SPRAVATO 28mg nose spray solution medication leaflet

Spravato 28 mg nasal spray, solution

Each nasal spray device contains esketamine hydrochloride corresponding to 28 mg esketamine.

For the full list of excipients, see section 6.1.

Nasal spray, solution.

Clear, colourless, aqueous solution.

Spravato, in combination with a SSRI or SNRI, is indicated for adults with treatment-resistant Major

Depressive Disorder, who have not responded to at least two different treatments with antidepressantsin the current moderate to severe depressive episode.

Spravato, co-administered with oral antidepressant therapy, is indicated in adults with a moderate tosevere episode of Major Depressive Disorder, as acute short-term treatment, for the rapid reduction ofdepressive symptoms, which according to clinical judgement constitute a psychiatric emergency.

See section 5.1 for a description of the populations studied.

The decision to prescribe this medicinal product should be determined by a psychiatrist.

It is intended to be self-administered by the patient under the direct supervision of a healthcareprofessional.

A treatment session consists of nasal administration and a post-administration observation period.

Both administration and post-administration observation should be carried out in an appropriateclinical setting.

Assessment before treatment

Prior to dosing with Spravato blood pressure should be assessed.

If baseline blood pressure is elevated the risks of short-term increases in blood pressure and benefit ofthe treatment should be considered (see section 4.4). The medicinal product should not beadministered if an increase in blood pressure or intracranial pressure poses a serious risk (seesection 4.3).

Patients with clinically significant or unstable cardiovascular or respiratory conditions requireadditional precautions. In these patients, the medicinal product should be administered in a settingwhere appropriate resuscitation equipment and healthcare professionals with training incardiopulmonary resuscitation are available (see section 4.4).

Post-administration observation

After dosing with Spravato, blood pressure should be reassessed at approximately 40 minutes andsubsequently as clinically warranted (see section 4.4).

Because of the possibility of sedation, dissociation and elevated blood pressure, patients must bemonitored by a healthcare professional until the patient is considered clinically stable and ready toleave the healthcare setting (see section 4.4).

Treatment-resistant Major Depressive Disorder

The dose recommendations for treatment-resistant Major Depressive Disorder are shown in Table 1and Table 2 (adults ≥65 years). It is recommended to maintain the dose the patient receives at the endof the induction phase in the maintenance phase. Dose adjustments should be made based on efficacyand tolerability to the previous dose. During the maintenance phase, dosing should be individualised tothe lowest frequency to maintain remission/response.

Table 1: Recommended dosing for Spravato in adults <65 years with treatment-resistant

Major Depressive Disorder

Induction phase Maintenance phase

Weeks 1-4: Weeks 5-8:

Starting day 1 dose: 56 mg 56 mg or 84 mg once weekly

Subsequent doses: 56 mg or 84 mg twice a week

From Week 9:56 mg or 84 mg every 2 weeks or onceweekly

Evidence of therapeutic benefit should be evaluated The need for continued treatment should beat the end of induction phase to determine need for re-examined periodically.continued treatment.

Table 2: Recommended dosing for Spravato in adults ≥65 years with treatment-resistant

Major Depressive Disorder

Induction phase Maintenance phase

Weeks 1-4: Weeks 5-8:

Starting day 1 dose: 28 mg 28 mg, 56 mg or 84 mg once weekly, all

Subsequent doses: 28 mg, 56 mg or 84 mg dose changes should be in 28 mg incrementstwice a week, all dosechanges should be in 28 mg From Week 9:increments 28 mg, 56 mg or 84 mg every 2 weeks oronce weekly, all dose changes should be in28 mg increments

Evidence of therapeutic benefit should be evaluated The need for continued treatment should beat the end of induction phase to determine need for re-examined periodically.continued treatment.

After depressive symptoms improve, treatment is recommended for at least 6 months.

Acute short-term treatment of psychiatric emergency due to Major Depressive Disorder

The recommended dosage for adult patients (<65 years) is 84 mg twice per week for 4 weeks. Dosagereduction to 56 mg should be made based on tolerability. After 4 weeks of treatment with Spravato,the oral antidepressant (AD) therapy should be continued, per clinical judgement.

In these patients, treatment with Spravato should be part of the comprehensive clinical care plan.

Food and liquid intake recommendations prior to administration

Since some patients may experience nausea and vomiting after administration of the medicinalproduct, patients should be advised not to eat for at least 2 hours before administration and not to drinkliquids at least 30 minutes prior to administration (see section 4.8).

Nasal corticosteroid or nasal decongestant

Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should be advisednot to administer these medicinal products within 1 hour before administration.

Missed treatment session(s)

Patients who have missed treatment session(s) during the first 4 weeks of treatment should continuewith their current dosing schedule.

For patients with treatment-resistant Major Depressive Disorder who miss treatment session(s) duringmaintenance phase and have worsening of depression symptoms, per clinical judgement, considerreturning to the previous dosing schedule (see Tables 1 and 2).

Elderly (65 years of age and older)

In elderly patients the initial Spravato dose for treatment-resistant Major Depressive Disorder is 28 mgesketamine (day 1, starting dose, see Table 2 above). Subsequent doses should be increased inincrements of 28 mg up to 56 mg or 84 mg, based on efficacy and tolerability.

Spravato has not been studied in elderly patients as acute short-term treatment of psychiatricemergency due to Major Depressive Disorder.

No dose adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pughclass B) hepatic impairment. However, the maximum dose of 84 mg should be used with caution inpatients with moderate hepatic impairment.

Spravato has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use inthis population is not recommended (see sections 4.4 and 5.2).

No dose adjustment is necessary in patients with mild to severe renal impairment. Patients on dialysiswere not studied.

The safety and efficacy of Spravato in paediatric patients aged 17 years and younger have not beenestablished. There is no relevant use of Spravato in children less than 7 years of age.

This medicinal product is for nasal use only. The nasal spray device is a single-use device that deliversa total of 28 mg of esketamine, in two sprays (one spray per nostril). To prevent loss of medicinalproduct, the device should not be primed before use. It is intended for administration by the patientunder the supervision of a healthcare professional, using 1 device (for a 28 mg dose), 2 devices (for a56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device.

Sneezing after administration

If sneezing occurs immediately after administration, a replacement device should not be used.

Use of the same nostril for 2 consecutive sprays

If administration in the same nostril occurs, a replacement device should not be used.

Treatment discontinuation does not require tapering off; based on data from clinical trials the risk ofwithdrawal symptoms is low.

- Hypersensitivity to the active substance, ketamine, or to any of the excipients listed insection 6.1.

- Patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (seesection 4.8):

- Patients with aneurysmal vascular disease (including intracranial, thoracic, or abdominalaorta, or peripheral arterial vessels).

- Patients with history of intracerebral haemorrhage.

- Recent (within 6 weeks) cardiovascular event, including myocardial infarction (MI).

Suicide/suicidal thoughts or clinical worsening

The effectiveness of esketamine in preventing suicide or in reducing suicidal ideation or behaviour hasnot been demonstrated (see section 5.1). Use of esketamine does not preclude the need forhospitalisation if clinically warranted, even if patients experience improvement after an initial dose ofesketamine.

Close supervision of patients and in particular those at high risk should accompany treatmentespecially in early treatment and following dose changes. Patients (and caregivers of patients) shouldbe alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts andunusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide(suicide-related events). This risk persists until significant remission occurs, therefore, patients shouldbe closely monitored. It is general clinical experience that the risk of suicide may increase in the earlystages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidalideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts orsuicide attempts and should receive careful monitoring during treatment.

