Spravato

Spravato

esketamine

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Esketamine.
Description
Each nasal spray device contains esketamine hydrochloride corresponding to 28 mg esketamine.
Excipients/Inactive Ingredients: Citric acid monohydrate, Disodium edetate, Sodium hydroxide (for pH adjustment), Water for injections.
Action
Pharmacotherapeutic group: Psychoanaleptics; Other antidepressants. ATC code: N06AX27.
Pharmacology: Pharmacodynamics: Mechanism of action: Esketamine is the S-enantiomer of racemic ketamine. It is a non-selective, non-competitive, antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. Through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulation and subsequently to increases in neurotrophic signalling which may contribute to the restoration of synaptic function in these brain regions involved with the regulation of mood and emotional behaviour. Restoration of dopaminergic neurotransmission in brain regions involved in the reward and motivation, and decreased stimulation of brain regions involved in anhedonia, may contribute to the rapid response.
Pharmacodynamic effects: Abuse potential: In a study of abuse potential conducted in recreational polydrug users (n=41), single doses of esketamine 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 subjective ratings of "drug liking" and on other measures of subjective drug effects.
Clinical efficacy and safety: The efficacy and safety of SPRAVATO nasal spray was investigated in five Phase 3 clinical studies in adult patients (18 to 86 years) with treatment resistant depression (TRD) who met DSM-5 criteria for major depressive disorder and were non 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 patients were exposed to SPRAVATO.
Treatment resistant depression - Short term studies: SPRAVATO 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 initiated treatment with SPRAVATO 56 mg plus a newly initiated daily oral AD or a newly initiated daily oral AD plus placebo nasal spray on day 1. SPRAVATO dosages were then maintained on 56 mg or titrated to 84 mg or matching placebo nasal spray administered twice-weekly during a 4-week double-blind induction phase. SPRAVATO 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 SPRAVATO 28 mg plus a newly initiated daily oral AD or a newly initiated daily oral AD plus placebo nasal spray (day 1). SPRAVATO dosages were titrated to 56 mg or 84 mg or matching placebo nasal spray administered twice-weekly during a 4-week double-blind induction phase. In the flexible dose studies, TRD3002 and TRD3005, up titration of SPRAVATO dose was based on clinical judgement and dose could 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. The selection of the newly initiated oral AD was determined by the investigator based on the patient's prior treatment history. In all short-term studies, the primary efficacy endpoint was change in MADRS total score from baseline to day 28.
Baseline demographic and disease characteristics for patient in TRD3002, TRD3001, and TRD3005 are presented in Table 1.

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In the flexible dose study TRD3002, at day 28, 67% of the patients randomised to SPRAVATO were on 84 mg. In study TRD3002, esketamine plus a newly initiated oral AD demonstrated clinically meaningful and statistical superiority compared to a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 2), and symptom reduction was observed as early as 24 hours post-dose.
In study TRD3001, a clinically meaningful treatment effect in change in MADRS total scores from baseline at the end of the 4-week induction phase was observed favouring SPRAVATO plus newly initiated oral AD compared with a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 2). In Study TRD3001, the treatment effect for the SPRAVATO 84 mg plus oral AD group compared with oral AD plus placebo was not statistically significant.
In study TRD3005, at day 28, 64% of the patients randomised to SPRAVATO were on 84 mg, 25% on 56 mg, and 10% on 28 mg. In study TRD3005, a clinically meaningful but not statistically significant treatment effect in change in MADRS total scores from baseline at the end of the 4-week induction phase was observed favouring SPRAVATO plus newly initiated oral AD compared with a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Table 2). Subgroup analyses suggest limited efficacy in the population over 75 years old. (See Table 2.)

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Response and remission rates: Response was defined as ≥ 50% reduction in the MADRS total score from baseline of the induction phase. Based on the reduction in MADRS total score from baseline, the proportion of patients in Studies TRD3001, TRD3002 and TRD3005 who demonstrated response to SPRAVATO plus oral AD treatment was greater than for oral AD plus placebo nasal spray throughout the 4-week double-blind induction phase (Table 3).
Remission was defined as a MADRS total score ≤ 12. In all three studies, a greater proportion of patients treated with SPRAVATO plus oral AD were in remission at the end of the 4-week double-blind induction phase than for oral AD plus placebo nasal spray (Table 3). (See Table 3.)

