By Robin Jay, BHC Editorial Director

More than 4 million children in the United States – or nearly 8 percent – have Attention Deficit Hyperactivity Disorder (ADHD), making it one of the most common psychiatric disorders among our youth. Traditionally, ADHD has been treated with amphetamine or methylphenidate-based stimulants; however, about 30 percent of these children are non-responsive to this sort of treatment – or they find side effects, such as inability to sleep, make the therapy difficult to manage. A solution may be at hand.

The Food and Drug Administration recently approved once-daily Intuniv (extended release guanfacine) by Shire, for the treatment of ADHD in children age 6 to 17. The medication is the first non-scheduled alpha-2A receptor antagonist indicated for ADHD that has demonstrated improvement with disruptive symptoms, such as inattention, arguing with adults, hyperactivity, impulsivity and anger. Intuniv has been approved as a mono-therapy for some time. Guanfacine has been on the market for about 40 years as a treatment for high blood pressure. Physicians have found over the past two decades that prescribing guanfacine, along with stimulant therapies, provided a significant improvement in some children. The study released by Shire was essentially the initial trial to prove the safety of this off-label strategy.

“Typically what had been done was it was being given because it does have some calming properties and can help with sleep,” said Andrew Cutler, MD, the lead investigator in this study. “It was being given as an adjunct to help with sleep because sleep can be a problem with kids with ADHD. The stimulants can interfere with sleep. It was also given to boost to augment the efficacy for ADHD. So it was felt that it would be a good idea to do a pilot study just to look at doing this combination, and because it’s sort of a pilot study, the most important thing first of all is to make sure that it’s safe to be used in combination.”

According to Dr. Cutler, one of the challenges with kids with ADHD is that two times of the day that are especially difficult – the morning and the evening. The morning is when they’re trying to get up and get ready for school and get out of the house – and the stimulant hasn’t kicked in yet. The second time that’s tough is in the evening when children are trying to wind down, get homework done, get ready for bed. At this point, the stimulant is wearing off because, otherwise, the child may never fall asleep. Augmenting stimulant therapy with Intuniv helps control symptoms of ADHD at times the stimulants are not.

“Most of the medicines that are FDA approved right now are stimulants in two different families,” explained Dr. Cutler. “There’s the methylphenidate family, which includes Ritalin and Concerta, and there’s the amphetamine family, which includes Adderall and Vyvanse. And what the stimulants all have in common is they are all increasing the amount of norepinephrine and dopamine in the brain. They are also are stimulating the parts of the body, parts of the nervous system, so you can get an increase in heart rate and blood pressure. The funny thing is that there’s this paradox that we take kids that tend to be hyperactive and we’re giving them a stimulant and it actually calms them down and for a long time. That was a little bit of a puzzle. Why you would give them a stimulant and they would calm down? And now we realize what you’re doing is you’re fixing the circuitry in the brain and you’re actually enhancing a function of a part of the brain called the prefrontal cortex.

“The PFC is the part of the brain that kind of is like the executive center; it modulates and regulates other parts of the brain. What happens with ADHD is, we think, that part of the brain is not doing it’s job. So what happens is other parts of the brain then become deregulated and you can get hyper activity, you can get inattention, your attention is not regulated properly, not sustained properly. And what the stimulant seems to do is improve the chemicals in the front part of the brain and enhance what the PFC does. They do it by an indirect method, they’re blocking re-uptake of norepinephrine and dopamine. Now the concept of re-uptake blockade may be familiar to a lot of doctors because that’s how a lot of our antidepressants work. For instance, SSRIs like Prozac or Paxil, are blocking re-uptake of serotonin. They are selective serotonin re-uptake inhibitors. So you’re increasing the amount of serotonin. Well, these drugs block the uptake of norepinephrine and dopamine and that effect is to increase the amount of those chemicals.

“Intuniv works by a different mechanism, but the concept is still to enhance the prefrontal cortex or the regulation of the brain. It’s binding to a norepinephrine receptor in the brain. This is a direct mechanism. It literally binds to that receptor and turns it on, and that seems to strengthen the function of the prefrontal cortex and enhance it’s control over the executive function of that part of the brain. That’s important because ADHD is a very complex disorder that probably has different subtypes with different parts of the brain being effected that all commonly kind of end up with the same clinical syndrome.”

