New FDA Approval: Ingrezza

Drug

Valbenazine [Ingrezza]

Indication

The treatment of adults with tardive dyskinesia.

Of note, this is the first and only drug approved by the FDA for this indication (we'll talk more about its place in therapy in a bit...)
 

How it Works

Ingrezza is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor. 

Does that clear it up? Good.

Wait. No? It doesn't? 

There's a burning question on your mind, isn't there?

Let me guess...

What the hell is a VMAT2 inhibitor?

"What the hell is a VMAT2 inhibitor?"

I had a feeling you'd ask that. 

Because I certainly did.

When I got an email alerting me about Ingrezza's approval last week, I remember having a conversation with my wife (who is not a pharmacist) about it:

Me: What the hell is a VMAT2 inhibitor?

Wife: Do you want tacos for dinner on Friday?

Anyway, it turns out that Ingrezza is the first VMAT2 inhibitor on the market, which is probably why most of us haven't heard of it. 

Vesicular monoamine transporter 2 is a (wait for it...) transporter of monoamines. It lives in the cell membrane, and its job is to transport things like dopamine, norepinephrine, serotonin, and histamine from inside the cell to the synaptic cleft (outside the cell). You see VMAT2 expressed in particularly high amounts in the nigrostriatal and mesolimbic regions of the brain.

So when you inhibit VMAT2 (as Ingrezza does), you are basically reducing the amount of dopamine et al. that makes it to the synapse.

But wait a second. Isn't it true that blocking dopamine at the synapse is what causes tardive dyskinesia?

Well, yes. But it depends on what part of the brain dopamine activity is blocked in.

Of course, there isn't a complete consensus on the exact cause of tardive dyskinesia (and so the exact mechanism of Ingrezza in treating TD isn't fully understood), so take the following explanation with a grain of salt. But my interpretation of the current thinking is this...

Long term blockade of D2 receptors (which is what 1st generation antipsychotics do) causes an up-regulation of dopamine receptors. This same phenomenon happens with beta blockers (and it's why you have to titrate someone off when discontinuing them).

However, with D2 blockade, some of those new up-regulated receptors are made in parts of the brain like the nigrostriatal region (which helps control movement). So although you're getting D2 blockade in parts of the brain that cause the symptoms of psychosis, you're getting a relative increase in dopaminergic activity in the nigrostriatal pathway. And this is what causes TD.

And Ingrezza just so happens to work specifically in the nigrostriatal region of the brain...because that's where most of the VMAT2 receptors are located.

Notable Adverse Effects

Before we get too heavy into these, let me first introduce a caveat: The Phase III trials for Ingrezza only included a total of 445 patients (and 183 of those were placebo). If you read the finer print of the package insert, it looks like only about 850 humans have ever taken Ingrezza.  

The drug received breakthrough status by the FDA and received a priority review because there's just nothing like it available. 

So the take home message is that more side effects are almost certainly going to start showing up when Ingrezza gets exposed to a larger population. So keep that in mind. 

Anyway, moving on; the only side effect experienced by > 10% of people taking Ingrezza is somnolence. Luckily, this is a once daily drug, so you can probably get around this by taking it at night time. 

What QT prolongation looks like on an EKG

The other side effect to be mindful of is QTc prolongation. The language in the package insert make it seem like the QT prolongation only occurred in poor CYP2D6 metabolizers (or patients on 2D6 or 3A4 inhibitors)...but the warning extends to everyone taking Ingrezza. Like many other interactions with QTc, one of your roles as a pharmacist will be watch out for synergistic interactions from other drugs that prolong QT.

Of course, antipsychotics just so happen to be one of the drug classes notorious for prolonging the QT interval. And presumably many of the people taking Ingrezza will also be taking an antipsychotic. So you've got that right there. Some other drug classes to be mindful of are macrolides, fluoroquinolones, and 5-HT3 antagonists. There's a nice comprehensive list here you can check out for more info. 

Some other things mentioned on the package insert include balance disturbance (so add this to your list of drugs that can contribute to falls), vomiting, increased blood glucose, anticholinergic effects (though the rate was comparable to placebo), and respiratory infections. But again, the incidence of these effects was either well below 10% or not noted. Again, you can probably expect these to become more clear (and helpful) as more people start taking Ingrezza.

