The causes of symptoms
The committee received over 100 submissions from veterans suffering from
chronic and complex symptoms which they attribute to taking mefloquine and/or
tafenoquine over 18 years ago. The Quinism Foundation in the USA has proposed that
there is a pattern of symptoms and has suggested the terms 'chronic quinoline
encephalopathy' or 'neuropsychiatric quinism'.
Others such as the Australian Quinoline Veterans and Families Association (AQVFA)
have used the terms 'mefloquine or quinoline poisoning',
or 'acquired brain injury'.
The Repatriation Medical Authority (RMA) notes other terminology used including
'chronic mefloquine toxicity syndrome', 'mefloquine intoxication syndrome', and
'chronic mefloquine-induced encephalopathy'.
The weight of medical evidence presented to the committee in response to
these claims is, in summary, that long term problems as a result of taking
mefloquine are rare and there is no compelling evidence that tafenoquine causes
long term effects. While committee members are not medical experts and can make
no medical findings, this chapter provides a summary of the evidence on this
issue provided to the committee.
This chapter contains a brief description of what is being claimed in
relation to the medications; the broad response from the medical community; the
safety profiles and side effects for mefloquine and tafenoquine; the use of
mefloquine in the civilian population; the domestic and international evidence;
the Therapeutic Good Administration (TGA) adverse event register; related medical
inquiries by the RMA and Specialist Medical Review Council (SMRC); and attempts
to explain what is occurring in some sections of the veteran community.
Disagreement over the cause of symptoms
Disagreement over the cause of symptoms was clearly evident during the
inquiry. Associate Professor Harin Karunajeewa succinctly captured the issue:
The point of controversy lies not in whether or not
individuals are suffering from these symptoms, but in whether or not they are
causally related to prior antimalarial drug use.
What is being asserted?
The AQVFA submitted that 'mefloquine poisoning', 'an accumulation of
symptoms associated with adverse reactions to mefloquine' is responsible for
the current symptoms being experienced by veterans. AQVFA advised that commonly
reported symptoms include:
...headache, tinnitus, dizziness, fatigue, anxiety, depression,
sleep disturbances including vivid or lurid dreams, changes in thought and
mood, confused thought processes and loss or diminution of working and / or
long term memory, heightened feelings of aggression and paranoia. Acute
physiological symptoms such as diarrhea, nausea, cutaneous rashes and cardiac
arrhythmias...Severe acute adverse reactions include frank psychosis,
hallucinations, and seizures. These symptoms represent a toxidrome which is clearly
identifiable subsequent to mefloquine exposure...
The AQVFA claim that 'an increasing body of evidence has established
that serious symptoms of central nervous system dysfunction occur far more
commonly tha[n] had been previously recognized[,] that had been originally
intimated in the safety information associated with the drug and that these could
be more prevalent and in military populations than has been previously
Mr Stuart McCarthy, President of and spokesperson for the AQVFA argued
that 'mefloquine is now known to be neurotoxic in some individuals, able to
cause lasting or permanent brain damage, with chronic symptoms typically
misdiagnosed as PTSD or other psychiatric disorders'.
He spoke of 'quinoline poisoning' and categorises symptoms as follows:
psychiatric disorders including depression, anxiety, bipolar
disorder and schizophrenia.
cognitive impairments including memory and concentration
hearing problems including tinnitus, hearing loss and
vestibular disorders including dizziness, vertigo and spatial
neurological disorders including neuropathies, seizures,
Parkinson's disease and motor neurone disease (MND).
The AQVFA refers to work of Dr Remington Nevin
who is Executive Director of the Quinism Foundation, a US non-profit charitable
organisation established on 1 January 2018 which 'promotes and supports
education and research on the family of medical disorders caused by poisoning
by quinoline drugs'.
Dr Nevin is the only staff member and there is a board of directors
consisting of five former US military officers or senior non-commissioned
officers. The Foundation relies entirely on private donations.
The Quinism Foundation:
...has proposed the term chronic quinoline encephalopathy,
otherwise known as neuropsychiatric quinism, to define the clinical disorder
caused by quinoline CNS neurotoxicity. The clinical features of
neuropsychiatric quinism reflect the localization of observed neurotoxic injury
across the broader quinoline class, with chronic dysfunction in affected areas
of the brain and brainstem providing the most parsimonious explanation for the
pattern of observed signs and symptoms from the disorder.
Dr Nevin claims that for a 'sizeable minority of users we see this
propensity to neuropsychiatric adverse effects and this risk of permanent
disability associated with their use'. He stated that mefloquine and
tafenoquine are 'idiosyncratic neurotoxicants at the doses used for
prophylaxis' explaining that 'the drug is acting as a toxicant in some users
and not in others—idiosyncratic. We don't know the reasons for that'.
He argued that it is inherently unsafe to use these drugs in a military
environment as it is 'likely that the user will confuse or misattribute side
effects from the drug to the stresses of travel, to the effects of crossing
time zones and to the effects of stress on deployment'. His theory is that
civilian users of mefloquine will stop taking the medication if they experience
unpleasant symptoms whereas veterans 'in many cases they were simply ordered to
take the drug' and 'never had the opportunity to stop [if they experienced
unpleasant side effects]'.
Dr Nevin believes that 'veterans are disproportionately represented because in
many cases they have been involuntarily intoxicated by these drugs'.
The response of the medical community
The view of the medical professionals is that this syndrome put forward
by Dr Nevin, AQVFA and others is not supported by the available medical evidence.
Associate Professor Karunajeewa summarised this alternative theory being put
In recent years some authors have proposed an alternative
theory that mefloquine (and tafenoquine) cause significant neurological
toxicity that results in neurological or psychiatric symptoms that can persist
for many years after the drugs are ceased or even be permanent. This has
variously been described using terms such as 'chronic mefloquine toxicity', 'mefloquine
induced chronic CNS syndrome', 'acquired brain injury', and 'mefloquine (or
quinoline) toxidrome'. This theory relies heavily on numerous assumptions,
especially in extrapolating findings from older, more toxic quinoline drugs to
mefloquine/ tafenoquine and from animal and laboratory studies to humans.
Associate Professor Karunajeewa advised the committee that this should
be regarded as a speculative hypothesis unless it can be supported by evidence
from human subjects treated with mefloquine.
He added that the terminology being used such as 'chronic mefloquine toxicity'
and 'mefloquine (or quinoline) toxidrome' are not 'widely used throughout the
mainstream medical community, having until now been restricted to a fairly
small core of authors with a particular interest and viewpoint on this matter'.
The view of Associate Professor Karunajeewa was supported by Professor
Geoffrey Quail, President, Australian College of Tropical Medicine:
The theory that mefloquine causes long-term neuropsychiatric
problems relates to work done with older drugs which were more toxic, and also
from animal studies. It's very difficult to extrapolate from animal studies to
humans. It [is] speculative unless supported by evidence from human treatment
with mefloquine. Based on well-conducted studies of over 360,000 US military,
which compared mefloquine with alternative drugs for malaria prophylaxis, the
long-term mefloquine toxicity is quite minor. If it occurs at all, it's really
topping up pre-existing neurological or neuropsychological problems. It is
extremely rare for it to occur long term in someone who didn't have other
problems. Thus in any subject with common psychological complaints—anxiety,
depression, post-traumatic stress disorder—it is overwhelmingly likely to have
existed due to factors other than mefloquine exposure.
Professor Dennis Shanks in his personal submission also stated:
As with all arguments of causation, there are elements of
truth contained within the assertions regarding the toxicity of antimalarial
drugs. However, the facts do not support the version of events put forward by
some veterans which has symptoms developing years after drug administration and
this causing current neuropsychiatric symptoms.
In looking at this issue, the RMA noted that '[t]here is no case
definition for chronic mefloquine toxicity syndrome and no unique or
distinctive group of symptoms has yet been specified...'.
The RMA concluded:
The claim that there are persistent symptoms that are due to
mefloquine is based on a small number of case reports and adverse event reports
of a variety of commonly experienced symptoms in a widely prescribed
medication. These same animal and human case reports are cited repeatedly as
the basis for the contention of a syndrome resulting from permanent brain
Professor Nick Saunders AO, Chairperson, RMA responded to questions from
the committee regarding the evidence presented by Dr Nevin:
Doctor Nevin's evidence is based on case reports—case series.
Epidemiologists have a hierarchy of evidence, and studies that generate
evidence, for medical conditions. We consider, and epidemiological analysis
considers, case reports to be the lowest level of evidence—very weak evidence.
The sort of evidence that one would use to then properly design an
epidemiological study to analyse or test the hypothesis that might come from
that. Doctor Nevin is basing his premises and his assertions on the basis of a
small number of case reports. It is very weak evidence, whereas there is much
stronger evidence from larger studies, cohort studies, studies that have got
controls in place, showing that, in fact, these drugs do not have demonstrable
long-term neurocognitive ill-effects on the brain.
