• for Pharmacists • Define the Different Pediatric Age Groups and Recognize Developmental Milestones Within Each

10/1/2017

Joshua Davis, PharmD

• For Pharmacists • Define the different pediatric age groups and recognize developmental milestones within each. • Appreciate the pharmacokinetic and pharmacodynamic differences between pediatric and adult patients. • Describe the rationale for weight-based dosing and how to safely confirm dosages for off-label use of medications. • (Time permitting) Review the basics of pediatric emergency preparedness. • Become familiar with a list of pediatric pharmacy references and resources.

1 10/1/2017

• For Pharmacy Technicians • Define the different pediatric age groups and recognize developmental milestones within each. • Appreciate the reasons why pediatric patients are not “little adults.” • Describe the various dosage formulations available for pediatric patients. • Understand why data for pediatric drug use is limited. • Understand the potential safety hazards associated with the verification, compounding, and dispensing of pediatric medications.

• Introductions • Part 1: The Science • Part 2: Pediatric Labeling History, Dosage Forms, and Safety Strategies • Part 3: (Time Permitting) Pediatric Emergency Preparedness • Final Questions

2 10/1/2017

• Presbyterian Hospital Children’s Medical Center • 60 Bed NICU • 21 bed PICU • 25 Bed PCU (not counting overflow) • Who we serve • NICU: Premature/unstable neonates • General Pediatrics: ID, surgery, chronic disease • PICU: congenital heart disease, hematology/oncology, ID, chronic disease • YOU! (contact info on last slide)

3 10/1/2017

• Lead Pediatric Pharmacist, Pediatric Pharmacy Clinical Specialist • My role • 75% staffing • Antibiotic consults, TPNs, IV to PO conversions, code response/post-op heart recovery • 25% specialist • Protocol development, EMR build validation, process improvement projects • Also big Doctor Who fan

• Definitions • Developmental Milestones • Pharmacokinetics and Pharmacodynamics • Questions

4 10/1/2017

• Neonates, babies, infants, kids, toddlers, children, rugrats… • Different definitions • FDA established definitions for Pediatric Exclusivity claims

Name Definition NEONATES NEWBORNS UP TO ONE MONTH INFANTS ONE MONTH TO TWO YEARS CHILDREN TWO YEARS TO TWELVE YEARS ADOLESCENTS TWELVE YEARS TO SIXTEEN YEARS

• Body weight • Doubles in the 1st 6 months • Triples by the first year • Body composition • Fat, protein, water percentages constantly changing • Organ maturation • Major organs mature over first 2 years • Will discuss in context of pharmacokinetics

5 10/1/2017

Pharmacokinetics Pharmacodynamics Definition What the body does to the drug What the drug does to the body

Characterized by ADME – Absorption, Distribution, Ligand  Receptor  Tissue effect Metabolism, Elimination

Pediatric Considerations Parameters that determine ADME vary by Some evidence supports differing age even when normalized by body receptor sensitivity and density weight

Pharmacokinetics

Absorption Distribution Metabolism Elimination Parameters: Rate and Parameter: Parameters: Hepatic Parameters: Extent V Glomerular Filtration, d Blood Flow, Drug-Drug Tubular Excretion, and Interactions Tubular Reabsorption

Vd = [drug]body : A = R + E Varies E = Gfilt + Texcr -Treabs [drug]plasma

Oral/GI Tissue binding Hepatic Renal

Transdermal Hydro or Other: Biliary Lipophilicity Renal Pulmonary Intramuscular Plasma protein Intestinal binding Skin Transmucosal 12

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• Total absorption driven by two parameters • Rate of absorption – determines onset • Extent of absorption – determines effective dose • What’s happening – drug is entering the body • Why it’s happening – therapeutic effect • Where it’s happening – oral/GI, transdermal, intramuscular • Why it matters for pediatrics – dynamic body composition and developmental stage affect absorption

• Gastric pH Gastric pH by Age • Normal adult pH = 1.5-3.5 8 • Pediatric pH varies 6 • ~7 at birth 4 2 Gastric pH • 1-3 at 24-48h by Age 0 • ~7 by day 8 • Adult levels by 2 years of age • Each drug is optimally absorbed or activated at certain pH • Example – β-lactam antibiotics (amoxicillin, cephalexin) • High pH may protect it from inactivation – higher bioavailability • Example – weak acids (phenytoin, acetaminophen, phenobarbital) • High pH may inactivate it – decreased bioavailability

