogenicity
• Antithyroid (carbimazole,methimazole) - thyroid
  suppression
• H2 antagonist (cemitidine )-because of their
  accumulation in breastmilk (6mg/L of milk could
  mean an average dose of 18mg /day for a newborn)-
  effect on gastric acidity and inhibition of cP450
• Ergotamine- risk of ergotism in infants

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Epidemiology

• Ave. of 0.9 medication/patient contact is
  prescribed in pediatric practice vs 1.1
  drugs/patient contact for all the disciplines
  together.
• 1st 5 years of life- 95 of children have been
  prescribed medications w/ ave. of 8.5 courses of
  prescriptions and 5.5 different medications
• Greatest number of prescriptions is given to
  children between 7 and 12 months

28
Therapeutic use of drugs in infants and children

• Unique aspects of
• Drug absorption
• Drug distribution
• Drug metabolism
• Drug excretion

29
Unique aspects of drug absorption in infants and
children

• Absorption from I.M. injection sites
• - Blood supply and flow, Muscle mass
• - Drug related factors
• Absorption from GIT
• - gastric PH
• - peristaltic rate and gastric
  emptying time
• - diarrhea
• - bacterial flora
• Absorption from the rectum

30
Drug absorption at IM injection sites-Local
factors

• a) Blood supply and flow
• - Conditions like low CO, RDS or shock may
  compromise blood supply to muscles severely
  leading to decreased absorption from the injected
  site.
• - Immobility slows absorption rate
• - Exercise enhances absorption Ex. After
  IM insulin- exercise-induced hypoglycemia
• Ex. Injected IM digoxin improves regional
  blood flow therefore drug absorption/toxicity
• b) Muscle mass - Ex. Infants, malnourished
  children has small muscle mass, Obesity

31
Drug Absorption from IM injection sites- Drug
-related factors

• Muscle is more acidic than blood
• Ex. Phenytoin after IM injection is converted
  into acid form. The sodium salt of Phenytoin
  precipitates at site of injection which leads to
  erratic and slower absorption

32
Drug absorption from GIT

• a) Gastric PH slowly rises in premature infants
• b) Gastric emptying time is prolonged in
  neonates. May increase absorption if drug is
  absorbed in stomach or delay if absorbed in
  intestines
• c) Peristalsis slower in neonates, could increase
  intestinal absorption
• d) diarrhea interfere with drug absorption from
  GIT, effect is exaggerated in neonates
• e)Bacterial flora affects hydrolysis of drug
  conjugates that are excreted in bile Ex Vit K
  other fat soluble vitamins

33
Oral drug absorption in neonates vs older children

• DRUG Oral Absorption
• Acetomenophen Dec
• Ampicillin Inc
• Diazepam N
• Digoxin N
• Penicillin Inc
• Phenobarbital Dec
• Phenytoin Dec
• Sulfonamides N

34
Rectal administration of drugs

• Useful in conditions such as nausea,vomiting,
  status epilepticus,for induction of anesthesia
  and for administration of drugs that have a large
  first-pass effect
• Ex. Diazepam solutions- well absorbed from the
  rectum compared with suppositories for which
  absorption is erratic and slow
• Other drugs- lorazepam,midazolam,atropine,
  
• barbiturates have been administered rectally
  with great success

35
Unique aspects of drug distribution in infants
and children

• Total body water content
• Fat content
• Protein binding

36
Drug distribution-Total body water content

• Neonate 70-75 (premature can be up to 85) vs
  50-60 in adults)
• ECW 40 in neonates, 20 in adults
• Neonates undergo diuresis in 1st 48 hrs
• Thus neonates have a larger relative plasma
  volume which affects distribution of water
  soluble drugs(Ex aminoglycosides,ampicillin)
• Water soluble drugs are distributed throughout
  ECW, therefore the volume of ECW compartment
  determines drug concentration

37
Drug distribution-Fat content

• Varies in neonates. Prematures can be 1, full
  term 15
• This affects distribution of lipid soluble drugs
• Ex. Digoxin which may accumulate in smaller
  amounts in immature infants

