Excipients in Pediatric Medicines: a Health Canada Perspective

Excipients in Pediatric Medicines: A Health Canada Perspective

CSPS Workshop: Excipients September 20, 2019

Susan Lum, RPh, PhD Therapeutic Products Directorate

1 Better medicines for children

Medical Needs of the Pediatric Population

Technical Public/Patient Pediatric Drug Formulation Market Development Development Expectations Challenges

Clinical Barriers

2 Pediatric Incentives – Access to Commercialized Pediatric Medicines Global regulatory incentives (US FDA, EMA) and regulations have been drivers of growth of the pediatric pharmaceutical market. Mandatory Measures** * *Excludes generic development unless changes to the FDA has the authority to require pediatric RLD (dosage form, route or API) would trigger Pediatric Research studies if meaningful therapeutic benefit exists conducting some form of pediatric investigation Equity Act (PREA) - for all NDAs and BLAs unless the applicant has obtained a waiver or deferral. Limited to same indication as in adults.

European Paediatric investigation plans (PIPs) are Medicines Agency required for all new products – submission is (EMA) incomplete without agreed PIP (specific or class-specific waiver or deferral) Voluntary Measures

Provides a six-month marketing exclusivity Best Pharmaceuticals for incentive to sponsors of marketed products Children Act (BPCA) that conduct pediatric studies in response to a written request from FDA .

Provides 10 years of market protection for drugs with specific pediatric authorization Pediatric use Market reward on off patent medicines marketed Authorization (PUMA) products to conduct pediatric studies

3 Canadian – Access to Commercialized Pediatric Medicines • Review* of globally approved oral pediatric formulations shows about 1/3 of commercially available medications are approved and marketed in Canada • Approx. 1/3* of the types of pediatric oral medications are marketed in Canada  Tablets (to swallow, scored, orally disintegrating, chewable)  Ready to use or powder for oral solution  Ready to use or powder for oral suspensions  Oral granules

• Improved access is needed for preservative free, taste masked medicines . mini-tablets, granules, multiparticulates, powders in stick packets or sachets . Soluble thin strips . Specific dose administration calibrated devices eg. Pre-filled syringes for buccal . Two piece capsules • Since 2007, new pediatric formulations approved and marketed in Canada include:  Tivicay (tablets) – antiviral  Aptiom (tablets) – seizure therapy  Orkambi (lumacaftor/ivacaftor, granules) – treatment of cystic fibrosis  Zofran (ondansetron, oral solution) – prevention of nausea  Isentress (raltigravir, chewable tablet) - antiviral  Posanol (posaconazole, oral suspn) – antifungal  Carbaglu (carglumic acid, dispersible tablet) – for chronic hyperammonemia  Afinitor (everolimus, oral suspns) – seizure therapy  Sabril (vigabatrin – pwd oral soln) – treatment of infantile spasms

*Refs: Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774 Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335- 1365 4 Use of Foreign Reviews – pediatric medications not otherwise broadly available

• International collaboration

• Use of Foreign Reviews would allow drug submissions, that might not otherwise be filed in Canada • Foreign decisions pathway aims to facilitated access for Canadians to therapeutic products that meet a medical need • Leverages the scientific reviews completed by trusted foreign regulators to reduce unnecessary duplication while maintaining the integrity of Health Canada’s regulatory review process (eg. relying on third party data) • Significant international post-market experience

• Improved access

5 Better Medicines for Children – Challenges (Time, Cost, Risks)

• Includes 20-fold increase in patient size/weight between birth and adulthood • Accompanying need to greatly increase dosages during growth • Masking a drug's taste to improve patient compliance • Identifying excipients to make the product palatable  Disease state can also impact taste/smell perception • Oral liquids are challenging to develop in a stable form  Increased susceptibility to microbial contamination vs. solid dosage forms • Formulations deemed acceptable by children have expiration periods too short for commercial viability • Achieving global regulatory acceptability • Rapid patient access • Accelerated development timelines

6 Pediatric Considerations

“The joint goal for industry, regulators, practitioners and patients is to encourage paediatric drug development in order to create a situation where substantially more children have access to safe and effective medication” European Federation of Pharmaceutical Industries and Associations (Efpi) 2009 position paper “Industry Perspectives on Pharmaceutical Development of Medicines for Paediatric Use” •Age-appropriate formulations Appropriate route of administration Appropriate dosing volumes (oral and injectable) Appropriate excipients and levels For oral formulations – Palatable •Appropriate stability and taste acceptance Ease of dosing and patient compliance •Dosage form child can take / caregiver can administer •Dose flexibility while maintaining accuracy and safety •Patient accessibility

