The independent […] Summary of Risk Management Plan for esketamine nasal spray. For TRD (defined by the manufacturer as MDD that has not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode), esketamine is formulated as a single-use nasal spray device.18 In contrast to intravenous ketamine, which is limited to outpatient clinics, intranasal administration is easier and could allow for increased access to therapy.19 Each device contains 28 mg of drug, delivered as one spray in each nostril.18 The maximum dose studied in clinical trials was 84 mg; therefore, multiple devices may be required. The FDA granted this application Fast Track and Breakthrough Therapy designations. Source: Janssen Inc.: personal communication, 2019 Feb 1; FDA briefing document.18, Safety information for the completed phase III trials are reported here and in Table 2. Recent Activity for . d TRD was defined as nonresponse (≤ 25% improvement) to two to nine oral antidepressants in the current episode of depression, at an adequate dose for at least six weeks in duration. d 2-sided P value. Definitions of treatment resistant depression vary; one accepted definition is lack of response to two or more antidepressants. Treatment-resistant depression: prevalence, risk factors, and treatment strategies.
On the basis of findings from the relapse prevention study ... in place for esketamine ‘implies approval without knowledge of the potential negative consequences of esketamine prescribing.’ Such is not the case. Whiteford HA, Degenhardt L, Rehm J, et al. This subpopulation of patients with TRD could benefit from esketamine. Two (0.3%) deaths occurred in the optimization and maintenance phase of the SUSTAIN 2 trial — one due to acute respiratory and cardiac failure, and the second due to completed suicide (Janssen Inc.: personal communication, 2019 Feb 1). Janssen Research & Development, LLC. Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The use of this document outside of Canada is done so at the user’s own risk. 2019; Gould TD, Zarate CA, Jr., Thompson SM. With subsequent esketamine dosing, the severity of dissociative symptoms appeared to lessen. Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policymakers make well-informed decisions and thereby improve the quality of health care services. Summary of Esketamine reviews: 5.7: 48 reviews : Reviews may be moderated or edited before publication to correct grammar and spelling or to remove inappropriate language and content. Inhaled esketamine is also being investigated in a phase II study for treatment-resistant bipolar depression.56, Cited concerns surrounding intravenous ketamine for depression may inform potential uptake issues for esketamine. In SUSTAIN 1, five patients reported one of the following adverse events: disorientation, hypothermia, lacunar stroke, sedation, and suicidal ideation; and one patient reported autonomic nervous system imbalance and simple partial seizure. Esketamine is the S-enantiomer of racemic ketamine and is being developed as a nasal spray device for potential therapeutic use in patients with TRD. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. There remains an unmet need for a safe and effective treatment of TRD for which esketamine offers the potential to address. SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. Investigational drugs in recent clinical trials for treatment-resistant depression. A very good summary of @eturnermd1’s recent Lancet Psychiatry ... the USA’s Food and Drug Administration approved Spravato (esketamine), on the basis of just one efficacy study. These symptoms could have served as a cue to indicate to patients that they had received the drug, thus compromising the blinding of treatment allocation in the randomized trials. We should cautiously welcome this new therapeutic option On 5 March 2019 the US Food and Drug Administration approved esketamine nasal spray in conjunction with an oral antidepressant for people with treatment resistant depression. Treating depression after initial treatment failure: directly comparing switch and augmenting strategies in STAR*D. AG-risperidone: 0.25mg, 0.5mg, 1mg, 2mg, 3mg and 4mg tablets [product monograph]. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. Of these serious adverse events, five were considered related to esketamine — anxiety, delusion, delirium, suicidal ideation, and suicidal attempt. The heterogeneity of the esketamine formulation for IN administration was moderate to high, and significant (p = 0.014, I 2 = 62.54%). Allergan. Two patients in the placebo group reported feelings of despair and dizziness. These adverse events all occurred rapidly after receiving a dose of esketamine, peaked around 40 minutes, and resolved within four hours, 1.5 hours, and one hour, respectively. Blood pressure elevations, dissociative symptoms, and sedation occurred more often in the esketamine treatment group. 