FDA Approves Esketamine Nasal Spray (Spravato™) for Treatment-Resistant Depression

FDA, MSAs, Rx/Pharmacy on March 13, 2019
Posted by Leah King, PharmD, JD, Pharmacy Consultant

Earlier this month, the Food and Drug Administration (FDA) approved esketamine nasal spray, which will be marketed by Johnson & Johnson (J&J) under the trade name of Spravato™. Spravato is approved for use in conjunction with an oral antidepressant for treatment-resistant depression. The term “treatment-resistant” refers to those patients who have failed to achieve relief of depression symptoms from at least two other depression therapies. Spravato is being hailed as the first breakthrough in the treatment of depression since the drug Prozac was approved by the FDA in 1987.

In 2016, the FDA granted fast-track designation for two depression drugs that were in the drug approval pipeline. One of those drugs was J&J’s esketamine and the other drug was Allergan’s rapastinel.  Fast track designation is intended to expedite the development and approval of drugs used to treat serious medical conditions for which there is an unmet medical need. No one can doubt the impact of depression in today’s world. The incidence of major depressive disorder, or MDD, is about 300 million people globally [1]. In the United States, it is the leading cause of disability in individuals ages 15 to 44 [2]. Approximately 50% of patients with depression are taking antidepressant drugs [3]. About one-third of those patients fail to achieve relief of depression symptoms with the medications they are taking [4].

Esketamine is structurally similar to another drug called ketamine; in fact, they are mirror images of each other. Ketamine was FDA approved in 1970 and has been used extensively as an anesthetic during surgical procedures for both humans and animals. When administered, ketamine produces a dissociative effect through its action on central nervous system receptors. In large part due to the dissociative effect it produces, ketamine became a drug of abuse and was ultimately classified as a schedule III controlled substance in 1999. On the street, ketamine is known as “Vitamin K” or “Special K.” Although ketamine is not FDA approved for depression or chronic pain, it has developed a reputation for being useful in both of these conditions. For these reasons, ketamine infusion clinics have surfaced all over the United States. As this therapy is often not covered by insurance for depression or pain, patients have resorted to paying for ketamine infusion therapy on a cash basis.

Esketamine produces similar effects to those of ketamine, through its activity in the central nervous system. Esketamine acts on a different group of receptors than traditional antidepressants. Drugs such as fluoxetine (Prozac) and venlafaxine (Effexor) exert their antidepressant effect by blocking serotonin and norepinephrine receptors. Esketamine, on the other hand, has affinity for N-methyl-D-aspartate (NMDA)/glutamate receptors and gamma-amino-butyric acid (GABA) receptors. Most notably, esketamine has been found to have an extremely short onset of action, which is believed to have tremendous value in those patients who experience episodes of major depression with suicidal tendencies. In clinical trials, esketamine has demonstrated a 60-70% response rate in study populations with treatment-resistant depression. Due to the abuse potential of esketamine, it will be available through a limited distribution network of pharmacies under a Risk Evaluation and Mitigation Strategy (REMS) program.

The approved label for Spravato will contain a warning that details possible side effects. Patients utilizing Spravato are at risk for sedation, difficulty with attention, judgment and thinking (dissociation), abuse, misuse and suicidal thoughts or behaviors. Patients with unstable or poorly controlled hypertension or certain types of pre-existing vascular disorders may be at higher risk of adverse cardiovascular or cerebrovascular side effects. Due to these risks, Spravato must be administered in a certified medical office where the health care provider can monitor the patient for at least two hours after administration of each dose. The recommended dosing is once or twice per week. With instruction from the health care provider, a patient will self-administer Spravato but will not be permitted to take the nasal spray home.  The health care professional will make a determination as to when the patient is ready to leave the medical office, at which point the patient must make arrangements to get home. Patients will be advised not to drive or operate heavy machinery for the rest of the day.[5]  

Even in the absence of preexisting disease, depression is a common occurrence for injured workers. For this reason, the FDA’s approval of esketamine will likely have a significant effect for workers’ compensation carriers and Medicare Set-Aside allocation amounts. Johnson & Johnson has stated that the wholesale cost of each treatment will range from $590 to $885, depending on the dose. Based on those costs, twice-weekly treatment will cost anywhere between $4,720 and $6,785 per month [6]. In addition to these costs, there will be costs associated with the instruction and monitoring which will be rendered by the health care provider. We’ll continue to post updates here as we learn more about this breakthrough therapy.

[1] World Health Organization. https://www.who.int/news-room/fact-sheets/detail/depression

[2] Anxiety and Depression Association of America. https://adaa.org/about-adaa/press-room/facts-statistics

[3] National Institute of Mental Health. https://www.nimh.nih.gov/health/statistics/major-depression.shtml#part_155720

[4] https://www.janssen.com/fda-advisory-committee-recommends-approval-spravato-esketamine-nasal-spray-ciii-adults-treatment

[5] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm

[6] https://www.npr.org/sections/health-shots/2019/03/05/700509903/fda-clears-esketamine-nasal-spray-for-hard-to-treat-depression