AFC0060

Written evidence submitted by Mr David Rimmington.

Introduction

This submission is respectfully presented by David Rimmington, a former British Army Warrant Officer of the Royal Logistic Corps with over 24years’ service within the All Arms Sector, including Operational deployments in the Balkans and Sierra Leone, with 1 Para Battle Group. Having been awarded the British Army’s Long Service and Good Conduct medal and discharged with exemplary, loyal service; I am submitting this evidence both as a chronic sufferer, and on behalf of those struggling veterans unable to write today, highlighting the significant issue and prejudice faced by veterans, particularly in the area of screening and valid assessment of the neurotoxic effects of Mefloquine (Lariam) and other Acquired Brain Injuries (ABI) when presenting military mental health.

Having featured in The Daily Telegraph in 02 March 2024[1] and presented to the International Trauma-Informed Care Network dated 12 November 2021[2] in which I told of my ‘lived experience’ to 450+ NHS clinicians, Veteran health service providers, Service charities, and other eminent speakers, I, along with many other long suffering veterans continue to be failed by the Armed Forces Covenant’s moral obligation to members of the Armed Forces Community in return for the sacrifices they make, and its failure to uphold the Covenant’s two core principles[3]:

“No disadvantage: no current or former member of the armed forces, or their families, should be at a disadvantage compared to other citizens in the provision of public and commercial services.”

“Special consideration: special consideration is appropriate in some cases, particularly for those who have been injured or bereaved.”

Executive Summary

This submission highlights critical failings within the Armed Forces Covenant in its treatment of veterans suffering from the neurotoxic effects of Mefloquine (Lariam) and Acquired Brain Injuries (ABI). Drawing from personal experience and the struggles of fellow veterans, it underscores the systemic neglect, misdiagnosis, and lack of appropriate support these individuals face. The submission outlines the failure to properly screen, diagnose, and treat these conditions within UK veteran services, despite extensive international evidence and reports, including from the European Medicines Agency and the Australian Royal Commission into Defence Veterans Suicides. It also highlights the detrimental impact of commercial interests, misinformation, and conflicts of interest within research and veteran service organisations, leading to widespread disadvantage, sanctuary trauma[1], and the erosion of the Covenant’s core principles. Inadequate training for clinicians, lack of public awareness, and the persistent dismissal of veterans’ concerns are contributing to a vicious cycle of harm. This submission calls for the immediate recognition of Mefloquine toxicity and ABI as service-related injuries, alongside urgent reforms to provide veterans with the care and support they are legally and morally entitled to under the Armed Forces Covenant.

BACKGROUND

The opportunity to contribute to Defence Select Committee, is extremely timely given the recent final report from the Australian Royal Commission into Defence Veterans Suicides, especially Volume 4: Health care for serving and ex-serving members, recommendation 61[4], and replicates the same disadvantages experienced by UK Veterans:

“Recommendation 61: Establish a brain injury program.

Defence and the Department of Veterans’ Affairs should establish a brain injury program that covers, at a minimum, relevant Army corps, special forces, Navy clearance divers, Air Force combat controllers, and serving and ex-serving members exposed to mefloquine and/or tafenoquine. The program should:

(a) aim to better understand, and mitigate, the impact of repetitive low-level blast exposure on brain processes

(b) assess and treat neurocognitive issues affecting serving and ex-serving members, whatever their cause.

To do this, it should:

(c) monitor and assess environmental exposure to blast overpressure

(d) record members’ exposure to traumatic brain injury and minor traumatic brain injury, including in medical records

(e) establish a neurocognitive program suitable for serving and ex-serving members experiencing a range of neurocognitive issues, whatever their cause. This could be adapted from the former ‘Mending Military Minds’ program.

(f) provide referral pathways for further medical assessment, when required.

On 10th May 2023, I was honoured to serve as the sole veteran representative at the All-Party Parliamentary Group on Acquired Brain Injury reception[5]. At this significant event, I briefed Members of Parliament and other key personnel on veteran brain injury solutions using the Australian ‘Mending Military Minds’ initiative as a model. To support this presentation, I provided prepared A5 leaflets[6]. outlining the proposed solutions. It is worth highlighting that my presence as the only veteran at such a critical event underscores a broader issue: the relatively low engagement with veteran-specific brain injury matters compared to the attention given to veteran mental health events. Notably, my own MP for Grantham and Bourne failed to attend the reception. Nevertheless, I proactively arranged a one-to-one session with the former Minister of State for Veterans' Affairs, during which the newly forming OP RESTORE initiative was discussed. The Minister identified OP RESTORE as the necessary solution to address veteran-acquired brain injuries, particularly those associated with Mefloquine. This promise has been found to be false, having tried to assist other struggling veterans with GP referrals, as evidenced in an email reply from OP RESTORE on 14 June 2024[7].

“I can confirm that we do not have any referral route to support with the GP request RE: Mefloquine (Lariam)”

This was later clarified by Head of Armed Forces Policy and Operations, in a response dated 04 October 2024[8]

“We have made some enquiries and can advise that unfortunately there is no specific test or set of investigations which could diagnose the circumstances you have set out. Any diagnosis would be a clinical judgement based on symptoms, probability and likely cause and effect.”  

The Mefloquine Single Point of Contact, published on 30 August 2016[9], claims to take “the health and well-being of its personnel seriously and acknowledges its duty of care to provide the best possible support to them.” However, it continues to serve merely as a signpost to nowhere, offering little more than empty promises.

In my case, not only did the Unit Medical Officer dismiss the reporting of adverse events from Mefloquine toxicity immediately upon returning from operations in 2000, but it also contributed to the induced suicide ideation and the completely out-of-character attempt on my own life. Further opportunities were missed by DCMH and Unit Medical Officers while serving, I was given a default PTSD diagnosis in an instant by civilian mental health services, simply for mentioning that I am a veteran. The resilience required to continue ‘fighting through’ this toxin-induced encephalopathy still takes its toll, and I am yet to be supported by those meant to help. During a meeting with the Deputy Director of a National Health Service Foundation Trust to explore a way forward, I was told that the toxicity of Lariam was “very interesting,” but that PTSD brought in significant funding, which seemed to redefine the concept of Duty of Candour. Ask yourself: how many UK veteran charities and clinical services include Lariam toxicity or Acquired Brain Injury in their literature, or on their websites[10]?

I have been vilified by Veteran UK at Tribunal, resulting in the withdrawal of my War Pension Tribunal case[11]. Even when Veteran UK finally recognises the side effects of Mefloquine in a War Pension claim[12]—entitling veterans to free prescriptions, aids, and appliances from the NHS—there is still no available support or provision. I have been repeatedly dismissed by untrained GPs and psychiatrists[13] while trying to find my own way forward, yet continually sent back to square one, even by doctors in Tropical Medicine[14] and civilian neurologists[15] —even when they agree on the root cause.

After sharing a mash-up video[16] on Veteran Brain Injury and Lariam toxicity, which subsequently contributed to evidence presented to the Defence Select Committee follow-up on Armed Forces and veterans' mental health on 12 January 2021[17], I engaged via social media with the UK's Independent Veterans Advisor to Ministers[18] in an attempt to seek assistance:

”I have to confess this one [Lariam Toxicity] slipped through the cracks.”

“In essence, the research we have looked at does not support the view that Lariam is a significant cause of long-term MH Problems for many people. It may be for a few but not many.”

“In terms of mTBI what we have seen suggests much the same; It’s a problem for a small number but not many. None of this means that the small numbers these conditions do affect should be ignored.”

His views on these Veteran injuries might not be as 'independent' as his title suggests. How can it be determined this only affects a few, if clinicians and veteran services are not screening or validly assessing soldiers and veterans for Lariam toxicity or acquired brain injury when veterans present veteran mental health symptoms? If current research doesn't support Lariam as a significant cause of long-term mental health issues, despite the European Medicine Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) report conclusions, dated January 2014[19], what alternative studies or expert opinions are guiding the current stance, and who are the key advisors influencing this perspective? Moreover, the small numbers of affected veterans who have raised these concerns have been consistently ignored and disadvantaged.

Following a social media post, engagement was made with the Veterans’ Commissioner for Wales. Despite presenting verified facts and credible evidence on Mefloquine (Lariam) toxicity, the Commissioner defaulted to the House of Commons Defence Select Committee (DSC) report, which notably omitted the conclusions of the European Medicine Agency’s (PRAC) report. The Commissioner’s reluctance to thoroughly analyse the information and his initial dismissal was disappointing[20].

“The issue is that it has not been raised once to me by Welsh Veterans in my 11 months as Commissioner. Get a Welsh Vet that is affected to contact me about it and I will see what I can do.”

“Yeah, but do you really want to get into a blame game?”

“The med is not being issued unless as last resort (which means it isn’t)”

“Well, if you trace culpability back it's the drug company Roche who are responsible. But Lariam is still available and listed as an antimalarial which suggests that there is not enough evidence to get it banned.”

“The problem is that the culpability chain runs right through, govt, MoD, the services , to formations, units, MOs, medics to the users immediate CoC and the individual. You continued to take it despite the side effects, if you told your SNCO or Pl Comd they did nothing, the medics did nothing etc. It's a group dynamic inertia kind of thing. Meanwhile in 80s & 90s MoD has large stocks of a drug that is much cheaper than alternatives and there is effectively only anecdotal evidence that there are problems and Roche, and advisors say it's safe.”

Even after attempts to educate the Commissioner on this hidden and unpopular issue, no forward action was taken to acknowledge, help, or support affected veterans. What hope would a Private soldier have, particularly if they had already been misdiagnosed and mistreated, if they approached the Commissioner to raise concerns about Lariam and its adverse events? This raises significant questions about the Defence Select Committee (DSC) findings, which appear to have fostered manufactured doubt about the effects of Lariam, resulting in misleading support and deflecting crucial assistance for those impacted.

In a letter from the CEO of Combat Stress, dated 08 December 2016[21], it was acknowledged that they were aware of the adverse events associated with Lariam. But by not specifically screening for Mefloquine use, despite its known neurotoxic effects, veterans are at a disadvantage when seeking appropriate care for conditions caused by this medication. The lack of awareness or recognition of Mefloquine’s role in mental health issues, combined with the fact that many veterans may not even realise they have taken it, undermines the duty of care owed to them. Further evidence of these concerns is highlighted in a letter from COMBAT STRESS’s Director of Medical Services, dated 12 March 2018[22].

