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Considerations for Sterile Compounding of Parenteral Products for Pediatric Use: Part 1PharMEDium Lunch and Learn Series

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Considerations for Sterile Compounding of Parenteral Products for Pediatric Use: Part 1

October 13, 2017

Featured Speaker: Kirsten H. Ohler, PharmD, BCPS, BCPPSNeonatal / Pediatric Clinical PharmacistClinical Associate Professor, Pharmacy PracticeProgram Director, PGY2 Pediatric Pharmacy ResidencyUniversity of Illinois at Chicago College of Pharmacy

LUNCH AND LEARN

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ProCE, Inc. (Pharmacist and Tech CE)

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Funding: This activity is self‐funded through PharMEDium.

It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Ohler has no relevant commercial and/or financial relationships to disclose.

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Considerations for Sterile Compounding of Parenteral

Products for Pediatric Use: Part 1

Kirsten H. Ohler, PharmD, BCPS, BCPPSClinical Associate Professor, Pharmacy Practice

Clinical Pharmacy Specialist, NICUUniversity of Illinois at Chicago

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Disclosure

• The speaker, Kirsten H. Ohler, has no actual or potential conflicts of interest related to the information included in this presentation.

• The practice of off‐label medication use in pediatric patients will be discussed.

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Objectives

At the conclusion of Part 1, participants will be able to:

1. Define the various age groups within the pediatric population.

2. Discuss the effect patient age has on pharmacokinetic parameters, pharmacodynamics, medication dosing, and monitoring parameters.

3. Identify considerations in drug formulation and drug delivery processes specific to the pediatric population.

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Who is a Pediatric Patient?

Neonate

Birth to 28 days

Infant

>28 days to 12 months

Child

1 to 12 years

Adolescent

13 to 17 years

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Neonates – A Week in the Life

Gestational Age (GA)

Postmenstrual Age (PMA)

Chronological Age

Or

Postnatal Age (PNA)

Conception Birth Today’s Date

• Term: born >37 weeks’ gestation• Preterm: born before 37 weeks’ gestation

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Age – It’s Not Just a Number

• Children are not small adults

• Diseases with the same name have different causes and presentation in children compared to adults

• Normal values for vital signs vary with age

• Normal values for laboratory parameters vary with age

• Age affects organ function

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Developmental Pharmacokinetics

• Effect of age/maturation on absorption, distribution, metabolism, and elimination (ADME) of medications

• Affects medication dosing, potential adverse effects, and efficacy

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• Absorption

– Transfer of medication into the bloodstream from the site of administration

– Drug delivery by parenteral, percutaneous, and enteral routes may all be affected

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• Absorption

– Parenteral

• Intravenous– May be affected by drug delivery system (more about this later…)

• Intramuscular – Low muscle mass / muscle activity in preterm neonates

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• Absorption

– Percutaneous

• May be faster and to a greater extent in neonates– Thin, poorly keratinized skin

– Increased skin hydration

– Relatively large body surface

area to weight ratio

• Caution when using

topical products because

they may produce

systemic effects15


• Absorption

– Enteral

• Relative achlorhydria in neonates

• Prolonged gastric emptying time

• Delayed peristalsis

• Frequent enteral feedings drug‐food interactions

– Rectal

• Not significantly affected by maturation

• Frequent stooling may reduce absorption

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• Distribution– Total body water

• Water‐soluble drugs have a higher volume of distribution (Vd) in neonates

– Higher dose per kilogram may be needed

0

20

40

60

80

100

Neonate Infant Adolescent

% of total body wt

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• Distribution– Total body fat

• Neonate (preterm): ~1% of body weight is fat• Neonate (term): ~10‐15% of body weight is fat• Infant: ~20‐25% of body weight is fat

– Protein binding• Low amounts of plasma proteins in neonates

– Increased unbound (“free”) fraction of highly protein bound drugs may increased risk for toxicity

» Example: Phenytoin– Drug may compete with other substances for binding sites

» Example: Trimethoprim‐sulfamethoxazole

– Blood brain barrier• More permeable in neonates

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• Metabolism– Hepatic enzyme activity varies significantly

