WASHINGTON -- The FDA (Spravato) nasal spray, to be used with an oral antidepressant, for treatment-resistant depression late Tuesday.
Esketamine is the S-enantiomer of ketamine, an FDA-approved anesthetic and a street drug called Special K which is known for its dissociative and hallucinogenic effects. Agency approval came with a Risk Evaluation and Mitigation Strategy (REMS) to restrict esketamine to certified treatment centers where patients are monitored for 2 hours, prohibit it from being dispensed directly to patients, and enroll patients in a registry.
Esketamine has the potential to be a game-changer in treating depression, said Walter Dunn, MD, PhD, of the University of California Los Angeles, and a member of the FDA's Psychopharmacologic Drugs Advisory Committee.
"The approval of esketamine is a groundbreaking advance in the treatment of depression, given its novel mechanism of action and time frame at which it produces clinically meaningful improvements," he told ľֱ.
The drug "is different than traditional antidepressants that modulate monoamine activity," he added. "This has implications for treatment-resistant patients who have not responded to standard antidepressants, as esketamine potentially offers a better chance at achieving remission than traditional medications."
Esketamine works on the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor in the brain. Its onset of action can be , improving depression symptoms in hours or days, as opposed to weeks for standard antidepressants.
The drug's approval came after only one positive short-term phase III trial. Drugmaker Janssen Pharmaceuticals brought five phase III studies to the FDA's advisory committee meeting in February: two of three short-term studies did not meet their primary endpoint, but a flexible dose trial in adults younger than 65 and a withdrawal maintenance-of-effect study were positive. Despite this, advisory committee members voted overwhelmingly to support the drug.
"There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition," Tiffany Farchione, MD, acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research, said in a statement. To date, the agency has approved only one other medication for treatment-resistant depression, a fixed-dose combination of fluoxetine and olanzapine (Symbyax).
Esketamine is designed to be administered intranasally twice a week for an initial 4 weeks, in conjunction with a newly initiated oral antidepressant. The proposed initial adult esketamine dose is 28-56 mg at each administration which can be titrated to 84 mg by week 2, with patients continuing treatment weekly for 4 more weeks, then weekly or every other week.
The drug will carry a that patients taking the drug are at risk for sedation and problems with attention, judgment, thinking, abuse, misuse, and suicidal thoughts and behaviors -- the major concerns underlying the REMS.
Also, patients with poorly controlled hypertension or pre-existing aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects. The most common adverse effects seen in the trials were disassociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, and vomiting.
Janssen said it plans to offer information about insurance coverage, out-of-pocket costs, and treatment support through its CarePath program. It did not, however, reveal the drug's list price. The company did not respond immediately to a request for comment.