“Bearing in mind we had just under 2,500 referrals last year, between us we have seen approximately seven individuals who though they may or may not have mefloquine toxicity.”

In December 2014, during a particularly difficult period of neuropsychiatric events, I reached out to COMBAT STRESS in a desperate state and was assigned the very same Director of Medical Services. Despite their prior awareness of the issues surrounding Mefloquine toxicity, at no point during our subsequent conversations did they inquire about my potential exposure to the drug. This glaring omission highlights a critical failure in service consistency and a concerning lack of education within veteran support services. Such oversight not only undermines trust but also effectively denies veterans the comprehensive care they are entitled to under the Armed Forces Covenant. The failure to consider Mefloquine toxicity contributes to misdiagnosis, delays appropriate treatment, and ultimately places veterans at further risk of harm.

The Chair of the NHS England Armed Forces and their Families Clinical Reference Group, and the Royal College of General Practitioners (RCGP), was instrumental in establishing the OP COURAGE Veteran Mental Health Service but appears notably selective in the 'military mental health research' utilised to shape veteran services. When directly questioned, he has consistently avoided addressing Lariam toxicity or other forms of Acquired Brain Injury. In a House of Commons Select Committee hearing he remained conspicuously silent when an eminent professor detailed the parallels between Acquired Brain Injury and PTSD in Veterans[23]. Furthermore, as overseer of the RCGP Veteran Friendly accreditation for GPs[24] no awareness or clinical training material was included on Mefloquine (Lariam) toxicity and other Acquired Brain Injuries in the packs sent or presented online. His failure to uphold a Duty of Candour has resulted in misguided clinical education, misdiagnosis, mistreatment, and inadequate referrals for veterans suffering from Lariam toxicity, thereby deepening their struggles and health issues, despite claims below

“The NHS Op COURAGE service is unique – our staff are not only highly trained clinical professionals, but they are also either ex-military or know the military culture first-hand. This sets them up to provide a non-judgemental service and build trust with those seeking help.

“Our research has found that veterans can often struggle to know when to ask for help, but by providing them with professionals who have a deeper understanding of what they are going through”[25]

The former Chief Executive of Defence Medical Welfare Services (DMWS) and 'independent' Armed Forces Chair to the NHS England Armed Forces Commissioning Team has repeatedly failed to support, recognise, or assist veterans suffering from acquired brain injuries or Mefloquine (Lariam) neurotoxicity. Alarmingly, she has often blocked, deleted, or hidden adverse posts by veterans who are genuinely challenging prevailing narratives and calling for balanced funding[26]. Whatever her motivations, she has been influenced by deeply entrenched military mental health narratives, which undermine the principles of the Armed Forces Covenant. Her actions suggest she does not represent the true voice of patients; despite the title she holds. With her links to NHS England, the NHS England Armed Forces Commissioning Team, and King's College Mental Health Research (KCMHR), this bias perpetuates disadvantage for those veterans who need support the most.

An Associate Director of Nursing, known for her pioneering work, established the first-ever mental health network between the MoD and NHS, leading to the creation of specialist NHS services for veterans. These services influenced a national rollout and were followed by bespoke programs addressing gambling, drug and alcohol issues. She also founded the first IPS Veterans Employment Support Service, multi-agency support groups, NHS carers’ programs, veteran anger management and PTSD therapies, and social prescribing activities for veterans. In correspondence with her on 02 October 2021 she reflected on the challenges of her work, saying[27 :

“I have treated several vets with Larium toxicity. It appears there is so much more work to be done on this”

It was this award-winning nurse who provided me with the invaluable opportunity to speak at the International Trauma-Informed Care Network event on 12 November 2021. However, my decision to participate led to significant backlash from her colleagues at the King’s Centre for Military Health Research (KCMHR), who expressed their disapproval, given the controversial nature of the event within their professional circles. Despite the recognition of her leadership and the positive impact she had in facilitating this opportunity, she faced considerable pressure from her associates at KCMHR for supporting my involvement.

“I’m someone who has devoted 20 years to helping veterans and gave you the chance to speak at my global network- even when I got a backlash from others for doing so”.

When challenging the lack of action despite the promised support from a self-acclaimed Champion nurse she appeared visibly influenced by the powerful presence of Simon, the Non-Executive Director on the NHS England board, and Nicola, Co-Director of the King’s Centre for Military Health Research (KCMHR). Their authority and credentials seemed to overshadow her concerns, effectively silencing her. As a result, Nurse Palmer appeared to defer, possibly feeling outmatched by their influence and expertise, despite the validity of her perspective. This moment underscores how their positions of power may have led to her reluctance to assert her concerns.

“my association with Simon (KCMHR NHS England) and Nicola (KCMR) is that I’ve known them 20 years as I’ve attended every conference then run - because I get to hear about research that has helped me in my job and meet other colleagues from across the UK and beyond. I’m a nurse not a doctor, I can’t change the diagnosis or treatment of those with larium toxicity- but I’ve always tried to support veterans who present to my services with symptoms they feel are related. I get your frustration”.

On 06 December 2021, after an attempt to find a way forward for injured Lariam veterans with the Associate Director of Nursing, she shared the following conversation, which seemed that KCMHR were manufacturing-doubt[2] about the credibility of the issue:

“I spoke at length to Neil (Professor of Defence Mental Health, and senior member of the military mental health research team) tonight. He’s worried that veterans are being manipulated by lawyers who are just interested in money, rather than ensuring the right diagnosis . I stressed that we must hear the voices of those with lived experiences, we must ask the question and tailor treatment accordingly . He asked me to explain to the network that it’s controversial and I said I would not do that as it’s not controversial . It’s a known fact Larium causes these symptoms - his point was that the evidence does not show long term symptoms , only sudden onset and immediate symptoms for short period. I explained that by asking veterans we can gain a better understanding” .

Upon recognising the name, I recalled that it was this very professor I had approached directly in May 2020, who stated[28]

“Our KCMHR team have looked at post deployment screening for psychological health problems & found it not effective. A recent expert review also found that pre-role/pre-employment mental health screening is also not effective”

When challenged about the confounding symptoms of ABI/mTBI and mental health, and the need to ensure appropriate treatment pathways, the Professor agreed with the importance of addressing these complexities. However, his response seemed to downplay the urgency of tailored care, further complicating the discussion.

“More work needed to tease out the apparent cases of mTBI which are in fact mental health(?) and as you say how to detect any form of subtle TBI (Since severe ones will be evident) that needs intervention”.

The ability to shift responsibility between organisations without accountability distorts the truth and obstructs the establishment of proper research and healthcare pathways, as mandated by the Armed Forces Covenant. In this case, after requesting clarification from the former Minister for Defence People and Veterans on when the MOD first became aware of the critical 2014 EMA PRAC report, I received a response from Headquarters Joint Medical Group dated 4 February 2020[29]. The letter stated that the Minister and the MOD took the health and wellbeing of the Armed Forces community very seriously and considered it a government priority.

It claimed that the Defence Select Committee was aware that the MOD adhered to the guidance of relevant national bodies in prescribing antimalarial drugs to service personnel. The letter also noted that the Medicines and Healthcare products Regulatory Agency (MHRA) worked closely with the European Medicines Agency (EMA). It highlighted the PRAC report's findings on long-term neuropsychiatric adverse events, even after discontinuation of the drug, and stated that the MOD was aware of the revised Mefloquine warnings in the December 2014 Drug Safety Update. If so, why did they not act, and why has this information been omitted from Veteran Services. The letter included a caveat noting that:

“The MHRA is the government agency responsible for ensuring that medicines and medical devices work and are acceptability safe”

The MOD claimed that both the Minister and the department took the health and wellbeing of the Armed Forces community very seriously, describing it as a government priority. However, despite referencing the MHRA’s accountability, the MOD knowingly concealed its research study on antimalarial chemoprophylaxis, including Lariam (713/MoDREC/15), from the MHRA. In a letter, dated 02 January 2020, the CEO of the MHRA confirmed[30]:

“The MoD informed us that as the results are intended for publication in the future, they had already refused disclosure of the protocol in response to a Freedom of Information request and had also taken the decision not to share the protocol with MHRA.”

Why was such critical research, which could have positively impacted services and care pathways for injured veterans, kept from the very agency responsible for oversight? Furthermore, given the MOD’s stated commitment to the health and welfare of the Armed Forces, why was there no accountability from the government agency to ensure the MOD upheld its duty of care? This raises serious questions about the integrity of both the MOD’s actions and the effectiveness of its oversight mechanisms to deliver the Armed Forces Covenant.

In November 2023, I submitted a question to the MHRA about adverse events linked to Mefloquine, at their Public Board Meeting, and received a written reply stating Mefloquine has been associated with a range of neuropsychiatric disorders, including insomnia, depression, anxiety, paranoia, suicidal behaviour, and hallucinations[31]. These risks are outlined in the product information and Patient Information Leaflet (PIL), with specific warnings for individuals with a history of psychiatric illness or those on medication for such conditions. The potential for these adverse effects highlights the need for careful consideration when prescribing mefloquine, particularly for vulnerable populations.

They confirmed the conclusions from the European Medicines Agency, including that the MHRA, also reviewed the safety data for Mefloquine/Lariam in 2013, leading to strengthened safety warnings. A range of regulatory actions was introduced across Europe and the UK, including enhanced warnings about psychiatric effects in product information, new prescribing guidelines, checklists for healthcare professionals, and an alert card for patients. The MHRA also went on to say:

“….that in addition to the guidelines set out by Roche (the manufacturer at the time), the MoD also takes advice on the use of Lariam from the Advisory Committee for Malarial Prevention (ACMP) through Public Health England. The ACMP is described as an expert committee, established to formulate guidelines on malaria prevention in the UK”

Given the limited measures recommended by the MHRA, it raises serious concerns as to why appropriate action was not taken within the Defence sector to identify and support vulnerable veterans affected by Mefloquine therapy. The lack of proactive steps to capture and address the existing harm is troubling, especially in light of the Armed Forces Covenant, which commits to ensuring that veterans receive the care and support they deserve. Despite the known risks outlined by the MHRA and the subsequent regulatory actions in 2013, there appears to have been a failure to adequately protect or monitor those at risk within the Armed Forces, leaving vulnerable veterans without the necessary interventions. This raises critical questions about the fulfilment of the Covenant's obligations and the responsibility of Defence authorities to prioritise the wellbeing of those who served.

