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

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LUNCH AND LEARN Considerations for Sterile Compounding of Parenteral Products for Pediatric Use: Part 1 October 13, 2017 Featured Speaker: Kirsten H.

Chicago College of Pharmacy CE Activity Information & Accreditation (Pharmacist and Tech CE) 1.0 contact hour Funding: This activity is self funded through PharMEDium.

1 LUNCH AND LEARN Considerations for Sterile Compounding of Parenteral Products for Pediatric Use: Part 1 October 13, 2017 Featured Speaker: Kirsten H. Ohler, PharmD, BCPS, BCPPS Neonatal / Pediatric Clinical Pharmacist Clinical Associate Professor, Pharmacy Practice Program Director, PGY2 Pediatric Pharmacy Residency University of Illinois at Chicago College of Pharmacy CE Activity Information & Accreditation (Pharmacist and Tech CE) 1.0 contact hour Funding: This activity is self funded through PharMEDium. It is the policy of 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

2 Online Evaluation, Self-Assessment and CE Credit Submission of an online self assessment and evaluation is the only way to obtain CE credit for this webinar Go to Print your CE Statement online Live CE Deadline: November 10, 2017 CPE Monitor CE information automatically uploaded to NABP/CPE Monitor upon completion of the self assessment and evaluation (user must complete the claim credit step) Attendance Code Code will be provided at the end of today s activity Attendance Code not needed for On Demand 3 Ask a Question Submit your questions to your site manager. Questions will be answered at the end of the presentation. Your question...? 4 2

3 Resources Visit to access: Handouts Activity information Upcoming live webinar dates Links to receive CE credit 5 Considerations for Sterile Compounding of Parenteral Products for Pediatric Use: Part 1 Kirsten H. Ohler, PharmD, BCPS, BCPPS Clinical Associate Professor, Pharmacy Practice Clinical Pharmacy Specialist, NICU University of Illinois at Chicago 6 3

4 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. 7 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

5 Who is a Pediatric Patient? Neonate Infant Child Adolescent Birth to 28 days >28 days to 12 months 1 to 12 years 13 to 17 years 9 Neonates A Week in the Life Gestational Age (GA) Chronological Age Or Postnatal Age (PNA) Conception Birth Today s Date Postmenstrual Age (PMA) Term: born >37 weeks gestation Preterm: born before 37 weeks gestation

6 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 11 Effect of age/maturation on absorption, distribution, metabolism, and elimination (ADME) of medications Affects medication dosing, potential adverse effects, and efficacy

7 Absorption Transfer of medication into the bloodstream from the site of administration Drug delivery by parenteral, percutaneous, and enteral routes may all be affected 13 Absorption Parenteral Intravenous May be affected by drug delivery system (more about this later ) Intramuscular Low muscle mass / muscle activity in preterm neonates

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

8 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 effects 15 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

9 Distribution Total body water % of total body wt Neonate Infant Adolescent Water soluble drugs have a higher volume of distribution (Vd) in neonates Higher dose per kilogram may be needed 17 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

10 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 19 Excretion Correlation between gestational age and renal elimination of drugs Reduced # of nephrons, reduced tubular secretion GFR (ml/min/1.73m 2 ) Preterm Term At Birth 2 weeks Changes in GFR correlate to postmenstrual age (PMA)

11 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: Ampicillin Ampicillin Weight < 1200 gm PNA 0 4 weeks Every 12 hours Weight gm Weight > 2000 gm PNA 0 7 days Every 12 hours PNA 8 28 days Every 8 hours PNA 0 7 days Every 8 hours PNA 8 28 days Every 6 hours 21 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 mg/kg/day

12 Inactive Ingredients 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/day 23 Inactive Ingredients 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

13 Ethanol Inactive Ingredients Used as a solvent Reports of neurotoxicity, cardiovascular effects Polysorbate 80 Used as an emulsifier Reports of liver and kidney failure, death 25 Peroxides Inactive Ingredients 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

14 Inactive Ingredients 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 27 Inactive Ingredients STEP database Safety and Toxicity of Excipients for Paediatrics 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

15 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 excipients 29 Dosage Forms 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 = ml/hr

16 Dosage Forms 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 31 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

Pediatric Drug Information References Pediatric & Neonatal Dosage Handbook (Lexicomp ) Comprehensive resource Contains information related to: Dosing by age group Adverse reactions, warnings,

17 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 books 33 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 Details.aspx?productId=

18 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 on injectable drugs/ 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

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.

19 References American Academy of Pediatrics, Committee on Drugs. Inactive ingredients in pharmaceutical products: update. Pediatrics 1997;99: American Academy of Pediatrics, Committee on Drugs. Off label use of drugs in children. Pediatrics 2014;133: American Academy of Pediatrics, Committee on Fetus and Newborn. Age terminology during the perinatal period. Pediatrics 2004;114: Hoff DS, Michaelson AS. Effects of light exposure on total parenteral nutrition and its implications in the neonatal population. JPPT 2009;14: Ivanovska V, Rademaker C, van Dijk L, et al. Pediatric drug formulations: a review of challenges and progress. Pediatrics 2014;134: Mallow EB, Fox MA. Phthalates and critically ill neonates: device related exposures and nonendocrine toxic risks. J Perinatol 2014;34: 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:

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