Professor James McCarthy, Professor of Tropical Medicine and Infectious Diseases,
Royal Brisbane Hospital and QIMR Berghofer Medical Research Institute spoke on
the theory being put forward regarding mefloquine:
Mefloquine is a drug that was discovered in the 1970s. Right
at its very discovery, it was realised that it caused particular mental,
psychologic and neurologic side effects in a small proportion of people who
took it. That's been very clearly recognised by doctors and people involved in
prevention and treatment of malaria, and I personally have observed that in
patients I've treated with malaria. As well, there is a small proportion of
people who take this drug for prophylaxis—that is, once a week—who
unequivocally develop neurologic side effects and therefore should cease taking
it, and certainly some groups of people are at higher risk of getting these
side effects. What is not, in my mind, certain is the relationship between
taking mefloquine for a short period of time and having long-term and permanent
neuropsychiatric problems that are clearly caused by a short-term exposure to
mefloquine. The literature and the scientific community do not believe that
there's a strong link between people who've taken it and having long-term
consequences. Certainly people have long-term consequences, but whether that's
due to the mefloquine or something else is always very hard to figure out.
When asked to respond to the evidence provided by Dr Nevin, Professor
I suppose, being a doctor and a scientist, I try to return to
what the evidence is and what's been published in the medical literature and
what has been subjected to peer review. As I said before, the problem is you've
got a situation where you've got a relatively common outcome in human
populations, more common in soldiers that were deployed, and you've got a
relatively low frequency of outcomes, and statistically it is very hard to be
certain that there is an association that meets the criteria of being statistically
significant. Although I may not be an epidemiologist, all of my work requires
that I understand statistics and risk-benefit analysis. My view is in
concurrence with the medical literature that there is no statistically
significant association of tafenoquine with any of these purported
problems—and, with mefloquine, for the long-term ones that I've described, not
the short-term ones, it's very difficult to discern a statistically significant
association between those things. That's not to say there might be an effect,
but, if there is, it's very hard to find from the population data that we have
available to us.
Professor Dennis Shanks, Director, ADF Malaria and Infectious Disease
Institute, also responded to the evidence by Dr Nevin:
...I think that just about everything Remington Nevin said [to
the committee] this morning was wrong. To make this short, when he stood up
before the USFDA and tried to explain to people who understood drugs why his
view of things—and it was the same view—was correct, he quoted two studies. One
was a large study looking at 8-Aminoquinolines in monkeys which was done in the
1940s, and the one was a summer-student stem project done at Walter Reed which
was never published. It's a poster. It's one-page long. I would be embarrassed
trying to hang anything on those two studies. One was done long before
mefloquine or tafenoquine were even synthesised, much less tested, and the
other was a completely uncontrolled—interesting, but uncontrolled—study. The
controlled studies with toxicity have come back with completely different
answers. Tafenoquine and mefloquine are not the same drug. They don't have the
same risk profile. What Remington Nevin says is wrong.
At a Canberra hearing Associate Professor Karunajeewa summarised his
In my submission I've done my best to summarise and
synthesise the available evidence as I see it regarding neurotoxicity of
mefloquine and tafenoquine. To restate my conclusions: for mefloquine I say
that if permanent or long-term mefloquine toxicity does exist—and I think it's
still a big 'if'—then it seems very unlikely that it causes a significant
number of additional neurological and psychiatric problems over and above that
which ordinarily occurs due to background rates of mental illness in the community.
With respect to tafenoquine, my conclusions are, I think, even stronger still,
and I say that there is no evidence at all that it causes increased rates of
significant neurological or neuropsychiatric problems, whether acute or
chronic, when used in conventional doses in humans.
It is important to note that some evidence provided by individuals does
not clearly distinguish between mefloquine and tafenoquine. Although they are
both quinolines, tafenoquine is 'not structurally related to mefloquine' and is
Given the numerous individual accounts of various symptoms the committee
looked at the possible side effects of mefloquine and tafenoquine as stated in
the advice to clinicians and patients as well as the possible duration of any
Overseas, mefloquine was first granted marketing approval in Switzerland
in 1984 and as at February 2018 was approved in approximately 27 countries
worldwide. Around 40 million patients around the world have been treated with mefloquine
since it was first made available. Mefloquine is listed as a malaria treatment
option by the World Health Organization (WHO) and US Centres for Disease
Control and Prevention (CDC). It is listed as a WHO essential medicine and is
recommended in other authoritative guidelines for the prevention of malaria.
In Australia, mefloquine is registered under the brand name Lariam,
receiving regulatory approval and entered on to the Australian Register of
Therapeutic Goods (ARTG) on 27 January 1993. It is indicated for malaria
treatment and malaria chemoprophylaxis (prevention).
The submission and additional information from Roche indicates that mefloquine
was approved in Australia on 3 September 1986.
Roche notes that this difference in dates:
...reflects the introduction of the Therapeutic Goods Act
1989 and the requirement for products to be listed on the Australian
Register of Therapeutic Goods (ARTG). After the commencement of the
legislation, products already approved and on the market were grandfathered
into the ARTG. On the 27 January 1993, mefloquine was grandfathered into the
ARTG. Mefloquine had indications for treatment and prophylaxis since is
original registration in 1986.
The Department of Health pointed out that as with all medicines there is
a balance of benefits and risks for the population that will use them and
regulatory approval by the TGA 'is based on an assessment that at a population
level the benefits of the medicine exceed the risks'.
Roche acknowledged that approval of a medication by the regulator does
not indicate that the medication is suitable for everyone. Companies therefore
work with regulators to develop and update Product Information (PI) and
Consumer Medicine Information (CMI) which assist clinicians, pharmacists and
patients to select the most appropriate medicine.
In the case of mefloquine, Roche advised that:
...important safety information from patient and clinician
reports have been included in PIs and CMIs since the medicine was made
available in Australia. This has included information about neuropsychiatric
side effects and precautions around use by people with existing mental health
conditions. The purpose of this is to allow healthcare professionals to make a considered
judgement on whether mefloquine or another antimalarial is most appropriate for
a given person.
The committee was told that long term problems as a result of taking
mefloquine are rare.
The Department of Health noted that the use of mefloquine is
contraindicated (i. e. not recommended for use) as follows: Patients with a
past history of active depression, a recent history of depression, generalised
anxiety disorder, psychosis or schizophrenia or other major psychiatric
disorders or convulsions should not be prescribed Lariam prophylactically (to
The adverse effects section of the Lariam Product Information (PI)
The rate of adverse events associated with Lariam is
published to be similar to that with other antimalarial prophylactic
medications. In chemoprophylaxis
the safety profile of Lariam adverse events is characterised by a predominance
of neuropsychiatric adverse reactions.
Due to the long half-life
of Lariam, adverse reactions to Lariam may occur or persist up to several weeks
after the last dose. In a small number of patients it has been reports that dizziness
or vertigo and loss of balance may continue for months after discontinuation of
the medicine. There have been rare reports of suicidal ideations. No
relationship to drug administration has been established.
At the doses given for acute malaria, adverse reactions for
Lariam may not be distinguishable from symptoms of the disease itself.
Among subjects who received lariam for treatment, the most
frequently observed adverse experiences included: dizziness, myalgia, nausea,
fever, headache, vomiting, chills, diarrhoea, skin rash, abdominal pain,
fatigue, loss of appetite and tinnitus. Those side effects occurring less
frequently included bradycardia, hair loss, emotional problems, pruritis,
asthenia, transient emotional disturbances and telogen effluvium (loss of
resting hair). Seizures have also been reported.
In summary Roche advised:
Based on Roche's evaluation of all available information,
including data from post-marketing experience, published literature and other
safety-risk management sources, the benefit-risk profile of mefloquine use in
the prevention and treatment of malaria remains positive. This is aligned with
the views of regulators such as the TGA and bodies such as the WHO and CDC. As
a result, it remains available as an option for clinicians and patients to
consider when selecting a medicine to prevent or treat the serious condition of
At the 8 November 2018 hearing in Canberra, Roche confirmed that the
'benefit-risk profile of mefloquine is well understood and remains positive'.
The RMA noted:
Given that mefloquine has been used by more than 35 million
travellers for chemoprophylaxis worldwide since 1985 in Europe and since 1990
in the USA, it would be expected that even rare effects would be able to be
detected with reasonable frequency if a causal relationship existed. Instead,
there are only five case reports of people with some long term symptoms
(especially vertigo or dizziness), together with reports of persistence of a
range of commonly experienced symptoms amongst some of the cases reported to
adverse event databases.
The RMA stated that in relation to the 'acute adverse effects of the
drug' which are the effects which occur at the time of taking the drug or soon
after it has been discontinued, 'there is undoubtedly evidence that mefloquine
is associated with a range of symptoms, some of which can be quite distressing...that
evidence has been translated into 16 statements of principles as a causal
factor in relation to particular diseases or injuries.'
