Two US Food and Drug Administration (FDA) panels jointly recommended approval of an esketamine 28-mg single-use nasal spray device (Spravato, Janssen Pharmaceuticals) for treatment-resistant depression.
The Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management (DSaRM) Advisory Committee together voted that the benefits outweigh the risks for esketamine on the basis of research findings to date and additional risk evaluation and mitigation strategies (REMS) proposed by the FDA.
"I think that ultimately, the benefits outweigh the risks, and the thing I'm most concerned about really is diversion and misuse and things like that," said temporary voting member Lee Hoffer, PhD, MPE, associate professor, Department of Anthropology, Case Western Reserve University, Cleveland, Ohio. Hoffer urged close monitoring of the REMS program.
The panels voted 14 yes, 2 no (with 1 abstention) in favor of the drug's effectiveness. They voted 15 yes, 2 no (with 0 abstentions) that the company had adequately characterized esketamine's safety profile.
Major depressive disorder (MDD) is a serious, chronic, potentially fatal condition. MDD can be debilitating and affects more than 16 million individuals in the United States.
First-line treatments for MDD include oral antidepressant medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants, in conjunction with psychotherapy if needed.
These medications can take several weeks to begin working, and patients often must try more that one medication before they find one that is effective. Those who have tried two or more antidepressants without success are considered to have treatment-resistant depression.
One advantage of esketamine is that it is fast acting, which means that patients can get symptom relief more quickly and potentially avoid self-injury, such as suicide.
The company conducted 19 phase 1, four phase 2, and five phase 3 clinical studies. "Data from both a short-term phase 3 study and a long-term phase 3 study demonstrated that esketamine nasal spray plus a newly initiated oral antidepressant provided statistically significant, clinically meaningful, rapid, and sustained improvement of depressive symptoms in this difficult-to-treat population," the company said in a February 12 news release.
"I voted yes because esketamine has the potential to be a game changer in the treatment of depression; I use the term 'game changer' because they've demonstrated the rates of response in this treatment-resistant population is better than what we've seen for any of our current modalities. Number two, the rapid timeline of response is unprecedented; there's nothing currently approved that gets patients better this fast," voting DSaRM committee member Walter S. Dunn, MD, PhD, staff psychiatrist and assistant clinical professor, Department of Psychiatry, West Los Angeles Veterans Administration Medical Center, University of California, Los Angeles, said at the meeting.
Dunn added that although the compound is not novel in terms of approved antidepressants, the mechanism of action is novel.
Three adverse events were particularly concerning: sedation, dissociation, and increased blood pressure. The majority of these events happened during the first 2 hours after drug administration, and the FDA is recommending an REMS to ensure patient safety when using esketamine.
The REMS would require esketamine to only be given in "certain healthcare settings where the patient could be monitored for 2 hours after administration, the drug would not be dispensed directly to patients, and patients would be enrolled in a registry to better characterize the risks associated with esketamine administration," the FDA explained in its briefing document.
"I was pleased with the REMS program as outlined by the sponsor and the FDA; I felt like it was less passive than some of the other REMS strategies...so I think the program as outlined will help set consistency with standards," voting DSaRM committee member Kelly Besco, PharmD, FISMP, CPPS, health system medication safety officer, OhioHealth Pharmacy Services, Dublin, Ohio, said at the meeting.
Cite this: FDA Panels Endorse Ketamine Nasal Spray for Resistant Depression - Medscape - Feb 13, 2019.