Esketamine (Spravato) FDA approved for Treatment Resistant Depression.

Esketamine is a glutamate receptor modulator: acts as noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.

On March 05, 2019: FDA approved Spravato (esketamine) nasal spray, as an augmentation agent to antidepressant, for the treatment resistant depression management. Read the details of FDA press announcement here: FDA press release.


This post will summarize the phase 3 studies conducted in adults and elderly patients with treatment resistant depression. This will help us in answering following questions (answers summarized in the end):

  1. Starting dose for adult and elderly (> 65 yr age) patients.
  2. Frequency of dosing and titration schedule for esketamine.
  3. How many sprays needed and amount included in each device.
  4. Which antidepressants were added to esketamine in phase 3 studies.
  5. What are the common treatment-emergent adverse events (seen in >10% of patients).
  6. What black box warnings are included in label.
  7. How long should patient be monitored in physician’s office after dosing.
  8. What instructions are given to patients.
  9. Contraindications for esketamine use.
  10. Can esketamine be given to pregnant female and during breastfeeding.

Study#1: Adults with Treatment Resistant Depression:

A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (TRANSFORM-2)

Participants includes:

  • moderate-to-severe, non-psychotic, recurrent or persistent depression.
  • history of non-response to ≥2 antidepressants.

Patients were randomized to:

  • flexible dose (56 mg or 84 mg) of esketamine nasal spray + newly initiated oral antidepressant.
  • placebo nasal spray + newly initiated oral antidepressant.
  • On Day 1: oral antidepressant initiated (duloxetine, escitalopram, sertraline, or venlafaxine XR).

Esketamine Titration Schedule:

  • given twice per week for 4 weeks with following flexible dose regimen
  • Day 1: 56 mg
  • Day 4: either (a) increase to 84 mg or (b) remain at 56 mg (investigator’s discretion).
  • Day 8 and Day 11: either (a) increase to 84 mg (from 56 mg); (b) remain same, or (c) reduce to 56 mg (from 84 mg) (investigator’s discretion).
  • Day 15: (a) no dose increase permitted; (b) can reduce dose from 84 mg to 56 mg (if required for tolerability).
  • After Day 15: dose must remain stable.
  • esketamine and placebo provided in single use disposable nasal spray devices containing 200 μl of solution (i.e., two sprays).

Results:

(1) MADRS (Montgomery-Åsberg Depression Rating Score):

  • statistically significant clinical improvement in esketamine augmentation group.
  • Least Squares Mean Difference Standard Error [SE] from placebo nasal spray plus a newly initiated oral antidepressant: -4.0 [1.69], 95% Confidence Interval: -7.31, – 0.64; one-sided p=0.01.

(2) Onset of clinical response by 24 hours post-dose that is sustained through day 28:

  • numerically favored esketamine group but did not meet statistical significance.

(3) Response Rate:

  • ≥ 50% improvement in MADRS from baseline.
  • esketamine group: 69.3% vs.
  • placebo group: 52.0% (at 28 days)

(4) Remission rate:

  • MADRS total score ≤12 at day 28.
  • esketamine group: 52.5%
  • placebo group: 31.0%

(5) Common Treatment-emergent adverse events (>10% of patients)

  • esketamine group: metallic taste, nausea, vertigo, dizziness, headache, drowsiness, short lived perceptual changes, blurred vision, paraesthesia (tingling sensation) and anxiety.
  • placebo group: metallic taste and headache.

For more details regarding this study: ClinicalTrials.gov


Study#2: Elderly (≥ 65 years) with Treatment Resistant Depression:

A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression (TRANSFORM-3)

Patients were randomized to:

  • flexible dose of esketamine nasal spray + newly initiated oral antidepressant.
  • placebo nasal spray + newly initiated oral antidepressant.
  • On Day 1: oral antidepressant initiated (duloxetine, escitalopram, sertraline, or venlafaxine XR).