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• Gastric motility/emptying • Small intestine – major site for absorption • Prolonged in neonates, affects rate of absorption • Examples: phenobarbital, digoxin, sulfonamides – delayed onset • Intestinal surface area • Smaller gut, less surface area, slower absorption • Biliary function and pancreatic enzymes • Underdeveloped – affects ability to solubilize lipophilic drugs to increase absorption • Example: erythromycin & other prodrug esters

• Transmucosal • Sublingual, nasal, rectal • Often convenient • Midazolam, acetaminophen • Intestinal metabolizing enzymes and drug transporters • Not well elucidated • Example: gabapentin – decreased absorption in <5 years due to decreased L-amino transporter activity • Other examples: • Mixed data on midazolam absorption • Decreased P-gp activity in neonates – implications not yet studied

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• Transdermal • Neonates and infants – increased skin permeability • Greater skin hydration, subcutaneous perfusion, increased BSA to mass ratio • Example – steroids; eg topical OTC hydrocortisone • Intramuscular • Neonates have less blood flow to musculature • Evidence shows variable and decreased absorption • Example – antibiotics, phenobarbital

A one month old baby boy and his 3 year old baby sister both come down with ear infections. The doctor prescribes amoxicillin for each of them.

1 month old – 40mg/kg/day q8h

3 year old – 80mg/kg/day q12h

The increased acidity of the 3 year old’s stomach will degrade more drug, so higher doses are required.

9 10/1/2017

Pharmacokinetics

Vd = [drug]body : A = R + E Varies E = Gfilt + Texcr -Treabs [drug]plasma

Oral/GI Tissue binding Hepatic Renal

Transdermal Hydro or Other: Biliary Lipophilicity Renal Pulmonary Intramuscular Plasma protein Intestinal binding Skin Transmucosal 19

• Volume of distribution is a ratio of total drug in body to the drug measured in plasma • Dependent upon • Hydrophilicity or lipophilicity of the drug • Plasma protein binding • Tissue binding • What’s happening – drug is dispersing through the body • Why it’s happening – equilibrium, chemistry, partition coefficient • Where it’s happening – throughout the body’s “compartments”

• Why it matters for pediatrics – understanding Vd helps guide loading doses; combined with clearance, affects t1/2

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• Compartmental Kinetics • Hydrophilicty and lipophilicity • Dictates which compartment drug is stored in • Compartment sizes change relative to age • Total body water as % of total body weight decreases with age • Neonates 80% then down to 60% at 1 year of age • Total body fat increases • Neonates 10-15% then up to 20-25% at 1 year of age

• Plasma protein binding • Neonates and infants have lesser degree of binding • Fewer plasma proteins • Decreased affinity • More competing substrates

• Results in increased Vd • Example – phenytoin • Free phenytoin is active, total is measured • Example – ceftriaxone displaces bilirubin • Kernicterus risk • Crosses BBB to cause encephalopathy • See also sulfonamides • Tissue binding • Changes in receptor affinity not well elucidated

11 10/1/2017

A doctor calls you asking for a dose recommendation. She has a two week old with a gonococcal infection and her resource says to use ceftriaxone 100mg/kg/day for severe infections but she wants to be sure. She says he weighs 8.5 pounds. How do you proceed?

Confirm the weight is current and change to kilograms.

Recommend alternative agent, if possible (e.g., cefotaxime)

Look under neonatal dosing section and recommend 25-50mg/kg, not to exceed 125mg.

Explain to the provider that the lower protein binding affinity in neonates allows for lower doses of drug since there will be more free drug available.

Finally, confirm that there is a recent bilirubin value that is within normal limits.

