Dr Jane Quinn BScu(U Westminister),PhD (Edin) with a background in biomedical research in neurology and neurophysiology AKA NEUROSCIENTIST Medical Expert Advisor for the Australian Defence Force Meflqouine and Tafenoquine Members and Veterans Group

1. Powered by
Australian Defence Force Mefloquine and
Tafenoquine Members and Veterans Group
Townsville Health Forum
Townsville RSL
13 March 2016

2. Agenda
10am Welcome, Mayor Jenny Hill and opening remarks
10.10am Dr Jane Quinn – Background and overview, the group experience
10.30am Dr Remington Nevin
10.50am Mrs Lavina Salter – The family experience
11.00am Major Stuart McCarthy – The Service Member’s experience
11.10am AVM Tracy Smart & Mr David Morton – Accessing services through Defence
11.40am BREAK
12noon Open Forum Q & A Session
12.45pm ADSO statement and concluding remarks

4. 4
Use and effects of Mefloquine and
Tafenoquine in the Australian Defence
Force:
Background and Experiences of the
Members and Veterans Group
Dr Jane Quinn
Charles Sturt University
Townsville Health Forum March 2016

5. Mefloquine
5
Mefloquine
was
first
iden1fied
by
the
US
Government
as
part
of
a
discovery
program
for
novel
synthe1c
an1-­‐malarial
compounds
undertaken
during
the
Vietnam
war
to
combat
increasing
chloroquine
resistance
Related
to
quinine,
which
is
a
known
neurotoxic
chemical,
but
a
very
effec1ve
an1malarial
agent
Licensed
to
Roche
for
produc1on
and
distribu1on
Expedi1ously
brought
to
market
without
full
Phase
3
trials
Used
for
military
and
civilian
travellers
since
1988
‘a
neurotoxic
drug
with
incidental
an1malarial
proper1es’
Mefloquine
https://web.stanford.edu/class/humbio153/GenToolsMalaria/Background.html

6. Mefloquine
6
Prescribing:
used
for
both
prophylaxis
and
treatment
Long
half-­‐life
gives
a
weekly
dosing
regime
Should
not
be
given
to
anyone
with
a
history
of
psychiatric
illness
themselves
or
in
their
family
Product
informa1on
leaflet
states
that
pa1ents
experiencing
any
neurological
symptoms
should
tell
their
doctor
or
go
to
A&E
Product
informa1on
leaflte
Iden1fies
that
symptoms
may
be
worse
with
alcohol
Double
doses
should
not
be
taken
Mefloquine
http://www.njpersonalinjury.lawyer/blog/automobile-accidents/brain-injury-attorney/
http://www.dailymail.co.uk/news/article-3312981

7. Mefloquine – uses and side effects
7
Growing
safety
concerns
over
last
20
years
Known
COMMON
(<1:100)
side
effects
include:
Anxiety,
depression,
sleep
disturbances,
nightmares,
abdominal
pain,
diarrhoea,
1nnitus,
ver1go,
visual
problems
UNCOMMON
1:100
and
1:1000
can
experience:
Mood
swings,
panic
a]acks,
hallucina1ons,
confusion,
bipolar
disorder,
delusions,
paranoia,
mania,
suicidal
idea1on,
suicide…
vision
problems,
hearing
loss,
balance
issues,
migraines………
Other
symptoms
include:
palpita1ons,
heart
block
and
others…
Respiratory
–
asthma
Mefloquine
http://www.dailymail.co.uk/news/article-3312981
http://fiddaman.blogspot.com.au/2015/08/mhra-blind-to-facts-over-lariam.html

8. Mefloquine – uses and side effects
8
Growing
safety
concerns
over
last
20
years
Known
COMMON
(<1:100)
side
effects
include:
Anxiety,
depression,
sleep
disturbances,
nightmares,
abdominal
pain,
diarrhoea,
1nnitus,
ver1go,
visual
problems
UNCOMMON
1:100
and
1:1000
can
experience:
Mood
swings,
panic
a]acks,
hallucina1ons,
confusion,
bipolar
disorder,
delusions,
paranoia,
mania,
suicidal
idea1on,
suicide…
vision
problems,
hearing
loss,
balance
issues,
migraines,
heart
block……
Respiratory
–
asthma
Mefloquine
Serious side effects require immediate withdrawal from treatment
http://www.dailymail.co.uk/news/article-3312981
http://fiddaman.blogspot.com.au/2015/08/mhra-blind-to-facts-over-lariam.html

