SPRAVATO® (esketamine) CIII Nasal Spray:
The First and Only N-Methyl D-Aspartate (NMDA) Receptor Antagonist Approved in Conjunction With an Oral Antidepressant for the Treatment of Adults With Treatment-Resistant Depression

INDICATIONS AND USAGE

SPRAVATO® is indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.

Limitations of Use:

  • The effectiveness of SPRAVATO® in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of SPRAVATO® does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO®.
  • SPRAVATO® is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO® as an anesthetic agent have not been established.

WARNING: SEDATION, DISSOCIATION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning

  • Risk for sedation and dissociation after administration. Monitor patients for at least two hours after administration (5.1, 5.2).
  • Potential for abuse and misuse. Consider the risks and benefits of using SPRAVATO® prior to use in patients at higher risk of abuse. Monitor for signs and symptoms of abuse and misuse (5.3).
  • SPRAVATO® is only available through a restricted program called the SPRAVATO® REMS (5.4).
  • Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO® is not approved for use in pediatric patients (5.5).

 

Significant Unmet Need for Patients with TRD

For decades, pharmacologic treatments for major depressive disorder (MDD) have focused on modulating the level of monoamine neurotransmitters in the brain.1 While antidepressants (ADs) have helped most patients with MDD, the landmark STAR*D trial2 found one-third of patients did not achieve remission by the third line of therapy.3 Remission rates were progressively lower in each subsequent therapy line and only 14% of patients achieved remission after the third line of therapy.3

 

For those with TRD, some patients may benefit from treatment with a different kind of medication.1,3 TRD may be defined as failure of treatment to produce response or remission for patients after two or more treatment attempts of adequate dose and duration.1,4

An option for adults with TRD is SPRAVATO® (esketamine) CIII Nasal Spray, the first and only NMDA receptor antagonist approved in conjunction with an oral AD for adults with TRD.5

THE FIRST NMDA Receptor Antagonist APPROVED FOR TRD

SPRAVATO®, the S-enantiomer of racemic ketamine, is the first and only treatment (in conjunction with an oral AD) formulated for nasal spray use in TRD (Figure 1).5 The mechanism by which it exerts its antidepressant effect is unknown.5

 

Clinical Program Overview

SPRAVATO® (esketamine) CIII Nasal Spray was evaluated for safety in more than 1700 adult patients with TRD.4 This program consisted of 5 phase 3 studies (3 short-term and 2 long-term) and 1 phase 2 study.5

Study 1 and Study 2 evaluated the efficacy and safety of SPRAVATO® plus a newly initiated oral AD in comparison to placebo nasal spray plus oral AD.7,8 In Study 1:

  • The patients were moderately to severely depressed with a mean baseline Montgomery-Asberg Depression Rating Scale* (MADRS) score of 376,9
  • A third of patients reported a history of suicidal ideation10,

*MADRS is a 10-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on MADRS range from 0 to 60, with higher scores indicating more severe depression.
†Observed at screening during Study 1. Patients with intent to act or recent suicidal behavior were excluded from the study.8

Short-Term Efficacy—Superior Improvement at Week 4

Study 17, was a pivotal phase 3, short-term (4-week), randomized, double-blind, multicenter, superiority trial in which the primary endpoint was change in MADRS score from baseline to day 28.7 Patients in both treatment arms were discontinued from their current oral AD to which they had previously not responded and initiated a new oral AD (Figure 2).7 The efficacy analyses included 223 adult patients randomized to receive flexible dosing of SPRAVATO® 56 mg or 84 mg plus an oral AD vs placebo nasal spray plus oral AD.7 SPRAVATO® plus an oral AD achieved superior improvement in depression symptoms vs placebo nasal spray plus and oral AD at Day 28.5

  • Most of the treatment difference between SPRAVATO® and placebo was observed at 24 hours5
  • Between 24 hours and Day 28, both SPRAVATO® and placebo groups continued to improve5
  • The difference between the groups generally remained but did not appear to increase over time through Day 285