Pharmacokinetics

Vd = [drug]body : A = R + E Varies E = Gfilt + Texcr -Treabs [drug]plasma

Oral/GI Tissue binding Hepatic Renal

Transdermal Hydro or Other: Biliary Lipophilicity Renal Pulmonary Intramuscular Plasma protein Intestinal binding Skin Transmucosal 24

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• Two Phases • Phase I: structural changes to drug • Phase II: conjugation • Both phases involve enzymes or transporters • Genetic polymorphisms can further complicate matters

• Phase I: Structural changes • What’s happening – enzymatic introduction or unmasking of functional group • CYP450s and FMOs • Phase II: Conjugation • What’s happening – previously attached functional group is being conjugated • Why it’s happening – increase hydrophilicity which allows for increased elimination • Where it’s happening – primarily in the liver • Why it matters – differences in metabolism affect elimination • Can extend active time - plays into dosing frequency • Can dictate metabolic pathway

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• What makes pediatrics different? • Each enzyme has a unique ontogeny • CYP3A7 – the “neo” enzyme • Others increase over time but not in a linear fashion • Reach adult levels by around 2 years of age

A 4kg, 3 week old baby is being treated for neonatal apnea. The doctor orders a dose of caffeine at 20mg/kg once, and then orders further doses at 5mg/kg q24h. A nurse calls concerned because she just gave an 80mg dose and now sees an order for 20mg. What do you tell her?

You’ve double checked your references and the doses are appropriate loading and maintenance doses.

The large loading dose is necessary due to the volume of distribution, and maintenance doses are much smaller because neonates have diminished ability to metabolize caffeine (specifically CYP1A2 activity).

In plain language, once we fill up the tank, we only need to top it off occasionally. Where a cup of coffee might last us a couple hours, it can last an infant a couple days!

14 10/1/2017

Pharmacokinetics

Vd = [drug]body : A = R + E Varies E = Gfilt + Texcr -Treabs [drug]plasma

Oral/GI Tissue binding Hepatic Renal

Transdermal Hydro or Other: Biliary Lipophilicity Renal Pulmonary Intramuscular Plasma protein Intestinal binding Skin Transmucosal 29

• Elimination driven by three parameters • Glomerular filtration – what the glomerulus can filter • Tubular excretion – what is excreted by in tubules • Tubular reabsorption – what gets reabsorbed by tubules • Elimination measured by clearance • Clearance is a measure of how much blood is cleared of drug in a certain time

• Clearance determines t1/2, how long to bring initial drug concentration down to 50% • What’s happening – drug is being eliminated from the body • Why it’s happening – final step in detoxification • Where is it happening – primarily kidney

• Why it matters for pediatrics – immature clearance increases t1/2

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• Glomerular Filtration Rate • GFR changes over months • Dependent on post-natal age • Proxy measurement: Creatinine clearance • Differences in SCr by age • More detailed breakouts available Age Group Serum Creatinine (mg/dL)

Neonate 0.3-1.0 Infant 0.2-0.4 Child 0.3-0.7 Adolescent 0.5-1

• Glomerular Filtration Rate • CrCl: Cockroft-Gault vs. Schwartz equation • Uses length, not age • Determined a set of constants to adjust for age • No adjustment for gender • 2009 update: “Bedside” Schwartz • Example – gentamicin • Tubular excretion and absorption • Develop more slowly • Example – digoxin

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A 18 month old boy is admitted for a sepsis secondary to presumed UTI, for which the doctor prescribes gentamicin at 5mg/kg q8h. You check your references and call the doctor to recommend he lower the dose to 2.5mg/kg. He wants to know why he can’t use a higher dose since the child “looks really sick.” What do you tell him?

Gentamicin is a concentration dependent antibiotic, and the available evidence indicates that a lower dose should achieve therapeutic concentrations.

Due to the decreased renal elimination of his age group, higher doses will result in increased serum concentrations that may cause nephro or ototoxicity.

Clinically, it may also be sound to start lower since the child is septic and may experience renal damage as a result, further increasing time for elimination and risk of toxicity.

The physician is grateful and impressed, and asks if pharmacy can manage the monitoring and dosing moving forward.

• Many definitions for age, best to follow FDA • Body weight, composition, and organ function are dynamic • Due to the above, AMDE parameters not the same as adults • Knowing general trends explains and guides safe and effective dosing

17 10/1/2017

• A Vulnerable Population • A Brief History of Pediatric Labeling and Indications • Pediatric Dosage Forms • Medication Safety and Error Prevention • Q and A

• Developmental differences • Dynamic PK/PD • Dynamic weight • Communication barriers • Limited buffering capacity • Electrolytes, anticoagulants • Limited evidence to support safety and efficacy • Lack of commercially available pediatric-friendly dosage forms

