A service commissioned by the HPA NPIS Edinburgh The role of medicines regulation in prevention of serious poisoning Nick Bateman Professor in Clinical Toxicology & Consultant Physician RIE Director, NPIS Edinburgh

1.Medicines Regulation Prescription and OTC products 2. Prevention strategies What works- and perhaps doesn’t 3. Some ideas for the future CONTENT

1.European licensing structure EMEA 2. Member states actions May take note of local circumstances Prescription only Pharmacy sale General sale products (OTC) Medicines Regulation

1.Changes to package/ presentation/ labelling (eg specific warnings) 2.Changes to category (eg drugs of potential abuse, prescription only, pharmacy supply, general sale) 3.Changes to indication (may limit supply, reduce hazard in “at risk” groups) via SPC, doctors letter etc 4.Licence revocation REGULATORY ACTIONS

Insist on entirely new formulations (eg antidote inclusion) if efficacy and safety in routine use demonstrated Withdraw products just because of problems in overdose if normal use acceptably safe WHAT THEY CANNOT DO

If it is not available you cannot take it: EXAMPLES OF “INCIDENTAL” BENEFIT 1.Reye’s syndrome and aspirin (1963) 1980s limitation on aspirin availability 1.Thioridazine withdrawal for arrhythmia risk autumn 2000 AVAILABILITY AND OVERDOSE

PROPORTION OF POISONING ADMISSIONS ROYAL INFIRMARY EDINBURGH

PROPORTION OF ADMISSIONS PER ANNUM ROYAL INFIRMARY EDINBURGH

PRESCRIBING OF ANTIPSYCHOTIC DRUGS PER QUARTER, EXPRESSED AS % OF TOTAL ANTIPSYCHOTICS - ENGLAND

TOXBASE accesses per quarter, expressed as % of total antipsychotics - England Bateman et al 2003 BJCP 55:

If it is is available can you make it safer? Child resistant containers Mode of supply Volume of purchase- generally for non prescription items (Opioid programmes) AVAILABILITY AND OVERDOSE

CHILD RESISTANT CONTAINERS 1.Ingestion rate for all substances requiring CRCs declined from 5.7/1,000 children in 1973 to 3.4/1,000 children in Reduction in exposures by 200,000 over 5 yr 3.20 yr decline in deaths by poisoning 2.0/100,000 children to 0.5/100,000 National Injury Surveillance System and National Center for Health Statistics (USA) Walton WW 1982 Pediatrics 69:363-70

Effectiveness of child-resistant packaging (Alabama) < 5 y-of-age 168 patients. Mean age 26 mo 71% original container 29% transferred to another container or found outside of its container 33% involved a child-resistant closure Lembersky et al 1996 Vet Hum Tox 38:380-3

Effectiveness of child-resistant packaging (Alabama) 20% of exposures opening properly closed child-resistant closure 18.5% by opening a properly closed non-child-resistant closure. Child-resistance did not ensure child impenetrability Lembersky et al 1996 Vet Hum Tox 38:380-3

If it is is available can you make it safer? Child resistant containers Mode of supply Volume of purchase AVAILABILITY AND OVERDOSE

IRON OVERDOSE IN CHILDREN USA pre 1978 CRC for >500mg elemental iron After 1978 CRC for >250 mg elemental iron 1998 strip packs for >30 mg elemental iron

Unit-dose packaging of iron supplements >30mg Tenenbein, 2005 Arch Ped Adol Med 159:

If it is is available can you make it safer? Child resistant containers Mode of supply Volume of purchase AVAILABILITY AND OVERDOSE

Legislation

Proportion of overdose deaths (95% CI) (censored) related to paracetamol Scotland British Journal of Clinical Pharmacology 2006: 62: Pre-legislationTransitionalPost -legislation F M Ratio Post/Pre: ( ) p= 0.013

ADD THE ANTIDOTE? Methionine ?? (UK Paradote product) Problems 1. How to prove efficacy in man 2. Mass medication 3. Increase in homocysteine in long term administration 4. Cost

ADD THE ANTIDOTE? Acetylcysteine? <200mg/tablet (Andrus et al) “The efficacy should be tested” Andrus JP et al 2001 BMJ 323:634

If it is is available can you make it safer? IF NOT : WITHDRAWAL? AVAILABILITY AND OVERDOSE

Withdraw products just because of danger in overdose without good reason WHAT REGULATORS CANNOT DO

Deaths mentioning paracetamol

Scotland Deaths in 3 categories Paracetamol (± ethanol) ONLY Paracetamol and other drugs Co-proxamol Paracetamol 325 mg Dextropropoxyphene 32.5 mg (opioid with Na + channel blocking effects)

Paracetamol deaths by category

Out of hospital deaths

Estimated Fatal Toxicity Scotland per million prescription (95%CI) Products Deaths/million prescription Co-proxamol24.6 (19.7, 30.4) Co-codamol2.0 (0.88, 4.0) Co-dydramol2.4 (0.5, 7.2)

Clinical data very weak- No evidence that better than paracetamol alone acutely and no chronic studies Sold to a Generic manufacturer in UK Coproxamol efficacy

Withdrew Coproxamol over a 2 year period WHAT UK REGULATOR DID

Analgesic prescribing, Items/quarter Scotland UK Legislation DEC 2004

Coproxamol deaths as % overdose deaths Scotland Legislation DEC 2004

Legislation DEC 2004 Overdose opioid analgesic deaths : Scotland Sandilands et al BJCP 2008 in press

IDENTIFYING OTHER TARGETS ?? A new role for poisons centres AVAILABILITY AND OVERDOSE

Studies on prescribing data and mortality in England + Wales 1980s and 90s FTI= deaths per million scripts Fatal toxicity index Study periodAuthorsAll antidepressants Amitriptyline Cassidy S, Henry J ( ) Henry J et al ( ) Buckley & McManus ( )

Fatal poisoningsFTI TricyclicsScotland prescriptions (thousands) No. observedNo. expectedNo. of deaths per million prescriptions Amitriptyline2, ( )*** Clomipramine ( )*** Dosulepin ( )*** Doxepin ( ) Imipramine ( ) Lofepramine Nortriptyline Trazodone ( ) Trimipramine Antidepressants13, ( ) *** significantly different at 0.1% level (p<0.001) Prescription data, fatal poisonings and fatal toxicity index for individual antidepressants in Scotland,

Wheeler et al. BMJ 2008;336:542-5.

Biddle et al. BMJ 2008;336:

1.Changes to package/ presentation/ labelling (eg specific warnings) 2.Changes to category (eg drugs of potential abuse, prescription only, pharmacy supply, general sale ) 3.Changes to indication (? limit supply, reduce hazard in “at risk” groups) 4.Licence revocation ACTIONS

Biddle et al. BMJ 2008;336: