Kelly Gable, PharmD, BCPP
Assistant professor of pharmacy practice Southern Illinois University, Edwardsville, School of Pharmacy
Daniel Carlat, MD
Editor-in-chief, The Carlat Psychiatry Report
They used to be called “depot” antipsychotics, but the powers that be have renamed them “long acting injectables” (LAIs), presumably to help remove some of the stigma associated with their use. But no matter what you call them, suddenly every drug company is racing to introduce its own LAI neuroleptic.
In 2009 Janssen introduced Invega Sustenna (paliperidone palmitate)—possibly because its older LAI, Risperdal Consta, will go off patent soon—and shortly thereafter Eli Lilly unveiled the LAI version of olanzapine, Zyprexa Relprevv. Over the next few years, we should expect to see LAI formulations of both aripiprazole (Abilify) and iloperidone (Fanapt).
Are these new formulations really any better than those old workhorses, haloperidol (Haldol Decanoate) and fluphenazine (Prolixin Decanoate)? In this review we will look at how the newer atypical LAIs compare with the conventionals, we will give you some practical tips for how to dose these agents.
Do depot meds really improve adherence? It’s no secret that our patients with schizophrenia often stop taking their medications; in fact, about 75% of these patients will discontinue their antipsychotic therapy within two years of hospital discharge (Weiden PJ and Zygmunt A, J Prac Psych Behav Health 1997;3:106–110). The obvious selling point of LAIs is that they might improve patient adherence, since the injections need be given only every two to four weeks, depending on the medication. But have any head-to-head studies actually demonstrated an adherence advantage of LAIs?
Surprisingly, the answer appears to be: “not really.” A 2005 Cochrane review, for example, looked at six randomized controlled studies (comprising 419 patients) comparing injectable fluphenazine with oral antipsychotics, and found that the depot medication did not reduce relapse more than oral neuroleptics (David A et al, Depot fluphenazine decanoate and enanthate for schizophrenia. Cochrane Database Syst Rev 2005, Issue 1).
A more recent study focused specifically on injectable risperidone (Risperdal Consta), finding the same lackluster performance. These researchers examined medication records of 11,821 VA patients with schizophrenia. Of the patients prescribed injectable risperidone, only 44.6% continued treatment for 18 months or longer, significantly fewer than those on oral agents such as clozapine (Clozaril) (77.1%) or other oral antipsychotics (57.9%) (Mohamed S et al, Psychiatr Q2009;80(4):241–249).
Finally, yet another study, this one of a large Medicaid sample, found that fewer than 10% of patients who started on LAIs in the hospital were still on them at six months post-discharge (Olfson M et al, Schizophr Bull 2007;33(6):1379–1387).
Which depot med should you choose? Though the research has not shown an adherence advantage for LAIs in the large populations studied, there are clearly some individual patients who will benefit from depot formulations. In such patients, which medication should you choose, and how should you dose it?
The first decision point is whether to prescribe a conventional or an atypical LAI. There have been no published trials comparing the two, so we have no real evidence base to guide us. In head to head trials of ora meds, however, atypicals have in general been no more effective than typicals, though the side effect profiles differ. High potency typical cause more extrapyramidal symptoms (EPS) and tardive dyskinesia, while some of the atypicals—especially olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal)—cause more obesity and higher diabetes risk (Lieberman JA et al, NEJM 2005;353(12):1209–1223).
Moderate potency conventionals, such as perphenazine (Trilafon) are potentially good choices, since they cause few EPS and little weight gain. Unfortunately, there is no depot version of perphenazine. The two available conventional LAIs—haloperidol and fluphenazine—are high potency neuroleptics, and the primary advantage of both of them is cost.
A monthly dose of 200 mg of haloperidol decanoate is around $15, versus $900 a month for Risperdal Consta 37.5 mg, or $1,185 a month for a 156 mg dose of Invega Sustenna (price data from Morris & Dickson, wholesale pharmaceutical distributor).
Thus, you can save the health care system a chunk of change by choosing haloperidol and using an anticholinergic to prevent EPS—about $12,000 per year, money that might be better spent for a good case worker, for example. Aside from cost issues, you might choose a conventional agent for patients who have responded well to either haloperidol or fluphenazine in the past with few side effects.
Among the atypical LAIs, we currently have three agents to choose from: Risperdal Consta, Invega Sustenna, and Zyprexa Relprevv. There are subtle differences among all the LAIs, and in order to understand how to make an informed decision, you need to know a bit of the nuts and bolts of how they are packaged.
Injection Packaging and Delivery System Differences Typical antipsychotic LAIs Because both haloperidol and fluphenazine are dissolved in oil, they are the most painful to inject. Once administered, fluphenazine peaks quickly, within eight to 10 hours after injection, so an oral fluphenazine overlap may not be necessary, though some clinicians choose to give oral fluphenazine for a few days just to play it safe.
The plasma concentration of haloperidol, on the other hand, rises gradually and peaks at about six days after the first injection. Strictly speaking, therefore, an oral overlap of about a week is necessary, though standard clinical practice is to continue oral haloperidol for two to three weeks to prevent symptom relapse.
Another major difference between the two agents is ease in dosing. Haloperidol is often preferred due to the simple oral to intramuscular conversion: 10 to 15 times the oral dose will provide you with a decent monthly injection dose (McEvoy JP, J Clin Psychiatry 2006;67(suppl 5); Haloperidol Decanoate [package insert]. Titusville, NJ: Ortho-McNeil Neurologics; 2004). The fluphenazine conversion is 1.2 times the oral dose, making the mathematics somewhat more complicated (Fluphenazine [package insert]. Richmond Hills, ONT: Novex Pharma; 2001).
Atypical antipsychotic LAIs Risperdal Consta differs from the other injectables in that it comes as a powder that must be refrigerated. Just prior to injection, you have to mix the powder in saline and shake it up. While none of this is a real deal breaker, the administration process is more involved than its counterparts. Because the drug is in saline, the injection is not too painful, and after the initial injection, only 1% of the drug is released immediately. It is not until week three that the tiny microspheres release the drug slowly into the body, meaning that a three week oral overlap is necessary to prevent the patient from becoming symptomatic.
Aside from the burden of an oral overlap, Risperdal Consta is rather easy to dose if you follow the general rule that 25 mg intramuscular is roughly equal to 2 to 4 mg oral (Risperdal Consta [package insert]. Titusville, NJ: Jansson; 2007; Kane JM, J Clin Psychiatry 2003;64(suppl 16)).
If your patient refuses or is unable to take oral medication, Invega Sustenna and Zyprexa Relprevv are potential alternatives (as is fluphenazine). Both Invega Sustenna and Zyprexa Relprevv begin acting right away, so no oral overlap is needed. Both medications are also conveniently packaged as pre-filled syringes; however, dosing can be a bit tricky.
For example, Invega Sustenna requires two separate loading doses one week apart (234 mg on day one, and 156 mg on day eight). The maintenance dose, usually 117 mg (the equivalent of 6 mg oral), is given every four weeks (Bishara D, Neuropsychiatr Dis Treat 2010;6(1):561–572).
We’ll get to Zyprexa Relprevv soon, but first, how do you choose between Risperdal Consta and Invega Sustenna? If you read our issue lambasting oral paliperidone (Invega) (TCPR, March 2007), you already know that it is simply 9-hydroxyrisperidone, ie, the active metabolite of risperidone.
Both Invega and Invega Sustenna are “me-too” drugs, and their only advantages over risperidone are that they are less prone to drug-drug interactions, and may be safer for patients with liver impairment. However, there have been no head-to-head trials comparing Risperdal Consta and Invega Sustenna, and we shouldn’t expect to see them anytime soon.
There are some practical differences between the two agents that psychiatrists should be aware of:
Risperdal Consta is administered every two weeks versus every four weeks with Invega Sustenna;
Consta requires a three week oral overlap, Sustenna does not; and
Sustenna is slightly more expensive than Consta, depending on your maintenance dose. It costs around $3,000 to initiate the two loading doses for Sustenna, but the eventual monthly maintenance cost is about $1,000, only a little more than Consta.
That leaves us with the last atypical antipsychotic LAI to reach the market, Zyprexa Relprevv. Clinical trials for Relprevv began in 2000 but it was not approved by the FDA until 2009. This delay was due to a potentially serious side effect—post-injection delirium/sedation syndrome.
During clinical trials there were 30 reported cases of accidental intravascular injection of a portion of the medication, which clinically presents like an olanzapine overdose. The side effect is rare, occurring in about 0.07% of injections (Citrome L, Int J Clin Pract
The time to onset of these symptoms is anywhere from zero to 300 minutes. For this reason, the patient must be observed for three hours post-injection by a healthcare professional (Lorenzo RD and Brogli A, Neuropsychiatr Dis Treat 2010;6(1):573–581).
In order to prescribe Zyprexa Relprevv, you must register with Eli Lilly’s Patient Care Program, a seemingly tedious proposition akin to the nationwide clozapine registry. Not only do you have to register as a prescriber, but the healthcare facility and pharmacy provider must also register to dispense the product.
The bottom line on LAIs is that their putative benefits in terms of getting patients to stay on meds have yet to be proven. While it’s true that the injection keeps the bloodstream rich in neuroleptic for two to four weeks, many patients just hate getting the injections and eventually stop submitting to them. They are best used for select patients who are clearly on board with the program.
In terms of which LAIs to choose, Haldol Decanoate is so much less expensive than the atypicals that you really have to think twice before prescribing one of the newer agents. If you do go with an atypical LAI, we recommend that you avoid Zyprexa Relprevv if humanly possible, and that you choose Risperdal Consta over Invega Sustenna. Why Consta over Sustenna? As it goes generic it will become much less expensive, and the need for every two week injections is paradoxically a benefit for many patients, since it forces them to show up at the clinic more frequently, allowing us to monitor their symptoms more closely.