However, the evidence shows that 'these reactions are not experienced by the
majority of people who take the drug':
These are reactions that occur in a minority of people. The
evidence shows that the vast majority of those reactions settle over weeks or
months, or sometimes symptoms have continued into more than 12 months. So,
there are these acute effects. They are uncommon. When they do occur they can
be very distressing. In their extreme form, they can have disastrous outcomes in
terms of psychotic episodes and the like, but they resolve after taking the
Adjunct Professor John Skerritt, Deputy Secretary, Health Products
Regulation, Department of Health provided his view on the safety profile of
Used in patients or individuals who do not suffer from
psychiatric disorders, mefloquine, as antimalarials go, is quite a respectably
safe medicine—I've taken it myself. Tafenoquine doesn't have as many adverse
events in people with psych issues as does mefloquine. But, as antimalarials
go, mefloquine definitely has a place.
This view was supported by Professor Quail:
Sure, mefloquine, as we've said, has this side effect
profile, but it really is reasonably clear of side effects in about 90 per cent
of cases. If it's taken, mefloquine is taken at a dose of 25 milligrams per
kilogram, which is a standard dose. The incidence of severe neurotoxicity is
less than one in 1,500. As I said, in almost every case that clears away unless
there's a pre-existing psychiatric problem.
Adjunct Professor Skerritt emphasised the need for second or third line
drugs due to antimalarial resistance in parts of Asia and Africa and because
some people cannot tolerate doxycycline.
Responding to concerns about whether a public health danger is being
missed, Associate Professor Karunajeewa stated:
The scale of this is that we're talking about 200 million
people a year. Most of those people are being treated with some form of
quinoline antimalarial of one type or another, and this has been going on for
decades—hundreds of tonnes per year. The quinoline antimalarial drugs are
probably the most-used drugs in human history, just to keep that in
perspective. 'Are we missing something actually causing long-term harm?'...I go
back to the evidence that we have. I don't think there's anything particular to
suggest that that is the case. We're in the business of trying to limit
sickness and death from one of the most serious illnesses that has ever
affected humans. It has killed 300 million people over the history of
humankind, and we're trying to put a stop to that. We're trying to put a stop
to that, and we've had, I think, not insignificant successes over the last 15
years or so. There have been profound advances in the control of malaria which
we think have saved about six million lives over the last 15 years. The
improvements in malaria control are related to the use of bed nets but also to
these new quinoline drugs that we're using for malaria. Six million people we
think are alive today who wouldn't be if we hadn't been instituting those
measures. We can't just sit around and watch it all happen; we have to try to
do something about it, and that involves some risks. Nothing is achieved without
risks, but our job is to try to manage those risks and minimise them.
The potential side-effects of mefloquine were known and taken into
consideration by Defence and are reflected in their cautious approach:
Defence has always acknowledged that mefloquine can cause
side effects, including neuropsychiatric problems, while individuals are taking
the drug. Our conservative approach is a direct acknowledgement of these
potential side effects. Generally, symptoms will disappear when the individual
stops taking the drug but they can persist for some time afterwards due to the
drug’s long half-life of two to four weeks. Defence also acknowledges that
neuropsychiatric side effects have been known to continue and become long term
in a small number of individuals.
Defence emphasised to the committee that at the time of the trials in
the late 1990s and early 2000s, mefloquine was approved by the TGA, however Defence
...mefloquine should not be taken for malaria prevention by
people who have, or have had, a psychiatric condition, seizures, kidney disease
or liver disease. For these reasons, Defence health policy requires that ADF
members be properly informed of the potential side effects of mefloquine and
that the drug only be prescribed by a qualified medical practitioner after the
member has been provided information about the drug’s side effects.
Defence indicated that the known possible side-effects are outlined in
the patient information:
Mefloquine is known to cause unusual dreams and can cause
psychiatric symptoms in some people, including disturbed sleep, anxiety,
paranoia, depression, hallucinations and psychosis. Dizziness and loss of
balance have also been reported as side effects from the use of mefloquine. For
this reason, the medication is not used in ADF aircrew.
The committee received a number of submissions from individuals
recalling the vivid dreams they experienced while taking mefloquine.
This was addressed by Professor McCarthy who explained:
When you take it, the levels of the drug go up in your blood
very quickly and then they go down quite quickly. During that phase of 12 hours
or so when the drugs are at high levels in the blood, people very frequently
describe how, in the evening after they take their mefloquine, they would have
a disturbed night's sleep or vivid dreams. But that is not a dangerous effect,
and that's an effect that does disappear. I would always warn somebody that
they should expect to have perhaps some disturbances in their sleep the night
they take their mefloquine.
Professor Sandy McFarlane AO, Director of the Centre for Traumatic
Stress Studies at the University of Adelaide was asked by Defence to conduct a
literature review on the adverse effects of mefloquine. The major findings of
this review were:
there are various theories on how mefloquine might cause
neuropsychiatric effects based on its underlying action.
there are varying conclusions about its potential toxicity.
these variations are, in part, explained by the differences of
the methodology used in the published reports.
the serious side effects of mefloquine have been known for many
years, but continuation of effects after ceasing medication is a concern raised
in recent years.
there is no specific way to diagnose chronic mefloquine effects
as many symptoms are shared with other conditions such as PTSD.
there is no specific treatment except to cease the drug when
symptoms develop and to treat the symptoms.
the literature available at the time of this review does not
address some questions, including:
Are some individuals pre-disposed to adverse effects?
Does mefloquine modify the response to trauma?
Duration of side effects
Regarding the length of any side effects, the committee was told that
they normally resolve after the medication is stopped. Defence indicated:
Normally side effects, including neuropsychiatric side
effects, resolve within days to weeks after stopping mefloquine. Mefloquine has
a half-life (persistence in the bloodstream) of two to four weeks, which is
longer than other antimalarials, therefore side effects that emerge while
taking mefloquine have been reported to persist after cessation of the
medication and sometimes for several months.
Roche provided further detail on how long the medication takes to be
eliminated from the body:
...the half-life of the drug is quite long—it's 21 days—so that
allows people not to have to take it daily—hence the weekly dosing regime that
I described. That is, of course, an advantage when one looks at compliance and
how well people adhere to medicines that have been prescribed to them. So the
fact that the drug itself and its metabolites have half-lives of about 21 days
means that, after 21 days, half the drug is eliminated from the body. The
general understanding is that, in five times the half-life for the drug, it
will be eliminated, which would be maximally 100 days. But they would be very
low doses at that time, very low concentrations.
Associate Professor Karunajeewa pointed to data from numerous clinical
studies which have consistently found that any mefloquine side effects:
develop early on in the drug's use;
are more likely to occur in those with pre-existing psychiatric
are dose-related (therefore more likely to occur or be more
severe if higher doses are used); and
generally resolve following cessation of the drug.
Associate Professor Karunajeewa emphasised that these findings have been
reinforced by the clinical experience with many millions of people treated with
mefloquine throughout the world.
Further explanation was provided:
...mefloquine, like virtually all drugs, can cause toxicity that
encompasses a spectrum from none at all on one side, to very severe on the
other. The key question then becomes, in practice, how many people taking the
drug fall into the "very severe" category with lasting or permanent
significant side effects. Is this likely to be very rare or quite common? To
answer this question, our best available approach is to draw on the results of
carefully constructed studies that apply the best statistical methods to
compare the prevalence of these symptoms in humans who have taken these drugs,
with a suitable group for comparison (often referred to as a control group).
Associate Professor Karunajeewa discussed the possible length of side
effects with the committee:
To actually understand whether that does occur or not [that
side effects are generally resolved following cessation of the drug] is the
difficult process that we need really good evidence for, and I believe that
large study of 360,000 is probably the best that we've got. There certainly
have been reports, case reports, of people who have had persisting dizziness,
persisting problems with ringing in the ears and that sort of thing, but it's
still hard to be absolutely sure that it's mefloquine that's the cause of the
problem. But, look, I'm perhaps a little bit more sanguine than some people in
terms of being absolutely on one side of the barge or the other. I still think
it's possible that in some rare, unlucky individuals that they do experience
longstanding effects from mefloquine. I still think that's possible. But my
reading of the literature and of the accumulated evidence is that, if that does
occur, it's highly likely that it's actually quite a rare event.
He further responded that these rare events are more likely to occur in those
who have a pre-existing psychiatric illness.
International and domestic studies
The committee was told about the international and domestic studies
involving mefloquine. Although the next section is not exhaustive, relevant
submissions contain further details.
Associate Professor Karunajeewa directed the committee to a large and
well-designed study published in 2017 of 367 840 US military personnel
which compared the incidence of neuropsychiatric diagnoses occurring up to a
year following drug exposure in 36 568 individuals who took mefloquine with 331
272 who took an alternative malaria drug such as doxycycline or Malarone.
Following analysis of the findings in his submission Associate Professor Karunajeewa
Based on these findings, we cannot absolutely with 100% [certainty]
disprove the theory that mefloquine causes long-term toxicity in humans. In
fact we can never do this - that’s just not how science works. However, based
on the study's findings, we can say, that if mefloquine did cause long-term toxicity
(and that is still a very big "if"), then this is likely to occur as
a fairly uncommon event and would only contribute to a very small proportion of
the background rates of psychiatric disease in the population.
Associate Professor Karunjeewa indicated that this US study '[b]y nature
of this [the use of appropriate methods] and its very large size, it
effectively constitutes the best evidence on this subject we currently have,
and probably the best evidence we are ever likely to have'.