Neuropsychiatric and motor impairments

Esketamine has been reported to cause somnolence, sedation, dissociative symptoms, perceptiondisturbances, dizziness, vertigo and anxiety during the clinical trials (see section 4.8). These effectsmay impair attention, judgment, thinking, reaction speed and motor skills. At each treatment session,patients should be monitored under the supervision of a healthcare professional to assess when thepatient is considered stable based on clinical judgement (see section 4.7).

Respiratory depression may occur at high doses following rapid intravenous injection of esketamine orketamine when used for anaesthesia. Rare cases of deep sedation have been reported. Concomitant useof esketamine with CNS depressants may increase the risk for sedation (see section 4.5). During post-marketing use, rare cases of respiratory depression have been observed. The majority of these caseshave been reported with concomitant use of CNS depressants and/or in patients with comorbiditiessuch as obesity, anxiety, cardiovascular and respiratory conditions. These events were transient innature and resolved after verbal/tactile stimulation or supplemental oxygen. Close monitoring isrequired for sedation and respiratory depression.

Effect on blood pressure

Esketamine can cause transient increases in systolic and/or diastolic blood pressure which peak atapproximately 40 minutes after administration of the medicinal product and last approximately1-2 hours (see section 4.8). A substantial increase in blood pressure could occur after any treatmentsession. Esketamine is contraindicated in patients for whom an increase in blood pressure orintracranial pressure poses a serious risk (see section 4.3). Before prescribing esketamine, patientswith other cardiovascular and cerebrovascular conditions should be carefully assessed to determinewhether the potential benefits of esketamine outweigh its risks.

In patients whose blood pressure prior to dose administration is judged to be elevated (as a generalguide: >140/90 mmHg for patients <65 years of age and >150/90 mmHg for patients ≥65 years ofage), it is appropriate to adjust lifestyle and/or pharmacologic therapies to reduce blood pressurebefore starting treatment with esketamine. If blood pressure is elevated prior to esketamineadministration a decision to delay esketamine therapy should take into account the balance of benefitand risk in individual patients.

Blood pressure should be monitored after dose administration. Blood pressure should be measuredaround 40 minutes post-dose and subsequently as clinically warranted until values decline. If bloodpressure remains elevated for a prolonged period of time, assistance should promptly be sought frompractitioners experienced in blood pressure management. Patients who experience symptoms of ahypertensive crisis should be referred immediately for emergency care.

Patients with clinically significant or unstable cardiovascular or respiratory conditions

Only initiate treatment with esketamine in patients with clinically significant or unstablecardiovascular or respiratory conditions if the benefit outweighs the risk. In these patients, esketamineshould be administered in a setting where appropriate resuscitation equipment and healthcareprofessionals with training in cardiopulmonary resuscitation are available. Examples of conditionswhich should be considered include, but are not limited to:

- Significant pulmonary insufficiency, including COPD;

- Sleep apnoea with morbid obesity (BMI ≥35);

- Patients with uncontrolled brady- or tachyarrhythmias that lead to haemodynamic instability;

- Patients with a history of an MI. These patients should be clinically stable and cardiac symptomfree prior to administration;

- Haemodynamically significant valvular heart disease or heart failure (NYHA Class III-IV).

Drug abuse, dependence, withdrawal

Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse ofesketamine. Prior to prescribing esketamine, each patient’s risk for abuse or misuse should be assessedand patients receiving esketamine should be monitored for the development of behaviours orconditions of abuse or misuse, including drug seeking behaviour, while on therapy.

Dependence and tolerance have been reported with prolonged use of ketamine. In individuals whowere dependent on ketamine, withdrawal symptoms of cravings, anxiety, shaking, sweating andpalpitations have been reported upon discontinuing ketamine.

Ketamine, the racemic mixture of arketamine and esketamine, is a medicinal product that has beenreported to be abused. The potential for abuse, misuse and diversion of esketamine is minimised due tothe administration taking place under the direct supervision of a healthcare professional. Spravatocontains esketamine and may be subject to abuse and diversion.

Other populations at risk

Spravato should be used with caution in patients with the following conditions. These patients shouldbe carefully assessed before prescribing Spravato and treatment initiated only if the benefit outweighsthe risk:

- Presence or history of psychosis;

- Presence or history of mania or bipolar disorder;

- Hyperthyroidism that has not been sufficiently treated;

- History of brain injury, hypertensive encephalopathy, intrathecal therapy with ventricularshunts, or any other condition associated with increased intracranial pressure.

Elderly (65 years of age and older)

Elderly patients treated with Spravato may have a greater risk of falling once mobilised, therefore,these patients should be carefully monitored.

Due to expected increase in exposure and lack of clinical experience, Spravato is not recommended inpatients with Child-Pugh class C (severe) hepatic impairment.

Hepatotoxicity has been reported with chronic ketamine use, therefore, the potential for such an effectdue to long-term use of Spravato cannot be excluded. In a long-term clinical trial with patients treatedfor a mean total duration of exposure of 42.9 months (up to 79 months), no evidence of hepatotoxicitywas observed.

Urinary tract symptoms

Urinary tract and bladder symptoms have been reported with Spravato use (see section 4.8). It isrecommended to monitor for urinary tract and bladder symptoms during the course of treatment andrefer to an appropriate healthcare provider when symptoms persist.

Concomitant use of Spravato with CNS depressants (e.g., benzodiazepines, opioids, alcohol) mayincrease sedation, which therefore should be closely monitored.

Blood pressure should be closely monitored when Spravato is used concomitantly withpsychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) or other medicinalproducts that may increase blood pressure (e.g., xanthine derivatives, ergometrine, thyroid hormones,vasopressin, or MAOIs, such as, tranylcypromine, selegiline, phenelzine).

Spravato is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

There are no or limited data on the use of esketamine in pregnant women. Animal studies have shownthat ketamine, the racemic mixture of arketamine and esketamine, induces neurotoxicity in developingfoetuses (see section 5.3). A similar risk with esketamine cannot be excluded.

If a woman becomes pregnant while being treated with Spravato, treatment should be discontinued,and the patient should be counselled about the potential risk to the foetus and clinical/therapeuticoptions as soon as possible.

It is unknown whether esketamine is excreted in human milk. Data in animals have shown excretion ofesketamine in milk. A risk to the suckling child cannot be excluded. A decision must be made whetherto discontinue breast-feeding or to discontinue/abstain from Spravato therapy taking into account thebenefit of breast feeding for the child and the benefit of therapy for the woman.

Animal studies showed that fertility and reproductive capacities were not adversely affected byesketamine.

Spravato has a major influence on the ability to drive and use machines. In clinical studies, Spravatohas been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances,dizziness, vertigo and anxiety (see section 4.8). Before Spravato administration, patients should beinstructed not to engage in potentially hazardous activities requiring complete mental alertness andmotor coordination, such as driving a vehicle or operating machinery, until the next day following arestful sleep (see section 4.4).

The most commonly observed adverse reactions in patients treated with Spravato were dizziness(31%), dissociation (27%), nausea (27%), headache (23%), somnolence (18%), dysgeusia (18%),vertigo (16%), hypoaesthesia (11%), vomiting (11%), and blood pressure increased (10%).