 

Long-Term Efficacy—Significantly Delayed Time to Relapse

Study 28 was a long-term, randomized, double-blind, multicenter, controlled, maintenance-of-effect study conducted in adult patients with TRD who had achieved stable remission or stable response after 16 weeks of SPRAVATO® plus oral AD (induction and optimization phases).8 The primary endpoint was time to relapse during the maintenance phase among stable remitters (Figure 3).8

 

Stable remitters who continued treatment with SPRAVATO® plus oral AD:

  • Demonstrated statistically significant superiority in delayed time to relapse (P = .003)8
  • Were 51% less likely to relapse5

The study also showed that patients who were stable responders to SPRAVATO® plus an oral AD and continued treatment were 70% less likely to relapse than patients who switched to placebo nasal spray plus oral AD during the maintenance phase (Figure 4).5 Additionally, time to relapse was significantly delayed in stable responders (2-sided P = .001).8

  • Stable remission was defined as MADRS total score ≤12 at least 3 of the last 4 weeks of the optimization phase5
  • Stable response was defined as ≥50% reduction in the MADRS total score from baseline in each of the last 2 weeks of the optimization phase but not meeting criteria for stable remission5,8
  • Stable remitters and stable responders were not overlapping groups8
  • Relapse was defined as a MADRS total score of ≥22 for 2 consecutive weeks and/or hospitalization for worsening depression, or any other clinically relevant event determined per clinical judgment to be suggestive of a relapse of depressive symptoms5

 

Test Your Knowledge Question

Discussion of the Test Your Knowledge Question

Preferred response: C. Both of the above.
Explanation: (a) In Study 1, there was superior improvement in depression symptoms observed with SPRAVATO® plus oral AD compared with placebo nasal spray plus oral AD at Week 4. (b) The most common adverse reactions with SPRAVATO® plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increase, vomiting, and feeling drunk.
Here is how your colleagues answered:

 

Safety and Tolerability

Table 1 lists the adverse reactions occurring in 2% or more of patients treated with SPRAVATO® plus oral AD at any dose and at a greater rate than patients treated with placebo nasal spray plus oral AD in short-term studies.

 

Contraindications.

SPRAVATO® is contraindicated in patients with:

  • Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation5
  • History of intracerebral hemorrhage5
  • Hypersensitivity to esketamine, ketamine, or any of the excipients5

Sedation.

  • In clinical trials, 48% to 61% of SPRAVATO®-treated patients developed sedation, and 0.3% to 0.4% of SPRAVATO®-treated patients experienced loss of consciousness.5
  • Because of the possibility of delayed or prolonged sedation, patients must be monitored by a healthcare provider 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.5
  • Closely monitor for sedation with concomitant use of SPRAVATO® with CNS depressants [see Drug Interaction (7.1)].5
  • SPRAVATO® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).5

Dissociation.

  • The most common psychological effects of SPRAVATO® were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO®-treated patients developed dissociative or perceptual changes). Given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO®; treatment should be initiated only if the benefit outweighs the risk.5
  • Because of the risks of dissociation, patients must be monitored by a healthcare provider 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.5
  • SPRAVATO® is available only through a restricted program under a REMS.5

Blood Pressure.

  • SPRAVATO® causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after SPRAVATO® administration and last approximately 4 hours.5
  • Approximately 8% to 19% of SPRAVATO®-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO® is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage). Before prescribing SPRAVATO®, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO® outweigh its risk.5
  • Assess BP prior to administration of SPRAVATO®. In patients whose BP is elevated prior to SPRAVATO® administration (as a general guide: >140/90 mmHg), a decision to delay SPRAVATO® therapy should take into account the balance of benefit and risk in individual patients.5
  • BP should be monitored for at least 2 hours after SPRAVATO® administration. Measure blood pressure around 40 minutes post-dose and subsequently as clinically warranted until values decline. If BP remains high, promptly seek assistance from practitioners experienced in BP management. Refer patients experiencing symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, or focal neurological deficits) immediately for emergency care.5
  • Closely monitor blood pressure with concomitant use of SPRAVATO® with psychostimulants or monoamine oxidase inhibitors (MAOIs) [see Drug Interactions (7.2, 7.3)].5
  • In patients with history of hypertensive encephalopathy, more intensive monitoring, including more frequent blood pressure and symptom assessment, is warranted because these patients are at increased risk for developing encephalopathy with even small increases in blood pressure.5