However, he also pointed to a smaller study conducted by the US CDC in 2016
which invited former Peace Corps volunteers (from 1995 to 2014) to participate
in an internet based survey related to malaria prophylaxis and medical
diagnosis. Noting the methodological problems (only 11 per cent participation)
and recall bias, the overall conclusions were that:
(1)'Malaria prophylaxis use by
Peace Corps Volunteers is safe', (2) 'When excluding those with prior psychiatric
illness there were no difference in psychiatric diagnosis rates' in mefloquine
users and (3) In those with pre-existing psychiatric diagnoses, 'certain
psychiatric diagnoses were more likely among Mefloquine users'. This last point
is consistent with existing knowledge regarding risk factors for neuropsychiatric
effects of mefloquine and emphasizes the importance of good screening for these
contraindications prior to prescribing.
Associate Professor Karunajeewa stated that '[o]verall I think their
findings were consistent with and supported by the larger and more rigorous
subsequent  study'.
Responding to a question about taking mefloquine long-term, Professor
McCarthy also referred to the study of US Peace Corps volunteers who took
mefloquine for years while working in sub-Saharan Africa and that 'the rate of
these side effects went down as people took the mefloquine for longer'.
Associate Professor Karunajeewa emphasised that the results of these
...are also borne out by the now very extensive clinical
experience with mefloquine. Until as recently as 2011, up to 17,000 Australian
travelers were being prescribed mefloquine by GPs and travel clinics. As many
as 35 million people a year receive the drug (mostly in much higher
treatment doses than are used for prophylaxis). This represents the very large 'denominator'
of total mefloquine use in the community and suggests that the isolated reports
of serious side effects represent an extremely small fraction of the total
Professor McCarthy also spoke about his own research involving
mefloquine in small groups in three different doses:
With the people on the highest dose, I think three or four of
the eight people had what I would consider to be unacceptable side effects of
the mefloquine when given very high doses to cure their malaria. So, without a
doubt, the mefloquine did cause those transient side effects that went away
once the mefloquine went out of their system.
Defence also pointed to a 2006 study
which was a retrospective analysis of US military health records between 2002
and 2004 to examine the adverse effects of antimalarials. The study compared
numbers of hospitalisations of military personnel who had been prescribed mefloquine
and were deployed to active duty in malarial areas with those who had not and
resided in Europe or Japan and those who were otherwise deployed. It found that
'[m]efloquine users were statistically less likely to be hospitalised (after
deployment) with mood disorders, or for any cause, than military personnel who
did not receive any antimalarial agents but who were deployed to a war zone'.
Dr Nevin criticised the studies cited, saying they have not been
informed by 'methods of modern psychiatric epidemiology'.
This was not supported in evidence to the committee.
Adjunct Professor Skerritt commented that in general, 'neuropsychiatric tools
are used to determine fairly subtle changes...You don't need a neuropsychiatric tool
to say you've had severe insomnia or bad dreams or bad depression...so I'm not
sure that that's necessarily required if you're looking for a serious adverse
Dr Peter Stewart, Roche, told the committee that 'mefloquine is the most
studied of all the antimalarials' and '[t]here is a very large volume of
evidence that has been collected around the safety and efficacy of this drug'.
He referred the committee to the most recent publication on the safety of
efficacy published in 2017 by the Cochrane Collaboration
which is 'one of the most respected, independent, evidence based scientific
bodies in the world'.
It reviewed a million patients using a variety of information sources including
clinical trials, non-clinical trials, hospital records, and health authority
records. It found that the 'risk benefit profile is very well understood and
very well described and remains positive'.
Dr Stewart pointed to some of the findings of the Cochrane Collaboration that
'mefloquine does not have more frequent serious side effects overall than the
two commonly used other antimalarials, doxycycline and atovaquone-proguanil [Malarone]'.
'They [the Cochrane Collaboration] did note, as we know, that people taking
mefloquine are more likely to have [transient] abnormal dreams, insomnia,
anxiety and a depressed mood for the period during travel than those who take
doxycycline or atovaquone'.
Dr Stewart also noted the large volume of clinical research data and
real world data collected over 32 years and stated that this body of evidence
does not support the hypothesis of brain injury from antimalarial treatment
generally or mefloquine specifically.
He pointed to one of the conclusions of the Cochrane Collaboration which was:
We believe it is important that the large retrospective
healthcare record analyses did not demonstrate a clear quantitative association
between mefloquine use and formal mental health disorders.
As the AQVFA points to metabolisation of the drugs as a possible reason
for potential adverse reactivity,
the committee discussed the metabolisation of mefloquine with Roche which
advised that metabolisation occurs through a class of enzymes called the
cytochrome P450 enzymes. While there are more than 50 types of cytochrome P450
enzymes, the two most common are CYP3A4 and CYP2D6 and mefloquine is
metabolised by CYP3A4. Dr Stewart noted the hypothesis that if a patient has a
low level of CYP3A4 then potentially the body might not be able to metabolise
mefloquine as well as others or it might not be cleared as rapidly. He explained
that all medicines are metabolised by one of these enzymes and it has not been
determined that routine use of testing to discover genetic variations in people
would improve outcomes. He also pointed to the large body of evidence in
relation to mefloquine which does not support the hypothesis that mefloquine
causes brain injury
or long term mental health disease or conditions.
See below for further discussion of metabolisation in relation to tafenoquine.
Professor McFarlane speculated about the role of antimalarials which may
modify the risk of developing a range of psychiatric disorders including PTSD.
This was addressed by Dr Dow from 60 Degrees Pharmaceuticals:
It is not disputed by most travel physicians that mefloquine
at prophylactic doses statistically increases the risk of the following adverse
events relative to doxycycline and atovaquone-proguanil: insomnia, abnormal
dreams, anxiety and depression. Professor McFarlane speculates that
antimalarial drugs that are ''psychotropic'' and cause such events in some
individuals might increase the risk of rarer and more severe post-deployment
psychiatric events, particularly in stressful situations. However, he neglects
to mention that, at a population level, the scientific literature does not
support such a causal association in practice. In fact, recent reports from
reputable U.S. government agencies have demonstrated that (i) deployment and
combat experience not antimalarials increases the risk of PTSD and other
serious psychiatric events, (ii) mefloquine and atovaquone-proguanil result in
a similar increase in the total burden of neuropsychiatric illness during
deployment and (iii) the long term risk of serious psychiatric events is not
increased for mefloquine relative to other antimalarial prophylactics if prescribing
information is followed.
Use by the civilian population
Defence advised that its use of mefloquine has been conservative
compared to its use in other militaries around the world and in the civilian
population. It is commonly prescribed in the broader Australian community.
Estimated Australian Civilian Prescription Data
Source: Australian statistics on medicines/Roche Products Pty
Roche advised that 8,810 scripts for mefloquine were issued in Australia
with approximately 40 million patients treated with mefloquine globally since
it was made available.
Approximately 300,000 Australian patients have been prescribed mefloquine.
The RMA noted that mefloquine has been used by more than 35 million
travellers for chemoprophyaxis worldwide since 1985 in Europe and 1990 in the
USA and therefore 'there is a strong likelihood that even rare effects would be
able to be detected with reasonable frequency if a causal relationship existed.
Nevertheless, there are relatively few case reports of long term adverse
effects given the high level of usage'.
The committee spoke to Dr Penny Burns, GP representative of the Royal
Australian College of General Practitioners to discuss the use of mefloquine in
the civilian population. Emphasising that 'malaria is a very serious and deadly
disease', she confirmed that 'GPs are still regularly prescribing mefloquine
and the '[c]urrent evidence based resources used by many GPs as reference on
best management of patients, including therapeutic guidelines up to date, still
include mefloquine as an option for malarial prophylaxis'.
Dr Burns spoke about her personal experience:
...I've seen a lot of patients prescribed mefloquine with
minimal percentage, in my experience, having had side effects. I've probably
only seen about three people with side effects from mefloquine that have been
impacted over that period of time.
Potential to assist the region
It was noted that the approval of tafenoquine would be the first new
medicine for the prevention of relapse of P. vivax malaria in more than 60
years, addressing the need for a single dose, effective medicine.
Evidence noted the potential public health value of tafenoquine for the Asia
The Asia Pacific Leaders Malaria Alliance reported:
As expressed during the recent Malaria World Congress in
Melbourne (1-5 July 2018) by world experts on P. vivax, the promise of
Tafenoquine as a single dose radical cure is revolutionary. Not only will
Tafenoquine improve patient adherence by reducing a current standard regimen from
14 days, but will also reduce the risks of resistance, because of its
single-dose formulation as a radical cure. This is particularly relevant in settings
where regular follow-up with patients is a challenge due to poor geographic accessibility
to public health services.
