NPIS

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The role of medicines regulation in prevention of
serious poisoning  
Nick Bateman Professor in Clinical Toxicology
Consultant Physician RIE Director, NPIS Edinburgh

NPIS Edinburgh
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CONTENT

• Medicines Regulation
• Prescription and OTC products
• 2. Prevention strategies
• What works- and perhaps doesnt
• 3. Some ideas for the future

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Medicines Regulation

• European licensing structure
• EMEA www.emea.europa.eu/
• 2. Member states actions
• May take note of local circumstances
• Prescription only
• Pharmacy sale
• General sale products (OTC)

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REGULATORY ACTIONS

• Changes to package/ presentation/ labelling (eg
  specific warnings)
• Changes to category (eg drugs of potential abuse,
  prescription only, pharmacy supply, general sale)
• Changes to indication (may limit supply, reduce
  hazard in at risk groups) via SPC, doctors
  letter etc
• Licence revocation

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WHAT THEY CANNOT DO
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
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AVAILABILITY AND OVERDOSE

• If it is not available you cannot take it
• EXAMPLES OF INCIDENTAL BENEFIT
• Reyes syndrome and aspirin (1963)
• 1980s limitation on aspirin availability
• Thioridazine withdrawal for arrhythmia risk
  autumn 2000

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PROPORTION OF POISONING ADMISSIONS 1981-2000
ROYAL INFIRMARY EDINBURGH
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PROPORTION OF ADMISSIONS PER ANNUM1981-2000
ROYAL INFIRMARY EDINBURGH
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PRESCRIBING OF ANTIPSYCHOTIC DRUGS PER QUARTER,
2000-2001 EXPRESSED AS OF TOTAL ANTIPSYCHOTICS
- ENGLAND
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TOXBASE accesses per quarter, 2000-2001 expressed
as of total antipsychotics - England
Bateman et al 2003 BJCP 55 596-03
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AVAILABILITY AND OVERDOSE
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)
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CHILD RESISTANT CONTAINERS

• Ingestion rate for all substances requiring CRCs
  declined from 5.7/1,000 children in 1973 to
  3.4/1,000 children in 1978.
• Reduction in exposures by 200,000 over 5 yr
• 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 69363-70
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Effectiveness of child-resistant packaging
(Alabama) lt 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 38380-3
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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 38380-3
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AVAILABILITY AND OVERDOSE
If it is is available can you make it safer?
Child resistant containers Mode of
supply Volume of purchase
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IRON OVERDOSE IN CHILDREN
USA pre 1978 CRC for gt500mg elemental iron After
1978 CRC for gt250 mg elemental iron 1998 strip
packs for gt30 mg elemental iron
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Unit-dose packaging of iron supplements gt30mg
Tenenbein, 2005 Arch Ped Adol Med 159 557-60
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AVAILABILITY AND OVERDOSE
If it is is available can you make it
safer? Child resistant containers Mode of
supply Volume of purchase
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Legislation

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Legislation
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Legislation
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Proportion of overdose deaths (95 CI) (censored)
related to paracetamol Scotland 1995-2003
Ratio Post/Pre 1.347 (1.076-1.639) p 0.013
British Journal of Clinical Pharmacology 2006
62 573-581.
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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

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ADD THE ANTIDOTE?

• Acetylcysteine?
• lt200mg/tablet (Andrus et al)
• The efficacy should be tested

Andrus JP et al 2001 BMJ 323634
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AVAILABILITY AND OVERDOSE
If it is is available can you make it safer? IF
NOT WITHDRAWAL?
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WHAT REGULATORS CANNOT DO
Withdraw products just because of danger in
overdose without good reason
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Deaths mentioning paracetamol 1995-2003
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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)

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Paracetamol deaths by category 1995-2003
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Out of hospital deaths 1995-2003
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Estimated Fatal Toxicity Scotland per million
prescription (95CI)
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Coproxamol efficacy
Clinical data very weak- No evidence that
better than paracetamol alone acutely and no
chronic studies Sold to a Generic manufacturer
in UK
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WHAT UK REGULATOR DID
Withdrew Coproxamol over a 2 year period
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Analgesic prescribing, Items/quarter Scotland
2002-7
UK Legislation DEC 2004
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Coproxamol deaths as overdose deaths Scotland
2000-06
Legislation DEC 2004
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Overdose opioid analgesic deaths Scotland
2000-06
Legislation DEC 2004
Sandilands et al BJCP 2008 in press
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AVAILABILITY AND OVERDOSE
IDENTIFYING OTHER TARGETS ?? A new role for
poisons centres
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Studies on prescribing data and mortality in
England Wales 1980s and 90s FTI deaths per
million scripts
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• Prescription data, fatal poisonings and fatal
  toxicity index for individual antidepressants in
  Scotland, 2002-5

significantly different at 0.1 level
(plt0.001)
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Wheeler et al. BMJ 2008336542-5.
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Wheeler et al. BMJ 2008336542-5.
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Biddle et al. BMJ 2008336539-42.
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ACTIONS

• Changes to package/ presentation/ labelling (eg
  specific warnings)
• Changes to category (eg drugs of potential abuse,
  prescription only, pharmacy supply, general sale
  )
• Changes to indication (? limit supply, reduce
  hazard in at risk groups)
• Licence revocation

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Biddle et al. BMJ 2008336539-42.