Outline

Pharmacoviglance
Arrangements in New Zealand
New Zealand Pharmacovigilance Centre
Extending NZ initiatives
Future directions

Pharmacovigilance in
New Zealand
Dr Michael Tatley

PRIMUM
NON
NOCERE
First do no harm

Earliest ADRs
The Foxglove, when given in very large and quickly repeated
doses, occasions sickness, vomiting, purging, giddiness,
confused vision, objects appearing green or yellow,
increased secretion of urine with frequent motions to part
with it, and sometimes inability to retain it; slow pulse,
even as low as 35 in a minute, cold sweats, convulsions,
syncope and death.
William Withering 1785

Hippocrates (500BC)

Withering established
The adverse effects of digitalis
ADRs occur with every medicine
A dose-response relationship and, possibly, the
concept of therapeutic index
Harms can be reduced by dose titration

Examples of Drug Induced Disease

1880
1946
1952
1953
1958

Chloroform
Streptomycin
Chloramphenicol
Phenacetin
Isoniazid

Cardiac Arrest
Deafness, Renal failure
Aplastic anemia
Nephropathy
Hepatitis

1977
1978
1979
1980
1981

1961 Thalidomide

Phocomelia

1962
1963
1964

SLE
Retinopathy
GI Bleeding
Agranulocytosis
Agranulocytosis
Addiction
Thromboembolism
Haemolytic anemia
Nephrotic syndrome
Polyneurophathy/Pneumonitis
Urinary tract carcinoma
Hepatic injury
Vaginal carcinoma (offspring)
Cholestatic hepatitis
Hypo/Hyper thyroid
Stevens Johnson
Sclerosing peritonitis
Agranulocytosis
Anaphylactic shock

1965
1966
1968
1970
1971
1972
1973
1974
1975
1976

Procainamide
Choroquine
Aspirin & NSAIDs
Anti-thyroids
Sulphonamides
Barbiturates
OCs
Methyldopa
Hg Diuretics
Nitrofurantoin
Phenacetin
INH/Rifampicin
Diethylstilbestrol
Erythromycin
Amiodarone
Co-trimoxazole
Practolol
Clozapine
Glafenine

1982
1983
1984
1985
1986
1988
1989
1990
1991
1994
1995
1996
1997
1999
2000
2001
2004
2009
2010

Influenza Vaccine

Guillian- Barre .. (?+-)

Perhexiline
Triazolam
Tielenic acid
Ticlodipine
Penicillamine
Fenfluramine
Ketoconazole
Zomepirac
Valproate Sodium
Mianserin
Nomfenasine
Ceftriaxone
Fenoterol
Pirprofen
Deferrioxamine
Fluoroquinolones
Tiaprofenic Acid
Mefloquine
Indinavir

Polyneuropathy, Hepatitis
Psychosis/Behaviour problems
Hepatic/Renal Injury
Agranulocytosis
Auto-immune disease induction
Pulmonary HPT
Hepatitis
Anaphylactic shock
Spina bifida
Agranulocytosis
Fever, Hepatitis, Haemolytic anem
Biliary lithiasis
Asthma mortality increases
Hepatitis
Opportunisitic infection
Achilles Tendinitis & Rupture
Cystitis
CNS effects
Haemolytic Anemia

OCs - 3rd Generatn

Cerivastatin
Rofecoxib
Glitazones
Sibutramine

Thromboembolism (NZ)
Rhabdomyolysis
Cardiovascular Mortality
Cardiac Safety
Cardiac Safety

Rotavirus Vaccine

Intussusception

Paradox of Modern Drug Development

1. Clinical trials provide evidence of efficacy and
safety at usual doses in populations

A safe medicine does not exist

Efficacious & Safe

The use of medicine involves

2. Physicians treat individual patients who can vary

widely in their response to drug therapy

balancing benefits and harms

No Response

Efficacious & Safe

Adverse Drug Reaction

Bruce Carleton BC, Canada

Pharmacovigilance
- the early detection of unknown adverse
reactions and interactions.
including
adverse events that follow immunisation that are
believed to be caused by the immunisation

Adverse Drug Events

- a cause for concern

Account for ~ 6 % of hospital admissions

Pirmohamed, et al. "Adverse drug reactions as cause of admission to hospital:

prospective analysis of 18 820 patients." Bmj 329.7456 15-19;2004.