It also advised that:
In addition, Tafenoquine as a preventive treatment is crucial
from a public health perspective to mitigate the risk of malaria spreading
beyond borders, as well as to reduce the number of imported malaria cases,
which could reverse efforts to eliminate malaria. What is more, Tafenoquine as
a prophylaxis could support efforts to prevent transmission from asymptomatic
Professor McCarthy also supported the approval of tafenoquine:
I think it's a really useful drug and will protect lots of
people from catching malaria—as long as we've got adequate mechanisms in place
to give surveillance for these unusual side effects, which are of uncertain
relationship to tafenoquine. Certainly if I was to go to one of these malaria
areas I would be wanting to have tafenoquine available. I think it will be a
fantastic drug for the prevention of malaria, if we can continue to monitor for
the unusual outcomes.
Mr David Herd, Director, Market Access and Communications and Government
Affairs, GlaxoSmithKline Australia Pty Ltd emphasised the importance of the
treatment as a 'critical step towards the effective elimination of P. vivax
GSK spoke about their work with Medicines for Malaria Venture (MMV)
to address the 'very significant unmet medical need in malaria-endemic
countries for an alternative treatment to the current standard of care, which
you have to give for 14 days'.
Responding to concerns raised by Dr Nevin about the safety of
tafenoquine, and the effect in poorer countries
Professor McCarthy responded:
It's obviously morally really important that we don't
relegate drugs as 'second class' so, therefore, they can be tested or deployed
in populations where they will never be accepted in Australia. But you've got
to remember that these drugs have been approved for use in the US on US
citizens, so I don't believe that we can do any better than that. As long as
we've got a robust process in place for surveillance after licensing these
drugs, I think, to turn it on its head, it would be unethical and immoral to
deprive the people who are most at risk of malaria of getting a new drug that's
going to be the first prophylactic drug available for many years. I think that
you could turn that around and say that it would be inappropriate to deny them
access to this drug.
At the time of the ADF trials tafenoquine was not registered in
Australia. However, in July 2018 it was approved by the US FDA for malaria
radical cure (prevention of relapse)
of liver-stage infections under the trade name Krintafel.
On 8 August 2018 it was approved by the US FDA for malaria prevention under the
trade name Arakoda.
In September 2018 it was also approved by the Australian TGA for prevention
under the trade name Kodatef
and radical cure under the trade name Kozenis.
Dr Geoffrey Dow, CEO and Chairman, 60 Degrees Pharmaceuticals explained
the relationships between GSK, 60 Degrees Pharmaceuticals and Biocelect in
relation to tafenoquine in evidence to the committee.
The committee was told that there is no compelling evidence that
tafenoquine causes long term adverse effects.
Dr Dow addressed the assertions made by some groups:
Activist groups such as the Quinism Foundation, in common
cause with some veterans' groups, (hereafter referred to as the 'anti-tafenoquine
activist community') bluntly assert that all quinoline antimalarials are
neurotoxic. This is false. Primaquine...is an 8-aminoquinoline. It is activated
in the body to form unknown oxidative intermediates that confer an indirect
antimalarial effect on hepatic stages without causing neurologic deficits....In
contrast, mefloquine is a 4-aminoalcohol with a side chain and confers both a
potent and direct effect only on blood stage malaria parasites, while inducing
an increased rate of some specific neuropsychiatric events relative to the
standard of care in travelers. Since tafenoquine is an 8- aminoquinoline analog
of primaquine, and is not structurally related to mefloquine, there is no
reason, a priori, to expect it to exhibit the same adverse event profile as
Biocelect also addressed the claims:
We are aware of a small group of veterans and their
supporters who attribute their mental health issues to having been given
Tafenoquine in trials conducted within the Australian Defence Force during
their deployment in East Timor. We wholeheartedly sympathise with these veterans
and while we recognize and appreciate that they have served our country, based
on the evidence available we do not attribute these mental health issues
experienced by the veterans to Tafenoquine....We believe that this position has
been confirmed by the recent approval for Tafenoquine as a treatment (radical
cure) for malaria by the U.S. Food and Drug Administration (FDA) and the recent
recommendation by the U.S. FDA expert Advisory Committee for the approval of
Tafenoquine for the prevention of malaria. This recent FDA approval for
treatment and FDA expert Advisory Committee recommendation, for approval by the
FDA for prevention, was conducted by highly qualified scientific and medical
experts based on their review of the scientific evidence.
GSK emphasised to the committee that they take safety very seriously.
'We have been fully transparent with all of the safety data that we've gathered
across all of the studies that were done—not just the ones done more
recently—that are relevant to a radical cure. They have been evaluated very
thoroughly by the regulators'.
GSK advised that they will continue to review the safety profile as tafenoquine
is rolled out in the US and working with WHO when it is available for radical
cure in endemic countries.
GSK advised that the full report of safety data was submitted to the FDA
and TGA for review. GSK added 'there is no evidence that tafenoquine
concentrates at toxic levels in the brain causing permanent brain injury'.
GSK advised that 13 clinical trials were submitted to US and Australian
regulatory authorities involving more than 800 patients.
GSK noted that the FDA and its Antimicrobial Drugs Advisory Committee were
aware of the concerns raised by ADF veterans.
Dr Nevin confirmed that he was the only submittor to the FDA against approval
MMV, a product development partnership in the field of antimalarial drug
research and development, reported:
...it should be noted that no serious neurological or
psychiatric adverse events (AEs) were noted in the clinical efficacy &
safety studies that investigated the single 300mg tafenoquine treatment dose
(GSK-MMV clinical trials program for TQ), and no subjects withdrew from the
studies or discontinued treatment due to central nervous system (CNS) AEs. All
CNS events seen in these studies were mild to moderate in severity and were
We therefore conclude that in the >800 subjects who have
received a total single-dose of 300mg TQ, no serious CNS events have been
reported and the observed events have been mild to moderate and self-limiting. Therefore,
the single 300 mg TQ dose + [chloroquine] CQ for radical cure of P. vivax
malaria is anticipated to have a low risk of significant CNS effects in
patients without an active or past history of serious psychiatric disorders.
The Australasian Society for Infectious Diseases said that the extensive
experience with the structurally similar primaquine is reassuring:
In more than 36 million exposures, there has only been 1
report of neurotoxicity in a 55 year old man who developed depression and
psychosis after the 2nd dose of primaquine which resolved within 24
hours on stopping the drug.
Dr Dow noted that the US prescribing information for Arakoda includes a
contraindication for those with psychotic illness and explained this as precautionary
because three clinical trial participants with an undisclosed history of
psychosis experienced psychotic events at doses which were not the approved
MMV provided information on non-clinical animal studies which do not
suggest a signal for CNS toxicity with tafenoquine.
We believe its use will transform case-management of P. vivax
infection, improve compliance, help achieve improved rates of radical cure and
contribute to achieving both the Sustainable Development Goals and malaria
elimination targets set by WHO.
Professor McCarthy spoke about his clinical trials using small groups of
people. He reported that in the case of tafenoquine, '[a]ll of the subjects who
were given tafenoquine had no neurologic side effects at all'.
Dr Dow confirmed that during its review of tafenoquine, the US FDA included
specialists from their division of psychiatry as well as the pharmacovigilance
and epidemiology areas to review the data.
He also outlined the additional work undertaken in an attempt to address the
concerns of some advocates.
The Department of Health took the committee through the approval process
for drugs which tafenoquine has just been through and the ongoing safety
monitoring of drugs.
Adjunct Professor John Skerritt, Deputy Secretary, Health Products Regulation,
Department of Health, confirmed that experts within the TGA include medical
doctors, toxicologists and pharmaceutical chemists. He also advised that the
TGA sought external advice 'from an advisory committee of doctors, community
representatives, epidemiologists, statisticians'.
Adjunct Professor Tim Greenaway, Chief Medical Adviser, Health Products
Regulation, Department of Health, pointed out that there is much more data
available than just the ADF trial involving tafenoquine. He pointed to a review
of 22 trials of tafenoquine where 'the safety profile of tafenoquine was very,
very good and the risk-benefit analysis was favourable' and this was considered
by Australia's Advisory Committee on Medicines (ACM)
and the US FDA independently.
The US FDA and TGA approval processes included an audit of the Defence
studies involving tafenoquine:
The U.S. FDA, with TGA observing, audited study records for
Study 033 and 049. The auditor, commented...that the level of oversight by ADF
medical officers, in particular Lieutenant Colonel Peter Nasveld, [of soldiers]
receiving tafenoquine and mefloquine in these studies was of a very high
Dr Dow stressed:
The 'bottom line up front' of the testimony contained herein,
is that scientific studies in animals and humans do not suggest that
tafenoquine is neurotoxic. Furthermore, the suggestion by advocacy organizations
that a causal relationship exists between tafenoquine administration and
anecdotal reports of adverse events on social media 15+ years later is not
supported by the facts. The U.S. FDA has concluded in regulatory briefing
documents that tafenoquine is effective and reasonably safe.
Professor McCarthy responded to the view put forward by Dr Nevin that
tafenoquine had not been tested on monkeys:
There are good reasons not to do studies on monkeys. I'm sure
you're aware of the, obviously, ethical issue about doing studies on monkeys.