7 Physiological concerns – once size does not fit all

Spectrum within the pediatric population

Source: Kearns, G.L. et al. Developmental Pharmacology- Drug Disposition, Action and Therapy in Infants and Children,, N.Eng. J. Med., 349 (2003) ; Tetelbaum, M, et. Al. Back to basics: Understanding drugs in children: Pharmacokinetic Maturation, Pediatrics in Review (2005) 26: 321-328 1160 8 Developmental Physiological Changes – impact on drug disposition

Source: Kearns, G.L. et al. Developmental Pharmacology- Drug Disposition, Action and Therapy in Infants and Children,, N.Eng. J. Med., 349 (2003) 1160

9 Evolution in Age Appropriate Dosage Forms

Pediatric Dosage Form Suitability

Term Preterm newborn Infants and Children Children newborn infants toddlers (pre-school) (school) Adolescents Dosage form infants (0d – 28d) (1m-2y) (2-5y) (6-11y) (12-16/18y)

Solution/drops

Emulsion/suspension

Effervescent dosage forms

Powders/multiparticulates/ mini-tablets

Orodispersable form

Chewable tablets

Tablets

Capsules

Not applicable or applicable with problems Acceptable/preferred Dosage form of choice

Source: European Medicines Agency: Reflection paper: formulations of choice for the pediatric population 28 July 2006 Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774

10 Assessment

Source: Case studies on pharmaceutical development of pediatric products for the global market, AAPS-PSWC Workshop 2010

11 Excipients – pediatric formulations Major difference for a pediatric formulation compared with an adult formulation is an added layer of investigation when selecting excipients Excipients chosen must be determined based on the specific drug under development as well as the pediatric product profile • Effects of excipient in children of different ages, developmental stages • Exposure, metabolism, elimination – safety of excipients (ICH S11 (draft)) • National databases for registered products • FDA IID – not updated – not stratified to pediatric indications • UK Electronic Medicines Compendium • Publically available excipient databases • Endorsed by regulatory agencies? • eg. Safety and Toxicity of Excipients for Paediatrics (STEP) EuPFI

Refs: Buckley, L.A., et al. Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients, Int. J. Pharm. 536(2) 2018 pp. 563-569 Schmitt, G. Safety of Excipients in Pediatric Formulations – a call for toxicity studies in junvenile animals? Children (2) 2015 pp. 191-197 12 Excipient Safety “All substance are poisons, there is none which is not a poison. The right dose differentiates a poison from remedy.” (Paracelsus 1493-1541)

If all excipients = active chemical components of pharmaceutical products Requires the same ADME and pharmacodynamic evaluations as actives Ignores prior history of use in patients Adverse events linked to dosing excipients > recommended ADI (mg/kg) (ref. Shehab, N., et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates, Pediatric critical care medicine, 10(2) 2009 256-9. Cumulative dose in neonates median 4.5 mg/kg/day (0.6-319.5 mg/kg/day) for benzyl alcohol and 204.9 mg/kg/day (17.3-9472.7 mg/kg/day) for propylene glycol) Nahata, MC., Safety of “inert” additives or excipients in pediatric medicines, Arch Dis Child Fetal Neonatal Ed 94 (2009) F392-393 Brown WJ, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit Lancet 1982;1250 - benzyl alcohol preserved intravascular flush from 99-234 mg/kg/day >> 5mg/kg/day ADI Excipients of concern in adults – particular concern in children Ref. Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668) – Excipients and information for the package leaflet EMA/CHMP/302620/2017 corr. 1*

13 Excipient Evaluation • Compilation of all nonclinical and human safety data • Assessment of an excipient based on exposure – context of use • Context of the data with the risk and the anticipated health benefit of the formulation to the patient • Leverage experience if excipients used in foods • Risk management decisions informed by specific risk assessment methods and choices - scope • ADIs established by the WHO based on epidemiologic and toxicological data evaluated to determine ‘critical effect’ used in dose response evaluation --Joint FAO/WHO Committee on Food Additives (JECFA) and European Food Safety Authority (EFSA). • No-observed-adverse-effect-level (NOAEL) adjusted by safety factors to establish an acceptable dose of exposure usually >100 x below dose causing no effects in animals (NOEL) • Based on long-term studies and observations of humans – safe intake level for an adult that may be ingested over a lifetime without an appreciable health risk “Biological pathways involved in the response to the drugs in infants and children is often available from studies in adults – basic information about the actions of already-approved and investigational medications.* • Internal datamining (use and levels /exposure in other approved therapeutic products) • Uncertainty in extrapolation of exposure and effect between adults and children • Extrapolation between non-clinical species and humans • Toxicology studies in juvenile animals may be needed (novel excipients in pediatric medicines) • Characterize effects on growth and development • Neonates – vulnerability to adverse effects