Increasing trend in ADEs . awareness?

Australia: 5-fold increase in hospitalisations due to ADRs in

>65yr olds 1995-2002
Burgess C, etal, Adverse drug reactions in older Australians, 19812002,
MJA 182: 267270; 2005

ACC (NZ)

~16% of claims for medication

~ $6 million (2013/14)

. but

Poor ADE/ADR reporting . ~10%?

Hazell l, etal. Under-reporting of adverse drug reactions.
Drug Safety 29.5 (2006): 385-396.

2001, NZ Quality in Healthcare Study

Medicines 3rd leading cause of adverse event

Why Pharmacovigilance ?
Action of drugs not purely selective
Many drug safety related issues have been identified

Considerable impact

Clinical trial has only limited capacity to inform safety

& adverse effects

Prolonged hospital admission by mean 7.8 days

12.3% associated with permanent disability & death
Costly: Average cost per AE = $10,264 (Preventable Events = $590
million p.a)

43.9% of cases preventable (associated with error)

efficacy oriented
too small
patient exclusions

Massive personal & societal costs

Opportunities for prevention

Davis P, et al. Adverse events in New Zealand public hospitals Principal findings
from a National Survey. Occasional Paper No3 www.moh.govt.nz
Paul Browne et al Cost of medical injury in NZ: a retrospective cohort study. J. Health Serv Res Policy,7,s1, July 2002

New Zealand Pharmacovigilance

Centre
National monitoring centre established in 1965
Joined WHO monitoring programme in 1968
Monitoring programmes

Medsafe is the NZ Drug Regulator

Medsafe is a unit within the Ministry of Health

National ADR Monitoring independent from Regulator

University of Otago since 1965
Pharmacovigilance Services provided to Regulator under Contract to MoH

spontaneous reports

Independence recognised as valuable

medicines, vaccines, NHPs

selected medicines
selected vaccines
medication error

Arrangements in New Zealand

Reporter
Ministry

VMP

NZPhvC as a Pharmacovigilance Resource

Clinical decision making support
Research

New Zealand Pharmacovigilance Centre in 2003

Adverse Reaction Monitoring

Structure in New Zealand

academic
patient

Anyone can report

Pharmacovigilance Stakeholders

Ministry of Health

M2

MedSafe

Medicines Adverse Reactions

Committee (MARC)

HQSC

Medicines Assessment
Advisory Committee (MAAC)

Immunisation
Programme
GPs & PHOs

NZ Pharmacovigilance Centre

Community
Pharmacists

Pharma

bpac
Spontaneous
Reporting
Programme

Medication
Error
Reporting
Programme

PHARMAC

MARC
Medsafe
NZPhvC

Media
Health Quality &
Safety Commission
District Health
Boards

National Minimum
Dataset (NHI/MWS)
NPC

Universities &
Teaching Institutions
Public

What to Report ?
ANY EVENT OR REACTION
THOUGHT TO BE MEDICINE OR
VACCINE RELATED
adverse reactions of clinical concern
all adverse reactions to new medicines
all serious allergic reactions
drug interactions

Report Sources

Annual Total Reports Received by

NZPhvC

www.otago.ac.nz/carm

PMS ADR tool

Reporting Rates 2014

Source of ADR reports 2000-2010

100%
90%
80%

Other

70%

Drug Co.

