Veterans Affairs Committee on Oct. 25th, 2016

[The Chair, Liberal, Neil Ellis]

Go ahead, Dr. Ritchie.

[Dr. Elspeth Ritchie]

The medication that you're referring to, Chantix, has been associated with a lot of neuropsychiatric side effects; another one, Zyban, or Wellbutrin, much less so. I don't prescribe Chantix to my psychiatric patients because they're coming to me because they have suicidal thoughts and ideation.

Going back to your other question, are there other medications that have this many side effects, if you look at the medications that are the top 10 in side effects, and neuropsychiatric side effects, just about all of them are psychotropic drugs, they are antipsychotic medications or antidepressant medications or medications for bipolar disorder or seizures, which are often the same. So mefloquine is up there. I think if we had any other medication that caused this many side effects, it would have been pulled from the market a long time ago.

One historical piece that we did not mention is that mefloquine, which was developed by the Army and Hoffmann-Laroche, did not have post-marketing surveillance, by that I mean after it was put on the market nobody was gathering the side effects, unlike other medications that were done in a more conventional way. That is part of the problem here, and Dr. Nevin can elaborate on that.

One other piece I wanted to mention that I think is very important is we've briefly said this drug causes toxicity in the brain stem and in the limbic system. We see that when we look at rats and chop off their heads and look at their slices. They have vacuoles, places where the mefloquine has poisoned the brain stem, and the brain stem is what causes your balance. The problem with it is the dizziness, the nystagmus. Dr. Nevin mentioned the limbic system. The limbic system is where our emotions are, that lead to the amygdala, which is affected by post-traumatic stress disorder. The hypothesis—again, not proven—is that these changes to the limbic system are what leads to this intense aggressiveness and anger, and that's what I think makes this medication so dangerous.

Why do some people react to it and some not? It could be genetics. A theory of mine is that in Somalia it was very hard to get hydrated, to get enough water. That was a very primitive environment. I remember the truckloads of water that we'd all be scrounging for. It was hot and people didn't drink enough. I think the damage to the veterans in Somalia was greater than, say, to those in Iraq or Afghanistan, where there was a mature theatre and people got more water. Again, that's a hypothesis. Another piece is that some people have changes in the blood-brain barrier. They metabolize agents more. It is clear that while some people are severely affected, others are not affected at all, and that's led to some of the questions of, this is just an hysterical reaction on the part of the journalist, because I took mefloquine and I was okay. I did take mefloquine and I was okay, but I was also in a medical unit, so could get water. I'd be curious about Claude's experience, whether he was able to stay hydrated. Similarly with the Canadian Airborne Regiment, I believe they were in primitive conditions.

Finally, what I often see with mefloquine is it's the straw that breaks the camel's back. You're in nasty, difficult circumstances, you are irritable, the food sucks, the water sucks, there's not a place that you can go, excuse my language, and take a dump so you're irritated about that, your wife is going to leave you. But then you have this pill on top of that that just revs up your rage, and you hear it over and over again, and you have these crazy bad dreams, these vivid dreams, nightmares, and you just snap.

[The Chair, Liberal, Neil Ellis]

Thank you.

Mr. Rioux.

[Jean Rioux, Liberal, Saint-Jean, QC]

Thank you, Mr. Chair.

I want to thank the witnesses for participating in this committee meeting.

Apparently mefloquine, marketed by the F. Hoffmann-La Roche AG pharmaceutical company under the name Lariam, stopped being available in Canada in 2013. However, the generic drug is still available.

First, can you explain why the brand name drug was withdrawn and not the generic drug?

Second, were comparative studies of mefloquine carried out with civilians?

I'll leave the question open. I think Mr. Nevin has some answers.

[Dr. Remington Nevin]

Yes, thank you.