In direct correspondence to former British Army, Chief of General Staff on 11 March 2020[32] I was informed by him:

In direct correspondence, the former Chief of the General Staff expressed serious concerns regarding the use of Mefloquine (Lariam), describing it as a potentially dangerous drug, particularly in a significant number of cases. He stated that he had campaigned against its use for over a decade, recognising the well-documented link between Mefloquine and severe mental health issues. His concerns date back to 1999, when the drug was prescribed to his son, although his active involvement in efforts to restrict its use came later. Despite his senior position, he asserted that he had no direct authority over the distribution of medications to soldiers and, while he could advocate against Mefloquine, he was unable to ban it. However, Joint Service Publication (JSP) regulations allow for administrative orders to override medical officers' decisions, revealing systemic barriers that hinder timely interventions. This underscores the military’s failure to act swiftly on known health risks, the bureaucratic obstacles to meaningful reform, and the ongoing, unaddressed impact on the physical and mental health of service personnel.

“I am in no doubt that Mefloquine – Lariam – is a potentially dangerous drug in an unacceptably high proportion of instances when it is prescribed. I have been campaigning against its use for over a decade”.

“The link between mental health and Mefloquine is well established, I understand. My suspicions about Mefloquine do indeed go back to its prescription to my son Berite, back in 1999, however I only began to engage in the campaign against its use some time after that. During my years as the Chief of General Staff, the issue was not highest on my priority list as the battle for resources to conduct properly our campaigns in Iraq and Afghanistan was all-consuming. As CGS I had no direct authority over what prophylactics were issued to our soldiers. The Defence Medical Services did not answer directly to me and, although I could argue against the use of Mefloquine/Lariam, I could not order it not to be used”.

Every member of the armed forces who has sustained service-related injuries should be entitled to proper screening, valid assessment, diagnosis, and appropriate treatment and care. Lariam as a ‘drug of last resort’ may help prevent further harm to Armed Forces personnel, but failing to assist those who have already been affected contradicts the very principles of the Armed Forces Covenant.

Areas Where the Armed Forces Covenant is Failing the Armed Forces Community

1. Failure to Uphold the Covenant's Core Principles:

a)        The Armed Forces Covenant's principles of "No disadvantage" and "Special consideration" are not being honoured for veterans suffering from Mefloquine (Lariam) toxicity or other acquired brain injuries.

b)        Affected veterans are denied the medical attention they need, leading to systemic neglect, misdiagnosis, and a lack of proper support.

2. Lack of Proper Screening and Assessment:

a)        Despite growing research and international findings (e.g. European Medicines Agency, Australian Royal Commission), there is still no comprehensive recognition of Lariam’s neurotoxic effects in UK veteran services, defaulting to ‘PTSD’ diagnosis of convenience.

b)        Veterans suffering from these conditions are not properly screened, validly assessed, or diagnosed, which contravenes the Covenant’s duty of care.

3. Dismissal of Veterans' Concerns by Key Figures:

a)        Veterans’ concerns have been repeatedly disregarded by key individuals, including NHS, COMBAT STRESS, Veteran Commissioners, Service Charity Chief Executives and other healthcare leaders.

b)        The failure to incorporate Lariam toxicity into clinical training and support services highlights a disregard for veterans' needs.

4. Lack of Clinical Training and Education:

a)        NHS clinicians, including those in veteran mental health services, lack specific training on Lariam toxicity and its long-term effects, resulting in continued misdiagnoses and mistreatment.

5. Neglect of Evidence:

a)        Despite credible findings from respected organisations such as the European Medicines Agency (EMA) and multiple international reports, there remains a persistent and unjustifiable reluctance to acknowledge the long-term effects of Mefloquine toxicity and acquired brain injuries on veterans. This ongoing failure directly undermines the Armed Forces Covenant’s fundamental commitment to ensuring special consideration and support for those who have served and suffered life-altering health consequences. The significance of the evidence presented in the January 2014 EMA Pharmacovigilance Risk Assessment Committee (PRAC) report cannot be overstated, and the Defence Select Committee is urged to review the conclusions.

b)        The Ministry of Defence (MoD) has yet to submit critical data from the 713/MODREC/15 study to the Defence Select Committee (DSC), despite being instructed to do so in 2016. This continued delay obstructs informed decision-making, hinders vital research, and exacerbates systemic neglect of Armed Forces welfare concerns.

6. Inaction and Refusal to Address the Issue:

a)        Veterans raising concerns about Lariam toxicity face continuous barriers, including indifference from senior officials and unhelpful responses from veteran services (e.g. OP RESTORE, COMBAT STRESS, Veterans’ Commissioner).

b)        The lack of action and acknowledgment exacerbates the suffering of veterans, leaving them at a significant disadvantage and sanctuary trauma.

7. Contradiction of the Covenant’s Values:

a)        The ongoing failure to provide timely diagnoses, effective treatment, and proper support to veterans with Lariam toxicity directly contradicts the Armed Forces Covenant’s values.

b)        This systemic neglect deepens the mental and physical suffering of veterans, undermining the Covenant's core commitment to support those who have served.

Main Causes for These Failings

1. Epidemic of Misinformed Doctors and Patients:

a)        Widespread lack of knowledge and education among doctors, clinicians, and patients regarding the neurotoxic effects of Mefloquine (Lariam) and the prevalence of Acquired Brain Injuries (ABIs) among veterans.

b)        Medical professionals often fail to diagnose neurotoxicity or misdiagnose it as PTSD, leading to inappropriate treatment and exacerbation of symptoms.

2. Bias in Research and Reporting:

a)      Research funding is biased towards projects likely to be profitable rather than those truly beneficial for patients, contributing to a lack of comprehensive research into the long-term effects of Mefloquine and ABIs.

b)      Medical journals and the media are complicit in biased reporting, perpetuating misleading narratives that prevent accurate awareness and appropriate action on these issues.

3. Commercial Conflicts of Interest:

a)        Conflicts of interest, particularly within organisations like the King's College Mental Health Research (KCMHR), have manufactured doubt and misdirect funding away from neurology, undermining independent research on Mefloquine toxicity and ABIs.

b)        This has obstructed the implementation of effective screening, assessment programmes, and evidence-based solutions by non-biased organisations unaffiliated with commercial interests.

4. Veteran Services and Charities’ Failure to Address the Issue:

a)      Key veteran services and charities such as the Royal British Legion (RBL), Combat Stress, Help for Heroes, DMWS, OP COURAGE, OP RESTORE, Veteran Gateway, SSAFA, ABF, and others do not include information about Mefloquine toxicity or Acquired Brain Injuries on their websites or literature, despite sufficient evidence available, including the conclusions of the January 2014 European Medicines Agency (EMA) PRAC report.

b)      This omission reflects a systematic failure to acknowledge the issue, leaving veterans without the support or resources they need, while highlighting the Conflicts of interest by those who significantly fund such veteran charities.

5. Lack of Information and Resources for Clinicians:

a)        Medical training, clinical guidance, and resources on the neurotoxic effects of Mefloquine and ABIs are severely lacking.

b)        The Royal College of General Practitioners' (RCGP) Veteran Friendly GP initiative fails to include information on Mefloquine toxicity or Acquired Brain Injuries, preventing GPs from offering proper care or making accurate referrals.

6. Failure to Uphold the Duty of Candour:

a)        Due to lack of awareness, clinicians are unable to uphold their duty of candour, failing to inform patients of the full scope of their medical conditions, or misinforming them about the root causes of their symptoms.

b)        Veterans continue to suffer due to the lack of transparency and honest communication from healthcare providers.

7. Inadequate Diagnosis and Follow-up:

a)      Misinformation and lack of appropriate training led to misdiagnoses, such as PTSD being used as a ‘diagnosis of convenience’ when the true cause may be Mefloquine toxicity or an acquired brain injury.

b)      There is no long-term follow-up for veterans who present with adverse symptoms, making it impossible to track the progression of their conditions or provide proper care over time.

c)      Insufficient veteran medical records and the absence of comprehensive screening prevent proper diagnosis of conditions like Mefloquine toxicity, leaving veterans without the care they need.

8. Cover-Up of Critical Reports and Evidence:

a)        The Ministry of Defence (MOD) has failed to address or even acknowledge the January 2014 European Medicines Agency PRAC report, which highlights the neurotoxic effects of Mefloquine, leading to a cover-up of vital information that could help veterans, including research 713/MODREC/15.

b)        The Defence Select Committee inquiry has also been tainted by omissions of this critical evidence, further delaying the implementation of necessary changes.

9. Failure to Address Veteran Suicides:

a)        The lived experiences of veterans suffering from the effects of Mefloquine toxicity and ABIs, particularly those impacted by suicides, have been ignored by the MOD, and not adequately investigated during Ministry of Justice (MoJ) inquests.[33]

b)        This failure to properly investigate the root causes of veteran suicides contributes to the ongoing disadvantage faced by affected veterans, deepening the sanctuary trauma they experience.

Recommendations to the Defence Select Committee

1.                Uphold the Core Principles of the Armed Forces Covenant: The principles of "No disadvantage" and "Special consideration" must be upheld for veterans suffering from Mefloquine (Lariam) toxicity and acquired brain injuries (ABIs). It is essential to provide affected veterans with appropriate medical attention to prevent systemic neglect, misdiagnosis, and lack of support.

2.                Implement Comprehensive Screening and Assessment: Comprehensive screening protocols for Mefloquine neurotoxicity and ABIs should be developed and mandated within UK veteran services. Findings from the European Medicines Agency and international research, such as the Australian Royal Commission, must be incorporated into diagnostic practices throughout our veteran services.

3.                Address Dismissal of Veterans' Concerns: Accountability mechanisms need to be established to ensure veterans’ concerns are taken seriously by the NHS, veteran charities, and healthcare leaders. Furthermore, Lariam toxicity should be introduced into clinical training and veteran support frameworks to ensure veterans receive the care they deserve.

4.                Enhance Clinical Training and Education: NHS clinicians and veteran mental health service providers should be given specific training on the neurotoxic effects of Lariam and the long-term impacts of ABIs. This training must also be integrated into the Royal College of General Practitioners’ (RCGP) Veteran Friendly GP initiative to enhance the overall quality of care.

