Alkermes’ Antipsychotic Clears US FDA Panel Amid Calls For Broader Professional Education Plan
Executive Summary
Communication and education on samidorphan’s opioid antagonistic effects should focus on health care providers that prescribe opioids as well as psychiatrists that prescribe olanzapine, advisory committee says in endorsing the safety and efficacy of ALKS 3831.
A US Food and Drug Administration joint advisory committee endorsed the efficacy and safety of Alkermes plc's combination antipsychotic drug ALKS 3831 (olanzapine/samidorphan) on 9 October but cited the need to ensure that health care providers in different clinical specialties, and not just prescribing psychiatrists, understand the potential risks stemming from the drug’s opioid antagonist component.
The Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 11-6 that labeling would be sufficient to mitigate the risks related to the opioid antagonistic effects of samidorphan in ALKS 3831, an oral, fixed-dose combination that also contains the antipsychotic olanzapine.
Advisory Committee Votes
- Has the applicant presented adequate evidence that samidorphan meaningfully mitigates olanzapine-associated weight gain? Y – 16, N – 1
- Has the applicant adequately characterized the safety profile of ALKS 3831 (olanzapine/samidorphan)? Y – 13, N – 3, A – 1
- Is labeling sufficient to mitigate the risks related to the opioid antagonist action of samidorphan? Y – 11, N – 6
Alkermes is seeking approval for use in adults to treat schizophrenia and bipolar disorder.
The theoretical risks of samidorphan, a mu opioid receptor antagonist, include precipitation of opioid withdrawal or overdose in patients who chronically use opioids, and ineffective analgesia in patients for whom opioids are medically necessary.
The vote on the adequacy of labeling followed more favorable votes relative to the ability of the samidorphan component to mitigate weight gain with olanzapine, and with the characterization of the combination drug’s safety profile. (See box.)
A Need To Educate Opioid Prescribers
Alkermes is proposing to contraindicate use of ALKS 3831 in patients who are opioid-dependent or chronically using opioids. The sponsor also has proposed language in the Warnings and Precautions section of labeling on the vulnerability to opioid overdose, including the potential for increased sensitivity to opioids and risks due to attempts to overcome blockade, as well as the potential for inadequate opioid analgesia. (Also see "Alkermes’ Antipsychotic Combo Faces US FDA Questions On Metabolic Effects, Opioid-Related Safety" - Pink Sheet, 7 Oct, 2020.)
The company also outlined an education and communication plan directed at potential prescribers of the drug, as well as a patient-directed education plan that would include a wallet card containing important safety information for emergency pain management and a warning that the patient is taking an opioid receptor antagonist.
Panelists on both sides of the vote on the labeling question said Alkermes’ plans for educating health care providers about the opioid antagonistic effects of samidorphan must go beyond psychiatrists and other clinicians who typically prescribe antipsychotics. Rather, they should encompass health care professionals who prescribe opioids.
“I think labeling will do absolutely nothing to mitigate the risks related to the opioid antagonist qualities of this drug,” said Steven Meisel, system director of medication safety at M Health Fairview, who voted “no” on the labeling question.
“I’m mindful of the fact that the prescribers of this drug will generally be psychiatrists, and psychiatrists will seldom be prescribing opioids. The people who would be prescribing opioids are emergency room doctors, orthopedic surgeons, oral surgeons, anesthesiologists,” Meisel said.
“All they’re going to see if they happen to look at a patient’s medication list would be the fact that they’re on some form of olanzapine antipsychotic, and the notion that there’s going to be a negative interaction or a problem with the prescribing of the opioid is going to fly right by them,” he said.
Jess Fiedorowicz, head and chief of the department of mental health at The Ottawa Hospital, voted “yes” on the labeling question but raised concerns similar to those cited by Meisel.
There needs to be a “robust educational campaign” targeting more than just prescribers of antipsychotics, Fiedorowicz said.
“Even though we have a lot more experience now with opioid antagonists, I think some of these concerns could be magnified because this is a new entity, and it’s not well known,” he said in reference to samidorphan, which is a new molecular entity.