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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, multicenter, relapse prevention study. The primary outcome measure to assess the prevention of depressive relapse was measured as time to relapse. Overall a total of 705 patients were enrolled; 437 directly enrolled; 150 transferred from TRD3001, and 118 transferred from TRD3002. Patients directly enrolled were administered SPRAVATO (56 mg or 84 mg twice weekly) plus oral AD in a 4-week open label induction phase. At the end of the open label induction phase, 52% of patients were in 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 with SPRAVATO plus oral AD in a 12-week optimisation phase. After the induction phase, patients received SPRAVATO weekly for 4 weeks and starting from week 8, an algorithm (based on the MADRS) was used to determine the dosing frequency; patients in remission (i.e., MADRS total score was ≤ 12) were dosed every other week, however, if the MADRS total score increased to > 12, then the frequency was increased to weekly dosing for the next 4 weeks; with the objective of maintaining the patient on the lowest 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 with SPRAVATO or stop SPRAVATO 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 response was defined as ≥ 50% reduction in the MADRS total score from baseline for the last 2 weeks of the optimisation phase, but not in stable remission.
Stable remission: Patients in stable remission who continued treatment with SPRAVATO plus oral AD experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Figure 1). Relapse was defined as a MADRS total score ≥ 22 for 2 consecutive weeks or hospitalisation for worsening depression or any other clinically relevant event indicative of relapse. The median time to relapse for a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray group was 273 days, whereas the median was not estimable for SPRAVATO plus oral AD, as this group never reached 50% relapse rate. (See Figure 1.)

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For patients in stable remission, the relapse rate based on Kaplan-Meier estimates during the 12- and 24-weeks double-blind follow up period was 13% and 32% for SPRAVATO and 37% and 46% for placebo nasal spray, respectively.
Stable response: The efficacy results were also consistent for patients in stable response who continued treatment with SPRAVATO plus oral AD; patients experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on a newly initiated oral AD (SNRI: duloxetine, venlafaxine extended release; SSRI: escitalopram, sertraline) plus placebo nasal spray (Figure 2). The median time to 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 SPRAVATO plus oral AD group (635 days). (See Figure 2.)

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For patients in stable response, the relapse rate based on Kaplan-Meier estimates during the 12- and 24-weeks double-blind follow up period was 21% and 21% for SPRAVATO and 47% and 56% for placebo nasal spray, respectively.
Enrollment in TRD3003 was staggered over approximately 2 years. The maintenance phase was of variable duration and continued until the individual patient had a relapse of depressive symptoms or discontinued for any other reason, or the study ended because the required number of relapse events occurred. Exposure numbers were influenced by the study stopping at a pre-determined number of relapses based on the interim analysis. After an initial 16 weeks of treatment with SPRAVATO plus oral AD, the median duration of exposure to SPRAVATO 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 SPRAVATO for greater than 6 months and 7.9% of patients received SPRAVATO 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 4. Of the patients randomised to SPRAVATO, 60% received 84 mg and 40% received 56 mg dose. (See Table 4.)

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Depressive symptoms in patients with major depressive disorder with acute suicidal ideation or behavior: SPRAVATO was evaluated in two identical Phase 3 short-term (4-week) randomized, double-blind, multicenter, placebo-controlled studies, Study 3 (NCT03039192) and Study 4 (NCT03097133), in adults with moderate-to-severe MDD (MADRS total score >28) who had active suicidal ideation and intent. In these studies, patients received treatment with SPRAVATO 84 mg or placebo nasal spray twice-weekly for 4 weeks. After the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant (AD) (AD monotherapy or AD plus augmentation therapy) as determined by the investigator. After completion of the 4-week treatment period with SPRAVATO/placebo, study follow-up continued through Day 90.
The baseline demographic and disease characteristics of patients in Study 3 and Study 4 were similar between the SPRAVATO plus standard of care or placebo nasal spray plus standard of care treatment groups. The median patient age was 40 years (range 18 to 64 years), 61% were female; 73% Caucasian and 6% Black; and 63% of patients had at least one prior suicide attempt. Prior to entering the study, 92% of the patients were receiving antidepressant therapy. During the study, as part of standard of care treatment, 40% of patients received AD monotherapy, 54% of patients received AD plus augmentation therapy, and 6% received both AD monotherapy/AD plus augmentation therapy.
The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after first dose (Day 2). In Study 3 and Study 4, SPRAVATO plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care (see Table 5).