In the drug-development community, which I'm very closely involved in, we would
require two non-human mammal species to be tested. Monkey studies are almost
never done these days because of all of the problems that you'd be well aware
of. I don't believe it would be appropriate to do a monkey study with
tafenoquine when we've got clear evidence from some of the other species, and
we've got good guidelines from the USFDA about what studies need to be done for
licensing a drug. The USFDA, as you know, recently licensed tafenoquine for
both prophylaxis of malaria and clearing the liver of malaria parasites. That
was done based upon all the scientific information available to the FDA.
Professor McCarthy spoke further about the findings in rat studies:
Going back to some of the rat studies that were done, if you
give a rat a really high dose of mefloquine, that rat looks very dizzy and
doesn't do well neurologically. You can't replicate that when you give tafenoquine
to the rat. To me, that says that we've got good information that the
neurotoxicity of tafenoquine is much lower than mefloquine.
Long term study
Dr Dow from 60 Degrees Pharmaceuticals advised that prior to marketing
approval in the US, 60P and its partners 'committed to conducting a long-term
study in which the safety and tolerability of the drug is being evaluated
following 12 months exposure (current safety database is six months)'. Dr Dow
provided further information:
This study will take several years and is being conducted at
considerable expense. This study includes, as secondary endpoints, specific and
validated neuropsychiatric assessments to monitor those events which were
elevated in incidence in the ADF Timor deployment (general psychiatric events,
insomnia and motion sickness/dizziness). Since we attribute the higher
incidence of such effects to the operational environment, not tafenoquine, we
expect a similarly low incidence of psychiatric events to be reported in the placebo
and tafenoquine arms of this study. More details of the study can be found at www.clinicaltrials.gov
(reference number NCT03320174). Additional studies in pediatric subjects and
travelers are being planned with regulatory input from FDA.
Regarding possible side effects Defence advised:
Tafenoquine has not been shown to have any serious
neuropsychiatric side effects, including in the long term. Like primaquine, the
main concern regarding tafenoquine relates to people who are deficient in the
G6PD enzyme. In those people, tafenoquine can cause red blood cell problems, potentially
leading to anaemia.
Defence acknowledges that mild and moderate neuropsychiatric
side effects have been reported in individuals participating in tafenoquine
studies, including in Defence studies. These include vertigo, sleepiness,
abnormal dreams, dizziness and insomia.
Defence is not aware of any clear evidence that tafenoquine
produces serious neuropsychiatric side effects, including in the long term.
GSK advised that tafenoquine is contraindicated in the following: G6PD
deficiency (see below); pregnancy; breastfeeding an infant who is
G6PD-deficient or if the G6PD status of the infant is unknown; and patients
with known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any
component of the formulation. These contraindications have been fully reviewed
by the US FDA and TGA and appropriate labelling describing the warnings and
precautions has been agreed.
Tafenoquine and primaquine share a key safety concern which is the
potential to cause hemolysis (destruction of red blood cells) in individuals
with a hereditary disorder, deficiency of Glucose-6-Phosphate-Dehydrogenase
(G6PD) enzyme. Individuals must be tested for this deficiency before receiving
either of these drugs.
All ADF members are checked for this deficiency before being administered
The committee discussed with 60 Degrees Pharmaceuticals the test that could be
made available in developing countries in the context of a sponsored aid
program to undertake the G6PD testing.
Some ADF trial participants experienced the benign, reversible eye
condition vortex keratopathy (small deposits in the cornea) while taking
This is covered in further detail in Chapter 3.
The AQVFA calls for 'CYP450 pharmacogenomic profiling' to be implemented
for current ADF members and veterans involved in the trials contending that of those
experiencing long term adverse health effects and volunteering the information,
92 per cent were poor or intermediate metabolisers of the CYP2D6 enzyme.
In relation to the claims that the absence or poor functioning of an
enzyme called CYP2D6 has implications for the efficacy and safety of
tafenoquine, Defence responded:
While the CYP2D6 metaboliser status of individuals may be
significant in terms of the effectiveness of the medication, it has no known
relationship to adverse events. If anything, failure to generate active
metabolites would be expected to stop/limit adverse events.
GSK also responded to these claims:
The Committee has been advised in other submissions to this
Senate Inquiry that tafenoquine requires activation by the CYP 2D6 enzyme to be
effective (as is the case for primaquine), and two studies in mice are
referenced in support of this. Clinical trials of tafenoquine for radical cure
of P. vivax malaria show no difference in efficacy resulting from CYP 2D6
metabolizer status (extensive, intermediate or poor) [St Jean 2016]. The
results of the mice studies are likely accounted for by differences in substrate
metabolism and tissue expression between the CYP2D orthologues (mouse and
human) [Miksys 2005, Scheer 2012]. The Committee has also been advised in
that CYP alleles have been linked to treatment failure for antimalarials, which
is documented in the case of primaquine, however, GSK has found no evidence
that this is the case for tafenoquine.
AVM Tracy Smart AM, Commander Joint Health, Defence, added that the US FDA
and TGA did not recommend that CYP2D6 enzyme testing be conducted before
TGA database of adverse events
The TGA is Australia's regulatory authority for therapeutic goods,
including prescription medications. As it is not possible to know all potential
adverse events of a medicine before it is approved for use, the TGA monitors
adverse events (such as side effects) related to medicines to safeguard the
health of the Australian community. Most adverse events reports are made by
sponsors such as pharmaceutical companies or medical device suppliers, others
by state and territory health department, hospitals, health professionals and
Roche advised that following registration, 'sponsors such as Roche are
to collect and evaluate safety information about the product continuously, in
order to report serious adverse reactions and significant safety issues to the
TGA, identify any changes to the benefit-risk balance of the product and to
take action where necessary'.
The Department of Health advised that the TGA receives adverse event
reports associated with medicines and medical devices which come from a wide
variety of sources including members of the public, general practitioners,
nurses, other health professionals and the therapeutic goods industry. It
maintains a public database of suspected adverse events. The Department of
Health indicated at the 11 October 2018 hearing that for the period January
1971 (when the adverse event database started) to 20 June 2018, 242 adverse
events were received.
The most commonly-reported events are neuropsychiatric
(depression 55 reports, dizziness 53, anxiety 51, headache 29, nightmare 28, insomnia
24, agitation 22) and gastrointestinal (nausea 52 reports, abdominal pain 19,
diarrhoea 17). This is in keeping with the known adverse effect profile of the
In that...period there were 11 reports of suicidal ideation,
and 4 reports of completed suicide, with no other reports of fatalities. The
database does not contain any reports describing adverse events arising from
the use of mefloquine in a clinical trial. The four cases of suicide reported
in the database contained insufficient information to determine
In relation to the TGA database of suspected adverse events, the
Department of Health emphasised:
It is important to emphasise that the search results cannot
be used to determine the incidence of an adverse event (that is, how often the
adverse event has occurred in patients taking a particular medicine), or the
likelihood of a patient experiencing that reaction, as they do not include information
on the total number of patients who have taken the medication or the total
number of adverse events occurring (because reporting of adverse events is not
mandatory, other than for industry sponsors). As a result the search results
cannot be used to make accurate numerical comparisons between adverse events
associated with different medicines.
Adjunct Professor Skerritt emphasised that the adverse reports received
up until the last few years were largely related to the short term impacts of
the drug or the 'immediate psychological and psychiatric adverse events'. This
resulted in the warnings being updated.
Roche confirmed to the committee that there are robust mechanisms in
place to capture and act on adverse event reports and that the risk benefit
profile of mefloquine remains positive:
We are very, very confident that the mechanisms in place to
capture, record and analyse adverse events associated with all our medicines,
including mefloquine, are very robust. It's not only what we as a company do.
Just to illustrate this to you, in my medical department in
Australia alone, there is a department of drug safety of 20 professional
people, whose role it is to monitor, review, follow up and discuss with people
who have reported adverse events, to ensure that we understand things fully.
This happens in every single country around the world.
Globally, Roche has a drug safety department that
specifically looks at this daily for all of our medicines. We very closely
monitor the safety profile of all of our medicines. Our safety department
produces documents called PBRERs, or periodic benefit-risk evaluation reports.
They run to hundreds of pages. The most recent one was completed on 17 April
2018, and it essentially concluded that there was no new information: 'The
risk-benefit profile of mefloquine remains positive and favours its use in the
approved indications and adheres to the prescribing information.'
Chapter 3 details the adverse events reported during the tafenoquine
trials involving ADF members. Following the trials, Defence noted:
An administrative error by TGA allowed entry of adverse
events to the database subsequent to the study period. This was unusual as this
would normally only be possible for a registered medication on the market in
Australia. The remaining 26 of the 32 total entries relating to the use of
tafenoquine have been entered into the database since 2016, some 15 years after
the study. 18 of these were entered in a ten day period following a social
media campaign in early in 2017. The entries related to tafenoquine have since
been removed from the online [Database of Adverse Event Notifications] DAEN by
There is no way to establish definitive links between the symptoms
recorded in the anonymous entries made to the DAEN since 2016 and tafenoquine
use. Indeed, there could be many other causes for these symptoms. As such this
is does not constitute clear evidence of long term tafenoquine-related effects.
60P advised that these more recent reports were examined and 'in all
instances but one, contemporaneous accounts of adverse events could not be
verified as actually having occurred'. 60P noted that 'GSK reached broadly the
same conclusion as did the FDA in an independent audit of ADF records'.