• In general, neonates have prolonged elimination

– Majority of maturation of enzymatic pathways occurs within the first 6 months after birth

• Metabolic rate in young children exceeds adults

– Liver function tests (e.g. AST, ALT) are not good markers of metabolic function

– Example: Gray Baby Syndrome• Reduced glucuronidation in infants chloramphenicol toxicity

– Example: Acetaminophen• Primarily sulfation in neonates, minimal hydroxylation so toxicity less likely

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Developmental Pharmacokinetics• Excretion

– Correlation between gestational age and renal elimination of drugs

• Reduced # of nephrons, reduced tubular secretion

– Changes in GFR correlate to postmenstrual age (PMA)

0

20

40

60

80

Preterm Term

GFR

(mL/min/1.73m

2)

At Birth

2 weeks

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• Excretion

– “Normal” dosage of medications are adjusted for renally eliminated drugs based on age

– Example: Aminoglycosides

• If < 36 weeks’ PMA, administer every 36 hours

• If > 36 weeks’ PMA, administer every 24 hours

– Example: AmpicillinWeight

< 1200 gmWeight 1200 – 2000 gm Weight > 2000 gm

PNA 0 – 4 weeks

PNA 0– 7 days

PNA 8‐28 days

PNA 0 – 7 days

PNA8‐28 days

AmpicillinEvery 12 hours

Every 12 hours

Every 8 hours

Every 8 hours

Every 6 hours

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Drug Formulation Challenges: “Inactive” Ingredients

• Benzyl alcohol– Used as a preservative

• Often in injectable products

– Reports of:• Neonatal death

• Gasping syndrome including gasping respirations, metabolic acidosis, seizures, renal failure, cardiovascular collapse, intraventricular hemorrhage

• Kernicterus

– Toxicity reported at 32 – 105 mg/kg/day

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• Propylene glycol– Used as a solvent

• Contained in topical, oral, and injectable products

– Reports of:• Respiratory arrest

• Seizures

• Serum hyperosmolality

• Lactic acidosis

– Rapid infusion respiratory depression, arrhythmias, hypotension, seizures

– Toxicity reported at >3000 mg/day23


• Sulfites– Used as an antioxidant

– Reports of wheezing, dyspnea, chest tightness in patients with underlying lung disease

– Sensitivity increases with age of the child

• Methylparabens– Used as a preservative

– May displace bilirubin from albumin binding sites

– No reports of major adverse events

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• Ethanol

– Used as a solvent

– Reports of neurotoxicity, cardiovascular effects

• Polysorbate 80

– Used as an emulsifier

– Reports of liver and kidney failure, death

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• Peroxides

– Lipid peroxides and hydrogen peroxide form in light‐exposed parenteral nutrition

– Concern for association with morbidities in preterm neonates (e.g. bronchopulmonary dysplasia) due to oxidant stress

– Light shielding the bag, syringe, tubing may be of benefit

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• Phthalates

– Plastic devices made of polyvinyl chloride (PVC) contain di(2‐ethylhexyl)phthalate (DEHP)

• IV bags, IV tubing, feeding tubes, endotracheal tubes

– DEHP can leach into fluids and tissues

• More toxic metabolite mono(2‐ethylhexyl)phthalate

– Concern for anti‐androgenic effects, inflammatory effects, neuronal defects, retinal damage

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• STEP database

– Safety and Toxicity of Excipients for Paediatrics– http://pharmacyapp‐a.ucl.ac.uk:8080/eupfi/appDirectLink.do?appFlag=login

– Free database, registration required

– Compiles safety and toxicity data of excipients from multiple sources

– Does not make recommendations or provide a summary of data or a list of safe/unsafe agents

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Drug Formulation Challenges: Dosage Forms

• One size does NOT fit all

– Weight‐based dosing is typically used for medications

– And don’t forget about development pharmacokinetics

• Lack of “pediatric friendly” dosage forms

– Inability to swallow a solid dosage form

– Lack of liquid formulation / Unpalatable taste

– Parenteral products may be too concentrated to measure the desired dose

– Beware of excipients29


• Parenteral products– May require dilution to deliver proper dose

• Stability and sterility concerns

– Example: Gentamicin injection 40 mg/mL• 0.4 kg neonate x 5 mg/kg/dose = 2 mg

• 2 mg = 0.05 mL of Gentamicin 40 mg/mL

– Example: Dopamine infusion 3200 mcg/mL• 0.4 kg neonate x 5 mcg/kg/min x 60 min/hr