I can address that question, as it relates to Canada as well as to some other jurisdictions. To my knowledge, Roche stopped manufacturing, or distributing, or marketing its brand, Lariam, some time in the past few years. It was this decade, anyway. This is coincident with a trend of Lariam being discontinued in a number of other markets. Roche discontinued the sale of Lariam in the United States, I believe, in 2009. It recently discontinued the sale of the drug in Ireland and in a number of other European countries.

It is decidedly unusual for a drug company to discontinue the sale of a drug that has such good name recognition. The marketing value of the brand name typically means that the drug will remain profitable, even up against possibly lower-priced generics. There's widespread speculation that the decision by Roche to cease the marketing of Lariam in the United States, Canada, and other jurisdictions was arrived at for legal reasons, for concerns of legal exposure due to a potential for lawsuits related to the drug's use.

The company claims that it was a commercial decision based on declining sales. That's certainly the case. In the United States, generic mefloquine remains available—and it is available for sale independently of concerns about legal liability. By a Supreme Court decision, generic drug manufacturers in the United States cannot be sued for deficits in the product labelling or for a failure to warn. I don't know enough about the legal systems in other jurisdictions, including Canada, to know if similar motivation informs the continued sale of mefloquine here.

I hope that addresses your question.

[Jean Rioux, Liberal, Saint-Jean, QC]

Yes.

Were there similar cases in the civilian world? We know that civilians experienced adverse effects after taking mefloquine.

[Dr. Remington Nevin]

Yes, I can address the question of whether civilians have also been affected by mefloquine. I should point out that I believe this issue attracts a lot of attention. The issue of adverse health effects among veterans attracts the most attention because this is a large group of persons, a large population that is given the drug at one time, and so perhaps problems with the drug will be more apparent within groups of military veterans. For example, in the United States we have been using mefloquine for quite some time on our Peace Corps volunteers, who are civilians. This is increasingly an area of concern and controversy. It's the subject of significant media attention at the moment in the United States. Of course, we would expect civilians to be as susceptible as military personnel to these adverse effects.

One thing I will say—and I think it's important to understanding why our veterans may have been more affected than other persons—is to keep in mind the product insert. The manufacturer's directions explicitly state that you must discontinue the drug at the onset of certain symptoms: anxiety, depression, restlessness, or confusion. This has been the advice given to Canadians, I believe, since the drug was first marketed. Today that advice is even more strict: if you experience any psychiatric symptom, you must immediately discontinue the drug. This is recommended in order to avoid these more serious effects.

Travellers on vacation would certainly abide by that advice if it were given to them, but soldiers often don't have that luxury. Soldiers may have been experiencing all of those symptoms and more, and may have been told to continue taking the drug. That is why I think we've seen many more serious side effects in military populations than among civilian travellers, because they were in essence ordered to take the drug, contrary to the product insert guidance.

I hope that addresses the question. Civilians may simply stop taking the drug, but military personnel are in many cases ordered to, and that increases the risk of these more serious effects.

[Dr. Elspeth Ritchie]

If I may briefly add to that, another population that has taken the medication is journalists, because they have often gone and followed the military. We don't have a good study there, but many journalists I talked to said they took it the first time but would never take it again. They didn't have to take it, or they went to a travel medicine clinic that told them to stay away from it, or they could afford the more expensive Malarone.

One challenge is that if you're at a small pharmacy, for example at Fort Polk, and you have 1,200 soldiers who are deploying, and you have a choice between Malarone, which costs $3 a pill, and mefloquine, which costs 30¢ or so for a week, and you're giving six months' supply to those 1,200 soldiers, choosing Malarone would add a significant cost to your budget.

[The Chair, Liberal, Neil Ellis]

Thank you.

Mr. Brassard.

[John Brassard, Conservative, Barrie—Innisfil, ON]

Thank you, Mr. Chair.

I do have a specific question for all three of you, but I want to pick up on something that Dr. Nevin just said, and it's to you, Dr. Passey. We all know that the job of a soldier is to follow orders, and if the orders are to take this pill, they would follow that order. What were the consequences to the soldiers, in your experience, who didn't take the pill as ordered?