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• 1906 Pure Food and Drug Act – prohibited the manufacture, sale, and transport of adulterated or misbranded drugs • 1938 Food, Drug, and Cosmetic Act – empowered the FDA • 1951 Durham-Humphrey Act – established Rx status, allowed for improved enforcement of efficacy standards • 1962 Kefauver-Harris Act – established drugs must be studied for safety

Law/Report Year Purpose/Result

American Academy of Pediatrics 1974 -Unethical to force physicians to use drugs in an experimental manner every time they prescribe Report -Ethical and imperative to study drugs in pediatrics as we do in adults FDA published guidance to aid in 1977 -Focus on unexpected toxicities, have evidence supporting efficacy before studying in pediatrics, enroll sick children, use study design active or historical controls over placebo

FDA mandated Pediatric Use 1979 -Must state if safety or efficacy data exist for pediatric population subsection under Precautions Pediatric Labeling Rule 1994 -Established rules allowing extrapolation of adult efficacy data as basis for pediatric use -Requested additional info for pediatric labeling (didn’t work)

FDA Modernization Act (Pediatric 1997 -Provided incentive of 6 months patent extension and marketing exclusivity Exclusivity Provision) Pediatric Rule 1998 -Mandated any drug under review must submit pediatric info if the indication is a disease that occurs in children (difficult to enforce)

Best Pharmaceuticals for Children 2002 -Renewed FDAMA incentives, established program for NIH to study off-patent drugs Act Pediatric Research Equity Act 2003 -New drugs that are likely to be used in pediatrics must be studied

19 10/1/2017

• Tale 1: A 2 year old boy is discharged from the PICU on amlodipine, mom is counseled upon discharge. The hospital is not an outpatient pharmacy, so she fills his prescription at another pharmacy…

• Tale 2: A 3 year old girl was admitted for SVT. She was treated and discharged with prescriptions for acetaminophen and propranolol. A prescription bag from the outpatient pharmacy in the hospital lobby is delivered and she is discharged home…

• Why are they needed? • Inability to take tablets • Weight-based doses • What are the requirements? • Minimal administration frequency • Minimal impact of lifestyle • Minimum, non-toxic excipients • Convenient, reliable, easy administration • Palatable, flexible dosing, reasonable size for patient • Stable, easy to produce if not commercially available • Affordable • Medication safety and dosage formulations go hand in hand

20 10/1/2017

• The answer: solutions, suspensions, and dilutions

Problem Solution Volume The right concentration Concentration Standardize Accuracy Good technique, measuring tools, commercial availability Crushability ISMP Do Not Crush List Palatability Flavorings when possible; sometimes a risk (buprenorphine) Bulk dispensing Unit dose dispensing, counseling

• Tale 1: Readmitted 2 days later, presenting with lethargy. Found to be hypotensive. Upon investigation, concentration of amlodipine dispensed outpatient was a different strength. Patient monitored overnight. Pharmacy consulted to counsel prior to discharge.

• Tale 2: Readmitted 2 days later through ED, found to be in SVT. Patient was treated again and rhythm stabilized. Upon investigation, bag from pharmacy only contained acetaminophen. Pharmacy consulted to counsel prior to discharge. Information provided in English and Spanish.

21 10/1/2017

• When compounding medications: • Good technique leads to appropriate absorption and distribution • Trituration, levigation, geometric dilution, etc. • Standardize concentration: http://www.mipedscompounds.org/

• When verifying medications: • Recall that 79% of pediatric med errors occur at the ordering stage – mostly overdose Order Type Units to check • Develop “trigger thoughts” and mental checklists • Weight-based dose Continuous mcg/kg/h or mcg/kg/min? • Is appropriate for age? infusions • Is it a current weight? • What about total dose? Electrolyte mEq vs. mmol vs. mg • Double check the units • Double check for common errors • Avoid trailing zeros, use leading zeroes Intermittent mg/kg/d q6h – is the “d” • cc or mL? doses per day or per dose? • Double check volume orders • Homework: develop your own approach • Refine it, use it for training Dosing weight lbs vs. kg? How recent is the • Stand up for safety weight? • Call to confirm ANYTHING unclear • Share your mistakes openly

22 10/1/2017

• When dispensing medications: • Dispense in unit dose when possible • Dispense bulk with appropriate administration tools • Oral syringes, graduated cups, etc. • Mark your syringes • Provide detailed counseling with caregiver readback • Ask about “day care” dispensing