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The secondary efficacy measure was the change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) score at 24 hours after first dose (Day 2). The CGI-SS-r is a one-item, clinician-rated assessment used to rate the current severity of a patient's suicidal ideation and behavior. Scores on the CGI-SS-r range from 0 to 6, with higher scores indicating more severe suicidal ideation and behavior. In Study 3 and Study 4, SPRAVATO plus standard of care did not demonstrate superiority compared to placebo nasal spray plus standard of care in improving CGI-SS-r.
Time Course of Treatment Response: In both Study 3 and Study 4, SPRAVATO's treatment difference compared to placebo was observed starting at 4 hours. Between 4 hours and Day 25, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 25. Figure 3 depicts time course of the primary efficacy measure of change in MADRS total score from Study 3. (See Figure 3.)

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* Note: In Study 3, after the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. Approximately 19% of patients had reduction in SPRAVATO dosage from 84 mg to 56 mg twice weekly.
Pharmacokinetics: Absorption: The mean absolute bioavailability of 84 mg esketamine administered as a nasal spray is approximately 48%.
Esketamine is rapidly absorbed by the nasal mucosa following nasal administration and can be measured in plasma within 7 minutes following a 28 mg dose. The time to reach maximum plasma concentration (tmax) is typically 20 to 40 minutes after the last nasal spray of a treatment session (see Dosage & Administration).
Dose-dependent increases in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of esketamine nasal spray were produced by doses of 28 mg, 56 mg and 84 mg.
The pharmacokinetic profile of esketamine is similar after a single dose and repeat dose administration with no accumulation in plasma when esketamine is administered twice a week.
Distribution: The mean steady-state volume of distribution of esketamine administered by the intravenous route is 709 L.
The proportion of the total concentration of esketamine that is bound to proteins in human plasma is on average 43 to 45%. The degree to which esketamine is bound to plasma proteins is not dependent on 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.
Biotransformation: Esketamine is extensively metabolised in the liver. The primary metabolic pathway of esketamine in human liver microsomes is N-demethylation to form noresketamine. The main cytochrome P450 (CYP) enzymes responsible for esketamine N-demethylation are CYP2B6 and CYP3A4. Other CYP enzymes, including CYP2C19 and CYP2C9, contribute to a much smaller extent. Noresketamine is subsequently metabolised via CYP-dependent pathways to other metabolites, some of which undergo glucuronidation.
Elimination: The mean clearance of esketamine administered by the intravenous route was approximately 89 L/hour. After Cmax was reached following nasal administration, the decline in esketamine concentrations in plasma was rapid for the first few hours and then more gradual. The mean terminal half-life following administration as a nasal spray generally ranged from 7 to 12 hours.
Following intravenous administration of radiolabelled esketamine, approximately 78% and 2% of administered radioactivity was recovered in urine and faeces, respectively. Following oral administration of radiolabelled esketamine, approximately 86% and 2% of administered radioactivity was recovered in urine and faeces, respectively. The recovered radioactivity consisted primarily of esketamine metabolites. For the intravenous and oral routes of administration, < 1% of the dose was excreted in the urine as unchanged drug.
Linearity/non-linearity: Esketamine exposure increases with dose from 28 mg to 84 mg. The increase in Cmax and AUC values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly dose proportional between 56 mg and 84 mg.
Interactions: 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 on the Cmax of esketamine administered as a nasal spray. The AUC of esketamine was increased by approximately 29%. The terminal half-life of esketamine was not affected by ticlopidine pre-treatment.
Pre-treatment with oral clarithromycin, an inhibitor of hepatic CYP3A4 activity, (500 mg twice daily for 3 days prior to and on the day of esketamine administration) increase the mean Cmax and AUC of nasally administered esketamine by approximately 11% and 4%, respectively. The terminal half-life of esketamine 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 enzymes such 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 by approximately 17% and 28%, respectively.
Other nasal spray products: Pre-treatment of subjects with a history of allergic rhinitis and pre-exposed to grass pollen with oxymetazoline administered as a nasal spray (2 sprays of 0.05% solution administered at 1 hour prior to 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 day for 2 weeks with the last mometasone furoate dose administered at 1 hour prior to nasal administration of 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.
Special populations: Elderly (65 years of age and older): The pharmacokinetics of esketamine administered as a nasal spray was compared between elderly but otherwise healthy subjects and younger healthy adults. The mean esketamine Cmax and AUC values produced by a 28-mg dose were 21% and 18% higher, respectively, in elderly subjects (age range 65 to 81 years) compared with younger adult subjects (age range 22 to 50 years). The mean esketamine Cmax and AUC values produced by an 84-mg dose were 67% and 38% higher in elderly subjects (age range 75 to 85 years) compared with younger adult subjects (age range 24 to 54 years). The terminal half-life of esketamine was similar in the elderly and younger adult subjects (see Dosage & Administration).
Renal impairment: 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 to 77 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 was 13 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.
Hepatic impairment: The Cmax and AUCof 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 of esketamine 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 Dosage & Administration and Precautions).
Race: 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 dose of esketamine were approximately 14% and 33% higher, respectively, in Chinese subjects compared to Caucasians. Both parameters were approximately 40% higher in Japanese subjects, relative to Caucasian subjects. On average, esketamine Cmax was 10% lower and AUC was 17% higher in Korean subjects, relative to Caucasian subjects. The mean terminal half-life of esketamine 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 gender and 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 similar in subjects with allergic rhinitis who were exposed to grass pollen compared to healthy subjects.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, neurotoxicity, reproductive toxicity, and carcinogenic potential. Animal studies with ketamine showed evidence of developmental neurotoxicity. The potential for esketamine to have neurotoxic effects on developing foetuses cannot be excluded (see Use in Pregnancy & Lactation).
Genotoxicity: Esketamine was not mutagenic with or without metabolic activation in the Ames test. Genotoxic effects with esketamine were seen in a screening in vitro micronucleus test in the presence of metabolic activation. However, intravenously-administered esketamine was devoid of genotoxic properties in an in vivo bone marrow micronucleus test in rats and an in vivo Comet assay in rat liver cells.
Reproductive toxicity: In an embryo foetal developmental toxicity study with nasally administered ketamine in rats, the offspring was not adversely affected in the presence of maternal toxicity at doses resulting in exposure up to 6-fold higher than human exposure, based on AUC values. In an embryo foetal developmental toxicity study with nasally administered ketamine in rabbits, skeletal malformations were observed and foetal body weight was reduced at maternally toxic doses. Exposure in rabbits was in the region of human exposure based on AUC values.
Published studies in animals (including primates) at doses resulting in light to moderate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain, that can be associated with prolonged cognitive deficiencies. The clinical significance of these non-clinical findings in not known.
Indications/Uses
SPRAVATO, in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for adults with treatment-resistant Major Depressive Disorder (MDD), who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode (see Pharmacology: Pharmacodynamics under Actions).
SPRAVATO is indicated, in conjunction with an oral antidepressant, for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior.
Limitations of Use: The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated (see Pharmacology: Pharmacodynamics under Actions). Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO.
SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established.
Dosage/Direction for Use
The decision to prescribe SPRAVATO should be determined by a psychiatrist.
SPRAVATO is intended to be self-administered by the patient under the direct supervision of a healthcare professional.
A treatment session consists of nasal administration of SPRAVATO and a post-administration observation period. Both administration and post-administration observation of SPRAVATO should be carried out in an appropriate clinical 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 of SPRAVATO treatment should be considered (see Precautions). SPRAVATO should not be administered if an increase in blood pressure or intracranial pressure poses a serious risk (see Contraindications).
Patients with clinically significant or unstable cardiovascular or respiratory conditions require additional precautions. In these patients, SPRAVATO should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available (see Precautions).
Post-administration observation: After dosing with SPRAVATO, blood pressure should be reassessed at approximately 40 minutes and subsequently as clinically warranted (see Precautions).
Because of the possibility of sedation, dissociation and elevated blood pressure, patients must be monitored by a healthcare professional until the patient is considered clinically stable and ready to leave the healthcare setting (see Precautions).
Posology: The dose recommendations for SPRAVATO are shown in Table 6 and Table 7 (adults ≥65 years). It is recommended to maintain the dose the patient receives at the end of the induction phase in the maintenance phase. Dose adjustments should be made based on efficacy and tolerability to the previous dose. During the maintenance phase, SPRAVATO dosing should be individualised to the lowest frequency to maintain remission/response. (See Tables 6 and 7.)