5.                Acknowledge and Act on Evidence: Evidence from agencies like the European Medicines Agency and international reports should be recognised and incorporated into veteran healthcare policies. Clinical transparency and adherence to the duty of candour are essential to ensure patients are informed about the root causes of their conditions.

6.                Address Systemic Barriers and Inaction: Barriers faced by veterans raising concerns about Lariam toxicity and ABIs must be reduced, with responsiveness ensured from veteran services such as OP RESTORE. Long-term follow-up programmes should be established to monitor symptoms and the progression of neurotoxic effects or ABIs.

7.                Ensure Proper Allocation of Research Funding: Research funding should be redirected towards independent neurological studies on Mefloquine toxicity and ABIs, free from commercial conflicts of interest and with integrity. Biases and manufactured doubt in medical research funding and reporting must be addressed to improve awareness and prompt effective action.

8.                Hold Veteran Services and Charities Accountable: Organisations such as the Royal British Legion, Combat Stress, and Help for Heroes should have the moral courage to include information on Mefloquine toxicity and ABIs in their resources and literature. These organisations must also ensure transparency and evidence-based solutions in their programmes.

9.                Address Failures in Diagnosis and Follow-up: A standardised approach to diagnose and treat conditions like Mefloquine toxicity and ABIs must be developed, minimising misdiagnoses such as PTSD being used as a diagnosis of convenience. Comprehensive veteran medical records and follow-up programmes are crucial to improving long-term care.

10.            Investigate Veteran Suicides: Thorough investigations into veteran suicides linked to Mefloquine toxicity and ABIs are necessary to properly address the root causes. Lived experiences of veterans should be included in Ministry of Defence (MOD) and Ministry of Justice (MoJ) inquiries to tackle sanctuary trauma and provide meaningful resolutions by those effected.

11.            Review Omitted Evidence: The Ministry of Defence (MoD) must review, acknowledge, and take decisive action based on critical reports, such as the 2014 European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) report at Appendix 1, to prevent further negligence and uphold the principles of the Armed Forces Covenant. The Defence Select Committee (DSC) must ensure that all omitted evidence is thoroughly examined and that those responsible for withholding crucial information are held accountable. Additionally, the DSC has the authority to demand the submission of the withheld 713/MODREC/15 research data and should prioritise commissioning an independent senior investigator—free from MOD influence—to complete the research. This independent review would enhance transparency, reinforce credibility, and ensure accountability in addressing the serious concerns faced by affected veterans. Furthermore, all research protocols must be presented to the Medicines and Healthcare products Regulatory Agency (MHRA) to guarantee adherence to the highest medical and ethical standards.

CONCLUSION

The Armed Forces Covenant will continue to fall short of its moral obligation to the Armed Forces Community and its core principles unless the Ministry of Defence (MoD) and wider clinical services acknowledge that many service personnel and veterans experiencing mental health struggles are, in fact, suffering from Mefloquine toxicity and other brain injuries[34] [35].

In the United States, Mefloquine poisoning is recognised as a distinct condition known as neuropsychiatric quinism or Chronic Quinoline Encephalopathy, with a documented pathophysiology (neurotoxicity). Similarly, Australia’s Royal Commission has underscored the issue, and the August 2024 Defence Health Agency Medical Surveillance Monthly Report (Volume 31, No. 8), co-authored by the director of the Australian Army Malaria Research Institute[36], explicitly excludes Mefloquine from the list of acceptable malaria prophylaxis for the Australian Defence Force (ADF).

Despite the findings of the 2015/16 Defence Select Committee (DSC) Lariam inquiry, the MoD continues to resist mounting medico-scientific evidence linking Lariam to long-term or persistent neuropsychiatric damage in service personnel. This resistance has led to the misattribution of symptoms, resulting in inappropriate and potentially life-threatening treatment for veterans with Lariam toxicity. While Lariam toxicity is a service-related condition, the Armed Forces Covenant has failed to measure the scale of this issue or adequately address it.

This submission does not aim to revisit prior Defence Select Committee discussions or ongoing MOD litigation. However, it is crucial to highlight serious evidence suggesting that omissions from the 31 January 2014 European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) report—by both the MOD and the drug manufacturer—have directly contributed to the sanctuary trauma endured by veterans today. Moreover, the derisory global settlement of £5,000 (before fees) imposed on Lariam victims and their families is not only inadequate but also an affront to those suffering, offering little more than the cost of their funerals. This lack of meaningful redress risks eroding hope and fuelling further veteran suicides.

Ultimately, the burden has been unfairly placed on the very individuals who have already suffered the most. Veterans damaged by these failings are being left to fend for themselves, with some, including myself, taking on the responsibility of supporting others who have been abandoned[37]. This failure to act dishonours the Covenant and betrays the trust of those who have served their nation.

Reference(s):

[1] Daily Telegraph article 02 March 2024 Soldiers harmed by anti-malaria drug launch landmark legal claim against MoD [link]

[2] International Trauma-Informed Care Network ‘Lived-Experience’ presentation dated 11 November 2021 [link]

[3] The Armed Forces Covenant Two core Principles [link]

[4] Recommendation 61: Establish a brain injury program Final Report - Volume 4: Health care for serving and ex-serving members Page 15 [link]

[5] All-Party Parliamentary Group for Acquired Brain Injury Reception, Jubilee Room, Houses of Parliament 10 May 2023 [link]

[6] 30 x A5 leaflets used to brief members of Parliament at the Acquired Brain Injury Reception [download]

[7] OP RESTORE email reply rejecting assistance with injured Mefloquine Veterans dated 14 June 2024 [download]

[8] Head of Armed Forces - Policy & Operations rejecting assistance with injured Mefloquine Veterans email dated 04 October 2024 [download]

[9] The Mefloquine Single Point of Contact, published on 30 August 2016 [link]

[10] COBSEO Veteran Charities and UK Clinical Services Overlook Lariam Toxicity and Acquired Brain Injury in Literature and Online Content [download]

[11] Vilified by Veteran UK at Tribunal, Leading to the HM Court & Tribunal Service withdrawing My War Pension Case [download]

[12] War Pension NHS Prescription Exemption Certificate: Veteran UK Acknowledges Mefloquine Side Effects in War Pension Claim, but NHS Provides No Care [download]

[13] Referrals by untrained GPs and NHS psychiatrists on Mefloquine injured veterans [download]

[14] Doctor of Tropical Medicine and Disease Leads to Back to Square One for Mefloquine Injured Veteran [download]

[15] Hypothesis on Mefloquine Toxicity and Brain Injury: Limited Research on Neuropsychological Effects and Cognitive Impacts [download]

[16] Video – Exposed: The Truth behind ABI, TBI, & Mefloquine cover-ups in veteran ‘mental health’ [link]

[17] Video - Brain Injury WIN at the Defence Select Committee's update on Armed Forces & Veterans Mental Health [link]

[18] UK ‘Independent’ Veteran advisors to Office of Veteran Affairs correspondence [download]

[19] European Medicine Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) report conclusion, dated 31 January 2014 [download]

[20] Veterans’ Commissioner for Wales correspondence [download]

[21] CEO Combat stress letter 08 December 2016 [download]

[22] COMBAT STRESS’s Director of Medical Services, dated 12 March 2018 [download]

[23] Video - Uncovering the Overlooked: The Omission of Mefloquine (Lariam) Toxicity in Veteran GP Training [link]

[24] RCGP Veteran Friendly GP Accreditation Fails to Address Mefloquine (Lariam) Toxicity and Acquired Brain Injuries in Veterans [link]

[25] NHS expands mental health support for veterans with more than half saying it’s hard to speak up. NHS England Website 09 January 2024 [link]

[26] Failure of Former DMWS Chief Executive and NHS Armed Forces Chair to Address Veteran Health Concerns on Acquired Brain Injuries and Mefloquine (Lariam) Toxicity [download]

[27] Associate Director of Nursing and Founder of International Trauma-Informed Care- Influence of KCMHR on Mefloquine (Lariam) Toxicity in Veterans [download]

[28] Conflicting Perspectives: Professor Acknowledges Complexity of ABI/mTBI and Mental Health, Yet Downplays Urgency of Tailored Care [download]

[29] HQ Joint Med Group Letter dated 04 February 2020 acknowledging the European Medicine Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) report conclusion [download]

[30] Letter from Dr June Raine CBE_Interim CEO, MHRA Research Study on antimalarial chemoprophylaxis including Lariam by the Ministry of Defence 713_MoDREC_15 [download]

[31] Medicines & Healthcare products Regulatory Agency (MHRA) Public Board Meeting reply on Mefloquine in Defence [download]

[32] Correspondence with Former Chief of General Staff’s on Mefloquine (Lariam): Disadvantaged by Military Health Structure and Mental Health Risks [download]

[33] Cpl Chris Small reached out for help suffering Mefloquine toxicity before taking his own life. [download]

[34] Minister for Defence People and Veterans , The Rt Hon Johnny Mercer MP knowledge of the critical 31 January 2014 EMA PRAC Report in December 2019 [link]

[35] Minister for Defence People and Veterans, The Rt Hon Johnny Mercer Facebook Live Lariam Question on the 31 January 2014 EMA PRAC Report in October 2019 [link]

[36] Defence Health Agency Medical Surveillance Monthly Report (MSMR) dated August 2024 MSMR August 2024. Volume 31, No. 8. [link]

[37] Captured testimonies of 'lived experiences' from veterans abandoned after their use of Mefloquine [download]

EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

31January 2014 EMA/63963/2014

Pharmacovigilance Risk Assessment Committee (PRAC)

Updated PRAC rapporteur assessment report on the

signal of permanent neurologic (vestibular) disorders with

mefloquine

7 Westferry Circus • Canary Wharf • London E14 4HB • United Kingdom Telephone +44

(0)20 7418 8400 Facsimile +44 (0)20 7418 8416

E-mail info@erna.eurnpa.cu  Website www.ema.europa.eu                                                                                          An agency of the European Union

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Table of contents

1.   Administrative information              3

1.1.    Timetable              3

1.2.    Product/class details              3

Background              4

2.   Scientific discussion              4

2.1.    PRAC initial analysis and prioritisation              4

2.2.    Marketing-authorisation holder's responses              4

2.3.    Rapporteur's position              30

3.   Conclusion and recommendations              .31

3.1.    Changes to the product information              31

3.2.    Request for supplementary information              32

3.3.    Communication              32

4.   Comments from member states              .32

S. Points for discussion/agreement              .34

6. References              .34

Summary PRAC assessment report on the signal of <issue> with <INN and/or product name(s) or product class>              35

Updated PRAC rapporteur· assessment report on the signal of permanent neurologic (vestibular) disorders with mefloquine

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1.      Administrative information

1.1.       Timetable

1.2.       Product/class details

Updated PRAC rapporteur assessment report on the signal of permanent neurologic

(vestibular) disorders with mefloquine

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Background

Mefloquine is a 4-quinoline methanol derivative and is structurally related to quinine.

