Off-label use of MISOPROSTOL Dr Andrew Weeks Clinical Lecturer

“Misoprostol seems excellent for use in obstetrics and gynaecology” “But its not licensed, and the drug company haven’t approved it. You will be in trouble if you use it”

Outline 1.History of misoprostol 2.Drug company attitudes 3.Licensing laws 4.The way forward

History of Misoprostol 1985Misoprostol licensed by Searle 1985Searle & Monsanto merger 2000Monsanto & Pharmacia merger = Pharmacia 2003Pharmacia and Pfizer merger = Pfizer

Misoprostol 1984 first licensed 1987 first use for abortion (1989 illegal use in brazil common) 1992 first use for IOL and miscarriage 1996 first use for PPH prevention 2000 FDA license for abortion (with mifepristone for medical abortion)

But - no license applied for Searle decision not to apply for it – Lucrative gastric ulcer market – Costs in price and reputation – US publicity on ‘abortion drug’ – Experience of Roussel with mifepristone 1997 gave miso to WHO for PPH trial Public letter in 2000

What is a license? Protect patients from drug companies NOT to guide doctors Costs $900 million to get a license National drug authorities (MHRA / FDA) - risk benefit analysis Drug company - cost-benefit analysis

Licensing of drugs Usually new expensive drugs in low risk indications NOT FOR Old drugs in new indications Cheap / generic drugs High risk situations (paeds / O&G)

Nitrofurantoin for UTI in pregnancy Nevirapine for reduction of mother-to- child HIV transmission Nifedipine for high bp in pregnancy Oxytocin 10iu im to prevent PPH Betamethasone for lung maturation 46% off-label use in European paediatric wards Conroy et al BMJ 2000;320:79-82.

Misoprostol use for Reproductive Health "Yes " –FDA –RCOG / ACOG –Specialist societies –British National Formulary " No " –Drug company

Who do you trust?

Legal Test in UK Bolam test ‘what a representative group of doctors at the same level would reasonably be expected to do’ 1.Government guidelines committee (NICE) 2.WHO / National O&G Society guidelines 3.Local guidelines 4.BNF 5.License

The Way Forward Produce evidence-based guidelines at national / international level Ignore drug license for now if better evidence available (consider joint licensing / guideline groups) RH organisations should produce statements to support local doctors