Risk Evaluation and Mitigation Strategy.

The FDA approved SPRAVATO® with a REMS.5 The goal of the SPRAVATO® REMS is to mitigate the risks of serious adverse outcomes resulting from sedation and dissociation caused by SPRAVATO® administration, and abuse and misuse of SPRAVATO®, by5:

  • Ensuring that SPRAVATO® is only dispensed to and administered in a medically supervised healthcare setting that monitors these patients.
  • Ensuring that pharmacies and healthcare settings that dispense SPRAVATO® are certified.
  • Ensuring that each patient is informed about the serious adverse outcomes resulting from sedation and dissociation and the need for monitoring.
  • Enrollment of all patients in a registry to further characterize the risks and support safe use.

Because of the possibility of delayed or prolonged sedation or dissociation, patients must be monitored by a healthcare professional for at least 2 hours following each treatment session until the clinician determines the patient is safe to leave.5

ADDITIONAL Safety INFORMATION

Abuse and misuse.

  • SPRAVATO® is a Schedule CIII controlled substance and may be subject to abuse and diversion. Assess each patient’s risk for abuse or misuse prior to prescribing SPRAVATO®, and monitor all patients receiving SPRAVATO® for the development of these behaviors or conditions, including drug-seeking behavior, while on therapy5
  • Individuals with a history of drug abuse or dependence are at greater risk; therefore, use careful consideration prior to treatment of individuals with a history of substance abuse disorder. Monitoring for signs of abuse is recommended5

Dependence.

  • Physical dependence has been reported with prolonged off-label use of ketamine. There were no withdrawal symptoms captured up to 4 weeks after cessation of SPRAVATO® treatment5
  • SPRAVATO®-treated patients should be monitored for symptoms and signs of physical dependence upon discontinuation of the drug5

Please see accompanying Brief Summary of the full Prescribing Information. Please see full Prescribing Information including Boxed WARNINGS at www.SpravatoHCP.com.

Discontinuation Rates Due to Adverse Reactions Were Less Than 5% Across Short- and Long-Term Clinical Trials5,‡,§

In short-term studies in adults, 4.6% of adults treated with SPRAVATO® plus oral AD discontinued treatment vs 1.4% of patients who received placebo nasal spray plus oral AD (Figure 5).5

 

Across all phase 3 studies, adverse reactions leading to discontinuation were5:

  • Anxiety (1.2%)
  • Depression (0.9%)
  • Blood pressure increased (0.6%)
  • Dizziness (0.6%)
  • Suicidal ideation (0.5%)
  • Dissociation (0.4%)
  • Nausea (0.4%)
  • Vomiting (0.4%)
  • Headache (0.3%)
  • Muscular weakness (0.3%)
  • Vertigo (0.2%)
  • Hypertension (0.2%)
  • Panic attack (0.2%)
  • Sedation (0.2%)

‡Induction phase only for Study 1 and a second similar 4-week study.7
§Maintenance phase only for Study 2.8

Dosing Schedule

SPRAVATO® does not require daily dosing and should be administered in conjunction with an oral AD.5 SPRAVATO® is patient-administered with a single-use device that delivers a total of 28 mg of SPRAVATO® in 2 sprays (1 spray per nostril) with each device. SPRAVATO® is self-administered using 2 devices (for a 56-mg dose) or 3 devices (for an 84-mg dose), depending on the dose prescribed, with a 5-minute rest between use of each device to allow medication to absorb.5