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After depressive symptoms improve, treatment is recommended for at least 6 months.
Food and liquid intake recommendations prior to administration: Since some patients may experience nausea and vomiting after administration of SPRAVATO, patients should be advised not to eat for at least 2 hours before administration and not to drink liquids at least 30 minutes prior to administration (see Adverse Reactions).
Nasal corticosteroid or nasal decongestant: Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should be advised not to administer these medicinal products within 1 hour before SPRAVATO administration.
Missed treatment session(s): In case one or two treatment sessions are missed, the next session should be scheduled when the next session was scheduled to occur based on current treatment frequency. If more than 2 treatment sessions have been missed, per clinical judgment, adjustment of the dose or frequency of SPRAVATO may be clinically appropriate.
Special populations: Elderly (65 years of age and older): In elderly patients the initial SPRAVATO dose is 28 mg esketamine (day 1, starting dose, see Table 7 previously). Subsequent doses should be increased in increments of 28 mg up to 56 mg or 84 mg, based on efficacy and tolerability.
Hepatic impairment: No dose adjustment is necessary in patients with mild (Child Pugh class A) or moderate (Child Pugh class B) hepatic impairment. However, the maximum dose of 84 mg should be used with caution in patients with moderate hepatic impairment.
SPRAVATO has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is necessary in patients with mild to severe renal impairment. Patients on dialysis were not studied.
Patients of Japanese ancestry: Efficacy of SPRAVATO in Japanese patients has not been established to date.
Paediatric population: The safety and efficacy of SPRAVATO in paediatric patients aged 17 years and younger have not been established. No data are available. There is no relevant use of SPRAVATO in children less than 7 years of age in the indication for treatment-resistant depression.
Depressive symptoms in patients with major depressive disorder with acute suicidal ideation or behaviour: Administer SPRAVATO in conjunction with an oral antidepressant (AD).
The recommended dosage of SPRAVATO for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior is 84 mg twice per week for 4 weeks. Dosage may be reduced to 56 mg twice per week based on tolerability. After 4 weeks of treatment with SPRAVATO, evidence of therapeutic benefit should be evaluated to determine need for continued treatment. The use of SPRAVATO, in conjunction with an oral antidepressant, beyond 4 weeks has not been systematically evaluated in the treatment of depressive symptoms in patients with MDD with acute suicidal ideation or behavior.
Method of administration: SPRAVATO is for nasal use only. The nasal spray device is a single-use device that delivers a total of 28 mg of esketamine, in two sprays (one spray per nostril). To prevent loss of medicinal product, the device should not be primed before use. It is intended for administration by the patient under the supervision of a healthcare professional, using 1 device (for a 28 mg dose), 2 devices (for a 56 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 with SPRAVATO does not require tapering off; based on data from clinical trials the risk of withdrawal symptoms is low.
Overdosage
The potential for overdose of SPRAVATO by the patient is minimised due to the product's design and the administration taking place under the supervision of a healthcare professional (see Dosage & Administration).
Symptoms: The maximum single esketamine nasal spray dose tested in healthy volunteers was 112 mg which showed no evidence of toxicity and/or adverse clinical outcomes. However, compared to the recommended dose range, the 112-mg esketamine nasal spray dose was associated with higher rates of adverse 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 usual anaesthetic dose. Clinical symptoms are described as convulsions, cardiac arrhythmias, and respiratory arrest. Administration of a comparable supratherapeutic dose of esketamine by the intranasal route is unlikely to be feasible.
Management: There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple medicinal products involvement should be considered. Management of SPRAVATO overdose should consist of treating clinical symptoms and relevant monitoring. Close supervision and monitoring should continue until the patient recovers.
Contraindications
Hypersensitivity to the active substance, ketamine, or to any of the excipients listed in Description.
Patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (see Adverse Reactions): Patients with aneurysmal vascular disease (including intracranial, thoracic, or abdominal aorta, or peripheral arterial vessels);
Patients with history of intracerebral haemorrhage;
Recent (within 6 weeks) cardiovascular event, including myocardial infarction (MI).
Special Precautions
Neuropsychiatric and motor impairments: SPRAVATO has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo and anxiety during the clinical trials (see Adverse Reactions). These effects may 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 the patient is considered stable based on clinical judgement (see Effects on ability to drive and use machines as follows).
Respiratory depression: Respiratory depression may occur at high doses following rapid intravenous injection of esketamine or ketamine when used for anaesthesia. No case of respiratory depression was observed in clinical trials with esketamine nasal spray (SPRAVATO); rare cases of deep sedation have been reported. Concomitant use of SPRAVATO with CNS depressants may increase the risk for sedation (see Interactions). Close monitoring is required for sedation and respiratory depression.
