A surefire way to bring a new drug to market is to identify a characteristic of everyday life which is annoying or a nuisance—or which, in some cases, might actually reflect an underlying disease state—test a drug which has some effect on that “feature” (even a drug already on the market), and obtain FDA approval for this “new indication.” And if that doesn’t work, you can just try to generate word-of-mouth about how well your drug works for some off-label purpose. Thus, we’ve seen atypical antipsychotics for “agitation” in autism, gabapentin for RLS, low-dose doxepin for insomnia, as well as the widespread off-label use of Seroquel for insomnia, modafinil for chronic fatigue, and Risperdal for disruptive behavior in kids.
Earlier this week, another new drug joined this list. Transcept Pharmaceuticals and its partner Purdue Pharma (yes, that Purdue, of Oxycontin fame) received FDA approval for “Intermezzo,” a new low-dose version of zolpidem, the drug more popularly known as Ambien. Specifically, Intermezzo was approved for “middle of the night [MOTN] waking followed by difficulty returning to sleep.” MOTN is not a disease in its own right, but a symptom seen in some patients with (and many patients without!) insomnia. Intermezzo seeks to capture this market.
Zolpidem, as you might know, is already available generically in two dose strengths, 5 and 10 mg. It’s also available in a long-acting “Ambien CR” form (actually a slow-release formulation encased in a rapidly-acting outer layer, sort of like an almond M&M or a Tootsie Pop without the stick) in 6.25 and 12.5 mg strengths. Intermezzo is available as a 1.75- or 3.5-mg rapidly dissolving tablet.
Would such a low dose even work? Well, if we assume that Ambien is an effective sedating agent (which it is, in most people), then patients who wake up in the middle of the night and can’t fall back asleep might truly benefit from this small dose. The low dose might be “just what the patient needs” to put him back to sleep but still allow him to wake up and function at work (or whatever) the next day.
But why do we need a new version of the drug, with a snappy new name and an impending multimillion dollar marketing campaign? Can’t a patient just cut a generic 5-mg zolpidem in half and use that? Well, Transcept says that there are some possible “advantages” of Intermezzo over this more time-consuming (and less lucrative) option. First, Intermezzo is designed to be taken sublingually (under the tongue), so it may have a more rapid effect than the conventional Ambien tablet. (Note: 5- and 10-mg zolpidem is already available as a sublingual tablet called Edluar, and as an oral mist called Zolpimist.) Second, and more importantly, Intermezzo’s very low dose might theoretically lead to less daytime sedation. Readers will recall that this was the “selling point” of Silenor (ultra-low dose doxepin) back in April.
Please note, though, that I say “theoretically.” There are so many factors determining blood levels—and subsequent effects—of medications, that there’s really no way to tell how any one individual will respond to a given dose. In fact, the FDA originally rejected Intermezzo (3.5 mg) in 2009, concerned that mid-night dosing may cause residual drowsiness and morning impairment. They requested more tests, including a highway-driving study, and even though Transcept’s studies showed no impairment, the FDA still rejected the request again earlier this year, concerned that some people might still have high blood levels of drug in the morning. Transcept “met with the FDA” in September, and (without performing additional tests) they modified their application, proposing that patients be warned against taking the medication with <4 hours of sleep remaining, and that a lower dose be made available: specifically, 1.75 mg in women (vs. 3.5 mg in men). This was acceptable to the FDA.
(As far as I can tell, there are no published data proving that women metabolize the medication more slowly than men, but the FDA approval documents have not yet been posted. It might just be that this was simply a reasonable explanation that would permit Transcept to get their drug to market without further phase III testing.)
Other writers have already commented on the fact that Intermezzo is just a new version of an existing drug, a sort of “me-too” agent whose niche has been cleverly created by its manufacturer. This indeed seems to be the case. But I have other concerns, too.
For one, conventional wisdom says that the frequent use of rapidly acting agents is a setup for substance dependence. The regular use of zolpidem—at any dose—may cause “down-regulation” of GABA receptors, requiring greater doses of zolpidem to have the same effect over time, a phenomenon commonly observed in clinical practice. (So a patient might start on Intermezzo and end up taking regular-dose zolpidem at 2AM anyway?? Wouldn’t that be ironic?)
But in addition to the physiological dependence, I’d be concerned about the development of psychological dependence on a drug like this one. Patients who use pills for short-term relief (of pain, of anxiety, of insomnia, etc) develop a need—almost a craving—for those pills. The craving is, in many cases, purely psychological. Over time, the drug may not even be necessary, or it may serve little to no biological effect; simply taking the pill is what provides relief. Now, if the pill were an innocuous placebo or some other mild intervention, I wouldn’t be too worried. But opiates, NSAIDs, benzos, and benzodiazepine-like agents (such as zolpidem) are not benign, particularly when taken long-term. Moreover, the psychological need for a bottle of pills by the bedside doesn’t cure insomnia, it creates a new dependency. Insomniacs will need that bottle. Moreover, they’ll be more likely to take a pill whenever they wake up, for whatever reason—whether it’s to grab a midnight snack, take a bathroom break, or to hush a snoring partner.
Of course, for some patients with insomnia, the opposite might be true: simply the knowledge that something is available if they wake up, might help them to sleep soundly throughout the night. Sort of like the patient with panic disorder who never experiences a panic attack—as long as she has the stash of Ativan in her purse. Certainly some patients may benefit in this fashion, but for most, the pill bottle may be just too tempting.
(A side note: in the published phase III sleep lab study for Intermezzo, 82 patients with insomnia were put to sleep in the lab, but then awakened by the researchers after four hours—in other words, they did not experience the “natural” overnight awakening they complained about. The patients were then given Intermezzo or placebo and, of course, the Intermezzo patients fared better. But to me, that’s like taking 100 patients, hitting each of them with a stick, and randomizing 50 to ibuprofen and 50 to a placebo to treat the resulting pain. Of course it’s going to work.)
In the end, we’re left with another new drug that we may not really need. Will it be prescribed? Of course. Will it be given to patients who are already taking Ambien, or using benzos, or drinking alcohol? Yes; trust me on this one (…making the FDA’s legitimate concerns about oversedation and impairment essentially irrelevant). Will Intermezzo be prescribed in lieu of behavioral or other psychological/lifestyle measures that might treat a patient’s insomnia? Absolutely.
So why does it exist? Transcept estimates a MOTN market of $1.9 to $3.4 billion per year, and they’re counting on the sales staff of Purdue Pharma to help sell Intermezzo to psychiatrists and pain docs. (As they say in their shareholder materials, “High value pain prescribers tend to be significant insomnia prescribers” and psychiatrists rank highly, too.) Just as people want rapid relief from pain—and take ever-increasing numbers of pills to do so—they want their sleep. Intermezzo is just one more way to satisfy that need. But at what cost?