Janssen’s marketing team apparently missed the fact that the word in the English language that sounds most like “Invega” is “inveigle,” meaning “to entice, lure, or ensnare by flattery or artful talk or inducements” (www.dictionary.com). You may have already heard some “artful talk” from your Janssen reps, who are keen to have you convert your patients from Risperdal to Invega. Will you be doing your patients a favor by taking the plunge? Or will you simply be giving them the same wine in a fancier bottle?
Approved by the FDA on December 20, 2006, Invega is an extended-release formulation of paliperidone, which is the major active metabolite of Risperdal. Invega uses the same delayed-release technology as Concerta, namely, the OROS osmotic drug-release technology. The Invega capsule contains three compartments: two layers of paliperidone and one “push” layer with an osmotically active polymer. Surrounding the whole thing is a semipermeable membrane that allows water to seep in, causing the drug to slowly escape through a precision-drilled orifice at the one end of the tablet. The result? Twentyfour hours of continuously released paliperidone.
The bottle is fancier, but will it make any difference to your patients? The best way to answer this question would be to do a double-blind study comparing Risperdal with Invega. Unfortunately, Janssen chose not to conduct such studies, presumably because the company was afraid of what it might find. So we are left with the task of comparing the two drugs based on other research the company has conducted.
Extended-release formulation. The least controversial difference between the two medications is that Invega is released gradually into the bloodstream, reaching a peak at 24 hours, whereas Risperdal reaches its peak in about one hour. The fact is, however, that when your patients take plain old Risperdal, their livers gradually convert it into paliperidone, with the peak paliperidone concentration occurring about three hours after patients take the Risperdal. Thus, although Risperdal reaches its peak in one hour, it gradually releases (via its metabolism) paliperidone over a severalhour time span.
Nonetheless, 24 hours of continuous release is genuinely smoother than a few hours of delayed release, and it theoretically would lead to fewer initial side effects in some patients. But the corresponding potential disadvantage of Invega is that it may not quell acute agitation and anxiety, whereas Risperdal often does.
Is Invega easier to dose? Invega’s package insert suggests starting with 6 mg QD, which it describes as an effective dose in many patients. Risperdal, with its 24-hour half-life, is also often dosed once daily, so there’s no convenience advantage for Invega there. We usually have to titrate Risperdal upward to reach the effective dose of 3-4 mg/day. By contrast, Janssen says that we can start and end with 6 mg, no dose adjustments needed. How believable is this claim? Not very.
For example, we know that in two of the pivotal FDA trials, Invega 6 mg was less effective than Zyprexa 10 mg QD, though the studies did not include enough patients to assess statistical significance between the two drugs (Kane, et al., Schizophrenia Research 2007;90:147-161 and Marder, et al., abstract presented at ACNP meeting 2005). In both of these studies, researchers had to push the dose of Invega up to 12 mg QD to equal or exceed Zyprexa’s efficacy (imagine how poorly Invega would have looked if it had been compared with Zyprexa 15 mg or 20 mg/day, doses more commonly used in schizophrenia). Invega at 12 mg QD is not well tolerated, resulting in a 26% incidence of EPS, as opposed to a 10% incidence on Invega 6 mg QD and 11% on placebo in the Invega studies.
The bottom line on dosing is that many patients will likely end up needing more than 6 mg of Invega, and with upward titration comes side effects. Uh oh–I’m having a flashback to Lexapro’s launch, when we were told that Lexapro 10 mg QD would have the same efficacy as Celexa 40 mg QD, with fewer side effects. It didn’t quite turn out that way!
Fewer drug-drug interactions. Risperdal is metabolized in the liver primarily by 2D6, so its levels can be affected by drugs that affect 2D6. For example, carbamazepine decreases Risperdal levels by about 50%, whereas the 2D6-inhibitor Prozac increases Risperdal levels 2.5-2.8 fold. Invega, on the other hand, is metabolized primarily by the kidneys, and so is not subject to drug interactions, nor does its dose need adjusting in patients with liver disease. These are both potential advantages of Invega.
Side effects. EPS: Invega and Risperdal are comparable, though at the more robust dose range of 9 mg to 12 mg QD Invega leads to more EPS than is reported for Risperdal at doses of 6 mg to 8 mg QD (see package inserts of both medications for this data). Cardiac: Invega caused QT widening of 12 msec more than placebo at the highest dose tested (8 mg of immediate-release paliperidone, which results in maximum blood levels double that of 12 mg of Invega), similar to Geodon’s reported 10 msec drug-placebo difference on 160 mg daily. Is this a big deal? After hundreds of thousands of Geodon prescriptions, most prescribers have become comfortable with its cardiac safety, and we expect the same of Invega. Nonetheless, this is one disadvantage not shared by Risperdal. Invega also caused a 12%-14% incidence of tachycardia, about double that of placebo. This has not been reported as a side effect of Risperdal. Hyperprolactinemia: No differences between Invega and Risperdal were noted. Both drugs frequently cause hyperprolactinemia, although significant clinical consequences, such as lowered libido in men and amenorrhea in women, are uncommon. Weight gain: Probably no difference; both drugs can cause moderate weight gain, but not at the level of Zyprexa or Clozaril.
Cost. Risperdal goes off patent in June of 2008, and we will start seeing cheaper generic risperidone soon thereafter. Until then, Janssen will actually price Invega slightly below Risperdal (and will stop providing Risperdal samples) in order to encourage psychiatrists to prescribe Invega. The company’s strategy is to have psychiatrists convert as many patients as possible to Invega before cheap risperidone comes on the market.
Bottom line. When all is said and done, Invega looks like Risperdal without drug-drug interactions, but with more QT interval prolongation, more tachycardia, possibly more EPS, and the same amount of hyperprolactinemia. Not a very pretty picture. Get ready to be Invega’ed–I mean inveigled–by your neighborhood drug rep soon.
TCR VERDICT: Invega: How fancy the bottle!