Mefloquine is indicated for the prophylaxis, therapy and stand-by treatment of malaria.

Mefloquine acts on the asexual intraerythrocytic forms of the human malaria parasites:

Plasmodium falciparum, P. vivax, P. malariae and P. °vale. Mefloquine is effective

against malaria parasites resistant to other anti-malarials such as chloroquine, proguanil,

pyrimethamine and pyrimethamine-sulfonamide combinations.

A signal regarding permanent neurologic (vestibular) disorders was identified by FDA in July

2013 and the FDA-AR was analysed by DE. Subsequently DE introduced the signal to the

PRAC. During the meeting on 07 -10 October 2013 PRAC recommended that the MAH of

Lariam®, innovator product for mefloquine, be requested to submit a cumulative review of

neurologic (vestibular) disorders including a proposal for an update to the product

Information.

2. Scientific discussion

2.1. PRAC initial analysis and prioritisation PRAC Recommendations/Advice

During its meeting of 7-10 October 2013, in accordance with Article 107h of Directive

2001/83/EC and Article 21 of Commission Implementing Regulation (EU) No 520/2012 the

European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) has

analysed and prioritised a signal of possibly permanent neurologic (vestibular) side effects

with mefloquine (see PRAC Agenda under item 4.2.1.

https: //www.ema.europa.eu/ema/index.jsp?curl - pages/about us/document

listing/document listing 000353.jsp&mid-WC0bOlac05805a21cf).

Having considered the available evidence from the FDA communication the PRAC concluded

that the current sections 4.4 and 4.8 of SmPC (PL accordingly) of mefloquine-containing

medicinal products are not considered appropriate to inform about t h e possibility o f

persistent or permanent neurologic (vestibular) disorders.

Recommendation:

Therefore, the PRAC recommended that t h e Marketing Author is at ion Holder (MAH) of

Lariam®, innovator product f o r mefloquine, be requested to submit a cumulative review of

neurologic (vestibular) disorders including a proposal for an update to the product

FDA Drug Safety Communication, based on the requirements provided in Article 23(4) of

Directive 2001/83/EC. The cumulative review should be submitted by 6 December 2013.

2.1.      Marketing-authorisation holder's responses

Following PRAC's request, considering FDA's communication and the signal sent by BfArM to

PRAC related to the possible permanent character of these events, the MAH is submitting

two Drug Safety Reports (DSRs) which need to be reviewed in conjunction:

• Drug Safety Report (DSR) 1040001 (please refer to module 5.3.6); cumulative analysis

till 06 May 2010, to analyse all medically confirmed SAEs of psychiatric disorders and

nervous system disorders persisting for more than 90 days.

• Addendum DSR 1058255 (please refer to module 5.3.6), which is an addendum to the

DSR 1040001, and provides*:

Updated PRAC rapporteur assessment report on the signal of permanent neurologic

(vestibular) disorders with mefloquine

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a) A n analysis of all medically confirmed SAEs of psychiatric disorders and nervous

system disorders persisting for more than 90 days reported between 07 May 2010

and 27 October 2013.

b) A cumulative review (till 27 October 2013) of all vestibular disorders persisting

for more than 90 days.

• Based on the assessment in DSR 1040001, the MAH amended the Lariam Company Core

Data Sheet (CDS, refer to module 5.4 for the current CDS V. 4.0) regarding the duration of

neuropsychiatric disorders in the "Warnings and Precautions" section. The information that

adverse reactions to Lariam may occur or persist up to several weeks after discontinuation

of the drug and that dizziness or vertigo and loss of balance may continue for months after

discontinuation of the drug was added. The analysis within the current addendum DSR

1058255 confirmed this outcome for most of the cases; however the persistence of events in

a small proportion of patients may be possible.

• Based on the review provided in the addendum DSR 1058255, including case reports

from the Roche Global Drug Safety Database ARISg, the MAH will amend the "Warnings and

Precautions" section of the current Lariam CDS V. 4.0 (refer to module 5.4 for the current

CDS v4) to include information on the persistence of certain neuropsychiatric events after

discontinuation of the product.

Search strategy

Since the current DSR is an addendum to the DSR 1040001, prepared in 2010 (cutoff

date of 06 May 2010), the same search criteria were applied (see Section 5,

page 9 of DSR 1040001). Therefore, a multiaxial search in ARISg was conducted for

cases with events in the SOC "Psychiatric Disorders" and SOC "Nervous

System Disorders" reported between 07 May 2010 and 27 October 2013 (latest

report coding completed). Due to multiaxiality, this search includes relevant terms

from the SOC "Ear and Labyrinth Disorders".

However, a second search (cumulative, cut-off date of 27 October 2013) was

carried out for the broad SMQ "Vestibular Disorders" (see Appendix 1 for a

complete list of MedDRA PTs used in the search) and, for comprehensive reasons to

search within the primary SOC, t h e PT "Tinnitus", reported i n individuals who

received mefloquine f o r malaria chemoprophylaxis, malaria treatment, stand-by

treatment, or for an unknown indication.

These searches were carried out under the MedDRA version 16.0.

The following cases were excluded:

-             Non Substantive follow-up

cases

-          Inactive

Cases

-          Case reports including only non-serious

events

The aim of the searches was to identify the cases conforming to any of the

following event criteria groups:

Group I

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Based on the difference between AE Onset Date and AE Cessation Date, event duration was greater than or equal to 90 days.

-          Group II

For events where AE Cessation Date is missing, based on the difference between AE Onset Date and AER Company Received Date, event duration was greater than or equal to 90 days, and the event outcome was one of the following:

-          Fatal

-          Not recovered/not resolved

-          Recovered/resolved with sequelae

-          Recovering/resolving

-          Group III

For events where the AE Cessation Date is missing, event duration was greater than or equal to 90 days (based on the difference between AE Onset Date and AER Received Date), and the event outcome was:

-          Recovered/ resolved

The selected events under SOC "Psychiatric Disorders" are presented in Section 6.1.1, and the events under SOC "Nervous System Disorders" in Section 6.2.1. Case reports with both types of SAEs are cross-referenced. The events under the SMQ "Vestibular Disorders" and the PT "Tinnitus", if not covered previously, are discussed in Section 6.3, and Section 6.4, respectively.

The SAEs from groups I, II, and III were analysed in the same way as for the DSR 1040001:

a)         In the first step, all cases retrieved from ARISg were individually reviewed in order to determine whether mefloquine was used as treatment or chemoprophylaxis:

-   Indication: Malaria chemoprophylaxis

-   Indication: Malaria treatment

-   Indication: Unknown

This distinction is important, considering that subjects taking mefloquine for malaria chemoprophylaxis are generally healthy, while patients with malaria may develop complications of the disease (e.g. coma, convulsions, liver impairment) or use co- medications (e.g. quinine) that often provide an alternative explanation in the case assessment.

b)         In the second step, duration of the SAEs was manually reviewed, as the case selection was based on auto coding, which may not reflect case updates included in the narratives only. The following classification was applied:

-              1: SAE duration <90 days, or pre-existing to mefloquine exposure

-              2: SAE duration 90 days to 1 year

-              3: SAE duration 1 year to 2 years

-              4: SAE duration 2 to 3 years

-              5: SAE duration >3 years

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-   6: SAE duration unknown

If the individual relevant SAEs in one case have a differing duration, the longest

duration is taken for classification.

c)         In the third step, all cases were individually reviewed and classified according to

the following assessment criteria:

- Category A: Insufficient information for assessment, or controversial data

- Category B: Relevant medical history and/or confounding factors including e.g. co-medication present

- Category C: The relevant SAE occurred more than 6 months after mefloquine discontinuation

- Category D: No alternative Explanation found

- Category E: Case is out of scope of the review (mainly because of a duration of the relevant SAE of <90 days, or another drug clearly caused the SAE)

- Category F:

Overdose

It should be noted that "disability" is marked as a seriousness criterion at the time the event is reported and does not necessarily reflect the final outcome of the event. All case narratives were manually reviewed to determine if there was any evidence of disability outcome reported.

Based on the various cornerstones for defining SAE duration and the different outcomes in a single patient with more than one SAE, a patient may be included in more than one group.

Below the drug safety reports by Roche. have been summarized.

N=whole number of case reports in the category

D=number of case reports under category D with a known duration

Category D = No alternative Explanation found

Summary of Drug Safety report 104001 part of the PSUR-Worksharing for mefloguine 001 (cumulative search: cut- off date May 2010}

(Only case reports from category D with a known duration are mentioned in the summaries)

A) SOC Psychiatric Disorder

Group I

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1)    Indication: Malaria Prophylaxis (N=37; D=Sl

There were 37 patients in this group: of those patients one was out of the scope of this report as the duration of the relevant SAE was less than 90 days              In addition 12 patients with a relevant SAE duration of 90 days - 1 year from the 37 reports had only very limited information which did not allow for a causality assessment of the report, and 8 patients with a relevant history and/or other alternative explanations confounding their report will be excluded from discussion, while 6 patients are presented below as they had no explanation other than mefloquine for the occurrence of the relevant event. Likewise two further patients from group/category D with a SAE duration of 1 - 2 years are presented below, while a patient with insufficient information from category 3 is also excluded from the review.

Result of case review: Category A: insuff/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Duration 1: SAE< 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown

(2D): An 18-year-old female patient with a BMI of 19.4, no relevant medical history, and no comedication took 250mg/day mefloquine malaria prophylaxis for three days, when she experienced hyperventilation, dizziness, and anxiety with panic attacks, and then continued mefloquine once a week for another two weeks. She was

treated with paroxetine and improved subsequently; the psychiatric events were reported to be resolved within 117 days.

(2D): a 27-year-old male patient with no relevant medical history nor on comedications, and with a BMI of 25.81 took lx250mg/week mefloquine for 8 days.