Esketamine Titration Schedule:

  • given twice per week for 4 weeks with following flexible dose regimen
  • Day 1: 28 mg.
  • Day 4: either 28 mg or 56 mg.
  • All subsequent doses may be 28, 56 or 84 mg.
  • esketamine and placebo provided in single use disposable nasal spray devices containing 200 μl of solution (i.e., two sprays).

Results:

  • statistical significance for the primary endpoint for the overall patient population studied was narrowly missed.
  • results favored the esketamine nasal spray plus a newly initiated oral antidepressant group.

Common Treatment-emergent adverse events (>10% of patients)

  • esketamine group: dizziness, nausea, headache, fatigue, increased blood pressure, vertigo and short lived perceptual changes.
  • placebo group: none.

For more details regarding this study: ClinicalTrials.gov


ANSWERS (SUMMARIZED) BASED ON THESE PHASE 3 STUDIES AND PACKAGE INSERT

(1) Starting dose for adult and elderly (> 65 yr age) patients.

  • Adults: 56 mg
  • Elderly (> 65 yr): 28 mg

(according to phase 3 trials conducted- details above)


(2) Frequency of dosing and titration schedule for esketamine.

Induction Phase (Weeks 1 to 4):

  • Administer twice per week.
  • Day 1: starting dose: 56 mg.
  • Subsequent doses: 56 mg or 84 mg

Maintenance Phase (Weeks 5 to 8):

  • Administer once weekly: 56 mg or 84 mg.

Maintenance Phase (Weeks 9 and after):

  • Administer every 2 weeks or once weekly: 56 mg or 84 mg

(3) How many sprays needed and amount included in each device.

  • 2 sprays needed.
  • single use disposable nasal spray devices contains 200 μl of solution = 2 sprays.
  • nasal spray device delivers a total of 28 mg of esketamine.
  • use 2 devices: for a 56 mg dose
  • use 3 devices: for an 84 mg dose.
  • use with a 5-minute rest between use of each device.

(4) Which antidepressants were added to esketamine in phase 3 studies.

  • duloxetine
  • escitalopram
  • sertraline
  • venlafaxine XR

(5) What are the common treatment-emergent adverse events (seen in >10% of patients).

  • Adults: metallic taste, nausea, vertigo, dizziness, headache, drowsiness, short lived perceptual changes, blurred vision, paraesthesia (tingling sensation) and anxiety.
  • Elderly: dizziness, nausea, headache, fatigue, increased blood pressure, vertigo and short lived perceptual changes.
  • According to package insert (incidence ≥5% and at least twice that of placebo plus oral antidepressant): dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.

(6) What black box warnings are included in label.

  • sedation and difficulty with attention
  • judgment and thinking (dissociation)
  • abuse and misuse
  • suicidal thoughts and behaviors

(7) How long should patient be monitored in physician’s office after dosing.

  • minimum 2 hours.
  • Because of the risks of sedation and dissociation, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.

(8) What instructions are given to patients.

  • avoid food for at least 2 hours before administration.
  • avoid drinking liquids at least 30 minutes prior to administration.
  • monitored for 2 hours after each session.
  • patient should not drive or operate machinery until the next day after a restful sleep.

(9) Contraindications for esketamine use.

  • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation: Monitor blood pressure prior to dosing and check every 40 minutes.
  • Intracerebral hemorrhage.
  • Hypersensitivity to esketamine, ketamine, or any of the excipients.

(10) Can esketamine be given to pregnant female and during breastfeeding.

  • may cause fetal harm: not recommended during pregnancy.
  • women of reproductive potential should consider pregnancy planning and prevention.
  • advise patients that breast-feeding is not recommended during treatment.

REFERENCES:

  1. FDA news release (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761)
  2. Janssen Pharmaceutical Companies of Johnson & Johnson data press release (pdf)
  3. SPRAVATO package insert (pdf)

Dr. Harvinder Singh, M.D.

(Admin & Course Instructor)


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Responses

  1. Very interesting… we are thinking of starting it where I work…

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