ZyprexaRelprevv - Till Death Do Us Part

Let's face it.  If the Food and Drug Administration thought it was urgently life–threatening, they would have pulled the drug faster then you can say "ZyprexaRelprevv." But no rational person can honestly interpret the events surrounding June 18, 2013, as positive publicity for drug-maker, Eli Lilly.

What in the world is she talking about?You may be thinking. It's not surprising you'd have to ask, for there was a flurry of publicity around the event when it happened--and then it's as if the whole scary state of affairs just shook itself and went home, for all the press coverage there's been since the deaths--that's right, the deaths--of two people, possibly--very possibly--due to taking themedication ZyprexaRelprevv.

Most likely I need to back up even more, since most people have never even heard of ZyprexaRelprevv.  That's not so with Zyprexa itself.  Called an atypical antipsychotic, Zyprexa is officially approved to treat schizophrenia and bipolar disorder. However, off-label its uses are wide and varied, from anxiety and PTSD to eating disorders and Tourette syndrome to stuttering and sleep issues.  Lilly found Zyprexa enough niches to earn it a spot in the Pharmacy Times' top 200 drugs of 2010 and 2011--and to earn itself over $5 billion a year before the drug went generic in late 2011.

But drug-makers are always looking for new markets--and, truthfully, there was a real need. Zyprexa is a good drug for treating schizophrenia, but, unfortunately, schizophrenics have a high rate of noncompliance. Tellis (2008) writes that approximately one-third schizophrenics are non-medically compliant at any one time. This leads to the way to symptom relapse, hospital admissions, and around 125,000 deaths, in the U.S. alone.

Clearly, we need treatments that increase compliance.  One effective strategy is long-acting injectable (LAI) medications.  Many people find it easier to remember to go to an appointment once every few weeks than to take daily medication.

Welcome ZyprexaRelprevv. It can be injected once every 2 weeks, or, at larger doses, once every 4 weeks, obviating the need for daily doses of medications.

While the first LAI drug on the market (Johnson & Johnson's Risperdal) required supplementing with oral medication, Eli Lilly's injections need no such thing--once every four weeks a patient needs to show up, get a shot, and all, it seemed, would be well.

But the drug's entrance onto the scene--badly as it was needed--was anything but smooth. In the clinical trials, an unusual side effect occurred after injection, later named post-injection delirium/sedation syndrome (PDSS).

Apparently, when PDSS occurs, the drug enters the blood stream too quickly after injection, leading to "greatly elevated blood levels," with effects such as excessive sleepiness, confusion, anxiety, disorientation, high blood pressures, seizures, "marked sedation (possibly including coma) and/or delirium," according to the FDA.

The FDA was, understandably, a bit concerned upon receiving Eli Lilly’s application for the drug and wrote that the "PDSS events raised a serious safety concern because of severity of sedation, unpredictable characteristics, delayed onset (a few hours after injection) in some cases, and relatively high risk of occurrence (0.07% of injections and 1.5% of patients)."

So in March of 2008, they rejected the application, specifically due to concerns regarding PDSS.

However, the FDA did recognize they had a strong drug on their hands, and as of 2009 the PDSS numbers had changed, with the reaction occurring occurred in less than 0.1% of total injections. The FDA told Eli Lilly they would approve the drug if Lilly wrote what's called a "Risk Evaluation and Mitigation Strategy" or REMS, in essence, a plan to ensure that the drug's benefits outweigh its risks.

So Eli Lilly came up with an extensive Risk Evaluation and Mitigation Strategy  for ZyprexaRelprevv, initially approved in December of 2009--and right after its submission, on the 14^th, came the official FDA approval, as well. Major safety points include:

• ZyprexaRelprevv can never be given directly to a patient.
• It can only be prescribed by certified prescribers and dispensed only by certified dispensers.
• The drug must be dispensed only in registered healthcare facilities--and ones with immediate access to emergency services.
• Patients must be monitored at the facility for at least 3 hours following an injection.
• Patients must be accompanied home from the facility.
• Before the patient can go home a healthcare professional must make sure the patient is alert and oriented, and has none of the signs of PDSS.
• For the remainder of the day of each injection, patients should not drive or operate heavy machinery.

A bit restrictive, it’s true, but Eli Lilly made it work, and everything seemed hunky dory. According to the Wall Street Journal, around 50,000 patients have received injections of ZyprexaRelprevvworldwide, with no major complaints.

And then the unthinkable happened. On July 18, just over a month ago, the FDA announced that it was investigating two deaths in connection to ZyprexaRelprevv.

It was shocking.  As FiercePharma put it, "In the clinical trials . . .of ZyprexaRelprevv, cases of PDSS were observed within three hours after administration, but there were no deaths due to PDSS” [italics mine].  And the crazy thing is that these two patients died three to four daysafterthey received their injection. Thus it really isn't clear that they died from PDSS at all. But if not--then what?

Both Eli Lilly and the FDA have held their cards close to their chests.   Neither would say precisely when the deaths occurred, though an FDA spokeswoman did share that one death occurred in the U.S and the other in Europe. Lilly was mum.

The FDA put out an "FDA Drug Safety Communication" on the 18th, announcing that the two deceased persons had received appropriate levels of the medication, but, at death, had "very high" blood levels of the drug.

But, high blood levels or no, no one had died before--and certainly not 3-4 days after taking the medication.  It is quite perplexing, and Eli Lilly must surely be wondering.

"Based on the information available to us," a Lilly spokesperson said, "we are unable to conclude whether the two deaths were related to administration of ZyprexaRelprevv. However, we are continuing to evaluate this important safety issue and will communicate any clinically significant safety information that affects the product."

And that was that. That is the last communication we've had from the company—or the FDA--on the topic.

Interestingly enough, the FDA did not pull the drug from the market. Rather, in their "Communication" they wrote, "At this time, FDA is continuing to evaluate these deaths and will provide an update when more information is available."

Well, here we are, well over a month--and an official investigation--later--and do you know what we know about the possibility and probability that--and mechanism by which--  ZyprexaRelprevv may caused two deaths?

Nothing--not one thing--more than we knew when we awoke to a mass media frenzy about the drug on June 18th.