[Dr. Donald Passey]

We follow orders, you know? The mission comes before life and limb. It's very simple. That's what we're trained to do. In a deployment, the idea of not following orders is basically unthinkable and chargeable.

I believe there was—and I don't remember this gentleman's name—a military member who refused to have his vaccination before deploying, and he was court-martialled. I don't know the outcome of that. But if you're in a combat zone, it's not optional.

[John Brassard, Conservative, Barrie—Innisfil, ON]

So these soldiers had no choice?

[Dr. Donald Passey]

As far as I'm aware, no.

Particularly, a lot of the units—you have to realize—get down to platoon size, etc. You may not necessarily have any medical staff there at all, or the medics may not necessarily be aware of all the potential consequences of this type of medication. As I mentioned, I was a senior medical officer when I was deployed to Rwanda, and I didn't know. They told us about the dreams, that was it. We had no other information. Take the pill. Friday, take your pill.

[John Brassard, Conservative, Barrie—Innisfil, ON]

It has been a fascinating discussion today.

I'm going to ask all three of you to weigh in on this. I know we don't have much time, but in terms of recommending to the Canadian government or Veterans Affairs how to deal with this, Dr. Nevin, what would be your suggestion? I know, Dr. Ritchie, you touched on this briefly.

I would also ask this as well. We're dealing with this as the veterans affairs committee. Is this the kind of issue, for example, that Health Canada should be looking into, given the fact that there are some civilians who are still dealing with this? And, of course, there's the impact that it has had on the military.

I'll open it up to any one of the three of you.

[Dr. Remington Nevin]

I will address that question, Mr. Chair.

I recently published an analysis of drug safety labelling in six countries, including Canada, the United States, some European nations, New Zealand, and Australia. What's very clear from that analysis is that, of these developed western nations, the drug label for mefloquine here in Canada is far behind. It's quite out of date. I do believe, as we discussed in the manuscript, that Canadian travellers are being put at some risk for not receiving the same up-to-date directions that travellers from other countries received.

I don't know the reasons for the delay in updating the Canadian mefloquine drug label to reflect our new knowledge of the permanent effects of these drugs and also to reflect the stronger guidance that the drug be immediately discontinued at the onset of any neuropsychiatric symptom. Most drug regulators will reluctantly concede that most drug labels are actually out of date, but I think that our experience with mefloquine should reinforce the need to pay close attention to the accuracy and completeness of the information on that label.

The fact that the Canadian mefloquine drug label is somewhat out of date might explain the Department of National Defence's continued use or support of the drug. Perhaps if the drug label was updated to reflect our current understanding, Canadian policies for use of the drug would begin to reflect those of other western nations. I would certainly recommend that Health Canada examine—independently, of course—the evidence base.

[The Chair, Liberal, Neil Ellis]

Dr. Ritchie.

[Dr. Elspeth Ritchie]

This is my recommendation; stop mefloquine use completely. I disagree with Dr. Nevin. I don't think it should be used as a drug of last resort. I don't think it should be used at all. If somebody can't tolerate mefloquine, don't send them to a malarious area, send them to Antarctica. You have lots of cold weather up in Canada, I hear, where there are no bugs. Don't send them to that area.

Secondly, screen for mefloquine exposure. This should be done by civilians. You don't have the same Veterans Health Administration as we do in the U.S., so a lot of civilians are treating veterans. This should be part of a national discussion. Again, it's easy to do once a week versus once a day.

And then finally, the treatment part is harder, but we do need to get there. Just briefly to touch on the question of female service members' pregnancy and mefloquine, we probably need to do a better job of ensuring that female service members are on long-acting contraception before they deploy—for all kinds of reasons—because we don't know the effect of mefloquine on the developing fetus. Even if sex is banned in a combat zone, it happens, whether consensual or non-consensual, so we need to make sure that people are not pregnant on mefloquine.

