A service commissioned

by the HPANPIS

Edinburgh

The role of medicines The role of medicines regulation in prevention of regulation in prevention of serious poisoningserious poisoning  

Nick Bateman Nick Bateman Professor in Clinical Toxicology Professor in Clinical Toxicology & Consultant Physician RIE& Consultant Physician RIEDirector, NPIS Edinburgh 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 www.emea.europa.eu/

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

Salicylates

0

2

4

6

8

10

12

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Year

Pro

po

rtio

n o

f a

dm

iss

ion

s

PROPORTION OF POISONING ADMISSIONS 1981-2000 ROYAL INFIRMARY EDINBURGH

Paracetamol

0

10

20

30

40

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Year

Pro

po

rtio

n o

f ad

mis

sio

ns

PROPORTION OF ADMISSIONS PER ANNUM1981-2000 ROYAL INFIRMARY EDINBURGH

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

05

101520253035404550

Jan-M

ar 2

000

Apr-Jun

Jul-Sep

Oct-D

ec

Jan-M

ar 2

001

Apr-Jun

Jul-Sep

Oct-D

ec

Others

Risperidone/ Olanzapine

Chlorpromazine

Thioridazine

TOXBASE accesses TOXBASE accesses per quarter, 2000-per quarter, 2000-2001 expressed as % of total antipsychotics - 2001 expressed as % of total antipsychotics -

EnglandEngland

05

101520253035404550

Jan-M

ar 2

000

Apr-Jun

Jul-S

ep

Oct-D

ec

Jan-M

ar 2

001

Apr-Jun

Jul-S

ep

Oct-D

ec

Others

Risperidone/ olanzapine

Thioridazine

Chlorpromazine

Bateman et al 2003 BJCP 55: 596-03

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 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

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: 557-60

If it is is available can you make it safer?

Child resistant containers

Mode of supply

Volume of purchase

AVAILABILITY AND OVERDOSE

Paracetamol death and discharges, Scotland. 1995-2003

0

20

40

60

80

100

120

140

160

180

1995 1996 1997 1998 1999 2000 2001 2002 2003

Year

Rat

e/10

0,00

0

OverallMalesFemales

Legislation

Paracetamol death and discharges, Scotland. 1995-2003

0

20

40

60

80

100

120

140

160

180

1995 1996 1997 1998 1999 2000 2001 2002 2003

Year

Rat

e/10

0,00

0

OverallMalesFemales

Legislation

Deaths and discharges, poisonings other than Paracetamol:

Scotland 1995-2003

0

50

100

150

200

250

300

350

1995 1996 1997 1998 1999 2000 2001 2002 2003

Year

Rat

e/10

0,00

0

Overall

Males

Females

Legislation

Proportion of overdose deaths (95% CI) (censored) related to paracetamol

Scotland 1995-2003

British Journal of Clinical Pharmacology 2006: 62: 573-581.

Pre-legislation Transitional Post -legislation

F 29.4

23.5-36.2

35.3

27.6-44.0

39.7

33.6-46.1

M 21.6

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

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 Deaths mentioning paracetamol 1995-20031995-2003

0

20

40

60

80

100

120

140

1995 1996 1997 1998 1999 2000 2001 2002 2003

ScotlandScotland

• Deaths in 3 categories

Paracetamol (± ethanol) ONLYParacetamol and other drugsCo-proxamol

Paracetamol 325 mg Dextropropoxyphene 32.5 mg (opioid with Na+ channel

blocking effects)

Paracetamol deaths by category Paracetamol deaths by category 1995-20031995-2003

0

10

20

30

40

50

60

70

80

Paracetamol andethanolParacetamol andother drugsCo-proxamol

Out of hospital deaths 1995-2003Out of hospital deaths 1995-2003

0

10

20

30

40

50

60

Paracetamol andethanolParacetamol andother drugsCo-proxamol

Estimated Fatal Toxicity Scotland per million prescription (95%CI)

ProductsDeaths/million prescription

Co-proxamol 24.6 (19.7, 30.4)

Co-codamol 2.0 (0.88, 4.0)

Co-dydramol 2.4 (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

0

100000

200000

300000

400000

500000

600000

700000

Pres

crip

tion

item

s di

spen

sed

per q

uart

er

CO-CODAMOL

CO-DYDRAMOL

CO-PROXAMOL

DIHYDROCODEINE TARTRATE

PARACETAMOL

TRAMADOL HYDROCHLORIDE

Analgesic prescribing, Items/quarter Scotland 2002-7

UK LegislationDEC 2004

0

5

10

15

20

25

30

35

2000 2001 2002 2003 2004 2005 2006

Year

% o

f Dea

ths Total

Male

Female

Coproxamol deaths as % overdose deaths Scotland 2000-06

LegislationDEC 2004

0

5

10

15

20

25

30

35

40

45

50

2000 2001 2002 2003 2004 2005 2006

Nu

mb

er

of

de

ath

s Coproxamol

Cocodamol

Codydramol

Tramadol

Dihydrocodeine

Codeine

Legislation DEC 2004

Overdose opioid analgesic deaths : Scotland 2000-06

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 period Authors All antidepressants

Amitriptyline

1975-1984 Cassidy S, Henry J 34.9 46.5 (43.9-49.1)

1987-1992 Henry J et al 30.1 38.9 (35.6-42.4)

1993-1999 Buckley & McManus 21.2 38.0 (38.5-40.5)

Fatal poisonings FTI

Tricyclics Scotland prescriptions (thousands)

No. observed No. expected No. of deaths per million

prescriptions

Amitriptyline 2,378 65 26.8 27.3 (21.1-34.8)***

Clomipramine 209 8 2.4 38.3 (16.5-75.4)***

Dosulepin 686 31 7.7 45.2 (30.7-64.1)***

Doxepin 115 2 1.3 17.4 (2.1-62.9)

Imipramine 106 2 1.2 18.9 (2.3-68.3)

Lofepramine 264 0 3.0 -

Nortriptyline 31 0 0.4 -

Trazodone 662 1 7.5 1.5 (0.0-8.4)

Trimipramine 54 0 0.6 -

Antidepressants 13,551 153 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

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

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

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

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;336:539-42.