Effect on blood pressure: SPRAVATO can cause transient increases in systolic and/or diastolic blood pressure which peak at approximately 40 minutes after administration of the medicinal product and last approximately 1-2 hours (see Adverse Reactions). A substantial increase in blood pressure could occur after any treatment session. SPRAVATO is contraindicated in patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (see Contraindications). Before prescribing SPRAVATO, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of SPRAVATO outweigh its risks.
In patients whose blood pressure prior to dose administration is judged to be elevated (as a general guide: >140/90 mmHg for patients <65 years of age and >150/90 mmHg for patients ≥65 years of age), it is appropriate to adjust lifestyle and/or pharmacologic therapies to reduce blood pressure before starting treatment with SPRAVATO. If blood pressure is elevated prior to SPRAVATO administration a decision to delay SPRAVATO therapy should take into account the balance of benefit and risk in individual patients.
Blood pressure should be monitored after dose administration. Blood pressure should be measured around 40 minutes post-dose and subsequently as clinically warranted until values decline. If blood pressure remains elevated for a prolonged period of time, assistance should promptly be sought from practitioners experienced in blood pressure management. Patients who experience symptoms of a hypertensive crisis should be referred immediately for emergency care.
Patients with clinically significant or unstable cardiovascular or respiratory conditions: Only initiate treatment with SPRAVATO in patients with clinically significant or unstable cardiovascular or respiratory conditions if the benefit outweighs the risk. In these patients, SPRAVATO should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available. Examples of conditions which 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 symptom free prior to administration; Haemodynamically significant valvular heart disease or heart failure (NYHA Class III-IV).
Suicide/suicidal thoughts or clinical worsening: 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 should be closely monitored. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.
Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Suicidality in children and adolescents: Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.
Drug abuse, dependence, withdrawal: Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Prior to prescribing SPRAVATO, each patient's risk for abuse or misuse should be assessed and patients receiving esketamine should be monitored for the development of behaviours or conditions of abuse or misuse, including drug seeking behaviour, while on therapy.
Dependence and tolerance have been reported with prolonged use of ketamine. In individuals who were dependent on ketamine, withdrawal symptoms of cravings, anxiety, shaking, sweating and palpitations have been reported upon discontinuing ketamine.
Ketamine, the racemic mixture of arketamine and esketamine, is a medicinal product that has been reported to be abused. The potential for abuse, misuse and diversion of SPRAVATO is minimised due to the administration taking place under the direct supervision of a healthcare professional. SPRAVATO contains 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 should be carefully assessed before prescribing SPRAVATO and treatment initiated only if the benefit outweighs the 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 ventricular shunts, or any other condition associated with increased intracranial pressure.
Urinary tract symptoms: Urinary tract and bladder symptoms have been reported with SPRAVATO use (see Adverse Reactions). It is recommended to monitor for urinary tract and bladder symptoms during the course of treatment and refer to an appropriate healthcare provider when symptoms persist.
Effects on ability to drive and use machines: SPRAVATO has a major influence on the ability to drive and use machines. In clinical studies, SPRAVATO has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo and anxiety (see Adverse Reactions). Before SPRAVATO administration, patients should be instructed not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a vehicle or operating machinery, until the next day following a restful sleep.
Severe hepatic impairment: Due to expected increase in exposure and lack of clinical experience, SPRAVATO is not recommended in patients with Child-Pugh class C (severe) hepatic impairment.
Hepatotoxicity has been reported with chronic ketamine use, therefore, the potential for such an effect due to long-term use of SPRAVATO cannot be excluded.
Use in the 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.
Use In Pregnancy & Lactation
Women of childbearing potential: SPRAVATO is not recommended during pregnancy and in women of childbearing potential not using contraception.
Pregnancy: There are no or limited data on the use of esketamine in pregnant women. Animal studies have shown that ketamine, the racemic mixture of arketamine and esketamine, induces neurotoxicity in developing foetuses (see Pharmacology: Toxicology: Preclinical safety data under Actions). 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/therapeutic options as soon as possible.
Breast-feeding: It is unknown whether esketamine is excreted in human milk. Data in animals have shown excretion of esketamine in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from SPRAVATO therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: Animal studies showed that fertility and reproductive capacities were not adversely affected by esketamine.
Adverse Reactions
Summary of the safety profile: The most commonly observed adverse reactions in treatment-resistant depression patients treated with SPRAVATO were dizziness (30%), nausea (27%), dissociation (26%), headache (24%), somnolence (18%), vertigo (18%), dysgeusia (17%), hypoaesthesia (11%), and vomiting (10%).
Tabulated list of adverse reactions: Adverse reactions reported with esketamine are listed in the table as follows. Within the designated system organ classes, adverse reactions are listed under headings of frequency, using the following convention: very common (≥ 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). (See Table 8.)