9. Reported adverse events
Therapeutic Goods Administration (TGA) adverse event
notifications database - AUSTRALIA
To November 2015:
Number of cases: 199
Number of cases with single medicine: 180
Number of cases where death was an outcome: 2
--------------------------------------------------------------------------------------------
-------------
Medicines and Healthcare Regulatory Agency (MHRA) Drug
Analysis Print Database - UK
9 March 2016
Total number of adverse reactions: 6860
Total number ADR reports: 2307
Number of cases where death was an outcome: 23
Most common symptoms in both cases:
neuropsychiatric, gastrointestinal, cardiac
9
Incidence of 1:1000 - Uncommon
Incidence of 1:100 - Common
WHO definition:
‘A response to a drug which is
noxious and unintended, and which
occurs at doses normally used in
man for the prophylaxis, diagnosis, or
therapy of disease, or for the
modifications of physiological function'

10. 10
Mefloquine
causes
both
ACUTE
and
CHRONIC
(persis1ng
for
a
long
1me
or
constantly
recurring)
side
effects
The
incidence
of
ACUTE
effects
ranges
between
12%
and
54%
in
the
medical
literature
The
prevalence
of
CHRONIC
side
effects
is
NOT
KNOWN

11. 11
Mefloquine - Issues
for
use
within
the
military
Self-­‐repor1ng
of
mental
health
issues
is
uncommon,
even
to
medical
professional,
so
those
who
should
be
excluded
can
be
easily
missed
Loading
doses
(mul1ple
doses
or
reduced
interval
dosing)
are
commonly
used
due
to
1me
limita1ons
to
deployment
–
double
dosing
or
reduced
interval
dosing
is
not
advised
by
the
manufacturer
due
to
increased
risk
of
side
effects
Restric1ons
on
alcohol
–
variable
Commonly
used
for
long
periods
of
1me
(>6
months),
and
/
or
mul1ple
tours
of
opera1on
High
stress
environment,
influence
on
side
effects
is
unknown
http://www.geocities.ws/lariamactionaustralia/lariamlook.html
http://www.abc.net.au/worldtoday/content/2015/s4365966.htm

12. Tafenoquine
was
first
discovered
at
the
Walter
Reed
Army
Ins1tute
of
Research
USA
in
1978
and
was
licensed
to
between
GSK
Despite
20
years
of
clinical
trials,
tafenoquine
is
not
currently
registered
for
use
in
pa1ents
any
jurisdic1on
Currently
in
Phase
III
trails
with
GSK
and
Medicines
for
Malaria
Venture
(MMV)
Awarded
‘Breakthrough’
status
by
the
FDA
in
2013
and
is
being
progressed
through
Phase
III
trials
for
registra1on
now
8-­‐aminoquinoline
deriva1ve,
closely
related
to
primaquine
Tafenqouine
has
ac1vity
against
the
P.
vivax
lifecycle,
including
the
dormant
liver
form
that
causes
relapse
Tafenoquine
P.
vivax
P.
falciparum
P.
vivax
h#p://vivaxmalaria.com/template_disease.htm
h#p://vivaxmalaria.com/template_disease.htm
Tafenoquine

13. Suitable
for
both
treatment
and
prophylaxis
of
malaria
Can
cause
haemolysis
in
G6PD
deficient
pa1ents,
screening
required
Long
half-­‐life
–
single
weekly
dose
Known
ACUTE
side
effects:
Gastrointes1nal
–
diarrhoea,
nausea,
vomi1ng
Ophthalmological
–
keratopathy
and
re1nopathy
Haematological
-­‐
haemolysis
Neurotoxicity
–
unknown
Long-­‐term
side
effects:
unknown.
Cardiac?
Visual?
Neurological?
Tafenoquine
Tafenoquine
http://scienceblogs.com/startswithabang/2009/05/16/weekend-diversion-the-beetis-
a/

14. But all drugs can have side effects……..
Why the concern with these ones?
14/03/16
14

15. Mefloquine and tafenoquine use in the ADF
15
• Mefloquine
• Mefloquine introduced in 1993 – second line
prophylaxis
• Downgraded to 3rd line in mid 2000’s
• Limited numbers of prescriptions 2011-2015
• Tafenoquine
• Not currently part of the ADF pharmacy
• Tafenoquine is not approved for use by the
TGA
• Only used in AMI trials to date
Tafenoquine
Mefloquine

16. Who has been exposed?
14/03/16
16

17. Date Trials / Deployment Location Mefloquine Tafenoquine
1998-9 Post-exposure prophylaxis trial (2 doses,
primaquine comparison)
(Nasveld , Kitchener, Edstein & Rieckmann 2002, Trans Royal Soc Trop Med Hyg 96:683-4; Elmes, Nasveld , Kitchener, et
al, 2008, Trans Royal Soc Trop Med Hyg 102:1095-1101)
Bougainville
& Timor Leste
- 1164
1999 Open label pilot treatment trial
(Nasveld & Kitchener, 2005 Trans Royal Soc Trop Med Hyg 99:2-5; Kitchener, Nasveld & Edstein, 2007, Am J Trop Med
Hyg 76:494-96)
Timor Leste - 31
2000 –
2001
Randomised double blind trial
(Nasveld et al., 2010, Antimicrob Agents Chemother 54:792-8)
Timor Leste 162 492
2001 –
2002
Open label trial (with doxycycline)
(Kitchener, Nasveld et al., 2005, Med J Aust 182:168-71)
Timor Leste 1157 -
2001-20
15
Standard deployment 2001- 2015
http://www.defence.gov.au/Health/HealthPortal/Malaria/Resources/Default.asp
Various 659 0?
TOTALS 1987 1687
Mefloquine and tafenoquine use in the ADF
3674