38
Drug distribution-Protein binding

• Neonates esp preterm are at risk of altered
  drug protein intercation
• - ? concentration of albumin and protein lead
  to decreased drug protein binding. Ex Higher
  cord/adult free drug ratios for salicylates,
  sulfonamides, morphine, phenobarbital and
  phenytoin-greater drug effects/toxicity.
• - Changing affinity of albumin for different
  drugs at different stage of maturation (e.g
  acidic drug affinities for serum albumin increase
  dramatically over the first few weeks of life)

39
Drug distribution-Protein binding

• ?concentration of FFA and B 1 affect protein
  binding. FFA and B1 have high affinity for
  albumin which can result in competition or even
  displacement of drugs from albumin binding sites
  Ex sulfonamides,phenytoin
• CNS distribution of drugs- tighter junctions in
  the brain endothelial capillaries and the close
  approximation of glial connective tissues to the
  capillary endothelium limit drug distribution to
  brain tissues. Ex. Water soluble antibiotics
  (aminoglycosides)are less likely to cross blood
  brain barrier

40
Protein binding affect free drug
concentration-Example

• Diazepam - 98 protein bound in older children,
  plasma drug concentration of 300 ug/ml yields a
  free concentration of 6 ug/ml
• In neonates 90 protein
  bound and yields a free concentration of 30 ug/ml

41
Unique aspects of Drug Metabolism in infants and
neonates

• Liver- major organ of drug metabolism
• Other organs like lungs,GIT or blood are
  capable of metabolizing drugs
• Drug metabolism can result in either generation
  of weaker or inactive metabolites or
  transformation of a parent compound or prodrug
  into the active compound (theophylline to
  caffeine codeine to morphine)or an even more
  active metabolite
• Generally slower drug metabolism in infants and
  neonates

42
Drug metabolism in infants and neonates-2 major
steps

• Phase 1 reactions (oxidation, reduction,methylatio
  n)
• reach maximal maturity by 6 months of age.
• Ex. Theophylline- 10 is methylated to
  caffeine, with 50 excreted unchanged in urine.
  W/ maturation of hydroxylation and acetylation of
  hepatic enzymes, the rate of clearance increases
  resulting in short half life (3-5 hrs in infants
  and children vs 8 hrs in adult)

43
Drug metabolism in infants and children

• Hepatic Phase II reactions (glucorunidation,
  sulfation, acetylation)
• CP450 and conjugating enzymes are reduced in
  activity in the neonates (50-70 adult values)
  
• Glucorunide formation- reach adult levels in
  3rd-4rth year of life
• Sulfation pathway-reach adult levels just days
  after birth
• Decreased ability of neonates to metabolize drugs
  result in prolonged elimination half lives
  leading to ADR or toxicity from overdose
• Variation in enzyme activity make it difficult to
  predict plasma values of drugs Ex. Phenytoin
• Infants more susceptible to drug toxicity vs
  adults when drug must undergo hepatic elimination

44
Half life of Phenytoin in neonates

• Days after birth T 1/2
• 0-2 80
  hrs
• 3-14 18 hrs
• 14- 50 6 hrs
• Compared with carbamazepine which has identical
  plasma half lives in neonates and adults

45
Unique aspects of drug excretion in infants and
children

• i) GFR lower in neonates and children
• a) Week 1 GFR -30-40 of adult values (even
  lower in prematures)
• Week 3 - 50-60 of adult values
• By 6-12 months -reaches adult values (per
  unit surface area)

46
Drug excretion

• b) elimination is thus lower in children for
  most drugs vs adults
• c) conditions that reduce GFR (heart failure)
  also further reduce elimination
• ii) Tubular secretion rate is about 25-50 lower
  in newborn reaching adult levels at age 1- 3
  years

47
Drug excretion

• Renally eliminated agents- aminoglycosides,penici
  llins, digoxin
• Ex- Dose of gentamycin younger than 7days old
  neonate- 5mg/k x 2 Older than 7 days old- 7.5
  mg/k x 3
• Digoxin- renal clearance increases from 33
  mL/min/BSA in neonates to 98 mL/min/BSA at 3
  months and 144 mL/min/BSA at 1.5 years