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Description of selected adverse reactions: Dissociation: Dissociation (26%) was one of the most common psychological effects of esketamine. Other related terms included derealisation (1.9%), depersonalisation (1.7%), illusions (1.5%), and distortion of time (1.2%). These adverse reactions were reported as transient and self-limited and occurred on the day of dosing. 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 reduce over time with repeated treatments.
Sedation/somnolence: Adverse reactions of sedation (9.1%) and somnolence (18.0%) were primarily mild or moderate 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 stable over time during long-term treatment. In the cases of sedation, no symptoms of respiratory distress were observed, and haemodynamic parameters (including vital signs and oxygen saturation) remained within normal ranges.
Changes in blood pressure: In clinical trials, increases in systolic and diastolic blood pressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients receiving SPRAVATO plus oral antidepressants (see Precautions). The frequency of markedly abnormal 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) in patients 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. In long-term clinical trials, the effect of esketamine nasal spray on cognitive functioning 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. In clinical studies with esketamine, there were no cases of interstitial cystitis, however a higher rate of lower urinary tract symptoms was observed (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in esketamine-treated patients compared with placebo-treated patients.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Depressive symptoms in patients with major depressive disorder with acute suicidal ideation or behavior: SPRAVATO was evaluated for safety in 262 adults for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior (see Pharmacology: Pharmacodynamics under Actions) from two Phase 3 studies (Study 3 and Study 4) and one Phase 2 study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 184 (81%) received all eight doses over a 4-week treatment period.
Adverse reactions leading to discontinuation of treatment: In short-term studies in adults (pooled Study 3 and Study 4), the proportion of patients who discontinued treatment because of an adverse reaction was 6.2% for patients who received SPRAVATO plus oral AD compared to 3.6% for patients who received placebo nasal spray plus oral AD. Adverse reactions leading to SPRAVATO discontinuation in more than 1 patient were (in order of frequency): dissociation-related events (2.6%), blood pressure increased (0.9%), dizziness-related events (0.9%), nausea (0.9%), and sedation-related events (0.9%).
Most common adverse reactions: The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. Table 9 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD and greater than patients treated with placebo nasal spray plus oral AD. (See Table 9).