18. The Australian Mefloquine and Tafenoquine Veterans
Group
ADF member, veteran or family Primary service unit
Total respondents: 133
10
113
6
97%

19. Respondents: 113
War-like deployments:
21
23
100
22
13

20. Numbers of individual
involved in the drug trials:
Bouganville 1999 4
Timor 2000-2001 57
Timor 2001-2002 43
Also a member from of
unreported mefloquine
cohort:
Somalia 1993 1
73
26
23
1
13
Involvement in AMI drug trials / deployments
Which drug did you take?
Mefloquine was most common trial drug experienced by the group

21. Drug trials: Adverse events – self reported
Responses: 84
16.5%
15.5%
40%
5%
23%
Acute
Chronic
Acute and chronic
Total number
experiencing
an adverse reaction
to one or both
drugs:
72%
Q: Don’t all drugs have side effects?
1%

22. 22
16.5%
15.5%
40%
5%
23%
Other deployment: adverse events when compared to mef / taf trial group
Responses: 84 Responses: 75
19%
5.3%
18.5%
20%
36%
Most common antimalarial reported for normal deployment was doxycycline
Although % of AEs was approximately the same, number of chronic and acute /
chronic reactions was reduced compared to mefloquine / tafenoquine group, and
number of No / Unsure responses was significantly increased. Greater total incidence
of adverse events in the trial group? 72% vs 42.8%
Acute /
chronic &
chronic
reactions
reduced
in number

23. • Depressive disorder
• Bipolar disorder
• Epileptic seizure
• Heart block
• Myasthenia gravis
• Peripheral neuropathy
• Psoriasis
• Sensorineural hearing loss
• Tinnitus
• Trigeminal neuropathy
23
Claims to DVA –
SOPs containing reference to mefloquine SOPs under review
• Anxiety disorder
• Panic disorder
• Suicide & attempted suicide
If the 3 new SOPS are accepted, this
equates to 13 separate claims for
one clinical syndrome.
Potentially another 8 SOPS could also
be included if we are to give a full
description of all potential side effects.

24. Claims to DVA – Increased prevalence of mental health issues
24
0
5
10
15
20
25
30
%
Neither / not sure
Tafenoquine
Mefloquine
Mefloquine &
Tafenoquine
2.2x
1.5x
3.6x
Apparent relative increase ‘mefloquine-treated group’ to ‘neither / not sure’ group, needs to be confirmed with
larger study. Tafenoquine and Mef / Taf group too small to make assumptions.
(47)
(13)
(60)
(13)

25. Summary
• Both mefloquine and tafenoquine are known neurotoxic drugs which have been
used for malaria prophylaxis and treatment in ADF personnel, including in
clinical trials.
• Mefloquine has been administered to ADF personnel at higher than
recommended loading doses, correct dosing regime for tafenoquine has not
been fully established.
• Higher incidence of mental health issues in ADF members exposed to
mefloquine as part of AMI trials, dual exposure shows similar effect?
• Lack of long-term follow-up for trial participants, either within service or after.
• Given preliminary results of survey of veterans group, outreach is needed to
identify cohorts and assess their wellbeing.
25

26. What can we do, what should we do?
26
1. Follow-up (outreach) program for all those exposed during clinical trials and / or active service. Inquiry into trials.
2. Defined study into relationship between exposure to mefloquine / tafenoquine and long-term mental and physical
health issues, work and family outcomes.
Achievable? Yes.
- Research plan is already in place with Centre for Traumatic Stress Studies, Adelaide.
- Access to data request submitted.
- Funding required.
3. Currently diagnosis of mefloquine intoxication syndrome is by elimination, association and pattern of symptoms.
Imaging might provide a definitive diagnostic test.
Achievable? Yes.
- Study proposed with Centre for Translational Research, Brisbane and Centre for Traumatic Stress Studies,
Adelaide, which could be part of the outreach program.
- Funding required.
4. RMA SOP established for mefloquine intoxication syndrome.
Achievable? Yes.
- Collaboration between AMA, RMA, health professionals, Defence and DVA can achieve this goal.

27. Acknowledgements and thanks:
The Australian Mefloquine and Tafenoquine Veterans
Group
27

28. 28