After the first day he experienced hypomania, then after the next mefloquine dose he became psychotic with mania and paranoia for which he was hospitalized and treated with haloperidol. After repatriation he had a recurrence of the symptoms and was

rehospitalized and received depakote and venlafaxine. He recovered after a total duration of 265 days.

      (2D): A 67-year-old female patient with no history of psychosis nor on

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comedications received mefloquine 250mg/week (exact dates unknown) which was discontinued prior to her leaving for abroad. Some days later, she became very confused, and manifested psychotic features, and was hospitalized. She initially recovered within a few days, but psychosis and confusion recurred approximately 5 months later, and she was re-hospitalized, and recovered subsequently. Neurologic examinations were carried out which did not reveal dementia. This report is also included in Group I malaria prophylaxis: nervous system disorder events: SAE confusion, classified as 2D.

(2D): A 30-year-old male patient with no psychiatric history, taking a single dose of ibuprofen and of ketoprofen, respectively while on lx250mg mefloquine/week for malaria prophylaxis experienced intermittent dyspnea, anxiety attacks, suicidal ideation, psychosis, palpitations, numbness of the head, confusion and muscle cramps for which he was hospitalized after taking 7 doses. After discontinuation of mefloquine the SAE: suicidal ideations resolved slowly over 6 months.

This report is also included in Group II malaria prophylaxis: psychiatric system disorder events: SAE psychotic disorder, classified as lE (Appendix 2), and Group II malaria prophylaxis: nervous system disorders, classified as 2A (Appendix 10).

(3D): A 23-year-old female patient with no psychiatric history was taking lx250mg /week mefloquine for malaria prophylaxis for 9 months when she experienced psychosis, and depression. Comedication was a contraceptive. She was prescribed diazepam, mefloquine was maintained. Some eight months later she was repatriated, and discontinued mefloquine. Again three months later she was started on sertraline, she also took several antidepressants. Some weeks later, the symptoms had resolved, and sertraline was finally discontinued.

(2D): A 26-year-old female patient with no psychiatric history, and no comedication took lx250mg mefloquine/week for malaria prophylaxis and experienced hypomania. She was treated with haloperidol. Some weeks later, mefloquine was discontinued, and she recovered six weeks later.

(2D): A 25-year-old male patient with a BMI of 22.9, no psychiatric nor abuse history and was not on any comedication took lx250mg mefloquine/week for malaria prophylaxis. After completion the course of mefloquine (total dose: 1750mg) he slowly experienced increasing anxiety, persecutory delusions, and became overtly psychotic, he was hospitalized with paranoid psychosis, and he was treated with haloperidol and lorazepam which resulted in improvement of his symptoms. As he presented subsequently with extrapyramidal symptoms his medications was switched to risperidone. Some two weeks later the dose of risperidone was reduced, and he experienced euphoria. Risperidone dose was again increased and biperiden was added for treatment of the extrapyramidal symptoms. Eventually risperidone was replaced with olanzapine, and he presented with major depression for which he was treated with mirtazapine on an out-patient basis. Mefloquine level in serum was at that time below 20ng/ml. Seven months after start of psychosis the patient had completely recovered from all neuropsychiatric SAEs.

(3D): A 23-year-old male patient with no relevant history and no comedications was taking lx250mg mefloquine/week for malaria prophylaxis. He experienced amnesia, but he consulted his general practitioner only after discontinuation of mefloquine about this problem. ACT scan, 24hr blood pressure monitoring, and blood

tests were all normal. Some months later, he was treated with Ubidecarone which remained ongoing, and he slowly recovered. This report is also included in Group I malaria prophylaxis: nervous system disorder events: SAE amnesia, classified as 3D.

Comments: While all described psychiatric events are listed in the CDS. Following

review of the narrative it is questionable whether the events are persisting for a period of more than 90 days. Two patients exhibiting psychotic episodes are reported to have

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recovered initially after a short period of time but then had a recurrence of the symptoms after a prolonged period of time               . Likewise MCN              initially recovered from psychosis within approximately one month, but had later complications

of extrapyramidal symptoms and depression, and made a final recovery only 7 months after his symptomatology of neuropsychiatric events had started.

2) Indication: Malaria treatment (N=3; D=0)

3) Indication unknown N=0

Group II

1) Indication: Malaria Prophylaxis (N=250; D=8)

There were 250 patients in this group: of those 57 patients were out of the scope of this report as the duration of the relevant SAE was less than 90 days. In addition 46 patients with a relevant SAE duration of 90 days - 1 year from the 250 reports had only very limited information which did not allow for a causality assessment of the report, and 23 patients with a relevant history and/or other alternative explanations confounding their report will be also excluded from discussion, while 7 patients are presented below as they had no explanation other than mefloquine for the occurrence of the relevant event.

Likewise one further patient from group/category D with SAE duration of 2 - 3 years is presented below,....

Result of case review: Category A: insuff/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Duration 1: SAE< 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown

(2D): A 47-year-old female patient with a BMI of 23.6, no relevant medical history (history of vertigo reported for which she received prochlorperazine) was treated with 250mg/week mefloquine for malaria prophylaxis which he had taken twice in the past with no adverse effects. Approximately 8 weeks after mefloquine had been discontinued she experienced severe anxiety for which she was treated with clomipramine, thioridazine, and propranolol. At last follow-up, the SAE was persisting.

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(2D): A 24-year-old female patient with a BMI of 18.5 with no relevant medical history nor comedications took lx250mg mefloquine/week for malaria prophylaxis for a few weeks when she experienced severe panic attacks, dizziness and vertigo, headache, depression, and anxiety. Mefloquine was discontinued, and she was treated with psychotherapy, naproxen, sumatriptan, which gave no relief. The patient had been hospitalized for the SAEs, and citalopram and alprazolam were given. Complete blood count and liver function tests were all normal. The mefloquine drug level was 0.31 mg/ml. A MRI brain scan was normal. The treatment with alprazolam was maintained

and other unspecified treatment given. Six months later the SAEs were persisting. This report is also included in Group II malaria prophylaxis: nervous system disorder events: SAE vertigo, headache, classified as 2D.

(2D): A 42-year-old female patient with no relevant medical history and not taking comedications received mefloquine lx250mg/week for malaria prophylaxis. She took in total two doses of mefloquine and experienced disabling difficulty writing, optic neuritis, blurred vision, a panic reaction, anxiety, nightmares, delusion, memory loss, neurologic symptoms, irrational thinking, depression, demyelination disorder, hemiparesis, dizziness, memory dysfunction, hair loss, nausea, diarrhea, bloating and abdominal cramps. After repatriation she took a third dose of mefloquine, and her condition deteriorated. Brain MRI was normal, and she was treated with cortical steroids, but contracted Herpes zoster in the right C3-C4 thereafter. Her symptoms improved with gabapentin as well as many other medications. At last follow-up her neurological symptoms gradually improved, but dizziness, memory loss and nightmares were persisting. The cause of her symptoms was unclear. This report is also included in Group II malaria prophylaxis: nervous system disorder events: SAE amnesia, classified as 2D.

(2D): A 47-year-old male patient with no psychiatric history, on atenolol for hypertension took lx250mg mefloquine/week for malaria prophylaxis. After the second dose he experienced panic attacks with a feeling of confusion, mefloquine remained ongoing until the course was completed. Six months thereafter panic attacks were persisting, and he started treatment with clobazam. Paroxetine was then started and remained ongoing at last follow-up.

(2D): A 17-year-old female patient with a BMI of 18.4, on oral contraception, and with no psychiatric medical history, took lx250mg/week mefloquine for malaria prophylaxis for approximately 7 weeks, then she experienced hallucinations due to which mefloquine was discontinued. One month later she had nightmares and flashbacks which were persistent and caused disability. Another month later she experienced depression and irritability. Treatment with risperidone, quetiapine and venlafaxine was started. Risperidone was discontinued, and one month later also quetiapine, while venlafaxine remained ongoing. At last follow-up tiredness, terrifying nightmares, flashbacks, depressive symptoms, and irritability were persisting while the hallucinations had improved.

(2D): A male patient in his mid twenties with no relevant medical history (ex-soldier) experienced a panic disorder during the use of lx250mg/week mefloquine for malaria prophylaxis while on vacation. Within 24 hours of taking the first dose he presented with weakness, gait disturbance, vertigo, fever, confusion, aggressiveness, lethargy, sweating and loss of appetite. One week later he also had severe anxiety with feeling of suffocation and insomnia which worsened progressively. He was hospitalized,

all neurological and laboratory tests were normal. He was diagnosed with a panic state and received diazepam. He was repatriated. At that time, his mefloquine level in serum

was 200ng%. He was treated with clonazepam and fluoxetine. The events were persisting 9 weeks later, at last follow-up. This report is also included in Group II malaria prophylaxis: nervous system disorder events: SAE confusion, classified as 2D.

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(2D): A 35-year-old female patient with a BMI of 20.6, no relevant medical history nor on comedication took lx250mg/week mefloquine for malaria prophylaxis for four weeks. After the second dose she experienced gait disturbances which lasted three weeks, and also anxiety states. A week later she was briefly hospitalized for depression, sleep disorder, tachycardia, headache, and nausea. Ten days later mefloquine was discontinued, neurological exams and CT were without pathological findings. Promethazine and metoclopramide was started, and approximately four months later she had fully recovered.

(4D): A 20-year-old female patient with a BMI of 18.4, no relevant medical history and on no comedication took lx250mg/week mefloquine for malaria prophylaxis. Approximately one month later, she experienced some psychiatric problems. After further three months she took her last dose of mefloquine, and needed hospitalization for an acute psychotic reaction. She was then repatriated, and received unspecified psychopharmaca. The overt psychotic reaction resolved over time, but she remained in a subacute psychotic state which was waxing and waning. She received lithium which was replaced by thioridazine because of lack of effect. At the time of last report she had not recovered.

Comments: All relevant psychiatric disorder SAEs presented in this section are known to occur on occasions with mefloquine and are listed in the CDS. In addition because of the long half-life of mefloquine, adverse reactions may occur or persist up to several weeks

after discontinuation of the drug.

2} Indication: Malaria CN=28; D=ll

...27 patients of the 28 patients in this group are not discussed in further detail as they fail the review criteria to focus on.