60%

Hospital

50%
40%

Pharmacist

30%

Nurses

20%

Doctors

10%
0%

All Reports

Vaccines

NHP's

Assessing adverse event reports

Report processing
EACH REACTION IS:

Assign standard event term(s) that capture the clinical details

(Standardised WHOART dictionary)

coded according to WHO criteria

reaction terms applied
assessed for severity & seriousness
assessed for relationship

nature, temporal relation, dose

outcome of:
dechallenge/rechallenge
previous administration

FOR ALL SPONTANEOUS REPORTS

response is sent to reporting health professional

causality
number of similar reports in N.Z. and/or WHO
relevant additional information
at risk groups
prevention issues

PhV databases CARM, WHO-UMC

literature and data sources
Data sheets
PubMed, Medline, Scopus, etc
Thompsons Micromedex
Meylers, etc

exclusion of confounding factors

clinical plausibility
pharmacological mechanism

opinion of experts

- local / international

Certain
Probable

WHO-method
~ Karch & Lasagne

Possible
Unlikely
Unclassifiable

What can monitoring reveal?

Top Medications causing ADRs

last 10years

Commonest Adverse Reactions

1. Patterns of reactions

Reinforce established knowledge

Local context
Changing patterns of use
Monitoring for patient safety
Product quality issues

Medicines causing ADRs in the Elderly

Impetus for prescriber reminders

Childhood Immunisation Schedule

AEFI
rate per 1000 vaccines

Childhood Immunisation Schedule

AEFIs by Batch
rate per 1000 vaccines

MMR
7

Infanrix-Hexa

Prevenar

Hib

MMR

1.40

Infanrix-IPV

1.20
Rate/1000 vaccines

5
4
3
2
1

Reaction Groups

CV
S

IA
TR
IC
PS
YC
H

1.00
0.80
0.60
0.40
0.20
0.00
K0
90
3
K2
58
5
K5
74
1
K5
74
2
K5
98
3
N0
88
8
N1
76
6
N2
41
2
N2
56
3
N2
56
4
N2
74
6
N2
74
7
N3
10
0
N3
64
7
R0
54
0
R0
54
1

NE
UR
OL
OG
IC
AL

'T
Y
HY
PE
RS
EN
S

SO
MA
TI
C

0
LO
CA
L

Rate per 1000 vaccinations

July 2008 June 2011

Batch #

Oxycodone

Brandswitch patterns

FLUOXETINE Brandsw itch Reporting

ENALAPRIL Brandsw itch Reporting

12

12

10

10

6
4

6
4

0
Aug

Sep

Oct

Nov

Dec

Jan

Feb

Mar

Apr

May

Jun

01

01

01

01

01

02

02

02

02

02

02

Oxycodone
Impetus for
prescriber
reminders

What can monitoring reveal?

1. Patterns of reactions
2. Contribute to individual patient safety

medical warning system

NZ specific

Hospital-side MWS alert

What can spontaneous

monitoring reveal?
1. Patterns of reactions
Re-inforce established knowledge
Local context
Impetus for prescriber reminders

2. Contribute to individual patient safety

medical warning system
NZ specific

3. Signal new reactions

Reports with events possibly indicating

Cardiac Failure

Spontaneous Monitoring
Statins & psychiatric reactions
Leflunomide and pneumonitis

Dabigatran and cardiac events?

WHO Collaborating
Centre

Dyspnoea = 10
Peripheral oedema = 1
Peripheral oedema & Pulmonary symptoms = 2
Cardiac failure = 3
BNP increased = 2

Spontaneous Reporting

>124 countries

>12million reactions in
database

(SRPs)

The advantages

Uppsala, Sweden

Easy to implement
Inexpensive
Covers all medicines
Rare reactions identifiable

Spontaneous Reporting

Practolol

(SRPs)

The disadvantages

The oculomucocutaneous syndrome

Early symptoms delayed until 2 years
dry eyes
popping ears

Incomplete (<10%)
No denominator
proportional reporting rates at best
BCPNN

Caused blindness, retroperitoneal fibrosis, death

Markedly subject to biases

Delayed effects unnoticed
Common clinical problems not linked to drug

Syndrome unrecognised for 4 years with

spontaneous reporting even though symptoms
common

ADR confused with disease symptom

ADR may mimic common symptoms

NZPhvC Activities

Adapting Pharmacovigilance

Health Professional support ~50 years

Supporting Medsafe and Immunisation programs
Weekly teleconference with Medsafe on current developments
Weekly and adhoc reports on specific vaccines or medicines
Quarterly reports to the Medicines Adverse Reactions
Committee (MARC)