• Establish annual competencies and specialized training • Include calculations, compounding technique, and dilution preparation • Purchase commercially made products when possible • Use standardized concentrations • Circulate ISMP Safety Alert • Store look-alike, sound-alike medications separately • Establish safety protocols for high-alert medications • Double check system, error software • Keep a library of up-to-date pediatric references • In hospital • Automated dispensing cabinets, barcode administration, computerized physician order entry

23 10/1/2017

• Pediatrics are a vulnerable population • Dynamic bodies, ability to communicate • Not as much evidence based data as we’d prefer • Despite multiple voices, guidance, and incentives • Dynamic patients require flexible dosage forms • Good compounding technique, counseling a must • Error-prevention strategies are essential • Both in personal practice and at an institution level

• Code Preparation • Broselow Tape • Purpose/rationale • Drawbacks • Code Trays • Neonatal vs. Pediatric vs. Adult • Emergency Drug lists • PALS training • Respiratory then cardiovascular collapse • Resuscitation basics

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• Benavides S and Nahata MC, eds. Pediatric Pharmacotherapy. 1st Ed. Lenexa, KS: American College of Clinical Pharmacy; 2013. • Lu H and Rosenbaum S. Developmental Pharmacokinetics in Pediatric Populations. The Journal of Pediatric Pharmacology and Therapeutics 2014;19(4):262-276. • Amani A, York P. World Health Organization. Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children. 2008. • mipedscompounds.org [Internet] Michigan Pediatric Safety Collaboration; c2017 [cited Aug 2017]. Available from www.mipedscompounds.org • Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Addressing the Barriers to Pediatric Drug Development: Workshop Summary. Washington (DC): National Academies Press (US); 2008. 2, Regulatory Framework. Available from: https://www.ncbi.nlm.nih.gov/books/NBK3997/

1. Takemoto CK, Hodding JH, Kraus DM. Pediatric & Neonatal Dosage Handbook. 23rd ed. Wolters Kluwer; 2016. 2. Hughes HK, Kahl LK, editors. The Harriet Lane Handbook. 21st ed. Philadelphia: Elsevier; 2018. 3. Phelps SJ, Hageman TM, Lee KR, Thompson JA. The Teddy Bear Book: Pediatric Injectable Drugs. 10th ed. Besthesda, MD: American Society of Health Systems Pharmacists; 2013. 4. Gahart BL, Nazareno AR, Ortega MQ. Intravenous Medications: A Handbook for Nurses and Health Professionals. 33rd ed. St. Louis: Elsevier; 2016. 5. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. 6. Benavides S and Nahata MC, eds. Pediatric Pharmacotherapy. 1st Ed. Lenexa, KS: American College of Clinical Pharmacy; 2013. 7. Jew RK, Soo-Hoo W, Erush SC, Amiri E. Extemporaneous Formulations for Pediatric Geriatric, and Special Needs Patients. 3rd ed. Bethesda, MD: American Society of Health Systems Pharmacists; 2016. 8. Aronoff GR, Bennett WM. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 9. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Grove Village, IL: American Academy of Pediatrics.

LeBonheur Children’s Hospital Provider Resources http://www.lebonheur.org/providers DailyMed (FDA package insert Library) https://dailymed.nlm.nih.gov/dailymed/ Cornell University Critical Care Pediatrics Calculators: http://www- users.med.cornell.edu/~spon/picu/calc/medcalc.htm?name1=Medical+Calculators&type1=2Active UpToDate: https://www.uptodate.com/contents/search Institute for Safe Medication Practices: http://www.ismp.org/ NeoFax https://neofax.micromedexsolutions.com/neofax/neofax.php American Academy of Pediatrics: https://www.aap.org/en-us/Pages/Default.aspx

DI/Toxicology questions: NM Poison Control Center (800) 222-1222 Urgent Clinical Pharmacy Questions: Presbyterian Pediatric Pharmacy Satellite (505) 724-7721 Non-urgent Clinical Pharmacy Questions: Joshua Davis, PharmD, Pediatric Pharmacy Clinical Specialist (505) 841-1207 Presbyterian Pediatric Urgent Care: (505) 841-1819 Presbyterian Nursing Hotline: (505) 923-5570