Result of case review: Category A: insuff/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Duration 1: SAE< 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown

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history had been overseas for 15 months and on malaria prophylaxis with chloroquine and proguanil when he experienced fever and headache. He was hospitalized and treated with quinine for 3 days in addition to 6 tablets mefloquine for suspected malaria tropica. While under this regimen he presented with psychotic symptoms, circulatory disturbances, vomiting and dizziness. He was repatriated and re-hospitalized. He was temporarily treated with thioridazine. The suspicion of malaria was not confirmed at the new hospital, nor was there any other tropical infections diagnosed. The psychiatrist considered a mefloquine-induced psychosis. He was then treated with imipramine and

hydroxyzine. Two months later imipramine was reduced, and patient could return to work. This report is also included in Group II: malaria treatment: nervous system disorder SAES: dizziness, classified as 1E.

Comment: This is another report of CDS listed psychosis which resolved with appropriate treatment. In addition because of the long half-life of mefloquine, adverse reactions may occur or persist up to several weeks after discontinuation of the drug.

3) Indication: unknown (N=34; D=0)

Group III

1) Indication: malaria prophylaxis (N=19; D=0)

2) Indication: malaria treatment ( N = 0 )

3) Indication: Unknown (N = 8; D=0)

B) Nervous System Disorders

Group I

1) Indication: Malaria Prophylaxis (N 2 1 ; D=3 two of them are already included

in Group I malaria prophylaxis: psychiatric events)

There were 21 patients in this group: of those three patients were out of the scope of this report as the duration of the relevant SAE was less than 90 days. In addition four patients with a relevant SAE duration of 90 days - 1 year from the 21 reports had only very limited information which did not allow for a causality assessment of the report, and 5 patients with a relevant history and/or other explanations confounding their report will be excluded from discussion, while 2 patients are presented below as they had no explanation other than mefloquine for the occurrence of the relevant event. Likewise one further patient from group D with a SAE duration of 1 - 2 years is presented below...

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Result of case review: Category A: insuff/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Duration 1: SAE< 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown

(2D): A 67-year-old female patient with no history of psychosis nor on comedications received mefloquine 250mg/week (exact dates unknown) which was discontinued prior to her leaving for abroad. Some days later she became very confused, and manifested psychotic features, and was hospitalized. She initially recovered within a few days, but psychosis and confusion recurred approximately 5 months later, and she was re-hospitalized, and recovered subsequently. Neurologic examinations were carried out which did not reveal dementia. This report is also included in Group I malaria prophylaxis: psychiatric events: SAE psychotic features, classified as 2D (Appendix 1).

(2D): A 40-year-old male patient was taking lx250mg mefloquine/week for malaria prophylaxis. He had no relevant medical history nor was he taking any comedication. A few days after discontinuation of mefloquine he experienced dizziness, some days later, multidirectional nystagmus was observed, a brain MRI was normal. He then experienced headache, balance difficulties and memory disturbances. When his condition deteriorated he was hospitalized. Brainstem evoked responses were normal as was a spinal fluid exam. Nystagmus resolved after about 6 weeks. Except for headache and dizziness the patient had recovered approximately a further 3 months later.

(3D):              (3D): A 23-year-old male patient with no relevant history and no comedications was taking lx250mg mefloquine/week for malaria prophylaxis. He experienced amnesia, but only after discontinuation of mefloquine he consulted his general practitioner about this problem. ACT scan, 24hr blood pressure monitoring, and blood tests (NOS) were all normal. Some months later he was treated with Ubidecarone which remained ongoing, and he slowly recovered. This report is also included in Group I malaria prophylaxis: psychiatric system disorder events: SAE amnesia, classified as 3D.

Comment: While all nervous system disorder events are listed in the CDS, it is also specifically mentioned:" Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist up to several weeks after discontinuation of the drug. In a small number of patients it has been reported that dizziness or vertigo and loss of balance may continue for months after discontinuation of the drug.

2) Indication: Malaria Treatment (N = 3; D=0)

3) Indication: unknown ( N = 0 )

Group I I

1)    Indication: Malaria prophylaxis (N=225; D=4) two of the cases are already included in Group II malaria prophylaxis: psychiatric events)…

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Four patients from category 2 are presented below as they had no explanation other than mefloquine for the occurrence of the relevant event....

Result of case review: Category A: insuff/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Duration 1: SAE< 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown

(2D): A 24-year-old female patient with a BMI of 18.5 with no relevant medical history nor on comedications took lx250mg mefloquine/week for malaria prophylaxis for a few weeks when she experienced severe panic attacks, dizziness and vertigo, headache, depression, and anxiety. Mefloquine was discontinued, and she was treated with psychotherapy, naproxen, sumatriptan, which gave no relief. The patient had been hospitalized for the SAEs, and citalopram and alprazolam was given. Complete

blood count and liver function tests were all normal. The mefloquine drug level was 0.31 mg/ml. A MRI brain scan was normal. The treatment with alprazolam was maintained, and other unspecified treatment given. Six months later the SAEs were persisting. This report is also included in Group II malaria prophylaxis: psychiatric system disorder events: SAEs panic attacks, anxiety, and depression, classified as 2D (Appendix 3).

(2D): A 42-year-old female patient with no relevant medical history and not taking comedications received mefloquine lx250mg/week for malaria prophylaxis. She took in total two doses and presented with disabling difficulty writing, optic neuritis, blurred vision, a panic reaction, anxiety, nightmares, delusion, memory loss, neurologic symptoms, irrational thinking, depression, demyelination disorder, hemiparesis, dizziness, memory dysfunction, hair loss, nausea, diarrhea, bloating and abdominal cramps. After repatriation she took a third dose of mefloquine, and her condition deteriorated. Brain MRI was normal, and she was treated with cortical steroids, but contracted Herpes zoster in the right C3-C4 thereafter. Her symptoms improved with gabapentin as well as many other medications. At last follow-up her neurological symptoms gradually improved, but dizziness, memory loss and nightmares were persisting. The cause of her symptoms were unclear several theories from mefloquine toxicity to demyelination disorder were discussed. This report is also included in Group II malaria prophylaxis: psychiatric system disorder events: SAE nightmare, classified as 2D (Appendix 3).

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(2D): A male patient in his mid twenties with no relevant medical history presented with a panic disorder during the use of lx250mg/week mefloquine for malaria prophylaxis. Within 24 hours of taking the first dose he experienced weakness, gait disturbance, vertigo, fever, confusion, aggressiveness, lethargy, sweating and loss of appetite. One week later he also had severe anxiety with feeling of suffocation and insomnia which worsened progressively. He was hospitalized, all neurological and laboratory tests were normal. He was diagnosed with a panic state and received diazepam. He was repatriated. At that time, his mefloquine level in serum was 200ng%. He was treated with clonazepam and fluoxetine. The events were persisting 9 weeks later, at last follow-up. This report is also included in Group II malaria prophylaxis: psychiatric

system disorder events: SAE confusion, aggressiveness, panic state, classified as 2D (Appendix 3).

(2D): A 57-year-old male patient with a BMI of 27.7 and no relevant medical history took lx250mg mefloquine /week for malaria prophylaxis. Approximately six weeks later he had hypesthesia of the tight. Mefloquine was discontinued 5 weeks

later as planned. Three months later, hypesthesia worsened and extended to the left knee causing slight paresis of the leg. Left-sided mononeuropathy (pt peripheral neuropathy) was diagnosed subsequent to various investigations, and treatment of cytidylic acid/hydroxycobalamin was started. Further six weeks later the symptoms persisted.

Comments: All relevant nervous system disorder SAEs presented above are listed in the CDS, and because of the long half-life it is also mentioned that adverse reactions to mefloquine may occur or persist up to several weeks after discontinuation of the drug.

2)   Indication: Malaria treatment N=21; D=0

3)    Indication: unknown N=21; D=l

(2D): A 37-years-old female patient with no relevant medical history, no comedication took mefloquine for approximately 2 months, after six weeks upon her return home she experienced a static cerebellar ataxic syndrome and was hospitalized. A lumbar puncture , EMG and an MRI of the brain and spinal cord were normal. No inflammatory syndrome was noted. Two weeks after onset of the events, mefloquine treatment was discontinued. A gradual favourable outcome was reported. The events of ataxia and cerebellar syndrome improved. Consultation six months after onset of the events revealed the patient still had a mild ataxic syndrome of the lower extremeties.

Group III

1)    Indication: Malaria Prophylaxis (N=16; D=0)

In addition none of the remaining patients in Group III: malaria prophylaxis qualified for detailed discussion as they failed the review criteria to focus on....

2)   Indication: Malaria Treatment (N=l; D=0)

3)    Indication: unknown (N=4; D=0)

MAH - Discussion and Conclusion of Drug Safety report 104001

The review of the safety data from Roche's Global Safety Database ADVENT yielded a total of 369 patients reporting 623 medically confirmed psychiatric disorders SAEs, and 309 patients with 436 medically confirmed nervous system disorders SAEs which were selected as described in section 5.2.1 search and selection strategy. These reports are

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included in a tabular format in Appendices 1 - 15, according to the reported indication and the selection strategy criteria. All cases have been commented on individually.

According to the search and selection strategy the relevant SAEs, all of them were supposedly having a duration of > = 90 days. In a first step the case reports were then manually reviewed to verify the actual SAE duration, as reported in the narrative and in all report updates. This led to a significant reduction of the number of the reports as is shown in the overall tables presented below. Of all reports included in the psychiatric system disorder group 73 reports had a SAE duration of less than 90 days, as did 70 reports in the nervous system disorder group. In a second step reports with insufficient information were excluded (190/146) as were reports with relevant medical histories, confounding factors, and/or alternative explanations (82/75), with mefloquine overdoses (2/1) and with pre-existing events (3/13). Thus the focus of this report was directed at patients without a relevant medical history (reported as such), not receiving comedications which might impact on SAE duration, receiving appropriate doses of mefloquine according to the indication, and displaying a SAE duration of >= 90 days, which left 17 patients with psychiatric system disorder SAEs, and 8 patients with nervous system disorder SAEs, respectively which had a duration of more than 90 days. By this method 25 cases were identified which were described in detail, and of which some patients presented with both, psychiatric and nervous system disorder SAEs. It may be important to mention that a total of 1073 patients with 1977 psychiatric system disorder adverse events, and a total of 1022 patients with 1699 nervous system disorder adverse associated with the use of mefloquine are stored in the Roche Global Drug Safety database ADVENT and that only 25 of these reports include SAEs with a duration of

more than 90 days in patients who used mefloquine as prescribed, had no relevant medical history or alternative explanations, and were not taking comedications; and only four of these 25 cases presented with a duration of more than one year.