* Ref: Pediatric pharmacology expert J. Steven Leeder of Children's Mercy Hospitals and Clinics in St. Louis, Missouri, Pediatric subcommittee of the Oncologic Drugs Advisory Committee, 15 Dec 2009 14 Risk based assessments

• Identify the pediatric population and recommended dose based on weight or body surface area (BSA) • The excipient exposure should be calculated based on maximum recommended dose (mg/kg/day) for each pediatric category (eg. based on age, weight) • Permitted Daily Exposure (PDE) for the excipient should be estimated – based on available NOAEL from public literature (mg/kg/day) using the most conservative data eg weight – with several fold safety margins PDE = NOAEL (mg/kg/day) x Weight Adjustment (kg) / F1 x F2 x F3 x F4 x F5 x F6 F1= 5, to account for extrapolation from eg. rat to humans F2= 10, to account for differences between individual humans F3= 1, for a eg. 4 month study in rodents; F4= 5, for pre-cancerous lesion observed; F5= 1, given that a NOAEL was established F6 = 10 or 100 include also safety factor of a minimum of 10 for neonates and infants

* Ref: Pediatric pharmacology expert J. Steven Leeder of Children's Mercy Hospitals and Clinics in St. Louis, Missouri, Pediatric subcommittee of the Oncologic Drugs Advisory Committee, 15 Dec 2009

15 Notable Excipients

• Sweeteners (eg. aspartame, fructose, glucose, maltitol, mannitol, sorbitol, sucrose, xylitol) • Preservatives (eg. benzoates, benzyl alcohol, sulphites) • Enhancers (eg. cyclodextrins, ethanol, propylene glycol)

Sweeteners: For taste masking: Enhancers/surfactants: acesulfame K carbomers (polyoxyl) castor oil, lecithin aspartame celullose acetate docusate sodium dextrose, fructose, glucose ethylcellulose glycerol / macrogol stearate eErythritol glyceryl behenate medium chain triglycerides monoammmoniumglycyrrhizinate povidone/crospovidone PEG, propylene glycol maltodextrin, maltol methacrylate copolymers Poloxamers mannitol, sorbitol, xylitol sodium polystyrene polysorbates saccharin (Na) sulfonate (ion exchange TPGS resins) sucralose Sodium lauryl sulfate xanthan gum sucrose

*Refs: Annex to the European Commission guidline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668) – Excipients and information for the package leaflet EMA/CHMP/302620/2017 corr. 1* Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774 Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335- 1365 16 17 18 *carbomers, celullose acetate, ethylcellulose, glyceryl behenate, povidone/crospovidone, methacrylate copolymers, sodium polystyrene sulfonate (ion exchange resins), xanthan gum

*Refs: Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774 Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335- 1365 19 Sweeteners – approved in medications with pediatric indications

*Acesulfame K, aspartame, dextrose, erythritol, fructose, glycerol, high fructose corn syrup, monoammmonium glycyrrhizinate, maltodextrin maltol, mannitol, saccharin (Na), sorbitol, sucralose, sucrose Regulatory acceptance Liquid development Toxicity • Aspartame shows hydrolysis in Contribution to osmotic solution and high temperature storage load Gastrointestinal tolerance Physical chemical stability • Disaccharide type alcohols Manufacturability • Sucrose has no effect on small Flavor development intestinal transit rate Relative sweetness Low melting points, adhesion Onset and poor flow Duration • Managed with processing and Bitterness suppression particle size controls

*Refs: Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774 Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335- 1365 20 Contribution to osmolar effects – initial estimates

Source: Case studies on pharmaceutical development of pediatric products for the global market, AAPS-PSWC Workshop 2010 21 Flavour and Sweeteners – stability in aged product

• Flavors or sweeteners may be solid • Oil soluble carriers or liquid  soybean, other oils  Development studies eg. e-tongue • Water soluble carriers  water, ethanol, propylene glycol, • Evaluate chemical and organoleptic glycerin and emulsifiers stability • Dry carriers  Degrade with light, temperature, headspace oxygen, water etc.  maltodextrin, corn syrup solids, modified starches, gum arabic,  Some are not stable in liquids or sugars, whey protein form insoluble complexes

• Organoleptic / sensory evaluation  Or quantitative analytical assessment eg. HPLC/ GC chromatogram