2017; Thase ME. ... potential participants on the basis of nasal abnor- Withdrawal due to adverse events was not reported for two of the studies. SBDs for pharmaceuticals, biologics, and medical devices are now available exclusively on the Canada.ca … AVP-923 (Nuedexta, Avanir) and AVP-786 are combinations of dextromethorphan and quinidine, and being investigated in phase II trials for TRD. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. The most common definition of TRD is the inadequate response to two or more antidepressants.7,10,11 However, there is no clear consensus surrounding this definition, with only 17% of treatment studies closely matching this definition.10 Variations in this definition can be attributed to inconsistencies in the use of adjunctive therapies, variable dose and duration of an adequate treatment trial, and whether treatment failure occurred in the current depressive episode. f MADRS ≤ 12. NCT03739203: The object of this study is to evaluate the efficacy, safety and tolerability of cariprazine as an adjunctive treatment to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who have had an inadequate response to antidepressants alone. The information in the summary report is provided for general information only and the contents of the summary report do not constitute medical or other professional advice. Esketamine nasal spray was approved by the European Commission for use in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI), in adult patients with treatment-resistant major depressive disorder (TRD) in December 2019. While it was approved decades ago as an anesthetic by the FDA, it is used off-label to treat depression. ICH GCP. In SUSTAIN 2 — a longer-term, open-label safety study that followed participants for up to one year — 55 patients reported 68 serious adverse events, with the most common events occurring in greater than two patients including depression, suicidal ideation, suicide attempt, nephritis, anxiety, and gastroenteritis. Spravato contains the active substance esketamine. 2. No cases of psychosis, or ulcerative or interstitial cystitis, were reported. News release: FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. As with the response rates, remission rates were lower in the elderly patients studied in the TRANSFORM-3 trial: 17.5% for the esketamine plus antidepressant group versus 6.7% for the placebo plus antidepressant group. Orally administered ketamine has recently been investigated for TRD in a phase I proof-of-concept study.34 In this study, oral ketamine decreased depressive symptoms and was well-tolerated. The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that … TRANSFORM-2 and SUSTAIN-1 were the basis for regulatory approval in the United States. NCT03097133: A study to evaluate the efficacy and safety of intranasal esketamine in addition to comprehensive standard of care for the rapid reduction of the symptoms of major depressive disorder, including suicidal ideation, in adult participants assessed to be at imminent risk for suicide (Aspire II). van de Loo AJ, Bervoets AC, Mooren L, et al. The psychology of suicidal behaviour. The documents include regulatory, safety, effectiveness and quality (chemistry and manufacturing) considerations. Remission Rates: In the TRANSFORM-1 and TRANSFORM-2 trials, remission rates (i.e., defined as a MADRS score of 12 or less) ranged from 36.0% to 52.5% in the esketamine plus antidepressant group compared with 31% of patients in the placebo plus antidepressant group. Because of the trial design and choice of comparator, this evidence cannot be used to assess how esketamine compares with other options available to patients with TRD, such as adjunctive therapy. Tulrampator (CX-1632, RespireRx) is an orally administered drug that acts on the AMPA receptor. Subject to the aforementioned limitations, the views expressed herein do not necessarily reflect the views of Health Canada, Canada’s provincial or territorial governments, other CADTH funders, or any third-party supplier of information. Molecular pharmacology and neurobiology of rapid-acting antidepressants. Data sources include IBM Watson Micromedex (updated 3 Mar 2021), Cerner Multum™ (updated 1 Mar 2021), ASHP (updated … NCT02417064: A study to evaluate the efficacy, safety, and tolerability of fixed doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression (TRANSFORM-1). Rapastinel (GLYX-13, Allergan) is a weak agonist of the NMDA receptor being investigated in phase III trials for monotherapy in TRD. PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN. EJ Daly, JB Singh, M Fedgchin, K Cooper, P Lima - JAMA, 2018 2) Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. VTGN's