Adverse reactions reported with esketamine are listed in Table 3. Within the designated system organclasses, adverse reactions are listed under headings of frequency, using the following convention: verycommon (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to< 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

Table 3: List of adverse reactions

System Organ Class Adverse Drug Reaction

Frequency

Very common Common Uncommon Rare

Psychiatric disorders dissociation anxiety, euphoric psychomotormood, confusional retardation,state, emotionalderealisation, distress,irritability, dysphoriahallucinationincluding visualhallucination,agitation, illusion,panic attack, timeperception altered

Nervous system disorders dizziness, paraesthesia, nystagmus, seizureheadache, sedation, tremor, psychomotorsomnolence, mental hyperactivitydysgeusia, impairment,hypoaesthesia lethargy,dysarthria,disturbance inattention

Eye disorders vision blurred

Ear and labyrinth vertigo tinnitus,disorders hyperacusis

Cardiac disorders tachycardia bradycardia

Vascular disorders hypertension hypotension

Respiratory, thoracic and nasal discomfort, respiratorymediastinal disorders throat irritation, depressionoropharyngealpain, nasal drynessincluding nasalcrusting, nasalpruritus

Gastrointestinal disorders nausea, vomiting hypoaesthesia salivaryoral, dry mouth hypersecretion

Skin and subcutaneous hyperhidrosis cold sweattissue disorders

Renal and urinary pollakiuria,disorders dysuria,micturitionurgency

General disorders and feeling abnormal, gaitadministration site feeling drunk, disturbanceconditions asthenia, crying,feeling of bodytemperaturechange

Investigations blood pressureincreased

Long-term safety was assessed in a Phase 3, multicentre, open-label extension study (TRD3008) in1 148 adult patients with treatment-resistant Major Depressive Disorder representing3 777 patient-years of exposure. Patients were treated with esketamine for a mean total duration ofexposure of 42.9 months (up to 79 months) with 63% and 28% of patients receiving treatment at least3 years and 5 years, respectively. The safety profile of esketamine was consistent with the knownsafety profile observed in the pivotal clinical trials. No new safety concerns were identified.

Dissociation

Dissociation (27%) was one of the most common psychological effects of esketamine. Other relatedterms included derealisation (2.2%), depersonalisation (2.2%), illusions (1.3%), and distortion of time(1.2%). These adverse reactions were reported as transient and self-limited and occurred on the day ofdosing. Dissociation was reported as severe in intensity at the incidence of less than 4% across studies.

Dissociation symptoms typically resolved by 1.5 hours post-dose and the severity tended to reduceover time with repeated treatments.

Sedation/somnolence/respiratory depression

In clinical trials, adverse reactions of sedation (9.3%) and somnolence (18.2%) were primarily mild ormoderate in severity, occurred on the day of dosing and resolved spontaneously the same day.

Sedative effects typically resolved by 1.5 hours post-dose. Rates of somnolence were relatively stableover time during long-term treatment. In the cases of sedation, no symptoms of respiratory distresswere observed, and haemodynamic parameters (including vital signs and oxygen saturation) remainedwithin normal ranges. During post-marketing use, rare cases of respiratory depression have beenobserved (see section 4.4).

Changes in blood pressure

In clinical trials for treatment-resistant Major Depressive Disorder, increases in systolic and diastolicblood pressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose inpatients receiving Spravato plus oral antidepressants (see section 4.4). The frequency of markedlyabnormal blood pressure elevations of SBP (≥40 mmHg increase) ranged from 8% (<65 years) to 17%(≥65 years) and DBP (≥25 mmHg increase) ranged from 13% (<65 years) to 14% (≥65 years) inpatients receiving esketamine plus oral antidepressant. The incidence of increased SBP (≥ 180 mmHg)was 3% and DBP (≥ 110 mmHg) was 4%.

Cognitive and memory impairment

Cognitive and memory impairment have been reported with long-term ketamine use or drug abuse.

These effects did not increase over time and were reversible after discontinuing ketamine. Inlong-term clinical trials, including a clinical trial with patients treated for a mean total duration ofexposure of 42.9 months (up to 79 months), the effect of esketamine nasal spray on cognitivefunctioning was evaluated over time and performance remained stable.

Urinary tract symptoms

Cases of interstitial cystitis have been reported with daily and long-term ketamine use at high doses. Inclinical studies with esketamine, there were no cases of interstitial cystitis, however a higher rate oflower urinary tract symptoms was observed (pollakiuria, dysuria, micturition urgency, nocturia, andcystitis) in esketamine-treated patients compared with placebo-treated patients. In a long-term clinicaltrial with patients treated for a mean total duration of exposure of 42.9 months (up to 79 months), nocases of interstitial cystitis were observed.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The potential for overdose of Spravato by the patient is minimised due to the product’s design and theadministration taking place under the supervision of a healthcare professional (see section 4.2).

The maximum single esketamine nasal spray dose tested in healthy volunteers was 112 mg whichshowed no evidence of toxicity and/or adverse clinical outcomes. However, compared to therecommended dose range, the 112 mg esketamine nasal spray dose was associated with higher rates ofadverse reactions, including dizziness, hyperhidrosis, somnolence, hypoaesthesia, feeling abnormal,nausea and vomiting.

Life-threatening symptoms are expected based on experience with ketamine given at 25-fold the usualanaesthetic dose. Clinical symptoms are described as convulsions, cardiac arrhythmias, and respiratoryarrest. Administration of a comparable supratherapeutic dose of esketamine by the intranasal route isunlikely to be feasible.

There is no specific antidote for esketamine overdose. In the case of overdose, the possibility ofmultiple medicinal products involvement should be considered. Management of Spravato overdoseshould consist of treating clinical symptoms and relevant monitoring. Close supervision andmonitoring should continue until the patient recovers.

Pharmacotherapeutic group: Psychoanaleptics; Other antidepressants, ATC code: N06AX27.

Esketamine is the S-enantiomer of racemic ketamine. It is a non-selective, non-competitive, antagonistof the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. Through NMDAreceptor antagonism, esketamine produces a transient increase in glutamate release leading toincreases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulationand subsequently to increases in neurotrophic signalling which may contribute to the restoration ofsynaptic function in these brain regions involved with the regulation of mood and emotionalbehaviour. Restoration of dopaminergic neurotransmission in brain regions involved in the reward andmotivation, and decreased stimulation of brain regions involved in anhedonia, may contribute to therapid response.

Abuse potential

In a study of abuse potential conducted in recreational polydrug users (n=41), single doses ofesketamine nasal spray (84 mg and 112 mg) and the positive control drug intravenous ketamine(0.5 mg/kg infused over 40 minutes) produced significantly greater scores than placebo on subjectiveratings of “drug liking” and on other measures of subjective drug effects.

The efficacy and safety of esketamine nasal spray was investigated in five Phase 3 clinical studies(TRD3001, TRD3002, TRD3003, TRD3004, and TRD3005) in adult patients (18 to 86 years) withtreatment-resistant depression (TRD) who met DSM-5 criteria for major depressive disorder and werenon-responders to at least two oral antidepressants (ADs) treatments, of adequate dosage and duration,in the current major depressive episode. 1 833 adult patients were enrolled, of which 1 601 patientswere exposed to esketamine. Additionally, 202 patients were randomised (122 patients receivedesketamine) in Phase 2 study TRD2005 in Japan, 252 patients were randomised (126 patients receivedesketamine) in Phase 3 study TRD3006 primarily in China, and 676 patients were randomised(334 patients received esketamine) in Phase 3 study TRD3013.

The efficacy and safety of esketamine nasal spray was investigated in two Phase 3 clinical studies inadult patients (18 to 64 years) with moderate to severe MDD (MADRS total score >28) who hadaffirmative responses to Mini International Neuropsychiatric Interview (MINI) questions B3 (“Think[even momentarily] about harming or of hurting or of injuring yourself: with at least some intent orawareness that you might die as a result; or think about suicide [i.e., about killing yourself]?”) and B10(“Intend to act on thoughts of killing yourself in the past 24 hours?”). 456 adult patients were enrolled,of which 227 patients were exposed to Spravato.

