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An agreed, albeit with some dissent, that a combination of olanzapine and samidorphan for treating schizophrenia and bipolar disorder was safe as long as it comes with appropriate labeling.

In a 11-6 vote Friday, members of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee felt the sponsor Alkermes did provide sufficient labeling for the once-daily oral treatment that combines olanzapine () with the opioid antagonist samidorphan.

In other votes, the committee also said that Alkermes had adequately characterized the combination's safety and that the addition of samidorphan did effectively curb the weight gain commonly seen with olanzapine.

Feeling the proposed label was indeed sufficient, many "yes" voters said more importance should be placed on educating prescribers and patients with post-approval marketing.

"There's a lot more awareness about opioid antagonists. We have so many products like buprenorphine and naltrexone and long-acting Revia," said Rajesh Narendran, MD, of the University of Pittsburgh, on why he voted yes. "People are a lot more in tune in ER and surgical places to be aware. And I think when they're not, it can always be caught by a good pharmacy-based program to flag that."

"There's no reason to hold this drug to a completely different standard than where we hold naltrexone just because it's more widely known," Narendran continued. "I think we do need to definitely do an education of all the other providers [besides psychiatrists] like surgeons and ER docs. But it's going to be very hard to overdose and override such a high antagonist effect."

On the other side, "no" voter Steven Meisel, PharmD, of M Health Fairview in Minneapolis, said labeling will do "absolutely nothing to mitigate the risks related to the opioid antagonist."

He argued that the main prescribers of this agent would be psychiatrists, but the main prescribers of opioids that might interact with the olanzapine/samidorphan combination will be emergency room doctors, orthopedic surgeons, oral surgeons, and anesthesiologists.

Meisel argued that opioid prescribers, when they look at the patient's medication list, will only see they're on some form of olanzapine antipsychotic. "And the notion that there's going to be a negative interaction or problem with the prescribing of the opioids is going to fly right by them."

Other "no" voters called for broader education, especially given that this agent would be prescribed in patients at higher-than-average risk for opioid abuse.

The joint panel also voted 13-3 that Alkermes did a sufficient job in characterizing the product's safety profile. Dissenters seemed mainly concerned about the unknowns swirling around a new agent (samidorphan is not currently approved for any condition) and therefore called for more research.

Kevin Zacharoff, MD, of Stony Brook University Hospital in Smithtown, New York, was among those voting "no," saying he has a "number of questions" regarding the samidorphan component.

"I have no clear understanding as to what the appropriate course of action would be in the event that somebody does have an unintentional overdose," he said.

On the other hand, Karim Anton Calis, PharmD, MPH, of the National Institutes of Health in Bethesda, Maryland, gave what he called a "qualified yes" to the product while calling for more long-term, post-marketing safety data -- a sentiment many other "yes" voters agreed with.

And in what seemed to be the easiest vote of the meeting, members voted 16-1 that the sponsor did in fact present adequate evidence that samidorphan effectively reduced olanzapine-associated weight gain.

"I do think it's an important question about whether there would be mitigation of weight gain in people who are already on olanzapine because I think many people would wonder if switching to the new product would help them with weight gain or not," said Erin Krebs, MD, MPH, of the University of Minnesota in Minneapolis.

Many other members who also voted yes to this question cited compelling clinical data beyond the agent's ability to curb weight, but other metabolic benefits as well.

For example, Jessica Jeffrey, MD, MPH, MBA, of UCLA Semel Institute of Neuroscience and Human Behavior in Los Angeles, said she voted yes to this question in part because participants on olanzapine/samidorphan in one of the clinical studies also saw less increase in waist circumference and had favorable systolic blood pressure.

With the proposed trade name of Lybalvi, Alkermes was seeking indications for adult schizophrenia, as well as adult bipolar I disorder as acute treatment of manic or mixed episodes as monotherapy and maintenance monotherapy treatment or as adjunctive therapy to lithium or valproate for manic or mixed episodes. The fixed-dose combination pills would come in a variety of proposed strengths: 5 to 20 mg of olanzapine along with 10 mg of samidorphan.

Olanzapine, which has been approved for years as monotherapy, is a highly effective "atypical" antipsychotic drug, but it is associated with substantial weight gain.

This was echoed during Friday's open public hearing session, where several speakers shared personal tales of family and friends burdened with schizophrenia or bipolar disorder who were effectively treated with olanzapine, but were almost crippled by the weight gain that happened "almost overnight," as one said.

In adding the novel mu-opioid antagonist samidorphan -- not currently approved -- clinical studies showed patients had a significantly reduced amount of weight gain while maintaining efficacy. Specifically, the combination treatment showed patients had a 50% reduced chance of gaining a clinically significant amount of weight -- more the 7% of body weight -- versus olanzapine alone, but still had a significant improvement and maintenance in mean Positive and Negative Syndrome Scale (PANSS) score.

However, the pitfall of this combination treatment were the risks that come with an opioid agent, in which this patient population may be particularly at risk of. These include risk for potential opioid overdose, reduced opioid analgesia, and the potential for acute opioid withdrawal in already opioid-dependent patients.

Although the FDA is not required to follow its advisory committees' recommendations, it typically does.

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