Biocelect provided further detail:
For events alleged to have occurred during or after 2017, it
is not scientifically plausible based on the available evidence that
Tafenoquine could have been a causative factor. It is implausible for
Tafenoquine to cause long term psychiatric events if (i) there is no drug in
the patient's system when the events occur and (ii) it does not cause
meaningful increases in the risk of psychiatric adverse events compared to
placebo over the shorter term following administration of drug when drug levels
are at their highest. In other words you would need an initial psychiatric
event to plausibly claim a later psychiatric event was related. Therefore, with
the greatest respect to the veterans affected, their adverse experiences
cannot, in 60P’s view, be reasonably attributed to Tafenoquine. Biocelect
supports the position of 60P in this matter.
GSK reported that it has followed up with those who have recently
reported adverse events. The recent reports 'prompted a thorough evaluation by
GSK of all available clinical data and literature. To date it has not been
possible to make a connection between the mild to moderate side effects
reported during the ADF study and any permanent, serious long-term effects with
onset after completion of the study'.
Biocelect emphasised that it takes seriously its 'commitment to the TGA
to collect further safety information and provide it to the regulators in a
timely manner for their analysis'.
Adjunct Professor Skerritt told the committee that with new drugs such
as tafenoquine, a black triangle is placed on the patient leaflet which is to
make sure health professionals and consumers are encouraged to report adverse
Related medical inquiries
The AQVFA is calling for a single Statement of Principles (SOP) covering
the condition they term 'quinoline poisoning' to inform decisions made
regarding support available for veterans.
The AQVFA points out that without a single SOP for 'quinoline poisoning'
veterans have to lodge multiple claims which is an administrative challenge to
those who are unwell.
Administrative barriers are addressed in more detail in Chapter 4.
Serving and ex-serving ADF members can claim compensation at any time
for conditions they believe are related to their service. For DVA to accept
liability for compensation there has to be a causal link determined between the
person's service and their medical conditions. Under the Veterans'
Entitlements Act 1986 (VEA) and the Military Rehabilitation and
Compensation Act 2004 (MRCA) the potential link between a medical condition
and service is assessed using SOPs.
The main function of the Repatriation Medical Authority (RMA) is to
determine SOPs for the purposes of the VEA and the MCRA. SOPs determined by the
RMA are legislative instruments and apply to decisions about liability for
injuries, diseases and deaths made under both the VEA and the MCRA.
The RMA clarified that SOPs are made for diseases or injuries, not for
If an exposure can be causally related to a disease or injury
then it can become a factor within a statement of principles, but we do not
make statements of principles relating to exposures to drugs, toxins or those
sorts of things.
The RMA stressed that the VEA is 'beneficial legislation' 'and is
intended to be generous'.
This point was further emphasised by Professor Nick Saunders, Chairperson, RMA,
who stated 'we take a very generous view of the evidence when we write the statements
The claim that taking mefloquine or tafenoquine causes
chemically-acquired brain injury has been raised with the RMA.
The RMA received a request dated 6 February 2017 from the President of
the Repatriation Commission and Chair of the Military Rehabilitation and
Compensation Commission seeking an investigation of chemically-acquired brain
injury caused by mefloquine, tafenoquine or primaquine in order to find out
whether SOPs may be determined concerning the claimed condition. This was
agreed by the Authority on 7 February 2017 and an investigation notice
placed in the Commonwealth of Australia Gazette on 14 February 2017.
On 18 August 2017, the RMA declared that it 'does not propose to make a
Statement of Principles concerning chemically-acquired brain injury caused by
mefloquine, tafenoquine or primaquine for the purposes of subsection 196B(2) or
(3) of the [Veterans' Entitlements Act 1986]'.
The Authority is of the view that there is insufficient sound
medical-scientific evidence that exposure to mefloquine, tafenoquine or
primaquine causes chronic brain injury. Further, there is insufficient sound
medical-scientific evidence that there is a characteristic and persisting
pattern of signs and symptoms following exposure to mefloquine, tafenoquine or
primaquine that could be determined to be a particular kind of disease of, or
injury to, the brain.
The RMA provided further detail for this finding in its submission:
The hypothesis that mefloquine causes permanent brain damage
is based on proposed causal mechanisms and pathology identified in high dose
animal studies mostly conducted shortly after World War II. There is no direct
evidence that it causes permanent brain damage in humans given therapeutic
The claim that there are persistent symptoms that are due to
mefloquine is based on a small number of case reports and adverse event reports
of a variety of commonly experienced symptoms in a widely prescribed medication.
These same animal studies and human case reports are cited repeatedly as the
basis for the contention of a syndrome resulting from permanent brain injury.
Animal studies and case reports are considered
"hypothesis generating", since the associations they suggest need to
be evaluated in well-conducted comparative studies in humans. Human studies of
this type are considered higher quality evidence. Because of the lack of
supporting evidence from such studies, the RMA found that the evidence was not
persuasive when critical appraisal of the total body of SMSE [sound
medical-scientific evidence] was taken into account.
Professor Saunders told the committee that for a chronic brain injury to
be caused by a particular agent, damage to the brain needs to be demonstrated.
While this can be done through imaging of the brain and other tests in relation
to sniffing solvents or lead poisoning for example:
There is no evidence of that in terms of the quinoline class
of drugs—there is no evidence of that in relationship to mefloquine or
tafenoquine. Nobody has been able to demonstrate in humans that there are
imaging abnormalities or other evidence of structural abnormality of the brain.
The only evidence that we have for structural changes relates to animal experiments.
Also, I think there was one case where a massive overdose of a drug was taken,
which killed the person, and autopsy evidence showed that there was damage of
the brain. I think the person took twenty-fold times the prescribed dose. So,
we have no evidence that is sufficient to allow us to define a particular
condition, be that in terms of the constellation of symptoms and signs that
might be present, or indeed other evidence of structural abnormality.
The RMA emphasised the lack of evidence of harm despite widespread and
long term use of mefloquine and the inclusion of mefloquine by the WHO in its
Model List of Essential Medicines.
Professor Saunders summarised that with the millions of doses of mefloquine
One would have thought that even a rare adverse effect
causing chronic brain injury would have become evident given the scope of the
usage of this particular agent. There has been no defined syndrome or clinical
entity that one could recognise as chronic brain injury from the civilian use
of this drug.
Mr Paul Murdoch, Registrar, RMA advised that when individuals attempt to
link conditions to eligible service, it needs to be on the basis of a diagnosed
disease or injury, not symptom by symptom. Therefore getting a clear diagnosis
is key as a diagnosed injury or disease 'can then be matched very quickly to a statement
of principle, [which] is the key from a compensation point of view'.
Professor Saunders further explained that:
Although a range of symptoms have been reported following the
use of these drugs, the timing of these symptoms, their duration and severity,
and the set of individual symptoms which could define a condition have not
really been established.
Professor Saunders continued his explanation:
In 1994 the government of the day introduced this current
system, which, really, I think, has served the veteran community very well,
because the government felt that one would have greater transparency and
greater equity if decisions were based on sound scientific medical evidence. So
passionate opinion does not trump objective evidence in the system we have at
the moment. The fact that somebody has been given a drug and now they are
claiming to have a chronic brain injury from that drug is not sufficient in the
system we have today. Indeed, it would undermine the system if one were to
carve out exemptions to the system as a whole.
The AQVFA noted that a review of the RMA's decision was underway at the
time of lodging their submission.
In November 2017 the Specialist Medical Review Council
gave notice that it had been asked under section 196Y of the VEA to review the
decision of the RMA which should be finalised before the end of 2018.
The RMA indicated that the review was requested by the AQVFA.
On 17 September 2018 the SMRC announced that it had completed its review
and affirmed the RMA’s decision not to make a SOP for 'chemically acquired
Professor Saunders spoke about the composition of the RMA and the SMRC:
The council's composition is different from ours in terms of
the people who do the assessment. In our case the RMA is made up of five
medical academics, or epidemiological academics, who have their own specialties
but, as well as that, have a broad general experience. When this decision was
reviewed by the Specialist Medical Review Council, their committee was an
expert committee; it contained people who understood epidemiology but also were
drawn from pharmacology, neurology, mental health and neuropsychology. These
were expert people. They considered the same evidence that we considered, and
drew the same conclusions that we drew.
Professor Saunders answered assertions
about the evidence being relied upon:
...the evidence that we place highest reliance on—sound,
epidemiological evidence—is not being driven by the pharmaceutical industry or
the malarial specialists. These are people who are interested in population
based studies and who look at the evidence in an impartial way.
Inclusion of mefloquine and
tafenoquine in SOPs
The RMA has included mefloquine and tafenoquine, either by name or in
more general terms, as a potential causal factor in the SOPs for a total of 16
conditions – 15 for mefloquine and six for tafenoquine where there was a least
a reasonable hypothesis that the relevant condition can occur.
The RMA notes that 'the wording of the mefloquine- or tefenoquine-related
factors in these SOPs requires a close temporal link between the taking of the
drug and the onset of the condition...reflecting the well-accepted evidence that
these agents can have acute neuropsychiatric effects'.