  • The recommended treatment schedule for SPRAVATO® (esketamine) CIII Nasal Spray is divided into 2 phases: the induction phase and the maintenance phase5
  • SPRAVATO® is administered twice weekly during the induction phase. The recommended administration during this 4-week phase is a 56-mg dose on Day 1 with subsequent doses of 56 mg or 84 mg based on clinical judgment5
  • In the subsequent maintenance phase, the recommended dose is 56 or 84 mg once weekly from weeks 5 to 8, and then 56 or 84 mg every 2 weeks or once weekly5
  • Dosing frequency should be individualized to the lowest frequency needed to maintain remission/response5

Impaired Ability to Drive and Operate Machinery.

Patients should be instructed not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery until the next day, following a restful sleep.5

Become a Certified SPRAVATO® Treatment Center

Practices interested in becoming a certified SPRAVATO® treatment center11 should evaluate the following requirements and considerations:

  • Handling and storage of Schedule III products
  • Space requirements for self-administration and monitoring
  • Staff and equipment for post-administration monitoring
  • Ability and capacity for scheduling frequent appointments
  • Controlled distribution network
  • Insurance benefits investigation and reimbursement management

Certified SPRAVATO® treatment centers must comply with full SPRAVATO® REMS requirements, which can be obtained at www.spravatorems.com or by calling 855-382-6022.

Locate a Certified SPRAVATO® Treatment Center

To locate a certified SPRAVATO® treatment center, visit www.spravatohcp.com/findacenter, or call Janssen CarePath at 844-777-2828.

Conclusions

SPRAVATO® is the first and only NMDA receptor antagonist approved, in conjunction with an oral AD, for TRD in adults. It is one of the first unique pharmacologic approaches in decades for adults who have not experienced response or remission following at least 2 oral ADs of adequate dose and duration to treat their current depressive episode.

SPRAVATO® plus an oral AD demonstrated statistically superior improvement in depression symptoms after 4 weeks, based on the short-term study.5 In the long-term maintenance study, SPRAVATO® significantly delayed time to relapse.5

SPRAVATO® demonstrated safety in short- and long-term studies conducted in more than 1700 adult patients with TRD, signaling the opening of a new therapeutic frontier for appropriate adult patients with TRD.5

For information on how to become a certified
SPRAVATO® treatment center, please visit
spravatotreatmentcenter.com

REFERENCES

  1. Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015;23(1):1–21. PubMed CrossRef
  2. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. National Institute of Mental Health website. https://www.nimh.nih.gov/funding/clinical-research/practical/stard/index.shtml. Accessed March 6, 2019.
  3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917. PubMed CrossRef
  4. Gaynes BN, Asher GA, Gartlehner G, et al. Definition of Treatment-Resistant Depression in the Medicare Population. Rockville, MD: Agency for Healthcare Research and Equality (US); 2018. PubMed
  5. SPRAVATO® (esketamine) CIII Nasal Spray [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2020.
  6. Duman RS, Adhajanian GK, Sanacora G, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–249. PubMed CrossRef
  7. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–438. PubMed CrossRef
  8. Daly EJ, Trivedi M, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893–903. PubMed CrossRef
  9. Cusin C, Yang H, Yeung A, et al. Rating scales for depression. In: Baer L, Blais MA, eds. Handbook of Clinical Rating Scales and Assessment in Psychiatry and Mental Health. New York, NY: Humana Press; 2010:7–35.
  10. Data on file. Janssen Pharmaceuticals, Inc, Titusville, NJ.
  11. Janssen Pharmaceuticals, Inc. SPRAVATO® Treatment Center. https://www.spravatotreatmentcenter.com. April 2019.
Please see the Brief Summary of full Prescribing Information, including Boxed WARNINGS.

 

Go to www.spravatohcp.com to view SPRAVATO® full Prescribing Information, including Boxed WARNINGS.

September 2020 cp-158049v2

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