Electronic data transfer

MeNZB vaccine safety monitoring
. other uses with variation
. electronic data acquisition

Intensive Vaccine Monitoring Programme

IVMP

IVMP MeNZB reactions

IVMP Electronic data transfer

<6months age group

35
30
25

MeNZB+Routine

15
10
5

S
CV

OT
HE
R

SL
HA
EE
P
EM
AT
OL
OG
IC
AL

CA

SI
V

OG
I

NE
UR
OL

tic
ari
a
Ur

NV
UL

CO

AN
XI
ET
Y
HY
PE
RS
EN
S'
TY

SO
MA
TI
C

LO

6/52

Routine

20

CA
L

Rate per 1000 vaccinations

rate per 1000 MeNZB vaccinations

Reaction Groups

Feb 2008, QIC sentinel event report released

Extending Pharmacovigilance

MeNZB vaccine safety monitoring

Intensive Vaccine Monitoring Programme
IVMP
Electronic data transfer technology

Medication errors
Missed opportunities lessons

2001, NZ Quality in Healthcare Study

The Medical Error iceberg?

Administration

Medicines third leading cause of adverse event

Considerable impact

Wrong dose / drug / patient

Formulation
Preparation

Route

Dose adjustments

Prolonged hospital admission by mean 7.8 days

12.3% associated with permanent disability & death
Costly: Average cost per AE = $10,264 (Preventable Events = $590
million p.a)

43.9% of cases preventable (associated with error)

Device

Drug interactions

Drug omission
Under dosing
Monitoring in chronic Rx
Underlying disease

Davis P, et al. Adverse events in New Zealand public hospitals Principal findings
from a National Survey. Occasional Paper No3 www.moh.govt.nz
Paul Browne et al Cost of medical injury in NZ: a retrospective cohort study. J. Health Serv Res Policy,7,s1, July 2002

Medication Error Pilot

Pharmacovigilance Synergies

MeNZB vaccine safety monitoring

Medication errors

Psycho-active Substances Monitoring

Synthetic Cannabinoid Reports

Epidemiology

Report a Psychoactive substance

90
80
70
60
50
40
30
20
10
0
2012

2013

2014

90
80

Female

70
60

Male

50
40
30

Unknown

20
10

Pregnan
t female

0
<12 years 12-17
years

18-44
years

45-64
years

65-74
years

> 75
years

Unknown

10

Synthetic Cannabinoids
Adverse Reaction - SOCs

Using NZ Pharmacovigilance
Data

MeNZB vaccine safety monitoring

Medication errors

Psychoactive substances monitoring

Synthetic Cannabinoids
Psychiatric Events

M2

M2
Highlight potential safety issues from reports of suspected ADRs
Stimulate further reports & information about these potential safety signals.

Using NZ Pharmacovigilance
Data 2

MeNZB vaccine safety monitoring

Medication errors

Psychoactive substances monitoring

M2

SMARS

Suspected Medicine Adverse Reaction Search

SMARS

11

Using NZ Pharmacovigilance
Data

MeNZB vaccine safety monitoring

Medication errors

Psychoactive substances monitoring

M2

SMARS

New directions.
Broadening the PhV toolbox
New and Enhanced Pharmacovigilance tools Research
Phv Research Network

- targeted monitoring of drug-reaction combinations

- publically accessible ADR database

Medsafe Ministry of Health

.. Social Media as a source of Signals

Conclusion

SUMMARY

Pharmacovigilance can reveal

1. Patterns of reactions
Re-inforce established knowledge
Local context
Impetus for prescriber reminders

2. Signal new reactions

3. Contribute to individual patient safety
medical warning system
NZ specific

SRPs - a valuable National Resource

local patterns
drug interactions
rare reactions

IMMP methodologies - potent signal generator

important part of the PhV toolbox
enhances SRP

New PhV explorations ..

SRP/ IMMP/ IVMP/MERP synergy - unique resource
collaborative research opportunities

Signals generate further PhV studies

12