PH94B in Phase 3 clinical trial for treatment of social anxiety disorder was only able to beat placebo by 2 to 12 points on the 100-point LSAS scale. While definitions of so-called “treatment-resistant” depression vary, this generally refers to patients with persistent depression after attempted management with two or more medications. In addition to ketamine and esketamine, there are several other compounds in development for TRD: In addition to TRD, intranasal esketamine is being investigated in phase III trials for patients with MDD who are at imminent risk for suicide.52-54 Suicide remains a significant global burden, accounting for 1.5% of worldwide mortality.55 This indication received a breakthrough designation from the FDA in 2016. The need for medical supervision also poses the question of organizing the distribution of this drug in Canada: if patients are required to obtain the medication at their retail pharmacy, policies may be required to ensure that the patient does not self-administer the medication. Source: Janssen Inc.: personal communication, 2019 Feb 1). About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system. Furthermore, there remains a lack of evidence comparing intranasal esketamine to current adjunctive strategies for TRD. Axsome Therapeutics, Inc. NCT02741791: A study to assess the efficacy and safety of AXS-05 in subjects with treatment resistant major depressive disorder (STRIDE-1). This screening period allowed for the inclusion of patients who had previously failed one antidepressant to be randomized in the trial if they also demonstrated nonresponse to a second antidepressant treatment during the screening phase. Janssen Research & Development, LLC. Understanding intravenous ketamine infusion therapy. Regular alerts updated the search until project completion; only citations retrieved before March 13, 2019 were incorporated into the analysis. In comparison, 38.9% to 52% of patients who received placebo with a newly initiated antidepressant were stable responders. Table 2: Summary of Key Efficacy Outcomes From Four of the Phase III Trials. Cardiovascular effects of esketamine nasal spray, combined with an oral antidepressant, were evaluated in 1708 esketamine … Summary. National Institute of Mental Health (NIMH). Meanwhile, the hazards of using esketamine on a “maintenance” basis were unknown. In March this year, the USA’s Food and Drug Administration approved Spravato (esketamine), on the basis of just one efficacy study. CI = confidence interval; Esk = esketamine plus newly initiated oral antidepressant; IND = induction phase; LSM = least squares means; N/A = not applicable; MADRS = Montgomery-Åsberg Depression Rating Scale; PL = placebo nasal spray plus newly initiated oral antidepressant; SD = standard deviation. Although esketamine is formulated in a more convenient nasal spray device, it must be administered under direct medical supervision. None of the available options have demonstrated superiority in improving clinical outcomes for patients with TRD.7 Available therapies are also often limited by significant side effects, such as weight gain and sedation. Language Assistance Available: Español | ç¹é«ä¸æ | Tiếng Viá»t | íêµì´ | Tagalog | Ð ÑÑÑкий | اÙعربÙØ© | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | æ¥æ¬èª | ÙØ§Ø±Ø³Û | English, U.S. Department of Health and Human Services, Approval Date(s) and History, Letters, Labels, Reviews for NDA 211243, Instructions for Downloading Viewers and Players, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf
The U.K. approved the world’s first COVID-19 human challenge trial By Jonathan Lambert February 18, 2021. NIHR Innovation Observatory. Serafini G, Howland RH, Rovedi F, Girardi P, Amore M. The role of ketamine in treatment-resistant depression: a systematic review. Esketamine’s psychoactive properties give it the potential for addiction and abuse; policies to limit off-label use and guide esketamine distribution would be important to prevent diversion. NoP = number of patients; NR = not reported; N/A = not applicable. 05 May 2020 Schedule affected by COVID-19. It has not yet been approved in any country but is under priority review at Health Canada and recently received FDA approval. It was investigated in a phase II trial for TRD, which demonstrated preliminary efficacy and safety. The search was limited to English-language documents but not limited by publication year. Just two positive trials formed the basis of the FDA approval: one short-term trial that demonstrated efficacy up to 4 weeks, and -- in an unusual move by the FDA -- … Spravato™ or Esketamine was FDA approved for use in treatment resistant depression on March 5, 2019. This is a summary of the risk management plan (RMP) for esketamine nasal spray.