Dr. Cutler emphasize that right now, Intuniv is only FDA approved as being used by itself as mono-therapy, but he says many doctors are already familiar with the combination strategy. “I think this was an important study to give us a little measure of confidence that at least reassure it’s a safe thing to do. And what I always say is once the drug gets on that market, that’s when the real research begins. Doctors will try these medicines by themselves and then in combination and figure out how they really work and what’s really the best way to use them in particular patients. So I’m looking forward to hearing more as I go around and speak to other doctors about their experience with this particular strategy.”

Dr. Cutler says that the success of this initial safety study conducted with 75 children with ADHD will not lead to a larger study of children. To learn more about Intuniv and this study, you can read the full transcript of the interview that follows…

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BHC: Dr. Cutler thank you for joining us today to talk about Intuniv and the study from Shire that was published recently about the benefits of the therapy for ADHD. Let’s talk about the premise behind the study and what the major findings were for providers as the most important take away messages.

Dr. Andrew Cutler: Well, this was a study that was done to address a need an a niche of how it’s anticipated this medicine might be used, but it’s important to mention first that the medicine is actually FDA approved currently for use as mono-therapy, meaning given by itself, and there were two large pivotal trials that were done. A pivotal trial is the kind of study that is done to get a drug FDA approved and so these were done with Intuniv by itself, and both of these studies were positive. And by positive, I mean Intuniv worked better than placebo to control ADHD symptoms.

So Intuniv was found to be both effective and safe by the FDA and approved for use for ADHD in people ages 6 to 17. Intuniv is an extended release version of a chemical called guanfacine and guanfacine has been available as an immediate release compound for many years. It’s probably been around for over 40 years and it was known by the brand name Tenex and it was originally used for hypertension for blood pressure. But about 20 years ago or so doctors started using it for ADHD. It was found that it helped kids with ADHD. And one of the ways that it gets used in the real world is in combination with stimulants, which are also approved to treat ADHD.

Typically what had been done was it was being given because it does have some calming properties and can help with sleep. It was being given as an adjunct to help with sleep because sleep can be a problem with kids with ADHD, and sometimes some of the stimulants can interfere with sleep. It was also given to boost, augment the efficacy for ADHD. So it was felt that it would be a good idea to do a pilot study just to look at doing this combination, and because it’s sort of a pilot study, the most important thing first of all is to make sure that it’s safe to be used in combination. So this is really more of a safety study than a true efficacy study.

This is open label. A study in which we are looking at efficacy would usually be a double blind study, meaning that both the patient and their family and the doctor and treatment team wouldn’t know which treatment they were getting. And those are usually placebo controlled trials where you might get an inactive substance or you might get the active drug. Well this one is an open label trial, so we know that everybody was getting Intuniv along with the stimulant.

Basically this was a 9 week study and, as I said, kids in this study had ADHD. They were already taking stimulants and they could have been taking an amphetamine or a methylphenidate stimulant, and those are really all the stimulants that are on the market usually fall into one of those two categories.

It was a relatively small study, 75 patients, which is not tiny, but in order to do a definitive study to prove efficacy you would do a couple hundred patients. So this is about 75 kids, it lasted 9 weeks and basically as I said they were on a stimulant already and then they were given Intuniv at a gradually escalating dose. You start at 1 mg a day and then every week go up by a milligram until you hit the upper doses 4 mg, but it could be dosed flexibly so you didn’t have to go to 4 mg. Basically it was titrated based on tolerability and efficacy.

The bottom line was the outcome was basically looking at safety and the bottom line was it was felt to be a safe combination. There were no new safety concerns raised and no surprising or unexpected side effects that you wouldn’t have already predicted knowing the profiles of either a stimulant or Intuniv. So it was a successful study from that point of view and there was no bad outcomes, nobody had any kind of serious problems. Most importantly there was nobody who had syncope or passed out or got extremely dizzy or anything like that. So because of that, that gave the company the confidence to go ahead and design a large study, and so there is a larger study that is underway looking at this combination and looking a little more at the effectiveness end of it in addition to the safety.

