© 2011 A J Nunn

International initiatives on extemporaneous dispensing

Tony Nunn and Mark Turner

UK Medicines for Children Research NetworkUniversity of Liverpool

Industry ProfessorLiverpool John Moores University

Anita AindowAlder Hey Children’s Hospital, Liverpool

David WoodsUniversity of Otago, Dunedin, New Zealand

Partners’ meetingWHO, Geneva 21‐22 November 2011

© 2011 A J Nunn

Definitions

• "the manipulation by pharmacists of various drug and chemical ingredients using traditional compounding techniques to produce suitable medicines when no commercial form is available”*

• may also be prepared from authorized dosage forms and commercial or locally‐produced suspending agents

• “compounding” preferred term

*Brion F, Nunn AJ, Rieutord A. Extemporaneous (magistral) preparation of oral medicines for children in European Hospitals. Acta Paediatr. 2003; (294): 486-496.

© 2011 A J Nunn

• ‘Western’ countries– Practitioners

• ‘off‐label’ use of medicines– Industry

• clinical trials• small markets/difficult formulations

– Regulators• quality• bioavailability

• Resource‐poor countries– Access 

• liquid medicines not listed/purchased– Cost

• Liquid medicines  20x  more expensive than solid dosage forms

Need

© 2011 A J Nunn

EMLc

http://whqlibdoc.who.int/hq/2011/a95054_eng.pdf3rd edition March 2011

Lists some age-appropriate formulations but not available in all countries

© 2011 A J Nunn

WHO Model Formulary for Children

http://www.who.int/selection_medicines/list/WMFc_2010.pdf

Lists some age-appropriate formulations but not available in all countries

© 2011 A J Nunn

Availability of essential medicines for children

Robertson J et al (2009). What essential medicines for children are on the shelf? Bull World Health Org; 87(3):231-7

© 2011 A J Nunn

• Commonwealth Pharmacists Association (Farwell, J)– Survey results (initial)

• 11 Anglophone African respondents• 60 preparations• 33/60 (55%) available as authorised age‐appropriate formulations in UK

• Commonest– Oral furosemide; ciprofloxacin; digoxin; paracetamol– Oral quinine; isoniazid

• Woods, D– Information requests 2001‐2009 (paediatric formulations database)

• 332/475 (70%) about compounding of preparations available in other markets

• Commonest– Quinine; rifampicin; prednisone

Information about compounding

© 2011 A J Nunn

Availability of ingredients for compounding

• Active ingredients– Sources; cost; quality

• Suspending agents– Availability; cost

• Excipients– Availability; cost; qualitye.g. Tamiflu® authorized compounded liquid requires

• North American label– Cherry Syrup (Humco®) – Ora‐Sweet® SF (Paddock Laboratories) 

• EU SmPC– Sodium benzoate 0.1% 

© 2011 A J Nunn

Medication error potential

Choonara I. 

WHO wants safer medicines for children. 

Arch Dis Child 2008;93:456‐457

e.g.  diethylene glycol in place of propylene glycol

wrong strength chloroform water

© 2011 A J Nunn

WHO/UNICEFCopenhagen 2010

• Review commissioned– Existing guidance/advisory documents 

• how medicines should be administered to children

– General instructions on• compounded preparations

• manipulation of adult dosage forms

• Guideline to be prepared– Extemporaneous dispensing and administration of medicines to children

© 2011 A J Nunn

Progress

• Early draft guideline considered– EMLc committee meeting, Ghana, March 2011

• Final drafts– WHO informal consultation on paediatrics and generics guidelines development, Geneva, May 2011 (amended from comments)

– WHO Expert Committee on the Specification of Pharmaceuticals, Geneva, 11‐13 October 2011

© 2011 A J Nunn

WHO view• Concerned about risks of 

– inappropriate compounded preparations– diverting efforts aimed at the development of age‐appropriate 

dosage forms for children– potentially conflicting signals arising from a WHO publication 

that might appear to endorse wider use of manipulation of adult dosage forms for children

• Agreed– finalise for publication as a time‐limited guidance that 

addresses the current need for advice– amend title because of lack of clarity around ‘extemporaneous’

• ‘Provision by health‐care professionals of patient‐specific preparations for children that are not available as authorized products’

– ‘points to consider’ rather than ‘guidelines’

© 2011 A J Nunn

WHO view

• WHO endorsement of extemporaneous use should not be seen as indicating a lack of need for commercially available paediatric dosage forms

• Recommendations removed

© 2011 A J Nunn

WHO view

• WHO Expert Committee on the Specification of Pharmaceuticals, Geneva, 11‐13 October 2011 – unedited minutes– The Expert Committee expressed appreciation of the document as a source of general guidance.

– The Committee advised that the document could be further developed jointly by WHO and FIP as practice guidance for compounding.

– No mention of the recommendations

© 2011 A J Nunn

Main themes of guidance

• Ensure commercial age‐appropriate dosage forms available whenever possible– Compounding as a last resort

• Prescribers aware of the dosage forms available locally– Rationalised prescribing ‐ education– Dose rounding – information in Model Formulary– Therapeutic substitution – guidance required

• Manipulation of dosage forms– Investigation and information– Assurances and information from manufacturers

© 2011 A J Nunn

Main themes of guidance

• Compounding as a last resort– Use ‘adult’ dosage forms + suspending agent 

• Generic suspending base to be developed– Stability studies with common drugs– Dry powder version for reconstitution

• Information on validated, simple formulations– List of ‘safe’ excipients– Formulations with minimum of excipients

– Establish minimum standards• Education and information

– Drug administration and compounding– Link paediatric centres and share information

© 2011 A J Nunn

Industry can help

• Affordable– Age‐appropriate dosage forms

• WHO priority list• WHO EMLc

– Suspending vehicles• Validate

– Compounding from ‘adult’ dosage form• With ingredients readily available

– Manipulation of ‘adult’ dosage forms• Including addition to food, milk and liquids

• Make information available

© 2011 A J Nunn

Recommendations

• Abridged version vailable in hard copy

• Provide information in WHO model formulary

© 2011 A J Nunn

Conclusion

• ‘Western’ countries– ‘Therapeutic orphans’

• Harry Shirkey (1963)1• no authorised medicine• little information• no age appropriate formulation

• ‘Resource‐poor countries– May have no medicine at all– Action required– Recommendations should be fully evaluated

1 Shirkey H. Editorial comment: Therapeutic Orphans. J Pediatr 1968: 72: 119-120

© 2011 A J Nunn

Resources

• Draft ‘points to consider’ document

http://www.who.int/medicines/areas/quality_safety/quality_assurance/ProvisionHealthCareProfessionals_QAS11‐399Rev1_17082011.pdf

• Draft literature review

http://www.who.int/medicines/areas/quality_safety/quality_assurance/Review‐findings‐PaediatricMedicnesAdmin_QAS11‐400Rev1_22082011.pdf