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Sedation: Sedation was evaluated by adverse event reports and the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). In the MOAA/S, 5 means "responds readily to name spoken in normal tone" and 0 means "no response after painful trapezius squeeze." Any decrease in MOAA/S from pre-dose is considered to indicate the presence of sedation, and such a decrease occurred in a higher number of patients on SPRAVATO than placebo during the short-term TRD studies. Dose-related increases in the incidence of sedation (MOAA/S score <5) were observed in a fixed-dose TRD study [see Precautions]. Table 10 presents the incidence of sedation (MOAA/S score <5) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD. (See Table 10).

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In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, there was a higher incidence of sedation (MOAA/S score <5) in patients treated with SPRAVATO plus oral AD compared to patients treated with placebo plus oral AD, similar to the TRD study results in Table 10.
Dissociation/perceptual changes: SPRAVATO can cause dissociative symptoms (including derealization and depersonalization) and perceptual changes (including distortion of time and space, and illusions). In clinical trials, dissociation was transient and occurred on the day of dosing. Dissociation was evaluated by adverse event reports and the Clinician-Administered Dissociative States Scale (CADSS). A CADSS total score of more than 4 indicates the presence of dissociative symptoms, and such an increase to a score of 4 or more occurred in a higher number of patients on SPRAVATO compared to placebo during the short-term TRD studies. Dose-related increases in the incidence of dissociative symptoms (CADSS total score >4 and change >0) were observed in a fixed-dose TRD study [see Precautions]. Table 11 presents the incidence of dissociation (CADSS total score >4 and change >0) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD. (See Table 11.)