BHC: Dr. Cutler if I’m understanding correctly, in the information I received about the study, it indicated that up to 30 percent of children don’t respond to the most commonly prescribed medications presented by themselves by ADHD treatment. Was the industry finding that if those treatments weren’t effective that the children could be put on this combination as a way to keep them more compliant and on their treatment programs?

AC: Well that’s an interesting question. What I would say is that first of all, stimulant are extremely effective for ADHD and have some of the highest response rate, but I would say as you said, about 30 percent of kids have what we would call suboptimal response, and by that I mean that they still have some residual symptoms, or maybe the stimulant doesn’t last long enough, so certainly compliance is related to whether the drug works or not. I wouldn’t go so far as to say that adding a medicine to another would definitely enhance compliance because balancing that is the fact that the more medicines you have to take the harder it is to remember to take them and to be compliant. In the real world unfortunately, too, we have things like who’s going to pay for the medicine and remembering to go to the pharmacy and refill it and these kinds of things, but I would say that the combination is a very common thing that’s already done, combining a stimulant with another medicine especially a medicine from this class which we call the Alpha 2 A Agonist which includes guanfacine and clonidine.

Both guanfacine and clonidine are available; they were originally approved for high blood pressure and it was found a long time ago that they can also help ADHD. But it is true now if you think about stimulants are interesting, well let me back up. The problem with kids with ADHD is that two times of the day that are especially difficult are the morning and the evening because the morning is when you’re trying to get up and get ready for school, get going, get out of the house and a stimulant, if you take a stimulant it hasn’t kicked in yet, so that time is usually difficult until the stimulant kicks in which doesn’t usually happen until you’re already getting to school. And then the second time that’s tough is in the evening when you’re trying to wind down and get homework done, brush your teeth, get ready for bed and all of that and, again, the stimulant is not as active then, the stimulant wears off because if it didn’t, the kid would never go to sleep.

One of the thoughts is to augment the stimulant around those times of the day, and that’s one of the reasons that this is commonly done. What’s found with Intuniv, by itself as mono-therapy, is it’s working around the clock, so it’s already working at those times of the day, but I would say that this combination is especially rational because of that as well, that stimulants tend to work very well but even when they work very well, they still don’t work 24 hours, if you will. Intuniv is one ways of covering those times of the day and extending the efficacy of the stimulant.

BHC: I think we’ve been seeing more and more primary care providers, pediatricians caring for children with ADHD, where as in past years many children were referred directly to a specialist first. So with more and more primary care providers providing the care for ADHD, what are the indications that a child might benefit from taking both Intuniv along with the other?

AC: That’s also a really great question. First of all, what I would say again, I just have to put this out there, that Intuniv currently is FDA approved for mono-therapy, by itself so using this combination, while it’s a very rational thing to do and doctors have been adding the immediate release for years, it’s not approved, this particular preparation is not approved to be done that way. Now with that being said, doctors are free to do that, it’s called off label, we prescribe off label all the time. I would say that it’s a very rational thing to do, and we at least do now have some data here that says that it’s not a dangerous thing to do.

Now all that being said, it is something that I would certainly consider for any kid who has either a partial response as we talked about to a stimulant, meaning that they seem to get a little better, but there’s still some problems and you’ve tried different things with the stimulant like increasing the dose or maybe one of the things that’s important to do is to try one stimulant from each class. In other words, if you’re using a methylphenidate-based stimulant, such as Ritalin or Concerta, and they’re getting not the best outcome, you can switch over to an amphetamine-based stimulant like Adderall or Vyvanse. So assuming you tried some of those things and you still only have a partial response or lets say you’re dose is limited by side effects and so you can get them a little better but you can’t push the dose as high as you might like because of side effects, that’s certainly a situation where I would consider adding Intuniv.

Another situation would be that stimulants work especially well for attention and not necessarily for some of the behavioral aspects always of ADHD, and so the kid that especially has some behavioral issues or oppositional issues, emotionally over reactive, which can commonly be seen, that’s a kid where this medicine seems to work especially well. There was a study that I was eluding to earlier done of kids who have ADHD with prominent oppositional symptoms and that was a study with Intuniv as mono-therapy and it was flexible dosed and that study was very positive. So that gives us a clue maybe as to one type of kid, as well, that might be a good candidate here.