[John Brassard, Conservative, Barrie—Innisfil, ON]

I've been doing VA claims now for 23 years, and you ask a very good question. An individual's been deployed, they're on mefloquine, and if they develop symptoms during the use of the mefloquine, then you can at least have some sort of a trail. The difficulty is, what happens if the individual is not necessarily even aware of that or doesn't pay attention? They suck it up, with the macho sort of attitude and stuff, and then 20 years later, they come in and say, “I was on mefloquine, and I have all these symptoms.” Do they have a valid claim?

[Dr. Donald Passey]

That is a tough question, and that is something that needs to be very carefully considered by Veterans Affairs. Generally speaking, with our medical records within the Canadian military, if you're on medication, we should have a record of that, but records get lost.

[The Chair, Liberal, Neil Ellis]

Mr. Fraser.

[Colin Fraser, Liberal, West Nova, NS]

Thank you very much, Mr. Chair. Thank you to each of you for being here and for giving us some very interesting information.

I want to start with you, Dr. Nevin. With regard to just picking up on one of my friend's last questions, you had indicated that you would be okay with using this drug if it was a drug of last resort and you couldn't use the other malarials. Can you explain why? It's a little different from what Dr. Ritchie said. I'm curious to know. I assume it's because if you have no other option because of side effects of other drugs or for whatever reason, then it's better than being exposed to malaria. What would be your comment on that?

[Dr. Remington Nevin]

My position on this has developed somewhat over the years, and it's a complex and nuanced issue that also acknowledges the complex politics of this issue.

In the U.K., very recently, after our testimony and after a thorough parliamentary investigation, the Ministry of Defence essentially adopted a policy that mefloquine would be the drug of last resort. They didn't seemingly want to acknowledge it as such, but the policy is very clear. Mefloquine is to be used only when a soldier cannot tolerate any of the other safer and equally effective drugs.

If it takes allowing MOD to declare it a drug of last resort for the public health threat to be mostly mitigated, then that's fine. Perfect is the enemy of the good. I would prefer not to see any mefloquine used in military settings, because I believe it's virtually impossible for service members to abide by the product insert directions. How is it possible for a prescriber to counsel a patient who's going to a combat zone where they're going to be experiencing insomnia, where they're going to be experiencing anxiety, and where they may be experiencing nightmares as a result of what they're facing? How can a prescriber tell such a patient, “Here's a drug and to use it safely in accordance with the manufacturer's directions, you must discontinue it if you develop nightmares, insomnia, anxiety”? It would be malpractice for any civilian doctor to do that. I don't believe it's possible for us to use it safely in military settings.

That being said, I will concede there are some people who have good experiences with this drug and who have used it many times previously, For them, if they want to continue using it, I suppose that's okay, but for new soldiers who have no experience with the drug, I think it's a risk that's too great. I do believe that we will eventually be unanimous in our agreement that the drug has no place, but until then, I'm interested in reducing the use.

[Colin Fraser, Liberal, West Nova, NS]

Do you have a comment on how many people would not be able to take the other types of drugs?

[Dr. Remington Nevin]

Yes. We discussed this in a number of papers. There are two safer daily alternative drugs in most areas of the world where there's chloroquine resistance, and one is Malarone, which is extremely well tolerated, and true contraindications or intolerance to Malarone are exceedingly rare, with maybe 1%. For the 1% who can't tolerate Malarone, there's doxycycline. The use of doxycycline is maybe discontinued by 20% or more. Far fewer than 1% of people would need to take mefloquine through strict adherence to a policy of use as a drug of last resort.

I don't think it's plausible to imagine a scenario where large groups of soldiers would not be able to deploy were such a policy enacted, and the potential benefits of doing so could be profound.

[Colin Fraser, Liberal, West Nova, NS]

Are any of you aware of any lawsuits? Dr. Nevin, you touched on it, but are any of you aware of any lawsuits in any jurisdiction where this drug has been tested in civil court to determine whether or not liability was found in order to make a claim on this?