Because of the potential driving impairment shortly after esketamine administration, travelling to the physician’s clinic and back may be problematic for patients, especially in areas with limited public transportation. Depression and other common mental disorders: global health estimates. 2. Serious adverse events in the placebo group were only reported in TRANSFORM-3 (3.1%). NCT03039192: A study of the efficacy and safety of intranasal esketamine in the rapid reduction of symptoms of major depressive disorder, in adult at imminent risk for suicide (Aspire I). Table 4: Number of Patients With Adverse Events in the Phase III Trials. No statistical tests were reported. This information will be compiled in a Post-Authorization Activity Table (PAAT). This strategy includes both augmentation (i.e., adding a non-antidepressant medication) and combination (i.e., adding an antidepressant from a different class).11 There is low-quality evidence to suggest that adjunctive therapy is more effective than switching therapy in patients who had a partial response to the initial antidepressant and have residual symptoms.7,11,32 Adjunctive medications that are recommended to try first are the following atypical antipsychotic drugs: aripiprazole, quetiapine, and risperidone (off-label).11,33 If a patient fails to respond despite these first-line options, they can trial the following adjunctive treatments: bupropion, mirtazapine, brexpiprazole, olanzapine, lithium, and thyroid hormone.11 Lastly, non-drug approaches to be considered for patients with TRD include psychotherapy and neurostimulation (e.g., transcranial magnetic stimulation, electroconvulsive therapy). Some of the clinical studies leading to registration excluded potential participants on the basis of nasal abnormalities that could impede absorption. While both trials used flexible esketamine dosing, the objective of TRANSFORM-2 was to assess short-term (4 week) efficacy of esketamine while SUSTAIN-1 aimed to assess durability of treatment effect over the long-term (event-driven study with no fixed duration). Spravato™ or Esketamine was FDA approved for use in treatment resistant depression on March 5, 2019. Avanir Pharmaceuticals. Garay RP, Zarate CA, Jr., Charpeaud T, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 1. disease burden and principles of care. Lam RW, McIntosh D, Wang J, et al. I. Patients were specifically excluded from any of the five studies if they had MDD with psychotic features, had previously demonstrated nonresponse to ketamine in the current depressive episode, had a history of suicidal ideations in the past six months, or had a history of a substance or alcohol use disorder. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Transient cardiovascular stimulatory effects have been reported with ketamine. Thus far, most research has been on ketamine infusions. Approval Date: 03/05/2019 Drugs@FDA information available about Spravato Persons with disabilities having problems accessing the PDF files below may call (301) 796-3634 for assistance. Definitions of treatment resistant depression vary; one accepted definition is lack of response to two or more antidepressants. An adjunctive strategy involves adding a second medication to the initial antidepressant. But “esketamine inhaler therapy” was a different animal altogether: a lower dose designed to minimize these effects, and thus be suitable for long-term use. However, MDD is a complex, heterogeneous disorder, and 10% to 30% of MDD patients do not respond to a sequence of multiple traditional antidepressant therapies.6,7. Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec. How is Spravato used? The FDA reports six deaths with esketamine during the development program; however, five of these deaths occurred after the drug was stopped.18 Three of these deaths were due to completed suicide, and three were due to one of following: a motor vehicle accident, sudden death, and a heart attack. The U.S. Food and Drug Administration (FDA) approved esketamine nasal spray for use in … Major depressive disorder (MDD) is a common and debilitating condition; on an annual basis, it is estimated that nearly 14 million Americans will have at least one episode of MDD. Plain language summary. CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. For patients in the esketamine treatment group, the frequency of serious adverse events ranged from 3.9% to 6.9%. NCT02484456: Antidepressant effects of the glycine receptor antagonist AV-101 (4-chlorokynurenine) in major depressive disorder. b Includes 24 mg, 54 mg, and 84 mg doses.