The other thing that’s really interesting just intellectually is the fact that side effect profiles of a stimulant and Intuniv tend to be kind of complementary. By that I mean with a stimulant, one of the risks would be insomnia. Well Intuniv can help with sleep, so they seem to balance each other out there. The main side effect of Intuniv if it’s given by itself is sedation. Well a stimulant fights that during the day, so you kind of get the benefit during the day, and then when the stimulant wears off, you might get some improvement in sleep at night. The other thing is there’s a lot of concern about stimulants and blood pressure and the heart because they can increase heart rate and blood pressure. Well, this is a medicine that was originally proved as an anti-hypertensive medicine, so it tends to balance that as well. It tends to lower blood pressure a little bit. So there’s really a nice balance between them; they do help each other out, they augment each other with efficacy and they tend to balance each others side effects. So again it is a very rational thing to do but that’s sort of a little bit of guidance of what kind of kid to do it in.

BHC: Dr. Cutler, for caregivers and patient parents, can you talk about how Intuniv works differently as a mono-therapy compared to a mono-therapy of methylphenidate or one of the others?

AC: Most of the medicines that are FDA approved right now are in the class we call stimulant, and the stimulants break into two different families. There’s the methylphenidate family which includes Ritalin and Concerta and some others and there’s the amphetamine family which includes Adderall and Vivant. And what the stimulants all have in common is they are all increasing the amount of norepinephrine and dopamine in the brain, and they also are stimulating the parts of the body, parts of the nervous system, so you can get an increase in heart rate and blood pressure. The funny thing is that there’s this paradox that we take kids that tend to be hyperactive and we’re giving them a stimulant and it actually calms them down and for a long time. That was a little bit of a puzzle. Why you would give them a stimulant and they would calm down? And now we realize what you’re doing is you’re fixing the circuitry in the brain and you’re actually enhancing a function of a part of the brain called the PFC, which is the prefrontal cortex, and the PFC, which is in the front part of the brain, is the part of the brain that kind of is like the executive center and it modulates and regulates other parts of the brain. What happens with ADHD is, we think, that part of the brain is not doing it’s job and so what happens is other parts of the brain then become deregulated and you can get hyper activity, you can get inattention, your attention is not regulated properly, not sustained properly and what the stimulant seems to do is improve the chemicals in the front part of the brain and enhance what the PFC does and they do it by an indirect method, they’re blocking re-uptake of norepinephrine and dopamine. Now the concept of re-uptake blockade may be familiar to a lot of doctors because that’s how a lot of our antidepressants work, for instance SSRIs like Prozac or Paxil, they’re blocking re-uptake of serotonin, they’re called SSRIs, which is selective serotonin re-uptake inhibitors. So then that effect is you’re increasing the amount of serotonin. Well these drugs block the uptake of norepinephrine and dopamine and that effect is to increase the amount of those chemicals.

Now Intuniv works by a different mechanism, but the concept is still to enhance the prefrontal cortex or the regulation of the brain. The way it works is a more direct mechanism, it’s binding to a norepinephrine receptor in the brain, so instead of just increasing norepinephrine, which then binds to the receptor that would be an indirect mechanism and that’s how stimulants work. This is a direct mechanism. It literally binds to that receptor and turns it on and that seems to strengthen the function of the prefrontal cortex and enhance it’s control over the rest of the brain and the executive function of that part of the brain. So it is a very different mechanism and that’s important because ADHD is a very complex disorder that probably has different subtypes with different parts of the brain being effected that all commonly kind of end up with the same clinical syndrome.