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In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral AD also demonstrated a higher number (84%) with dissociation (CADSS total score >4 and change >0) compared to patients treated with placebo plus oral AD (16%).
Increase in blood pressure: The mean placebo-adjusted increases in systolic and diastolic blood pressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients with TRD receiving SPRAVATO plus oral antidepressants [see Precautions]. Table 12 presents increases in blood pressure in short-term trials with patients <65 years of age and ≥65 years of age with TRD. (See Table 12.)

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In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral antidepressants demonstrated similar mean placebo-adjusted increases in SBP and DBP compared to patient with TRD, as well as similar rates of increases to SBP ≥180 mmHg or ≥40 mmHg increases in SBP, and similar rates of increases to DBP ≥110 mmHg or ≥25 mmHg increases in DBP, compared to the TRD study results in Table 12.
Nausea and vomiting: SPRAVATO can cause nausea and vomiting. Most of these events occurred on the day of dosing and resolved the same day, with the median duration not exceeding 1 hour in most subjects across dosing sessions. Rates of reported nausea and vomiting decreased over time across dosing sessions from the first week of treatment in the short-term studies, as well as over time with long-term treatment. Table 13 presents the incidence and severity of nausea and vomiting in a short-term study with patients with TRD. (See Table 13.)

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In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients demonstrated similar incidence and severity of reported nausea and vomiting compared to the TRD study results described previously.
Sense of smell: Sense of smell was assessed over time; no difference was observed between patients treated with SPRAVATO plus oral AD and those treated with placebo nasal spray plus oral AD during the double-blind maintenance phase of Study 2 (see Pharmacology: Pharmacodynamics under Actions).
Drug Interactions
Concomitant use of SPRAVATO with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation, which therefore should be closely monitored.
Blood pressure should be closely monitored when SPRAVATO is used concomitantly with psychostimulants (e.g., amphetamines, methylphenidate, modafanil, armodafinil) or other medicinal products that may increase blood pressure (e.g. xanthine derivatives, ergometrine, thyroid hormones, vasopressin, or MAOIs, such as, tranylcypromine, selegiline, phenelzine).
Caution For Usage
Incompatibilities: Not applicable.
Special precautions for use and handling and disposal: This device is intended for administration by the patient, under supervision of a healthcare professional. Read this Instructions for Use in full before training and supervising patient.
Storage
Do not store above 30°C.
Shelf life: 36 months.
Patient Counseling Information
Nasal Spray Device: Indicator: One device contains 2 sprays. (1 spray for each nostril); 2 green dots (0 mg delivered): Device Full; 1 green dot: One spray delivered; No green dots (28 mg delivered): Device empty.
Step 1: Get ready: Before first device only: Instruct patient to blow nose before first device only.
Confirm required number of devices: 28 mg = 1 device; 56 mg = 2 devices; 84 mg = 3 devices.
Step 2: Prepare device: Healthcare professional: Check expiration date ('EXP'). If expired, get a new device. Peel blister and remove device.
Healthcare professional: Do not prime device. This will result in a loss of medication.
Check that indicator shows 2 green dots. If not, dispose of device and get a new one.
Hand device to patient.
Step 3: Prepare patient: Patient should: Hold device with the thumb gently supporting the plunger. Do not press the plunger.
Patient should: Recline head at about 45 degrees during administration to keep medication inside the nose.
Step 4: Patient sprays once into each nostril: Patient should: Insert tip straight into the first nostril. Nose rest should touch the skin between the nostrils.
Patient should: Close opposite nostril. Breathe in through nose while pushing plunger all the way up until it stops.
Patient should: Sniff gently after spraying to keep medication inside nose.
Patient should: Switch hands to insert tip into the second nostril. Repeat Step 4 to deliver second spray.
Step 5: Confirm delivery and rest: Healthcare professional: Take device from patient. Check that indicator shows no green dots. If you see a green dot, have patient spray again into the second nostril. Check indicator again to confirm device is empty.
Patient should: Rest in a comfortable position (preferably, semi-reclined) for 5 minutes after each device. Do not blow nose. If liquid drips out, dab nose with a tissue.
Next device (if required): Healthcare professional: Repeat Steps 2-5 if more than one device is required. Ensure that patient waits 5 minutes after each device to allow medication to absorb.
Dispose of used device(s) in accordance with local requirements.
MIMS Class
ATC Classification
N06AX27 - esketamine ; Belongs to the class of other antidepressants.
Presentation/Packing
Nasal spray 28 mg/2 sprays (clear, colourless, aqueous solution) x 1's, 2's, 3's, 6's.
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