Treatment-resistant depression - Short-term studies

Esketamine was evaluated in three Phase 3 short-term (4-week) randomised, double-blind,active-controlled studies in patients with TRD. Studies TRANSFORM-1 (TRD3001) and

TRANSFORM-2 (TRD3002) were conducted in adults (18 to < 65 years) and Study TRANSFORM-3(TRD3005) was conducted in adults ≥ 65 years of age. Patients in TRD3001 and TRD3002 initiatedtreatment with esketamine 56 mg plus a newly initiated daily oral AD or a newly initiated daily oral

AD plus placebo nasal spray on day 1. Esketamine dosages were then maintained on 56 mg or titratedto 84 mg or matching placebo nasal spray administered twice-weekly during a 4-week double-blindinduction phase. Esketamine doses of 56 mg or 84 mg were fixed in Study TRD3001 and flexible in

Study TRD3002. In Study TRD3005, patients (≥ 65 years) initiated treatment with Esketamine 28 mgplus a newly initiated daily oral AD or a newly initiated daily oral AD plus placebo nasal spray(day 1). Esketamine dosages were titrated to 56 mg or 84 mg or matching placebo nasal sprayadministered twice-weekly during a 4-week double-blind induction phase. In the flexible dose studies,

TRD3002 and TRD3005, up titration of esketamine dose was based on clinical judgement and dosecould be down titrated based on tolerability. A newly initiated open-label oral AD (SNRI: duloxetine,venlafaxine extended release; SSRI: escitalopram, sertraline) was initiated on day 1 in all studies. Theselection of the newly initiated oral AD was determined by the investigator based on the patient’s priortreatment history. In all short-term studies, the primary efficacy endpoint was change in MADRS totalscore from baseline to day 28.

Baseline demographic and disease characteristics for patient in TRD3002, TRD3001, and TRD3005are presented in Table 4.

Table 4: Baseline demographic characteristics for TRD3002, TRD3001, and TRD3005 (fullanalysis sets)

Study TRD3002 Study TRD3001 Study TRD3005(N=223) (N=342) (N=137)

Age, years

Median (Range) 47.0 (19; 64) 47.0 (18; 64) 69.0 (65; 86)

Sex, n (%)

Male 85 (38.1%) 101 (29.5%) 52 (38.0%)

Female 138 (61.9%) 241 (70.5%) 85 (62.0%)

Race, n (%)

White 208 (93.3%) 262 (76.6%) 130 (94.9%)

Black or African American 11 (4.9%) 19 (5.6%) --

Prior oral antidepressants with nonresponse (i.e., failed antidepressants)

Number of specific antidepressants, n (%)2 136 (61.0%) 167 (48.8%) 68 (49.6%)3 or more 82 (36.8%) 167 (48.8%) 58 (42.3%)

Newly initiated oral antidepressant medication initiated at randomisation, n (%)

SNRI 152 (68.2%) 196 (57.3%) 61 (44.5%)

SSRI 71 (31.8%) 146 (42.7%) 76 (55.5%)

Withdrawn from study (for30/227 (13.2%) 31/346 (9.0%) 16/138 (11.6%)any reason), n/N (%)

In the flexible dose study TRD3002, at day 28, 67% of the patients randomised to esketamine were on84 mg. In study TRD3002, esketamine plus a newly initiated oral AD demonstrated clinicallymeaningful and statistical superiority compared to a newly initiated oral AD (SNRI: duloxetine,venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 5), andsymptom reduction was observed as early as 24 hours post-dose.

In study TRD3001, a clinically meaningful treatment effect in change in MADRS total scores frombaseline at the end of the 4-week induction phase was observed favouring esketamine plus newlyinitiated oral AD compared with a newly initiated oral AD (SNRI: duloxetine, venlafaxine extendedrelease; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 5). In Study TRD3001, thetreatment effect for the esketamine 84 mg plus oral AD group compared with oral AD plus placebowas not statistically significant.

In study TRD3005, at day 28, 64% of the patients randomised to esketamine were on 84 mg, 25% on56 mg, and 10% on 28 mg. In study TRD3005, a clinically meaningful but not statistically significanttreatment effect in change in MADRS total scores from baseline at the end of the 4-week inductionphase was observed favouring esketamine plus newly initiated oral AD compared with a newlyinitiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plusplacebo nasal spray (Table 5). Subgroup analyses suggest limited efficacy in the population over75 years old.

Table 5: Primary efficacy results for change in MADRS total score for 4-week clinical trials(ANCOVA BOCF*)

LS mean

Mean change from LS mean

Number of

Study no. Treatment group§ baseline score baseline to differencepatients(SD) end of week 4 (95% CI)†(SE)

Spravato -4.3115 37.4 (4.8) -18.9 (1.3)56 mg + oral AD (-7.8, -0.8)#

Spravato -1.2

TRD3001 114 37.8 (5.6) -16.2 (1.3)84 mg + oral AD (-4.7, 2.3)#

Oral AD + placebo113 37.5 (6.2) -14.7 (1.3)nasal spray

Spravato (56 mg or -3.5114 37.0 (5.7) -17.7 (1.3)84 mg) + oral AD (-6.7, -0.3)‡

TRD3002

Oral AD + placebo109 37.3 (5.7) -14.3 (1.3)nasal spray

Spravato (28 mg,

- 2.956 mg or 72 35.5 (5.9) -10.1 (1.7)

TRD3005 (-6.5, 0.6)#84 mg) + oral AD(≥ 65 years)

Oral AD + placebo65 34.8 (6.4) -6.8 (1.7)nasal spray

SD = standard deviation; SE = standard error; LS Mean = least-squares mean; CI = confidence interval;

AD = antidepressant

* ANCOVA analysis using Baseline Observation Carried Forward, which means that for a patient who discontinues fromtreatment, it is assumed that the depression level returns to the baseline level (i.e. the depression level is the same asbefore start of treatment)§ Nasally administered esketamine or placebo; oral AD = a newly initiated AD (SNRI: duloxetine, venlafaxine extendedrelease; SSRI: escitalopram, sertraline)† Difference (Spravato + oral AD minus Oral AD + placebo nasal spray) in least-squares mean change from baseline‡ Treatment group that was statistically significantly superior to Oral AD + placebo nasal spray# Median unbiased estimate (i.e., weighted combination of the LS means of the difference from Oral AD + placebo nasalspray), and 95% flexible confidence interval

Response and remission rates

Response was defined as ≥ 50% reduction in the MADRS total score from baseline of the inductionphase. Based on the reduction in MADRS total score from baseline, the proportion of patients in

Studies TRD3001, TRD3002 and TRD3005 who demonstrated response to esketamine plus oral ADtreatment was greater than for oral AD plus placebo nasal spray throughout the 4-week double-blindinduction phase (Table 6).

Remission was defined as a MADRS total score ≤ 12. In all three studies, a greater proportion ofpatients treated with esketamine plus oral AD were in remission at the end of the 4-week double-blindinduction phase than for oral AD plus placebo nasal spray (Table 6).