The RMA told the committee that they 'are confident that we have
included mefloquine or tafenoquine in statements of principle for all diseases
or injuries which could be linked to taking these drugs based upon sound
medical scientific evidence that meets standard epidemiological criteria when
examining things for causation'.
Acknowledging the chronic and complex symptoms being presented to the
committee, Professor Saunders mentioned the SOP concerning 'chronic
determined in 2014:
We have a statement of principle on an illness called chronic
multisymptom illness. This arose out of an inquiry that we conducted in
relation to Gulf War syndrome. Although this did not satisfy the Gulf War
advocate group that was presenting to us, it became quite clear to us that
there were a significant number of veterans who had quite debilitating symptoms
that fitted into particular patterns of illness, but this wasn't related just
to serving in the Gulf War. In fact, it was related more broadly to deployment
into hazardous environments. So we wrote a statement of principle called
'Chronic multisymptom illness'. That statement of principle is available today
for those people who were deployed to, say, East Timor, took antimalarial drugs
and now have debilitating symptoms that are broad-ranging.
Professor Saunders again emphasised that the RMA takes a very generous
view of evidence when they write the SOPs.
Therefore in his view the key for many veterans is getting assistance from an
advocate for example to establish a causal link between their service and their
Review processes and ongoing
The RMA specifically searches for 'new evidence in relation to
factors that have a particular association with the veteran community'.
The RMA regularly reviews the evidence through a comprehensive
evidence-gathering process, using standard scientific methods and recognised
It reviews 'the entire literature that is available on the large public
databases in the English language'.
Each SOP is reviewed at least every ten years, with an aim of reviewing them
RMA experts can identify new evidence from their fields, and SOP reviews can be
initiated through the authority's own motion.
Individuals outside the RMA can also request reviews, as was the case for the
recent reviews completed by the RMA and Specialist Medication Review Council.
The committee also understands that consultation between the RMA and a range of
stakeholder organisations including Joint Health Command (JHC) in Defence, DVA,
and the RSL occurs regularly on a range of topics relating to the health of
The JHC seeks to ensure the health preparedness of ADF members by
developing evidence-based health policy. Among other things, it is responsible
for 'participating in research to inform and improve health policy, programs
and services', 'developing strategic health policy and programs' and 'reviewing
and assuring health policy, programs and services to drive continuous
ADF clinical and medical policy is developed with clinical medical input.
Defence also undertakes and supports a range of research activities, including
through the Mental Health Research and Evaluation section.
Searching for an explanation
As the concerns expressed by individuals appear to be manifested in military
and not civilian populations, the committee discussed possible explanations for
this with witnesses. Mr Mark Reid indicated that in his view:
I contend that these soldiers raising concerns about
chemically acquired brain injury resulting from use of tafenoquine have PTSD.
The PTSD has arisen more than 16 years after taking tafenoquine and mefloquine,
but the PTSD is not related to these anti-malarial drugs.
Professor Graham Brown, Australian College of Tropical Medicine posited:
I was explaining this to a layperson. For example, let's say,
you were trying a new flu vaccine in New South Wales two months ago. You did a three-month
review, and people had nightmares and couldn't sleep and were anxious and
depressed. You'd say, 'That's the flu vaccine.' Perhaps it was, but the fact
that they were firefighters fighting bushfires with people dying could surely
have contributed to the symptoms. We couldn't say, 'It's not the flu vaccine,'
but most of us would think it's highly unlikely. That's the sort of example.
It's a coincidence of things and trying to work out the underlying cause. So, I
would say that that's the importance of controlled trial evidence that we look
at. Many of the symptoms reported are found in other conditions. I'm also aware
of certain unproved hypotheses about what might cause these problems, and I
think it's important to start with the evidence based information and separate
this away from ideas or options or hypotheses, which are terribly important in
science but they need to be proved and not confused with opinion.
Professor Shanks pointed out the many potential contributors to a veteran's
Trying to assign any single cause to various post-military,
veteran's illnesses does not accurately reflect the many potential contributors
to a soldier's mental and physical health.
When asked his view on the issues raised with the committee, Professor
It's multifactorial...Mental illness is a broad category and a
very frequent one, but trying to blame a drug 20 years after the fact, when
it's long, long been cleared, isn't plausible. That isn't how drugs work.
Associate Professor Karunajeewa also emphasised the difficulty of
attributing causality to taking a drug nearly 20 years ago:
I suppose the first thing to say is that we want to avoid at
all costs being at all dismissive or belittling about their experiences and
their symptoms, and they should be regarded as real. Essentially the difficulty
comes down to the fact that a lot of the symptoms and a lot of the illnesses
being described, unfortunately, as you know, are highly prevalent in the
general Australian community. For example, I think the statistics are that two
or three million Australians are out there suffering from depression, and a
similar number have anxiety. The most common cause of death now in young people
under the age of 44 is suicide. So this mental health crisis that we have in
the country is obviously highly prevalent. There are an awful lot of other
people out there who haven't taken mefloquine, of course, who are dealing with
very, very similar problems. So the difficulty comes in ascribing causality
when you have conditions and symptoms that are very, very common throughout the
general community. So actually ascribing causality to something that happened
20 years ago becomes very difficult.
Vice Admiral David Johnston AO, VCDF, acknowledged the challenges of
dealing with PTSD:
There are many other possible causes of the symptoms that
these people are suffering. Indeed, many admit that they have been diagnosed
with PTSD but are frustrated that the treatment does not seem to be working.
The challenge for some people with PTSD to recover is a known problem, but it
doesn't mean that the diagnosis is wrong. Even if it were possible to connect
the use of mefloquine with these symptoms, it's unlikely to alter the
individual's treatment or management.
AVM Tracy Smart put forward that:
It's very hard to distinguish or diagnose what could be the
problem of someone who develops a health problem many years after an event.
We've heard today that there is some evidence—and certainly there have been
some reports—that people can get long-term effects from mefloquine. There are
no reports that someone can take the drug, get some symptoms, stop the drug,
have the symptoms stop and then get symptoms a long way down the track. There
is no evidence to suggest that. That's not been recorded in the literature.
You've also got to look at someone who is this many years down the track; what
other events have occurred in their life, including on deployment, in terms of
both traumatic events and the stressors in deployment, because there are many:
away from home, poor living conditions—all of these things can contribute to
having health problems.
I think this is one of the main problems we have got here:
what is the cause of this problem? The overwhelming evidence suggests that, in
the majority of cases, it is not the antimalarials. As some of the presenters
today have said, it's rare or very rare at best to see long-term symptoms of
AVM Smart continued:
Being exposed over a military career over a life to a number
of stressors can cause neuropsychiatric problems, can cause psychiatric
problems or can cause brain injury. Things like traumatic brain injury, which
you've heard about—a number of things can cause acquired brain injury down the
track. The important thing is that I can't tell you sitting here that someone
has or hasn't got a particular diagnosis. That is something that a doctor needs
to do one-on-one with the individual, looking at their symptoms. When did they
come on and when did they finish? That's what a diagnosis is all about. I would
say, though, that some of the people who've written to us through our malaria
email address have really told us they are suffering from severe problems
similar to the ones in the submission[s]. When we look back at their documents,
some of those have continued to deploy many time[s] after Timor, including to
the Middle East. To then say this condition was caused by this drug we took at
that time is very problematic.
Influence of social media
Many witnesses referenced social media as the catalyst for bringing them
together. An individual listing 32 symptoms
reported the following:
I read an article published by Stuart McCarthy in December
2015. After reading this article I realised that everything I had experienced,
physically and mentally, were very real. For the first time in 11 years there
was a diagnoses to 'fit' my medical situation.
Many others also referred to Mr Stuart McCarthy and his facebook page as
did a number of confidential submissions. A few of those that are public are
I came across a Facebook group started by fellow veterans,
namely Stuart McCarthy, who was also suffering. This was a God send for me. I
was not alone and was not the only one with these symptoms.
...in February, 2018 I became aware of Retired Major Stuart
McCarthy, who has been of great comfort and assistance to my family.
Well several years ago information started to appear from
fellow Vets, especially on Facebook. We started talking and finally telling
each other what had happened, how we felt etc.
For almost twenty years I felt isolated and alone with my 'creeping
madness' until I stumbled across a Facebook group for soldiers who had suffered
from Mefloquine poisoning. There in front of me were men and women detailing
strikingly similar symptoms that I had experienced.
Mr David Madsen also listed a number of diagnoses
and referred to the facebook page of Mr Stuart McCarthy:
I [knew] nothing about [mefloquine] toxicity or any potential
side effects prior to and after all of this until [I] saw Major McCarthy's Face
book page after being invited by an old army Friend.
Over time I have started to see the GLARING similarities
between where I am at and what many studies are showing now.
The committee was very concerned to hear the stories from individual
veterans and their families outlining their health and other challenges. Though
there may be disagreement between them and the medical professionals on the
cause or causes of their health conditions there was no disagreement that their
physical and mental symptoms are real and that they require assistance. This is
the focus of Chapter 4.
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