22 Parabens

In adults FDA has approved parabens in foods [methylparaben (21 CFR 184.1490) and propylparaben (21 CFR 184.1670)] are (GRAS) when used as chemical preservatives in foods, with use limits of 0.1% each. European Food Safety Authority (EFSA) Scientific Panel on Food Additives, Flavorings, Processing Aids and Materials in Contact with Food adopted the ADI of 0 to 10 mg/kg/day as an opinion on the safety of paraben usage in food (EFSA 2004, (Directive 2006/52/EC)) EMA reflection papers propose ADIs of 10 mg/kg/day for methylparabens and 2mg/kg/day propylparabens for pediatric and adult populations

Parabens concentrations in approved products (listed in IID 2019) FDA database Form Methyl- Na methyl - Na ethyl- Propyl Na propyl Butyl Oral / Soln 2mg/ dose 2.6 mg/mL 50 mg/mL 0.2 mg/mL 16.88 mg/75 mL 0.08 mg/mL Oral / Suspn 1000 mg/ 5 mL 3.43 mg/mL 2 mg/ 5 mL -- -- 8 mg/ 5 mL Oral/Liquid suspn 1 mg/ mL -- -- 200 mg/ 5mL 1mg/5mL 6 mg/ 120 mL Syrup 50 mg/mL ------28.4 mg/mL

Methylparaben Propylparabens Range % 0.015 – 0.2 0.02 – 0.06 Max/day (50kg adult) 2.8 mg/kg/day 1 mg/kg/day PDE 10 mg/kg 2 mg/kg Calculate the maximum intake per day based on the maximum recommended dose and compare to the permitted daily exposure (PDE) of the excipient

1 month infant Infant Child Adolescent/Adult weight ca. 4.5 kg < 7 kg conservative 10kg ~ 50 kg

In children ↑ risk of severe hypoglycemia due to acute ethanol intoxication < 5% and/or the medicinal product should not produce blood ethanol concentration > 0.125 g/L following the administration of only one dose* FDA limits OTC liquids to NMT 5% ethanol. WHO NMT 0.5% for children < 6yrs

Calculated limit example – should consider the dose volume For a 6-year old 20 kg child this is equivalent to the ingestion of 1.5 g ethanol = 1.9 mL ethanol = ingestion of 38 mL of solution containing 5% v/v ethanol = 75 mg/kg EMA (2014) limits to blood alcohol concentration Ethanol 2 – 6 yrs > 6 yrs Adult BAC 0.01 g/L 0.125 g/L 0.5 g/L – 3 g/L Dose (g)/ [Vol. Distrib (L/kg) x Wt (kg) ] As noted by the JECFA (reported by Joint FAO/WHO Expert Committee on Food Additives) ethanol poses no safety concern at its current level of intake when used in flavoring agents *Refs: EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2 EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005 EMA Questions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and 6 package leaflet of medicinal products for human use’ (CPMP/463/00) EMA/CHMP/507988/2013 (2014) 24 Ethanol and Propylene Glycol as an Excipient in Pediatric Medicines

1 month infant Infant Child Adolescent/Adult weight ca. 4.5 kg < 7 kg conservative 10kg ~ 50 kg

In neonates ↓ ability to eliminate propylene glycol may = adverse events including serious heart, kidney, breathing problems concomitant administration with ethanol inhibits metabolism

accumulation risk*

JECFA (reported by Joint FAO/WHO Expert Committee on Food Additives) ADI < 25 mg/kg

EMA limits

Propylene glycol neonates 1 month - 5 yrs > 5 yrs- Adult 1 mg/kg/day 50 mg/kg/day 500 mg/kg/day

*Refs: EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2 EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005 EMA Questions and answers on propylene glycol used as an excipient in medicinal products for human use (2017) EMA/CHMP/704195/2013 25 References • Buckley, L.A., et al. Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients, Int. J. Pharm. 536(2) 2018 pp. 563-569 • EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2 • EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005 • EMA reflection paper on the use of methyl- and propylparaben as excipients in human medicinal products for oral use (2015) EMA/CHMP/SWP/272921/2012 • Schmitt, G. Safety of Excipients in Pediatric Formulations – a call for toxicity studies in juvenile animals? Children (2) 2015 pp. 191-197 • Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations Ju. Pharm. Sci. 97(5) 2008 pp. 1731-1774 • Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335-1365 • Valeur, K.S., et al, Excipients in neonatal medicinal products: never prescribed, commonly administered, Pharmaceutical Medicine, 32 (2018) pp 251-258

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