48
Drug interactions

• Defined as clinically measurable modifications in
  either magnitude or duration of action of one
  drug caused by prior or concomittant
  administration of another substance
• 2 types 1) Desirable -such as seen in treatment
  of HPN by using multiple drugs with different
  mechanisms of action
• 2) Adverse- serious or life
  threatening (3 of hospitalized patient with 7
  of these caused by drug interaction.
• Mechanism pharmacokinetic and pharmacodynamic

49
Drug interactions affecting oral bioavailability

• GIT- Ex Tetracycline can chelate
  calcium,magnesium or iron leading to decrease
  absorption
• Oral neomycin or antineoplastic
  agents can damage the intestinal absorptive
  surface
• Metoclopramide,domperidone- can
  enhance gastric emtying which affects rate of
  absorption
• Morphine,anticholinergics,antacids-can
  delay gastric emptying which affects rate of
  absorption
• Relevance- when a rapid onset of drug effect is
  desired such as sedation or pain relief

50
Interactions affecting oral bioavailability

• Drugs that have an extensive first-pass
  effect(i.e. those that are extracted or
  metabolized during transit across the intestinal
  epithelium or during the first pass through the
  liver) such as beta blockers,Ca channel blockers,
• tricyclic antidepressants, morphine), the
  primary factor affecting clearance is hepatic
  blood flow
• Coadministration of drugs that decrease hepatic
  blood flow such as cimetidine would increase free
  concentration of these drugs

51
Protein binding drug interactions

• Serum concentration of a measured drug refers to
  the total drug concentration in the plasma (free
  protein bound).
• Only the free drug exerts its pharmacologic
  effect
• Drugs that are highly bound to protein are
  subject to displacement by other drugs that have
  high affinity for the same protein binding sites
  resulting to increase in the free concentration
  of the index drug Ex- salycylates, sulfonamides

52
Drug interactions affecting biotransformation

• Many of the prescribed drugs in children may
  inhibit or enhance the metabolism of other drugs
• Drugs that have an inhibitory effects on hepatic
  drug metabolism resulting in a functionally
  impaired or inactive enzyme that cannot oxidize,
  reduce or hydrolyze drugs (cimetidine,
  erythromycin, ciprofloxacin, omeprazole)
• Coadministration of these drugs with
  theophylline may result in increased plasma
  concentration and toxicity of theophylline

53
Drug interactions affecting biotransformation

• Enzyme induction can enhance the clearance of
  index drugs which can lead to decreased or even
  loss of efficacy. Drug enzyme inducers are the
  following
• a) Rifampicin - Coadministration with
  cyclosporine or prednisone leads to graft
  rejection or with oral contaceptives leads to
  failure because of increased metabolism
• b) Phenytoin- Coadministration with methadone
  leads to withdrawal symptoms
• c)Phenobarbital
• If an induction interaction is established,
  ?the dose of index drug. If the inducing drug is
  stopped, ?the index drug dose to avoid toxicity

54
Drug interactions due to altered renal function

• Drugs excreted by GFR are unlikely to be affected
  by other drugs
• Drugs that are actively transformed into the
  tubular lumen can be inhibited by other drugs Ex-
  Methotrexate toxicity can be induced by
  inhibition of its tubular secretion by
  salicylates
• Renal clearance of lithium is reduced in the
  presence of thiazides
• Probenecid enhances the tubular secretion of
  penicillin

55
Pharmacodynamic features of the neonate

• PDA - kept open by PGE
• - closed by Indomethacin
• PDA-vessels connecting LPA with aorta
• PGE infusion can be used to keep ductus
  arteriosus patent in infants with TOF or TGA

56
Drug dosage in infants and children

• Special dosage forms for infants
• Patient compliance
• Calculation of pediatric drug dosage
• FDA approval and safety assurance

