Safe Supply of Paediatric Unlicensed Medicines Steve Tomlin Consultant Paediatric Pharmacist Honorary Clinical Reader

Every Dose Is Different Is dosing in adults logical? One size fits all – useful for tablets Paracetamol, ranitidine When does a child become an adult? Mg/kg When can doses be rounded up or down? Paracetamol, cefuroxime Is Licensing Logical? Aciclovir

What do children take? Dose (mg) 30 60 120 250 500 Dosage form? Drops Liquid/melt Liquid/melt/ tablet Tablet/ capsule

Therapeutic Orphans Europe - >50% of medicines used in children have never been tested in children. Conroy S, Br Med J. 2000, 320:79-82 Australia - 25% of medicines licensed in children do not have appropriate formulations for children. Tan E, Med J Aust. 2003, 179(4):195-8 1/3 of research papers into children’s medicines did not allow for the work to be reproduced / 51% did not use a paediatric formulation. Standing J, Paediatrics. 2005, 116(4):559-562 Pandit S, Arch Dis Child. 2010, 95:754-756

Unlicensed & Off-Label Medication Proportion of medicines used not licensed: 80% Neonatal Intensive Care Unit (NICU) 40% Paediatric Intensive Care (PICU) 25% general paediatric in-patients 11% children at home Nunn A, 2003, Arch Dis Child. 2003. 88:369-371

Policy statement Joint RCPCH/NPPG Standing Committee on Medicines ‘it is not necessary to take additional steps, beyond those taken when prescribing licensed medicines, to obtain the consent of parents, carers and child patients to prescribe or administer unlicensed medicines or licensed medicines for unlicensed applications.’ Treatment Should Be The Best You Can Give!

Paediatric Patient Needs Age-appropriate formulations Type of formulation (liquid / solid) Dose flexibility Excipients and levels Ease of dosing and compliance Palatability Frequency of dosing Ease of manipulation (by carer) Perceptions of parent / carer?

What medicine are you getting? Licensed In Some Children Licensed Adult Medicine Import Special Extemporaneously Prepared Product aligned to Clinical Need

Intravenous Preparations Hospital Neonatal Unit 31% of prescriptions < 1/10 vial 4.8% of prescriptions <1/100 vial Arch Dis Child. 2000; 834:92-6 Dose calculations often involve decimal points Units often have to change – how to label Standard Concentrations

IV Formulation Benzyl alcohol harmful in infants contained in e.g. amiodarone and lorazepam injections Shehab N, Pediatr Crit Care Med. 2009. 10(2): 256-259 Phenobarbital injection – 90% propylene glycol  hyperosmolality in infants, pH 11 Ibuprofen – lignocaine in premature babies Paracetamol – 10 x overdoses Phenytoin – need to dilute, but it precipitates

Oral Formulations Phenobarbital elixir BP – 38% alcohol Sugar or Sorbitol? Dispersible Tablets (aspirin and diclofenac) The history of nifedipine Tuleu C, J of Drug Delivery Science & Tech. 2005. 15(4): 319-324 Captopril – bioequivalence? Mulla H, Arch Dis Child. 2007. 92:409-411 Clobazam – what’s left in the bottle Glass ampoules for oral solutions? (vitamin K, Caffeine)

Import/export of captopril oral liquid 10578 miles each way BMS, UK No MA for children Not bioequivalent to: tablets compounded liquids BMS, Victoria, Australia 12

Changing Medicines Crushing tablets can change profile Increase side effects Decrease duration

Pharmaceutical Issues when Crushing, Opening or Splitting Oral Dosage Forms June 2011 Changing the way in which a dosage form is presented can alter its absorption characteristics, result in medicines instability, produce local irritant effects, cause failure to reach the site of action, may produce occupational health and safety issues, and could result in a preparation with an unacceptable taste. .. In most circumstances in which no appropriate licensed medicine is available, the prime objective should be to provide patients with a ready-to-use unlicensed medicine.

Other Routes INTRANASAL TOPICAL RECTAL Midazolam – why do they cry? Chlorhexidine – it just cleans the skin!! RECTAL Glycerine Chips Paracetamol / Morphine

The Future Standardisation / Formulary BP? BNF-C? Directed Prescribing Defined Drop down boxes Tighter Tariff