It must be borne in mind that this analysis is mainly based on spontaneous reports (673), whereas only 5 reports originated from studies. Thus, even with fairly detailed

information received on the individual patients, factors such as social environment, personal circumstances, wrongly reported medical history, omitted comedications cannot be excluded. In addition the reporter who provided the case reports to the MAH may not always have been the physician treating the patient in the first place. This is also evidenced by the fact that only one report of a nervous system disorder SAE has been obtained from a country with potential malaria infections, and this report originated from a clinical trial. Some of the reports were also submitted by the reporter months if not years after the relevant SAEs occurred, thus some relevant case details may have been missed. The events were reported after the return from a trip and therefore retrospectively.

Nevertheless it may be concluded from this review that the observed relevant psychiatric and nervous system disorder SAEs of group D (no alternative explanation) patients are listed in the CDS, and as also specified in the CDS that they may persist for a prolonged period of time after discontinuation of mefloquine. In some of the cases it remains unclear whether other unreported factors contributed to the recurrence or persistence of the events.

Patients with a history of depression, psychosis or other major psychiatric disorders seem to be at particular risk of developing psychiatric AEs.

MAH - CONCLUSION:

Based on the review of reports from Roche Global Drug Safety Database ADVENT MAH decided to update the CDS and upgrade the information about the occurrence of neuropsychiatric disorders into the Warnings/Precautions section of CDS. As a further risk mitigation, the contraindication section will be updated not to allow mefloquine prophylaxis in patients with a history of depression and the other major psychiatric

disorders.

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Drug Safety Report 105825507

(06 May 2010 until 27 October 2013)

A) SOC Psychiatric Disorder

Group I (N=0)

Group I I

1) Indication: Malaria Chemoprophylaxis (N=14; 0 = 3 )

Of the 14 cases, three cases (AERs ) were substantive

follow-up reports of cases included in DSR 1040001. None of the follow-up reports

included new events fulfilling the inclusion criteria of the current analysis (see

Section 4.1.2). Relevant new information was received in a follow-up report of AER

which reported a negative psychiatric history, temporal relationship of event onset with

mefloquine therapy, and a long-lasting disability (after 3 years the patient was not able to

work full-time). Accordingly this case has been reclassified from category B to D.

Of the 11 initial cases, five cases provided information that allowed further evaluation of

the event duration. In three of these cases (AERs no

risk/contributory factors were identified (category D). One case included insufficient

information for a causality assessment (category A), but concluded that sleep disorder

was persisting (AER ) . In one case (AER ) the patient had a history of

major psychiatric disorders, but the persistence of the event was medically confirmed.

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The narratives of these cases are presented below. The remaining cases (AERs ,

and, , ,) did not provide sufficient information for

the assessment of the event duration.

Result of case review: Category A: insufficient/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Category for SAE duration - 1: SAE< 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown or *n/a [not applicable (for suicide cases where onset date is the date of suicide)]

: Major Depression

This spontaneous case concerns a 60-year-old female patient who received mefloquine (250 mg/week) for malaria chemoprophylaxis. She had no psychiatric medical history. Past treatment included doxycycline. No concomitant drugs were reported. She experienced insomnia and low mood about three weeks after start of mefloquine, and depression approximately three months after mefloquine discontinuation. Approximately a month thereafter, she experienced deterioration to psychotic depression, anxiety and

was hospitalized due to agitation and paranoia. She was treated with risperidone, mirtazapine, and lorazepam. About four years after onset of the event, it was reported that the patient had not been the same since use of mefloquine. However, in the followup

information received in psychotic depression had improved, suggesting

an SAE duration of more than three years.

Psychotic disorder, Self injurious behavior

This spontaneous case (reported by a health authority) concerns a 20-year-old male

patient who received mefloquine (250 mg/week) for malaria chemoprophylaxis (started

on an unspecified date in                   ) . He had a medical history of childhood

asthma, and high blood pressure. No concomitant or past drugs were reported. An

unspecified time after starting mefloquine, he experienced vivid dreams and anxiety.

Reportedly, he was on mefloquine for nine months and experienced events during

respectively four weeks after therapy. A small amount of alcohol caused significant

effects with regard to hallucination and disorientation. An unspecified time thereafter, he

was hospitalized for dehydration and had two episodes of self-harm (PT-self injurious

behavior). An unspecified time thereafter, mefloquine was discontinued for an

unspecified reason. Approximately a month after mefloquine discontinuation, he

experienced psychotic behavior. He was treated with escitalopram and zolpidem. At the

time of reporting (                    ) , the events of psychotic disorder, self injurious behavior,

: Delirium, Agitation, Aggression, Suicide attempt

This spontaneous case (reported by a health authority) concerns a 45-year-old male

patient who received mefloquine for malaria chemoprophylaxis. He had medical history

of mesancephalic cerebrovascular accident (CVA) and parinaud syndrome (diagnosedof mesencephalic cerebrovascular accident (CVA) and parinaud syndrome (diagnosed

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five years before mefloquine use). Concomitant medications included aspirin dl-lysine

and simvastatin. He was hospitalized due to acute delirious episode (PT-delirium),

agitation, aggressiveness (PT-aggression) and suicidal attempt approximately ten weeks

after starting mefloquine on a business trip to                     . The patient did not have any past

psychiatric history and did not take any anti-psychotic, antidepressant or any other CNS

drug. The events resolved with sequelae about one month after onset. Sequelae were

not specified. Follow-up information about one year later did not provide new information

on the outcome.

MAH comment: Most of the relevant psychiatric disorder SAEs reported in the cases

assigned to category D are known to occur with mefloquine and are listed in the current

Lariam CDS V. 4.0 [2]. Self-injurious behavior and suicide attempt are not listed but for

these events the provided information is limited and the duration is questionable ("two

episodes", "an attempt to jump out of the window"). Of note is the positive CVA of the

patient in case AER                       . This case is also included in Section 6.2.1.2.2.1 (Nervous

system disorders is the primary SOC for agitation). Based on the calculation applied to this

group events or sequelae of events persisted from about one to >3 years and in one case

long-lasting impairment of the patient is confirmed by the reporter.

2) Indication: Malaria Treatment (N=1; D = 1 )

One case (AER                     was identified in this group. This patient experienced

depression, which was resolving 92 days after event onset. No alternative explanations

for the occurrence of the relevant psychiatric disorder were identified (category D 2).

This case is briefly reviewed below.

                          : Depression

This spontaneous case concerns a 38-year-old female patient who experienced

depression seven weeks after starting and a week after the most recent dose of

mefloquine (250 mg/week). Mefloquine was discontinued and she was treated with

citalopram. The event of depression was resolving at the time of reporting. The patient

did not have a history of psychiatric treatment, alcohol/substance abuse, suicidal

ideation or suicide attempts and family history of suicide, or any recent losses, emotional

upsets or legal trouble.

MAH comment: Given the reported dose, the indication is suggestive of

chemoprophylaxis, rather than treatment. However, depression is a listed event in the

current Lariam CDS V. 4.0 [2]. In this case the patient was on mefloquine for about

seven weeks and for the event duration of about three months (after discontinuation),

the long half-life of mefloquine should be considered.

3) Indication: Unknown (N=1; D=1)

One case (AER              ) was identified in this group. This patient experienced an SAE

duration of about five months4and no alternative explanations for the occurrence of

anxiety and panic disorder were identified (category D 2). This case is briefly discussed

below.

Anxiety, Panic disorder, Dizziness, hypoaesthesia

This spontaneous case concerns a 20-year-old male patient who received mefloquinefor an unknown indication. Approximately two weeks after the first dose, he received a second dose of mefloquine (reported as  ) and visited            on             .Approximately two weeks thereafter (end of                   the experienced anxiety along with nervous system disorder AEs (dizziness and episodic feeling of numbness). Mefloquine was discontinued on             and doxycycline was started. An unspecified time after mefloquine discontinuation, he             

Updated PRAC rapporteur assessment report on the signal of permanent neurologic

(vestibular) disorders with mefloquine

EMA/63963/2014

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experienced episodic panic disorder-type symptoms (PT-panic disorder). Reportedly, the events started upon traveling to India while he was on mefloquine and were triggered by enclosed spaces, and also after returning home by other exciting occasions. He had not experienced similar symptoms or any psychiatric symptoms in the past.

MAH comment: Given the frequency of mefloquine use and patient's traveling, the indication is suggestive of chemoprophylaxis. However, anxiety and panic attacks are listed events in the current Lariam CDS V. 4.0 [2]. The information provided points to a duration of more than four months; however, medical confirmation is limited to a few symptoms. This case has also been discussed in Section 6.2.1.2.2.3.

Group III

1)      Indication: Malaria Chemoprophylaxis (N=9: D = 1 )

Of the nine cases, two cases provide information that allowed further evaluation of the

event duration. In one of the nine cases (AER               the patient experienced

depression and suicidal ideation with a calculated duration of around 3.5 months and no

alternative explanations were identified for the events (category D). In one case (AER        

the duration of psychiatric therapy suggested a long duration of events;

however, this case had insufficient information for causality assessment (category A).

The narratives of these cases are presented below.

The remaining cases AERs                  (a follow-up report),                ,                ,

did not provide sufficient information for an assessment of the event duration.

'

Result of case review: Category A: insufficient/controversial data, B: alternative explanation, C: SAE occurred > 6 months after mefloquine discontinuation, D: no alternative explanation, E: out of scope of the review, F: overdose. Event persistence: Category for SAE duration- 1: SAE < 90 d, 2: SAE 90 d to 1 yr, 3: SAE 1 yr to 2 yrs, 4: SAE 2 to 3 yrs, 5: SAE > 3 yrs, 6: SAE duration unknown

Suicidal ideation, Depression

This spontaneous case (reported by a health authority) concerns a 37-year-old female patient who received mefloquine for malaria chemoprophylaxis for an unknown duration. No concomitant or past drugs were reported. She did not have a medical history of any psychiatric disorder. Approximately five weeks after starting mefloquine, she developed depression and suicidal ideation (reported as "she wanted to throw herself in front of the metro") while on mefloquine. An unspecified time thereafter, mefloquine was discontinued and at the time of reporting (about three months after onset), the events resolved.