3200 mcg/mL

• = 0.0375 mL/hr

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• Parenteral products– Need for multiple concentrations

• Example: Dopamine 800, 1600, and 3200 mcg/mL

• 0.4 kg x 5 mcg/kg/min = 0.15 mL/hr using 800 mcg/mL

• 70 kg x 5 mcg/kg/min = 26 mL/hr using 800 mcg/mL

• 70 kg x 20 mcg/kg/min = 105 mL/hr using 800 mcg/mL

• 70 kg x 5 mcg/kg/min = 6.5 mL/hr using 3200 mcg/mL

– May be too hyperosmolar for peripheral administration

– Incompatibility with other drugs/solutions may necessitate multiple IV access sites

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“Off‐label” Medication Use

• Use of a drug in a way that is not addressed in the prescribing information (i.e., package insert, approved labeling)

• Does not mean:– Improper– Illegal– Contraindicated– Unstudied– Investigational

• ~2/3 of medications used in pediatric patients is “off‐label”

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Pediatric Drug Information References

• Pediatric & Neonatal Dosage Handbook (Lexicomp)– Comprehensive resource

– Contains information related to:• Dosing by age group

• Adverse reactions, warnings, contraindications

• Drug interactions

• Breast‐feeding and pregnancy considerations

• Pharmacokinetics/pharmacodynamics

• Drug administration

• Includes references

– Not the best reference for compatibility data

http://www.wolterskluwercdi.com/markets/pharmacists/#s‐books33

Pediatric Drug Information References

• Pediatric Injectable Drugs (The Teddy Bear Book)

– Contains information related to:

• Suitable diluents

• Maximum concentrations

• Additives

• Compatibility, stability, photosensitivity

• Infusion‐related cautions

• Medication error potential

• Dosing (may not be age‐specific especially for preterms)

• Includes references

https://store.ashp.org/Store/ProductListing/ProductDetails.aspx?productId=597629147 34



Other Drug Information References

• Handbook on Injectable Drugs (Trissel’s)– Good source for compatibility information

– May not have information on “pediatric” concentrations

• Micromedex Solutions– Pediatric dosing not specific

– Good source for compatibility & drug interactions

• Up‐to‐Date

– Drug monographs are from Lexicomp

• Updated more frequently than the print version

http://www.ahfsdruginformation.com/handbook‐on‐injectable‐drugs/https://www.micromedexsolutions.comhttps://www.uptodate.com 35

Conclusions

• The pediatric population is very diverse.

• Developmental pharmacokinetics have a large impact on medication selection, dosing, and toxicity.

• Adult data may not apply to children.

• Not all drug information references are created equal.

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References

• American Academy of Pediatrics, Committee on Drugs. “Inactive” ingredients in pharmaceutical products: update. Pediatrics 1997;99:268‐78.

• American Academy of Pediatrics, Committee on Drugs. Off‐label use of drugs in children. Pediatrics 2014;133:563‐7.

• American Academy of Pediatrics, Committee on Fetus and Newborn. Age terminology during the perinatal period. Pediatrics 2004;114:1362‐4.

• Hoff DS, Michaelson AS. Effects of light exposure on total parenteral nutrition and its implications in the neonatal population. JPPT 2009;14:132‐43.

• Ivanovska V, Rademaker C, van Dijk L, et al. Pediatric drug formulations: a review of challenges and progress. Pediatrics 2014;134:361‐72.

• Mallow EB, Fox MA. Phthalates and critically ill neonates: device‐related exposures and non‐endocrine toxic risks. J Perinatol 2014;34:892‐7.

• Massanari M, McLocklin A, Sayles R, et al. Age‐based competency assessment of pharmacists in pediatrics, part II: application of developmental pharmacokinetics to pediatric pharmacy practice. JPPT 1997;2:139‐157.

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Considerations for Sterile Compounding of ... - ProCE