57
Special dosage forms

• Elixir - alcoholic solution in which drug is
  dissolved ( No shaking is needed)
• Suspensions- undissolved particles of drug
  floating in thich vehicle ( Must shake, at first
  dose will contain less drug than last dose), can
  reduce efficacy in early treatment and enhance
  toxicity late in treatment (ex. Phenytoin)
• Chewable tablets-usually drug is to be chewed not
  swallowed for optimal absorption

58
Patient compliance

• 21 of adolescents noncompliant with AED therapy
• 28 of asthmatic children noncompliant with
  theophylline
• 30-40 of thalssemia major patients noncompliant
  with nightly subcutaneous infusions of
  desferrioxamine
• To improve compliance a) take time to explain the
  nature of the illness b) provide precise
  instructions for treatment (including the names
  and purposes of the drug or drugs prescribed) and
  c) give specific instructions about dosage

59
Patient compliance

• teaspoon- should be 5 ml but can vary from 2.5
  to 7.8 ml in common household spoons. Get a
  measuring syringe
• dosing often spilled, spit out, forgotten (Be
  clear in patient direction-e.g wake them to give
  drug or cant wait till morning etc)
• left over drugs- Give full dose especially
  antibiotics which are often discontinued upon
  cessation of symptoms (antibiotic resistance)

60
Calculation of pediatric drug dosage

• Youngs rule
• dose adult dose x (age in yrs)/ (age
  12)
• Clarks rule (more precise than Youngs rule)
• dose adult dose x wt (kg)/ 70
• dose adult dose x wt (lbs)/ 150
• BSA (Body Surface Area)
• Neonate BSA/Adult BSA x 100 of adult dose
  needed
• Often labeling info for manufactures contain no
  dosages for children lt 12. When using such a drug
  the dose must be started based on conversion
  factor

61
Determination of drug dosage from surface area

• Wt Approx age SA of adult
  dose
• 3 kg (6.6 lbs) NB 0.2
  12
• 6 kg (13.2lbs) 3 mos 0.3
  18
• 10 kg (22 lbs) 1 year 0.45
  28
• 20 kg (44 lbs) 5.5 years 0.8
  48
• 30 kg(66lbs) 9 years 1.0
  60
• 40 kg (88 lbs) 12 years 1.3
  78
• 50 kg (110 lbs) 14 years 1.5
  90
• 60 kg (132 lbs) adult 1.7
  102
• 70 kg (154lbs) adult 1.76
  103

62
Therapeutic Drug monitoring

• Measurement of drug concentrations and the use of
  pharmacokinetic principles to individualize drug
  dosing in an attempt to maximize therapeutic
  efficacy while minimizing potential toxicity
• Applicable for medications that possess narrow
  therapeutic indices and for agents that
  demonstrate a good correlation between serum
  concentrations and pharmacologic effect
• Trough levels- provide accurate interpretation of
  drug concentration
• Peak levels- less accurate because they are
  subject to significant variability due to
  differences in absorption and distribution rates.
• Reserved for medications with short
  half-lives in which peak levels are associated
  with efficacy or toxicity

63
Therapeutic drug monitoring-Examples

• Theophylline serum concentrations
• 10-20 mcg/mL- clinical bronchodilation in
  asthmatic children
• 5-10 mcg/ml- diaphragmatic stimulation
• gt20 mcg/mL -toxicity
• Aminoglycosides
• Peak levels of 12-14 mcg/mL or trough levels
  gt2 mcg/mL- ototoxicity/nephrotoxicity
• Chloramphenicol- 25 mcg/mL or higher- risk of
  reversible bone marrow suppression
• Vancomycin- trough levels gt 30 mg/L-
  nephrotoxicity
• 
  80-100 mg/L - ototoxicity

64
FDA approval and safety assurance

• New drugs need to have studies in pediatric
  patient for safety and efficacy if they are
  likely beneficial in children
• Certain existing classes of drugs need to be
  studied and labeled for use in children. Criteria
• - drug would represent an improvement in
  standard therapy for children
• - drug currently prescribed gt50,000
  times/year
• - drug is in a class or for use where
  additional option for children are needed