1. 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

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

3. 1.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) Medicines Regulation

4. 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

5. 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

6. 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

7. PROPORTION OF POISONING ADMISSIONS 1981-2000 ROYAL INFIRMARY EDINBURGH

8. PROPORTION OF ADMISSIONS PER ANNUM 1981-2000 ROYAL INFIRMARY EDINBURGH

9. PRESCRIBING OF ANTIPSYCHOTIC DRUGS PER QUARTER, 2000-2001 EXPRESSED AS % OF TOTAL ANTIPSYCHOTICS - ENGLAND

10. TOXBASE accesses per quarter, 2000-2001 expressed as % of total antipsychotics - England Bateman et al 2003 BJCP 55: 596-03

11. 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

12. 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 1978. 2.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

13. 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

14. 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

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

16. 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

17. Unit-dose packaging of iron supplements >30mg Tenenbein, 2005 Arch Ped Adol Med 159: 557-60

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

19. Legislation

22. Proportion of overdose deaths (95% CI) (censored) related to paracetamol Scotland 1995-2003 British Journal of Clinical Pharmacology 2006: 62: 573-581. Pre-legislationTransitionalPost -legislation F29.4 23.5-36.2 35.3 27.6-44.0 39.7 33.6-46.1 M21.6 16.7-27.5 26.5 20.0-34.3 30.3 24.7-36.5 Ratio Post/Pre: 1.347 (1.076-1.639) p= 0.013

26. 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

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

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

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

30. Deaths mentioning paracetamol 1995-2003

31. 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)

32. Paracetamol deaths by category 1995-2003

33. Out of hospital deaths 1995-2003

34. 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)

35. 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

36. Withdrew Coproxamol over a 2 year period WHAT UK REGULATOR DID

37. Analgesic prescribing, Items/quarter Scotland 2002-7 UK Legislation DEC 2004

38. Coproxamol deaths as % overdose deaths Scotland 2000-06 Legislation DEC 2004

39. Legislation DEC 2004 Overdose opioid analgesic deaths : Scotland 2000-06 Sandilands et al BJCP 2008 in press

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

41. Studies on prescribing data and mortality in England + Wales 1980s and 90s FTI= deaths per million scripts Fatal toxicity index Study periodAuthorsAll antidepressants Amitriptyline 1975-1984Cassidy S, Henry J34.946.5 (43.9-49.1) 1987-1992Henry J et al30.138.9 (35.6-42.4) 1993-1999Buckley & McManus21.238.0 (38.5-40.5)

42. Fatal poisoningsFTI TricyclicsScotland prescriptions (thousands) No. observedNo. expectedNo. of deaths per million prescriptions Amitriptyline2,3786526.827.3 (21.1-34.8)*** Clomipramine20982.438.3 (16.5-75.4)*** Dosulepin686317.745.2 (30.7-64.1)*** Doxepin11521.317.4 (2.1-62.9) Imipramine10621.218.9 (2.3-68.3) Lofepramine26403.0- Nortriptyline3100.4- Trazodone66217.51.5 (0.0-8.4) Trimipramine5400.6- Antidepressants13,551 153 11.3 (9.6-13.2) *** significantly different at 0.1% level (p<0.001) Prescription data, fatal poisonings and fatal toxicity index for individual antidepressants in Scotland, 2002-5

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

45. Biddle et al. BMJ 2008;336:539-42.

46. 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

48. Biddle et al. BMJ 2008;336:539-42.