Summary of pharmacokinetic parameters. Janssen-Cilag International N.V. 2014-005206-37: A double-blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. NCT03675776: Study of rapastinel as monotherapy in patients with major depressive disorder (MDD). Center for Drug Evalulation and Research. Source: Janssen Inc.: personal communication, 2019 Feb 1. CANMAT advises this strategy may be best employed for patients in their first antidepressant trial and therefore may not be the optimal strategy for TRD (i.e., failed two or more antidepressants). medicament” (see www.swissmedic.ch) approved and authorized by Swissmedic. NCT01882829: Nuedexta in treatment-resistant major depression. Of note, the FDA grants a Breakthrough Therapy designation for drugs intended to treat a serious or life-threatening disease and where initial clinical data suggests that the drug may demonstrate substantial improvement over current therapies.28, The Canadian cost of esketamine is unavailable, as this product is not marketed in the country. The results of the phase III trials are summarized here and depicted in Tables 2 and 3. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. J&J prices ketamine-like depression treatment at $590-$885 for two doses. Conference abstracts and grey literature were included when they provided additional information to that available in the published studies. Dissociative symptoms, blood pressure elevations, and sedation were reported to resolve within a few hours but may require patient monitoring shortly after drug administration. NCT02153502: Efficacy, safety, and tolerability study of AVP-786 as an adjunctive therapy in patients with major depressive disorder with an inadequate response to antidepressant treatment. 2019 Mar 5; Center for Drug Evalulation and Research. FDA briefing document: Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2019 Feb 12: Andreassen OA. Table 1: Summary of Esketamine Phase III Trials — Patient and Trial Characteristics. Summary of Risk Management Plan for esketamine nasal spray. In three of the phase III trials, discontinuation of esketamine due to adverse events ranged from 2.6% to 9.5% in the esketamine treatment group and 2.1% to 3.1% in the comparator group. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. Esketamine plus a newly initiated oral antidepressant also statistically significantly reduced relapse events and delayed the occurrence of a relapse event. Nasal administration of esketamine-a promising new antidepressant [abstract]. NCT03560518: Study of rapastinel as monotherapy in patients with MDD. Esketamine for treatment-resistant depression has now been rescheduled into the work programme and is due to be discussed at committee on Wednesday 5 August 2020. Naurex, Inc, an affiliate of Allergan plc. The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study. Another examination of Janssen’s FDA application for esketamine finds the drug to be ineffective as an antidepressant, and associated with a host of worrying side effects. In TRANSFORM-3, three patients in the esketamine group reported anxiety, blood pressure increase, and hip fracture. This is an intra-nasal form of ketamine which was shown to be effective in conjunction with an antidepressant in treating severe and debilitating depression labeled as treatment resistant depression or TRD. NCT02422186: 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). Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. Esketamine: new therapy for severe depression . esketamine studies indicate high efcacy of add-on esketamine in treatment-resistant MDD conditions compared with other well-established, e vidence-based pharmacological options such The medication is not yet available for use … Spravato Sherman Oaks Read More » Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/211243Orig1s000ltr.pdf
One author screened the literature search results and reviewed the full text of all potentially relevant studies. Ketamine’s potential for addiction and diversion was another important concern.57 However, post-marketing data suggests that ketamine abuse is in fact relatively uncommon.18 Much like ketamine, esketamine has psychotogenic properties that also make it susceptible to abuse; risk management could still be an important consideration.7,16,58. As studies of emerging treatments utilize diverse definitions of TRD, it can be difficult to translate research findings into practical guidelines. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. basis of non-clinical and clinical data available on the product, in a defined ... EAMS Summary • Open for applications since April 2014 ... featured on this site, in any form or medium is subject to the prior approval of the Medicines and Healthcare Products Regulatory Agency. At 21–28 days, esketamine had a g value of g = 0.417 (N = 3, 95% CI: 0.238 to 0.596, p < 0.01). While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. For acute treatment, esketamine nasal spray requires administration twice weekly for four weeks during treatment induction, then weekly for another four weeks, followed by weekly or every other week during ongoing maintenance.18 According to the manufacturer, it is intended to be used under the direct supervision of a health care professional.