Table 6: Response and remission rates in 4-week clinical trials based on BOCF* data

Number of patients (%)

Response rate† Remission

Treatment rate‡

Study No. group§ 24 hours Week 1 Week 2 Week 3 Week 4 Week 4

Spravato20 21 29 52 61 4056 mg + oral(17.4%) (18.3%) (25.2%) (45.2%) (53.0%) (34.8%)

AD

Spravato17 16 25 33 52 38

TRD3001 84 mg + oral(14.9%)# (14.0%) (21.9%) (28.9%) (45.6%) (33.3%)

AD

Oral AD +8 5 15 25 42 33placebo nasal(7.1%) (4.4%) (13.3%) (22.1%) (37.2%) (29.2%)spray

Spravato56 mg or 18 15 29 54 70 5384 mg + oral (15.8%) (13.2%) (25.4%) (47.4%) (61.4%) (46.5%)

TRD3002 AD

Oral AD +11 13 23 35 52 31placebo nasal(10.1%) (11.9%) (21.1%) (32.1%) (47.7%) (28.4%)spray

TRD3005 Spravato(≥ 65 years) 28 mg, 56 mg 4 4 9 17 11

NAor 84 mg + (5.6%) (5.6%) (12.5%) (23.6%) (15.3%)oral AD

Oral AD +3 8 8 8 4placebo nasal NA(4.6%) (12.3%) (12.3%) (12.3%) (6.2%)spray

AD = antidepressant; NA = not available

* Baseline Observation Carried Forward, which means that for a patient who discontinues from treatment, it is assumed that thedepression level returns to the baseline level (i.e. the depression level is the same as before start of treatment).§ Nasally administered Spravato or placebo; oral AD = a newly initiated AD (SNRI: duloxetine, venlafaxine extended release;

SSRI: escitalopram, sertraline)† Response was defined as ≥ 50% reduction in the MADRS total score from baseline‡ Remission was defined as MADRS total score ≤ 12# First dose was Spravato 56 mg + oral AD

Treatment-resistant depression - Long-term studies

Relapse-prevention study

The maintenance of antidepressant efficacy was demonstrated in a relapse prevention trial. Study

SUSTAIN-1 (TRD3003) was a long-term randomised, double-blind, parallel-group, active-controlled,multicentre, relapse prevention study. The primary outcome measure to assess the prevention ofdepressive relapse was measured as time to relapse. Overall a total of 705 patients were enrolled; 437directly enrolled; 150 transferred from TRD3001, and 118 transferred from TRD3002. Patientsdirectly enrolled were administered esketamine (56 mg or 84 mg twice weekly) plus oral AD in a4-week open label induction phase. At the end of the open label induction phase, 52% of patients werein remission (MADRS total score ≤ 12) and 66% of patients were responders (≥ 50% improvement in

MADRS total score). Patients who were responders (455), continued receiving treatment withesketamine plus oral AD in a 12-week optimisation phase. After the induction phase, patients receivedesketamine weekly for 4 weeks and starting from week 8, an algorithm (based on the MADRS) wasused to determine the dosing frequency; patients in remission (i.e., MADRS total score was ≤ 12) weredosed every other week, however, if the MADRS total score increased to > 12, then the frequency wasincreased to weekly dosing for the next 4 weeks; with the objective of maintaining the patient on thelowest dosing frequency to maintain response/remission. At the end of 16 weeks of treatment period,patients in stable remission (n=176) or stable response (n=121) were randomised to continue withesketamineor stop esketamine and switch to placebo nasal spray. Stable remission was defined as

MADRS total score ≤ 12 in at least 3 of the last 4 weeks of the optimisation phase and stable responsewas defined as ≥ 50% reduction in the MADRS total score from baseline for the last 2 weeks of theoptimisation phase, but not in stable remission.

Stable remission

Patients in stable remission who continued treatment with esketamine plus oral AD experienced astatistically significantly longer time to relapse of depressive symptoms than did patients on a newlyinitiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plusplacebo nasal spray (Figure 1). Relapse was defined as a MADRS total score ≥ 22 for 2 consecutiveweeks or hospitalisation for worsening depression or any other clinically relevant event indicative ofrelapse. The median time to relapse for a newly initiated oral AD (SNRI: duloxetine, venlafaxineextended release; SSRI: escitalopram, sertraline) plus placebo nasal spray group was 273 days,whereas the median was not estimable for esketamine plus oral AD, as this group never reached 50%relapse rate.

Figure 1: Time to relapse in patients in stable remission in study TRD3003 (full analysis set)

For patients in stable remission, the relapse rate based on Kaplan-Meier estimates during the 12- and24-weeks double-blind follow up period was 13% and 32% for esketamine and 37% and 46% forplacebo nasal spray, respectively.

Stable response

The efficacy results were also consistent for patients in stable response who continued treatment withesketamine plus oral AD; patients experienced a statistically significantly longer time to relapse ofdepressive symptoms than did patients on a newly initiated oral AD (SNRI: duloxetine, venlafaxineextended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Figure 2). The median timeto relapse for a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI:

escitalopram, sertraline) plus placebo nasal spray group (88 days) was shorter compared to esketamineplus oral AD group (635 days).

Figure 2: Time to relapse in patients in stable response in study TRD3003 (full analysis set)

For patients in stable response, the relapse rate based on Kaplan-Meier estimates during the 12- and24-weeks double-blind follow up period was 21% and 21% for esketamine and 47% and 56% forplacebo nasal spray, respectively.

Enrollment in TRD3003 was staggered over approximately 2 years. The maintenance phase was ofvariable duration and continued until the individual patient had a relapse of depressive symptoms ordiscontinued for any other reason, or the study ended because the required number of relapse eventsoccurred. Exposure numbers were influenced by the study stopping at a pre-determined number ofrelapses based on the interim analysis. After an initial 16 weeks of treatment with esketamine plus oral

AD, the median duration of exposure to esketamine in the maintenance phase was 4.2 months (range:1 day to 21.2 months) in Spravato-treated patients (stable remission and stable response). In this study,31.6% of patients received esketamine for greater than 6 months and 7.9% of patients receivedesketamine for greater than 1 year in the maintenance phase.

Dosing frequency

The dosing frequency used the majority of the time during the maintenance phase is shown in Table 7.

Of the patients randomised to Spravato, 60% received 84 mg and 40% received 56 mg dose.

Table 7: Dosing frequency used the majority of the time; maintenance phase (Study

TRD3003)

Stable Remission Stable Responders

Oral AD + Oral AD +

Spravato + Placebo Nasal Spravato + Placebo Nasal

Oral AD Spray Oral AD Spray(N=90) (N=86) (N=62) (N=59)

Majority dosing frequency

Weekly 21 (23.3%) 27 (31.4%) 34 (54.8%) 36 (61.0%)

Every other week 62 (68.9%) 48 (55.8%) 21 (33.9%) 19 (32.2%)

Weekly or every other week 7 (7.8%) 11 (12.8%) 7 (11.3%) 4 (6.8%)

Study TRD3013 (ESCAPE-TRD)

The efficacy of Spravato was evaluated in a long-term randomised, open-label, rater-blinded,active-controlled study (TRD3013) where esketamine was compared with quetiapineprolonged/extended-release (XR) in 676 adult patients (18-74 years) with TRD who continued to taketheir current oral AD (an SSRI or SNRI). Patients received treatment with flexibly dosed esketamine(28, 56, or 84 mg) or quetiapine XR, in line with the dosing recommendations in the SmPCs in use atthe time of study initiation.

The primary efficacy endpoint was remission (MADRS total score of ≤ 10) at Week 8 and the keysecondary endpoint was remaining relapse-free through Week 32 after remission at Week 8. Relapsewas defined as a MADRS total score ≥ 22 for 2 consecutive weeks or hospitalisation for worseningdepression or any other clinically relevant event indicative of relapse.

The baseline demographic and disease characteristics of patients were similar between the esketamineplus oral AD and quetiapine XR plus oral AD groups. The mean (SD) baseline MADRS total scoreswere 31.4 (6.06) for the esketamine plus oral AD group and 31.0 (5.83) for the quetiapine XR plusoral AD group.

Esketamine plus oral AD demonstrated clinically meaningful and statistical superiority compared toquetiapine XR plus oral AD on both the primary (Table 8) and key secondary (Table 9) efficacymeasure.