So for some people who may respond better to one treatment than another we need different mechanisms. So that’s it roughly. Now what’s really important for clinicians, a lot of clinicians out there may be familiar with the concept of guanfacine for ADHD, but we were taught a different way of how it worked. We were taught that guanfacine was decreasing an overactive norepinephrine part of the brain, so we thought it was calming an overactive hyperactive part of the brain, and that’s actually not what’s happening, it’s more the opposite. It’s more stimulating a part of the brain that then regulates this part of the brain, so the reason the brain is hyperactive is because it’s not being controlled or regulated, it’s not because it’s doing it on it’s own, so that’s a secondary problem. So the medicines actually much more specific then we thought it was and it’s doing something rather than a non specific just sedating or calming. It’s a very specific thing that it does and it’s not only calming, it’s also enhancing attention and executive function in the brain.

BHC: Doctor, is there anything else that you’d like to talk about Intuniv in regard to ADHD or this particular study that I haven’t asked you?

AC: Well I think we’ve talked about the study that mostly this study was done to look at the safety of doing this combination, so it certainly doesn’t prove the efficacy of doing this. However, I think a lot, and again the drug right now is only FDA approved as being used by itself as mono-therapy, but I think because a lot of doctors are familiar with doing this strategy, I think this was an important study to give us a little measure of confidence that at least it’s a safe thing to do. And what I always say is once the drug gets on that market that’s when the real research begins. Doctors will try these medicines by themselves and then in combination and figure out how they really work and what’s really the best way to use them in particular patients. So I’m looking forward to hearing more as I go around and speak to other doctors about their experience with this particular strategy.

Another question that we don’t have answered is what’s the best time of day to give Intuniv. Now Intuniv is a and again this is an extended release version of guanfacine, and guanfacine can be sedating especially if it’s given in the immediate release form which is a big bullish like release all at once, so a lot of doctors have given guanfacine in the evening because of that reason. But the Intuniv studies were actually dosed in the morning because the thought is that it does not release all the chemical at once, it’s a smooth release that builds up over the course of the day, so the thinking was that then you’d get the benefit during the day and then the sedation at night.

Sedation was the most common side effect seen however and one of the things the packet insert, the medicines actually approved for once a day dosing, so in the labeling it doesn’t specify morning or evening dosing even though the trials that got it approved were done with morning dosing. So one of the things we don;t know yet and actually there are studies underway right now looking at this question of differences between giving it in the morning and the evening and this is another way I think doctors can experiment a little and figure out what works best for their patients.

But again, if you’re giving it with a stimulant you’re going to see less sedation particularly if you dose it in the morning because the stimulant balances that out. So I think you have a little more confidence doing whatever you think works best. But I encourage doctors to try this, I think its a safe thing to do, from my experience in performing these studies and now that the medicines been on the market. I’ve been treating several kids with it both alone and in combination even though it’s off label and I’ve really been very impressed with the efficacy both in mono-therapy and especially in combination. It just seems like a really rational combination that not only do they help each others efficacy but again the side effects really balance each other out nicely.

I really do encourage doctors to get comfortable, dip their toe in the water and try this. The other thing I would say, just emphasize something I said earlier that one of the things that’s been found with this is there is a very clear dose response relationship and their does appear to be a milligram per kilogram relationship where by higher doses tend to work better. And if you can target a dose of about .1 milligrams per kilogram that seems to be a good target to shoot for. Now I’m not saying everybody has to be at that dose, but it does seem that when they looked at all the results, if you got into that range that’s where the most efficacy was seen. Lower ranges of milligrams per kilograms were effective but you especially saw a jump up in that range so that’s another little sort of guidance to help doctors in thinking about dosing it.

So again my concern is that because a lot of people are used to giving a half a milligram of guanfacine or a milligram, they may not feel confident in going as high as this, which we’re asking people to try to get up to three and four milligrams a day, and it’s important to realize that is different from regular immediate release guanfacine. In other words, I mentioned the immediately released guanfacine is released all in a big bullish and that limits how much you can give at a time, where as this is a much smoother release, a smoother blood level, it’s not bio-equivalent, in other words you can’t convert from someone who’s taking guanfacine to Intuniv, you can’t say how much total daily dose of guanfacine and just give them that much Intuniv. You have to give more Intuniv then you would of guanfacine, so again if doctors are kind of using one or two milligrams of Intuniv they may not be able to see the maximum efficacy and they really should feel confidant to push towards that target of .1 milligram per kilogram.
 

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