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Australian Defence Force Mefloquine and Tafenoquine Members and Veterans Group

Townsville Health Forum Townsville RSL 13 March 2016

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

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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

Mefloquine

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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

Mefloquine

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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

Mefloquine – uses and side effects

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 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

Mefloquine – uses and side effects

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 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

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

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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'

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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  

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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

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

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/

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

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Mefloquine and tafenoquine use in the ADF

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• 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

Who has been exposed?

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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 -

2001-2015

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

The Australian Mefloquine and Tafenoquine Veterans Group

ADF member, veteran or family Primary service unit

Total respondents: 133

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113

6

97%

Respondents: 113

War-like deployments:

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23 100

22

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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

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Involvement in AMI drug trials / deployments Which drug did you take?

Mefloquine was most common trial drug experienced by the group

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

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

•  Depressive disorder •  Bipolar disorder •  Epileptic seizure •  Heart block •  Myasthenia gravis •  Peripheral neuropathy •  Psoriasis •  Sensorineural hearing loss •  Tinnitus •  Trigeminal neuropathy

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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.

Claims to DVA – Increased prevalence of mental health issues

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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)

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.

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What can we do, what should we do?

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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.

Acknowledgements and thanks: The Australian Mefloquine and Tafenoquine Veterans Group

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