Table 8: Primary efficacy results for TRD3013 Studya

Treatment group Spravato + oral AD Quetiapine XR + oral AD

Number of patients in 91/336 (27.1%) 60/340 (17.6%)remission at Week 8

Adjusted risk difference in 9.5 (3.3, 15.8) -percentage (95% CI) b

P-value c P = 0.003 -

CI = confidence interval; AD = antidepressant; XR = extended releasea A patient who discontinued study intervention before Week 8 was considered as a negative outcome (i.e.

non-remission). For patients for whom no MADRS result was available at the Week 8 visit but who did not discontinuestudy intervention or withdraw from study before Week 8, LOCF of MADRS was applied.

b Mantel-Haenszel estimate of the risk difference, stratified by age groups (18-64; ≥65) and total number of treatmentfailures is used. This estimated difference indicates an advantage for esketamine.

c Cochran-Mantel-Haenszel (CMH) test, adjusting for age groups (18-64; ≥65) and total number of treatment failures.

Table 9: Key secondary efficacy results for TRD3013 Studya

Treatment group Spravato + oral AD Quetiapine XR + oral AD

Number of patients both in 73/336 (21.7%) 48/340 (14.1%)remission at Week 8 andrelapse-free at Week 32

Adjusted risk difference in 7.7 (2.0, 13.5) -percentage (95% CI) b

P-value c P = 0.008 -

CI = confidence interval; AD = antidepressant; XR = extended releasea A patient who discontinued study intervention was considered as a negative outcome. For patients for whom no

MADRS result was available at the Week 8 visit but who did not discontinue study intervention or withdraw fromstudy before Week 8, LOCF of MADRS was applied.

b Mantel-Haenszel estimate of the risk difference, stratified by age groups (18-64; ≥65) and total number of treatmentfailures is used. This estimated difference indicates an advantage for esketamine.

c Cochran-Mantel-Haenszel (CMH) test, adjusting for age groups (18-64; ≥65) and total number of treatment failures.

Treatment discontinuation rates over the 32-week treatment period due to adverse events, lack ofefficacy, and overall were 4.2%, 8.3%, and 23.2% respectively for patients in the esketamine plus oral

AD group and 11.5%, 15.0%, and 40.3% respectively for patients in the quetiapine XR plus oral ADgroup.

Treatment-resistant depression - Short-term study in Japanese patients

The efficacy of Spravato was also evaluated in a short-term (4-week) randomised, double-blind,active-controlled study (TRD2005) in 202 adult Japanese patients with TRD. Patients received4 weeks of induction treatment with esketamine fixed-dose of 28 mg, 56 mg, 84 mg or placebo nasalspray in addition to continued current oral AD. The primary efficacy endpoint was change in MADRStotal score from baseline to day 28. The baseline demographic and disease characteristics of patientswere similar between the esketamine plus AD and placebo nasal spray plus AD groups.

In study TRD2005, no statistically significant difference in change in MADRS total scores frombaseline at the end of the 4-week induction phase was observed for any of the esketamine plus oral ADdosages compared with oral AD plus placebo nasal spray (Table 10).

Table 10: Primary efficacy results for change in MADRS total score for 4-week TRD2005

Study in Japanese patients (MMRM)

LS mean

Mean change from LS mean

Number of

Treatment group baseline score baseline to differencepatients(SD) end of week 4 (90% CI)†,#(SE)

- 1.0

Spravato 28 mg + oral AD 41 38.4 (6.1) -15.6 (1.8)

- 5.77; 3.700.6

Spravato 56 mg + oral AD 40 37.9 (5.4) -14.0 (1.9)

- 4.32; 5.47

- 0.9

Spravato 84 mg + oral AD 41 35.9 (5.3) -15.5 (1.8)

- 5.66; 3.83

Oral AD + placebo nasal spray 80 37.7 (5.7) -14.6 (1.3)

SD = standard deviation; SE = standard error; LS Mean = least-squares mean; CI = confidence interval;

AD = antidepressant.† Difference (Spravato + oral AD minus Oral AD + placebo nasal spray) in least-squares mean change from baseline.# Confidence interval is based on the Dunnett adjustment.

Treatment-resistant depression - Short-term study in Chinese patients

The efficacy of Spravato was also evaluated in a short-term (4-week) randomised, double-blind,active-controlled study (TRD3006) in 252 adult patients (224 Chinese patients, 28 non-Chinesepatients) with TRD.

Patients received 4 weeks of induction treatment with flexibly dosed esketamine (56 mg or 84 mg) orplacebo nasal spray, in addition to a newly initiated oral AD. The primary efficacy endpoint waschange in MADRS total score from baseline to day 28. The baseline demographic and diseasecharacteristics of patients were similar between the esketamine plus AD and placebo nasal spray plus

AD groups.

In study TRD3006, no statistically significant difference in change in MADRS total scores frombaseline at the end of the 4-week induction phase was observed for esketamine plus oral AD comparedwith oral AD plus placebo nasal spray (Table 11).

Table 11: Primary efficacy results for change in MADRS total score for 4-week TRD3006

Study (MMRM)

LS mean

Mean change from LS mean

Number of

Treatment group # baseline score baseline to differencepatients(SD) end of week 4 (95% CI)†(SE)

All patients

- 2.0

Spravato (56 mg or 84 mg) + oral AD 124 36.5 (5.21) -11.7 (1.09)

- 4.64; 0.55

Oral AD + placebo nasal spray 126 35.9 (4.50) -9.7 (1.09)

Chinese population

- 0.7

Spravato (56 mg or 84 mg) + oral AD 110 36.2 (5.02) -8.8 (0.95)

- 3.35; 1.94

Oral AD + placebo nasal spray 112 35.9 (4.49) -8.1 (0.95)

SD = standard deviation; SE = standard error; LS Mean = least-squares mean; CI = confidence interval;

AD = antidepressant.# Two patients did not receive oral AD and were not included in the efficacy analysis.† Difference (Spravato + oral AD minus Oral AD + placebo nasal spray) in least-squares mean change from baseline.

Acute short-term treatment of psychiatric emergency due to Major Depressive Disorder

Spravato was investigated in two identical Phase 3 short-term (4-week) randomised, double-blind,multicentre, placebo-controlled studies, Aspire I (SUI3001) and Aspire II (SUI3002) in adult patientswith moderate to severe MDD (MADRS total score >28) who had affirmative responses to MINIquestions B3 (“Think [even momentarily] about harming or of hurting or of injuring yourself: with atleast some intent or awareness that you might die as a result; or think about suicide [i.e., about killingyourself]?”) and B10 (“Intend to act on thoughts of killing yourself in the past 24 hours?”). In thesestudies, patients received treatment with esketamine 84 mg or placebo nasal spray twice-weekly for4 weeks. All patients received comprehensive standard of care (SOC) treatment, including an initialinpatient hospitalisation and a newly initiated or optimised oral antidepressant (AD) therapy (ADmonotherapy or AD plus augmentation) as determined by the investigator. In the physician’s opinion,acute psychiatric hospitalisation was clinically warranted due to the subject’s immediate risk ofsuicide. After the first dose, a one-time dose reduction to esketamine 56 mg was allowed for patientsunable to tolerate the 84 mg dose.

The baseline demographic and disease characteristics of patients in SUI3001 and SUI3002 weresimilar between the esketamine plus SOC or placebo nasal spray plus SOC groups. The median patientage was 40 years (range 18 to 64 years), 61% were female; 73% Caucasian and 6% Black; and 63% ofpatients had at least one prior suicide attempt. Prior to entering the study, 92% of the patients werereceiving antidepressant therapy. During the study, as part of standard of care treatment, 40% ofpatients received AD monotherapy, 54% of patients received AD plus augmentation regimen, and6% received both AD monotherapy/AD plus augmentation regimen.

The primary efficacy measure was the reduction of symptoms of MDD as measured by the changefrom baseline MADRS total score at 24 hours after first dose (Day 2).

In SUI3001 and SUI3002, Spravato plus SOC demonstrated statistical superiority on the primaryefficacy measure compared to placebo nasal spray plus SOC (see Table 12).