“A well-known antagonist like naltrexone might be easily recognized by emergency physicians or anesthesiologists, but they may not recognize that samidorphan is an opioid antagonist especially when it’s buried in with olanzapine in the same name.”
In voting “yes” on the labeling question, Erin Krebs, chief of general internal medicine at VA Minneapolis Health Care System, said that the potential risks related to the samidorphan’s opioid antagonistic effects fall into three buckets.
Two of these risk buckets – precipitated withdrawal and overdose in patients who regularly use opioids – can be addressed through careful patient selection in prescribing ALKS 3831, she said.
The prescriber of the antipsychotic “is really the one who is going to be reading the label and needing to know that information in terms of patient selection,” because only certain patients will be at risk for such events, she said. “So I think labeling is most helpful there.”
The third bucket of potential risk – ineffective analgesia resulting from the failure of health care providers to recognize samidorphan’s opioid antagonistic effect – “is a real issue in clinical practice right now as we see increasing use of opioid antagonists for a variety of conditions.”
This latter category would mostly involve patients with acute pain due to severe trauma, or those undergoing a planned surgical procedure. “It’s really a relatively narrow group of clinicians who are involved in those clinical scenarios,” she said, suggesting targeted education could suffice.
Education Plan Inside Or Outside Of REMS?
While ALKS 3831 now appears on track for approval by the new drug application’s 15 November user fee date, Alkermes may need to broaden its health care educational program based on the committee’s recommendations.
In addition, it’s unclear whether such an education program would be inside or outside the regulatory confines of a Risk Evaluation and Mitigation Strategy.
In referencing the sponsor’s education and communication plans, Tiffany Farchione, acting director of the FDA’s Division of Psychiatry, said “we’re not necessarily looking at a REMS, per se.”
“It’s not clear to me as to why this medication would not have a REMS.” – Stony Brook University’s Kevin Zacharoff
Her comment surprised panel member Kevin Zacharoff, pain and addiction course director at the Renaissance School of Medicine at Stony Brook University who voted “no” on the labeling question.
“It’s not clear to me as to why this medication would not have a REMS,” Zacharoff said. “I cannot understand why this would be treated as a traditional educational initiative, as compared to a REMS.”
“In no way, shape or form would I consider this to be a traditional label covers, black box warning covers, the risk,” he said. “In the event that there is going to be that card that the sponsor discussed this morning, that sounds to me much more like a REMS initiative. And I’m not understanding whether this is some kind of blend of a traditional risk mitigation strategy versus a modified REMs approach, but that’s why I voted no.”
A Warning Against Marketing For Weight Loss
In a 16-1 vote, the panel concluded that samidorphan’s effect in mitigating weight gain associated with olanzapine was clinically meaningful, even though no benefit was seen on lipid and glycemic parameters.
However, the panelists cautioned against any attempt by the sponsor to market the combination drug as effective for weight loss.
It is important “to avoid any kind of misinformation about expectations,” said Karim Anton Calis, director of clinical research and compliance at the National Institute of Child Health and Human Development. “This is not a weight-loss drug. The modest effect that we see on mitigation of weight gain does not obviate the need for healthy lifestyle, diet, exercise, etc.”
“One concern would be that a lot of people would be switched for no benefit but greater cost with this new product.” – Minneapolis VA’s Erin Krebs
Panelists said longer-term studies were warranted to see if the combination drug could mitigate the occurrence of metabolic syndrome; the pivotal studies ran only for 24 weeks.
For both pivotal trials, patients must not have received treatment with olanzapine for six months prior to study entry. However, committee members said they would like to see weight mitigation efficacy data in patients who were stable on olanzapine monotherapy before switching to ALKS 3831.
“We don’t have evidence that switching to this drug from plain olanzapine would have any benefits in terms of preventing further weight gain, much less weight loss,” Krebs said. “One concern would be that a lot of people would be switched for no benefit but greater cost with this new product.”