Lillys Zyprexa LAI trips up over sedation effects

Despite a favourable recommendation - albeit with some restrictions - from the US Food and Drug Administration's (FDA) Psychopharmacologic Drugs Advisory Committee on 6 February, the FDA has issued a non-approvable letter for Zyprexa LAI (long-acting injection). The agency says it needs more information to understand better the risk and cause of excessive sedation events observed in around 1 per cent of patients in clinical trials with the Zyprexa line extension. Zyprexa LAI combines the atypical antipsychotic olanzapine with pamoate salt, giving an extended drug delivery period of up to four weeks. The FDA's advisory committee voted unanimously that, subject to appropriate labelling about the risk of excessive sedation, the long-acting version was effective and, as Lilly put it, "acceptably safe" for the treatment and maintenance treatment of schizophrenia in adults. The panel also recommended that Zyprex LAI should be reserved for patients who had difficulty staying on oral medication. Post-injection excessive sedation events include dizziness, confusion and altered speech. In clinical trials with Zyprexa LAI, they were seen with 0.07 per cent of injections and in 1.2 per cent of patients, all of whom fully recovered, Lilly pointed out. What particularly concerned the FDA, though, was a new excessive sedation event with Zyprexa LAI that occurred shortly before the advisory committee meeting. Lily said it had alerted the agency and the advisory committee about a possible new case at the 6 February hearing, noting that the company was "investigating the details of the event including conflicting information about the time of onset​". Following the meeting, Lilly "was able to confirm … that this was a case of excessive sedation and that it began between 3 to 5 hours after injection​". All previous excessive sedation events had started within three hours of objection. While the patient in this case again fully recovered, the delayed onset of the event clearly had implications for the risk-benefit profile of Zyprexa LAI, particularly as the potential for excessive sedation in already vulnerable patients had been a source of concern in the advisory committee's deliberations. It also undermined the risk management plan presented by Lily to the committee, which included a proposed recommendation on labelling that a three-hour precautionary period should be observed following depot injection with Zyprexa LAI. This would include a one-hour, on-site observation period post-injection, after which healthcare professionals would "consider each patient's individual circumstance when determining whether it is appropriate for the patient to leave the site or remain on site for a longer observation period​"; and further recommendations that patients, for three hours post-injection: should not drive or operate heavy machinery; should be vigilant for signs and symptoms of potential 'inadvertent intravascular' (IAIV) injection events; and should be able to obtain assistance if needed. The reference to IAIV injection events reflects Lilly's belief that the excessive sedation observed in clinical trials was most likely a result of the drug being injected accidentally into a blood vessel rather than muscle - a common enough hazard with other drugs administered through intramuscular injection, the company says. "The weight of evidence obtained by reviewing IAIV injection event data and from additional investigations into the cause of these events suggests that accidental contact between the olanzapine pamoate suspension and blood is the proximate cause for IAIV injection events,​" Lilly stated in its briefing document for the advisory committee meeting. The reasons why the suspension might come into contact with blood "could be various​", it added. "For instance, direct injection into a blood vessel may be one method, but the nicking of a blood vessel during the injection procedure or development of a hematoma could also be methods by which blood comes into contact with the suspension.​" Whatever the cause, and while proper injection technique was "absolutely essential"​ to minimise the risk of an IAIV injection, "such events can still occur, even when proper technique is used"​, Lilly noted. The main rationale for introducing the new formulation of Zyprexa, apart from the convenience of patients not having to take daily medication, is that long-acting injectable antipsychotics - first launched in the 1960s - have been associated with improved treatment adherence and fewer treatment failures. In particular, Lilly explained, physicians administering a long-acting formulation know when patients have received their medication and can immediately detect non-adherence when a patient fails to return for a scheduled injection. And unlike oral and injectable short-acting formulations, long-acting antipsychotics enable stable concentrations of the active drug to remain within a therapeutic range for an extended period. Lilly already markets Zyprexa IntraMuscular (olanzapine for injection), indicated for the control of acute agitation associated with schizophrenia and bipolar mania, alongside Zyprexa Tablets and Zyprexa Zydis (olanzapine orally disintegrating tablets). Zyprexa IntraMuscular provides a much higher plasma concentration than the same dose of orally administered olanzapine, taking effect within 15 to 45 minutes. However, its half-life is similar to that seen with oral dosing. Lilly also cites the narrow range of long-acting injectable antipsychotics currently available on the US market: namely, two typical antipsychotics, haloperidol decanoate and fluphenazine decanoate; and one atypical, risperidone long-acting injection (Johnson & Johnson's Risperdal Consta). According to Lilly, these products have their drawbacks, including refrigeration requirements, the risk of movement disorders or tardive dyskinesia, limited options for dosing intervals, and the need in some cases to supplement with oral antipsychotics. Whether the FDA's non-approvable letter will prove the death knell for Zyprexa LAI remains to be seen. It might mean Lilly having to conduct additional studies with the new formulation, which at the least implies a significant delay to its approval schedule. "We are disappointed by the FDA's decision and we are committed to ongoing discussions to better understand the agency's perspective regarding this recent case of excessive sedation and to define the path forward and the associated timeline," commented Dr Jennifer Stotka, vice president of US regulatory affairs. "Given the chronic and severe nature of schizophrenia, persistent challenges with adherence, and the limited number of approved depot formulations, we continue to believe that, if approved, Zyprexa LAI would provide a valuable treatment option for patients suffering from schizophrenia," she added. Independent regulatory reviews of approval applications for Zyprexa LAI are "ongoing" in the European Union and other countries including Canada and Australia, Lilly noted. Zyprexa is the company's biggest product by some distance, bringing in sales of $4.76bn worldwide in 2007, 9 per cent more than in the previous year. US sales were 6 per cent higher at $2.24bn. But patent expiry is looming in the US in 2011, although analysts disagree over how much the sedation risk might limit the ability of a long-acting formulation to ease the pain of generic erosion.