Table 12: Primary efficacy results for change from baseline in MADRS total score at 24 hoursafter first dose (Studies SUI3001 and SUI3002) (ANCOVA BOCF*)

LS Mean

Mean Change from

Number Baseline Baseline to 24 hr LS Meanof Score Post First Dose Difference

Study No. Treatment Group‡ Patients (SD) (SE) (95% CI)§

- 3.7

Study 1 Spravato 84 mg + SOC 112 41.2 (5.87) -15.7 (1.05) (-6.41; -0.92)#(SUI3001) P=0.006

Placebo nasal spray + SOC 112 41.0 (6.29) -12.1 (1.03) -

- 3.9

Study 2 Spravato 84 mg + SOC 114 39.5 (5.19) -15.9 (1.02) (-6.65; -1.12)#(SUI3002) P=0.006

Placebo nasal spray + SOC 113 39.9 (5.76) -12.0 (1.06) -

Pooled -3.8

Spravato 84 mg + SOC 226 40.3 (5.60) -15.8 (0.73)

Studies 1 (-5.69; -1.82)and 2 Placebo nasal spray + SOC 225 40.4 (6.04) -12.1 (0.73) -

SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval; SOC=standard of care

* ANCOVA analysis using Baseline Observation Carried Forward: In SUI3001, 2 subjects (1 subject in each group) did nothave the Day 2 (24 hours post first dose) MADRS total score and in SUI3002, 6 subjects (4 subjects in Esketamine and2 subjects in Placebo) did not have the Day 2 (24 hours post first dose) MADRS total score. For these subjects, it is assumedthat the depression level returns to the baseline level (i.e., the depression level is the same as the start of treatment) and the

MADRS total scores from baseline were carried forward for the analysis‡ Nasally administered esketamine or placebo§ Difference (Spravato + SOC minus placebo nasal spray + SOC) in least-squares mean change from baseline# Treatment groups that were statistically significantly superior to placebo nasal spray + SOC.

The treatment differences (95% CI) in change from baseline in MADRS total score at Day 2 (24 hourspost first dose) between esketamine + SOC and placebo + SOC were -4.70 (-7.16; -2.24) for thesubpopulation that reported a prior suicide attempt (N=284) and -2.34 (-5.59; 0.91) for thesubpopulation that did not report a prior suicide attempt (N=166).

Time course of treatment response

In both SUI3001 and SUI3002, esketamine’s treatment difference compared to placebo was observedstarting at 4 hours. Between 4 hours and Day 25, the end of the treatment phase, both the esketamineand placebo groups continued to improve; the difference between the groups generally remained butdid not appear to increase over time through Day 25. Figure 3 depicts time course of the primaryefficacy measure of change in MADRS total score using pooled studies SUI3001 and SUI3002.

Figure 3: Least squares mean change from baseline in MADRS total score over time in

SUI3001 and SUI3002* (pooled data, safety analysis set) - ANCOVA BOCF

* Note: In these studies, after the first dose, a one-time dose reduction to Spravato 56 mg was allowed forpatients unable to tolerate the 84 mg dose. Approximately 16% of patients had reduction in Spravato dosagefrom 84 mg to 56 mg twice weekly.

Remission rates

In the Phase 3 studies, the percentage of patients who achieved remission (MADRS total score ≤12 atany given time during the study) was greater in the esketamine + SOC group than in the placebo +

SOC group at all timepoints during the 4-week double-blind treatment phase (Table 13).

Table 13: Patients who achieved remission of MDD; double-blind treatment phase; full efficacyanalysis set

Pooled Studies

SUI3001 SUI3002 (SUI3001 and

SUI3002)

Placebo + Spravato + Placebo + Spravato + Placebo + Spravato +

SOC SOC SOC SOC SOC SOC112 112 113 114 225 226

Day 1, 4 hours post first dose

Patients with Remission of9 (8.0%) 12 (10.7%) 4 (3.5%) 12 (10.5%) 13 (5.8%) 24 (10.6%)

MDD

Day 2, 24 hours post first dose

Patients with Remission of10 (8.9%) 21 (18.8%) 12 (10.6%) 25 (21.9%) 22 (9.8%) 46 (20.4%)

MDD

Day 25 (predose)

Patients with Remission of38 (33.9%) 46 (41.1%) 31 (27.4%) 49 (43.0%) 69 (30.7%) 95 (42.0%)

MDD

Day 25 (4 hours postdose)

Patients with Remission of42 (37.5%) 60 (53.6%) 42 (37.2%) 54 (47.4%) 84 (37.3%) 114 (50.4%)

MDD

SOC = standard of care

Note: Remission is based on a MADRS total score of ≤12. Subjects who did not meet such criterion or discontinued prior to thetime point for any reason are not considered to be in remission.

Effects on suicidality

Overall patients in both treatment groups experienced improvement in the severity of their suicidalityas measured by the Clinical Global Impression - Severity of Suicidality - revised (CGI-SS-r) scale atthe 24-hour endpoint, though there was no statistically significant difference between treatmentgroups.

The long-term efficacy of esketamine to prevent suicide has not been established.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Spravato in the treatment of major depressive disorder in one or more subsets of the paediatricpopulation (see section 4.2 for information on paediatric use).

The mean absolute bioavailability of 84 mg esketamine administered as a nasal spray is approximately48%.

Esketamine is rapidly absorbed by the nasal mucosa following nasal administration and can bemeasured in plasma within 7 minutes following a 28 mg dose. The time to reach maximum plasmaconcentration (tmax) is typically 20 to 40 minutes after the last nasal spray of a treatment session (seesection 4.2).

Dose-dependent increases in the maximum plasma concentration (Cmax) and area under the plasmaconcentration-time curve (AUC∞) of esketamine nasal spray were produced by doses of 28 mg, 56 mgand 84 mg.

The pharmacokinetic profile of esketamine is similar after a single dose and repeat dose administrationwith no accumulation in plasma when esketamine is administered twice a week.

The mean steady-state volume of distribution of esketamine administered by the intravenous route is709 L.

The proportion of the total concentration of esketamine that is bound to proteins in human plasma ison average 43 to 45%. The degree to which esketamine is bound to plasma proteins is not dependenton hepatic or renal function.

Esketamine is not a substrate of transporters P-glycoprotein (P-gp; multidrug resistance protein 1),breast cancer resistance protein (BCRP), or organic anion transporter (OATP) 1B1, or OATP1B3.

Esketamine does not inhibit these transporters or multi-drug and toxin extrusion 1 (MATE1) and

MATE2-K, or organic cation transporter 2 (OCT2), OAT1, or OAT3.

Esketamine is extensively metabolised in the liver. The primary metabolic pathway of esketamine inhuman liver microsomes is N-demethylation to form noresketamine. The main cytochrome P450(CYP) enzymes responsible for esketamine N-demethylation are CYP2B6 and CYP3A4. Other CYPenzymes, including CYP2C19 and CYP2C9, contribute to a much smaller extent. Noresketamine issubsequently metabolised via CYP-dependent pathways to other metabolites, some of which undergoglucuronidation.

The mean clearance of esketamine administered by the intravenous route was approximately89 L/hour. After Cmax was reached following nasal administration, the decline in esketamineconcentrations in plasma was rapid for the first few hours and then more gradual. The mean terminalhalf-life following administration as a nasal spray generally ranged from 7 to 12 hours.

Following intravenous administration of radiolabelled esketamine, approximately 78% and 2% ofadministered radioactivity was recovered in urine and faeces, respectively. Following oraladministration of radiolabelled esketamine, approximately 86% and 2% of administered radioactivitywas recovered in urine and faeces, respectively. The recovered radioactivity consisted primarily ofesketamine metabolites. For the intravenous and oral routes of administration, < 1% of the dose wasexcreted in the urine as unchanged drug.

Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in Cmax and AUC valueswas less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly doseproportional between 56 mg and 84 mg.

Effect of other medicinal products on esketamine

Hepatic enzyme inhibitors

Pre-treatment of healthy subjects with oral ticlopidine, an inhibitor of hepatic CYP2B6 activity,(250 mg twice daily for 9 days prior to and on the day of esketamine administration) had no effect onthe Cmax of esketamine administered as a nasal spray. The AUC∞ of esketamine was increased byapproximately 29%. The terminal half-life of esketamine was not affected by ticlopidinepre-treatment.

Pre-treatment with oral clarithromycin, an inhibitor of hepatic CYP3A4 activity, (500 mg twice dailyfor 3 days prior to and on the day of esketamine administration) increase the mean Cmax and AUC∞ ofnasally administered esketamine by approximately 11% and 4%, respectively. The terminal half-life ofesketamine was not affected by clarithromycin pre-treatment.

Hepatic enzyme inducers

Pre-treatment with oral rifampicin, a potent inducer of the activity of multiple hepatic CYP enzymessuch as CYP3A4 and CYP2B6, (600 mg daily for 5 days prior to esketamine administration)decreased the mean Cmax and AUC∞ values of esketamine administered as a nasal spray byapproximately 17% and 28%, respectively.

Other nasal spray products

Pre-treatment of subjects with a history of allergic rhinitis and pre-exposed to grass pollen withoxymetazoline administered as a nasal spray (2 sprays of 0.05% solution administered at 1 hour priorto nasal administration of esketamine) had minor effects on the pharmacokinetics of esketamine.

Pre-treatment of healthy subjects with nasal administration of mometasone furoate (200 mcg per dayfor 2 weeks with the last mometasone furoate dose administered at 1 hour prior to nasal administrationof esketamine) had minor effects on the pharmacokinetics of esketamine.

Effect of esketamine on other medicinal products

Nasal administration of 84 mg esketamine twice a week for 2 weeks reduced the mean plasma AUC∞of oral midazolam (single 6 mg dose), a substrate of hepatic CYP3A4, by approximately 16%.

Nasal administration of 84 mg esketamine twice a week for 2 weeks did not affect the mean plasma

AUC of oral bupropion (single 150 mg dose), a substrate of hepatic CYP2B6.

Elderly (65 years of age and older)

The pharmacokinetics of esketamine administered as a nasal spray was compared between elderly butotherwise healthy subjects and younger healthy adults. The mean esketamine Cmax and AUC∞ valuesproduced by a 28 mg dose were 21% and 18% higher, respectively, in elderly subjects (age range 65 to81 years) compared with younger adult subjects (age range 22 to 50 years). The mean esketamine Cmaxand AUC∞ values produced by an 84 mg dose were 67% and 38% higher in elderly subjects (age range75 to 85 years) compared with younger adult subjects (age range 24 to 54 years). The terminal half-lifeof esketamine was similar in the elderly and younger adult subjects (see section 4.2).

Relative to the subjects with normal renal function (creatinine clearance [CLCR], 88 to 140 mL/min),the Cmax of esketamine was on average 20 to 26% higher in subjects with mild (CLCR, 58 to77 mL/min), moderate (CLCR, 30 to 47 mL/min), or severe (CLCR, 5 to 28 mL/min, not on dialysis)renal impairment following administration of a 28 mg dose of esketamine nasal spray. The AUC∞ was13 to 36% higher in the subjects with mild to severe renal impairment.

There is no clinical experience with esketamine administered as a nasal spray in patients on dialysis.

The Cmax and AUC∞ of esketamine produced by a 28 mg doses were similar between subjects with

Child-Pugh class A (mild) hepatic impairment and healthy subjects. The Cmax and AUC∞ ofesketamine were 8% higher and 103% higher, respectively, in subjects with Child-Pugh class B(moderate) hepatic impairment, relative to healthy subjects.

There is no clinical experience with esketamine administered as a nasal spray in patients with

Child-Pugh class C (severe) hepatic impairment (see section 4.2 and 4.4).

The pharmacokinetics of esketamine nasal spray was compared between healthy Asian subjects and

Caucasian subjects. Mean plasma esketamine Cmax and AUC∞ values produced by a single, 56 mg doseof esketamine were approximately 14% and 33% higher, respectively, in Chinese subjects comparedto Caucasians. On average, esketamine Cmax was 10% lower and AUC∞ was 17% higher in Koreansubjects, relative to Caucasian subjects. A population pharmacokinetic analysis was conducted thatincluded Japanese patients with treatment-resistant depression, in addition to healthy Japanesesubjects. Based on this analysis, for a given dose, the plasma esketamine Cmax and AUC24h in Japanesesubjects were approximately 20% higher relative to non-Asian subjects. The mean terminal half-life ofesketamine in the plasma of Asian subjects ranged from 7.1 to 8.9 hours and was 6.8 hours in

Caucasian subjects.

Gender and body weight

No significant differences in the pharmacokinetics of esketamine nasal spray were observed for genderand total body weight (> 39 to 170 kg) based on population PK analysis.

Allergic rhinitis

The pharmacokinetics of a single, 56 mg dose of esketamine administered as a nasal spray was similarin subjects with allergic rhinitis who were exposed to grass pollen compared to healthy subjects.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity, genotoxicity, neurotoxicity, reproductive toxicity, and carcinogenic potential. Animal studieswith ketamine showed evidence of developmental neurotoxicity. The potential for esketamine to haveneurotoxic effects on developing foetuses cannot be excluded (see section 4.6).

Esketamine was not mutagenic with or without metabolic activation in the Ames test. Genotoxiceffects with esketamine were seen in a screening in vitro micronucleus test in the presence ofmetabolic activation. However, intravenously-administered esketamine was devoid of genotoxicproperties in an in vivo bone marrow micronucleus test in rats and an in vivo Comet assay in rat livercells.

In an embryo foetal developmental toxicity study with nasally administered ketamine in rats, theoffspring was not adversely affected in the presence of maternal toxicity at doses resulting in exposureup to 6-fold higher than human exposure, based on AUC values. In an embryo foetal developmentaltoxicity study with nasally administered ketamine in rabbits, skeletal malformations were observedand foetal body weight was reduced at maternally toxic doses. Exposure in rabbits was in the region ofhuman exposure based on AUC values.

Published studies in animals (including primates) at doses resulting in light to moderate anaesthesiademonstrate that the use of anaesthetic agents during the period of rapid brain growth orsynaptogenesis results in cell loss in the developing brain, that can be associated with prolongedcognitive deficiencies. The clinical significance of these non-clinical findings in not known.

Citric acid monohydrate

Disodium edetate

Sodium hydroxide (for pH adjustment)

Water for injections

Not applicable.

4 years

This medicinal product does not require any special storage conditions.

Type-I glass vial with a chlorobutyl rubber stopper. The filled and stoppered vial is assembled into amanually-activated nasal spray device. The device dispenses two sprays.

Within each pack, each device is individually packaged in a sealed blister.

Pack sizes of 1, 2, 3, or 6 nasal spray devices and in multipacks containing 12 (4 packs of 3) or24 (8 packs of 3) nasal spray devices.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/19/1410/001 (1 spray container)

EU/1/19/1410/002 (2 spray containers)

EU/1/19/1410/003 (3 spray containers)

EU/1/19/1410/004 (6 spray containers)

EU/1/19/1410/005 (24 spray containers)

EU/1/19/1410/006 (12 spray containers)

Date of first authorisation: 18 December 2019

Date of last renewal: 22 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.