And as a final note, let's talk dose adjustments.

No adjustment for renal failure; but use is not recommended in severe renal failure.

For hepatic dose adjustments, you use a lower dose for patients with mild - severe hepatic impairment (Child Pugh 7 - 15).

Ingrezza has an active metabolite that goes through CYP2D6 metabolism. Ingrezza itself is also active, and it goes through primarily 3A4 metabolism.  So you'll have to be mindful of drug interactions and pharmacogenomic interactions with poor metabolizers of 2D6. 

The package insert recommends avoiding Ingrezza with strong CYP3A4 inducers, and lowering the dose with strong inhibitors. It recommends "monitoring and considering a reduced dose" for patients identified as poor metabolizers of 2D6 or those taking strong 2D6 inhibitors. 

Current Place in Therapy

Let's start with a breakdown of how much tardive dyskinesia sucks. It takes a long time to develop (hence the 'tardive'), but once it does it's usually thought of as irreversible. 

What you get are involuntary movements. Grimacing, lip smacking, eye blinking, and even arm and leg twitching are possible. It can really cause a social stigma that's felt deeply by the patients. It's embarrassing.

You can get an idea of what these all look like with this video:

(This video surprised me...I have encountered A LOT of patients with similar mannerisms. I may have been witnessing TD for years and haven't realized it. But now at least, going forward, I have something to watch out for). 

And up until this point, we haven't had much available to treat tardive dyskinesia (TD). Our most common approach is to lower the dose or stop altogether the drug that we believe is causing TD. We sometimes try switching to a different drug (usually if a patient is taking a first generation antipsychotic we'll try switching them to a second generation).

But all of these solutions are less than desirable. It can take months (or even years) to stabilize a patient on an the right drug/dose of an antipsychotic. Remember, it usually takes years for TD to develop in the first place, meaning that the patient has probably been taking the offending drug for years. It's a real pain to start from scratch, knowing that it may not be effective. The second generation antipyschotics were basically made to avoid TD, and all of them have a pretty low risk.

Clozapine has effectively zero risk of TD. Of course, it's clozapine (i.e. it replaces the risk of TD with the risk of agranulocytosis, heart block, orthostatic hypotension, and weight gain). 

Are there any other drugs we can use to "combat" TD in the way that Ingrezza now does? Something to use as adjunctive therapy to the antipsychotic treatment we've already stabilized? 

Nothing is FDA-labeled for it. We've got a few things that have been used off-label. But nothing with particularly noteworthy success. You might see Vitamin E, Vitamin B6, melatonin, or even the Alzheimers standby donepezil.  

So in effect, our treatment strategy has been to avoid TD in the first place. You'll see this in medical practice (or at least I think I have in my limited pysch experience). As much as possible we try to start patients on second generation antipsychotics. We've moved to reserving first generation drugs like for acute agitation. This isn't just for TD...first generation drugs are associated with a whole slew of problems (like QTc prolongation).

So, with all of that in mind...valbenazine [Ingrezza] seems like a welcome addition to the fray. It's the only drug officially labeled for TD (somewhere in the near future, that is going to be on a test question in pharmacy school). It allows the patient to continue with their existing meds. And, for now at least, it seems extremely well tolerated (but again, keep an eye on it once more patients start using it).

Of course, there's the financials (isn't there always?). Because there is no FDA-approved treatment for TD, the market is wide open. It's like the wild west. There's an estimated 500,000 patients in the US currently with TD. And Neurocrine (the manufacturer of Ingrezza) is asking for $5,275 for a 30 day supply of Ingrezza 40mg. Multiply that by 12 months, and you're looking at a over $60,000 per year. 

And therein lies the crux we come to with so many new treatments these days. For your rich and/or well-insured patients with TD, Ingrezza is almost certainly a good option to try. For your less privileged patients, you're going to have more of an uphill battle to fight.

The irony of this, is that many of the less privileged patients are the ones more at risk for TD...since they are often taking first generation antipyschotics because they are cheaper than the new second generation drugs. I don't have data to back that statement up, it's just my opinion. But at the very least, that has been my anecdotal experience.