Spravato

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 

1. NAME OF THE MEDICINAL PRODUCT

Spravato 28 mg nasal spray, solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Nasal spray, solution.
Clear, colourless, aqueous solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 antidepressants
in the current moderate to severe depressive episode (see section 5.1).

4.2 Posology and method of administration

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 section 4.4). Spravato should not be administered if an 
increase in blood pressure or intracranial pressure poses a serious risk (see section 4.3).

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 section 4.4).

Post-administration observation
After dosing with Spravato, blood pressure should be reassessed at approximately 40 minutes and 
subsequently as clinically warranted (see section 4.4).



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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 section 4.4).

Posology

The dose recommendations for Spravato are shown in Table 1 and Table 2 (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.

Table 1: Recommended dosing for Spravato in adults <65 years
Induction phase Maintenance phase
Weeks 1-4:
Starting day 1 dose: 56 mg
Subsequent doses: 56 mg or 84 mg twice a week

Weeks 5-8:
56 mg or 84 mg once weekly

From week 9:
56 mg or 84 mg every 2 weeks or once 
weekly

Evidence of therapeutic benefit should be evaluated 
at the end of induction phase to determine need for 
continued treatment.

The need for continued treatment should be 
reexamined periodically. 

Table 2: Recommended dosing for Spravato in adults ≥65 years
Induction phase Maintenance phase
Weeks 1-4:
Starting day 1 dose: 28 mg
Subsequent doses: 28 mg, 56 mg or 84 mg

twice a week, all dose 
changes should be in 28 mg 
increments

Weeks 5-8:
28 mg, 56 mg or 84 mg once weekly, all 
dose changes should be in 28 mg increments

From week 9:
28 mg, 56 mg or 84 mg every 2 weeks or 
once weekly, all dose changes should be in 
28 mg increments

Evidence of therapeutic benefit should be evaluated 
at the end of induction phase to determine need for 
continued treatment.

The need for continued treatment should be 
reexamined periodically.

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 section 4.8).

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.



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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 2
above). 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 sections 4.4 and 5.2).

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

Race
For patients of Japanese ancestry, initial Spravato dose is 28 mg esketamine (day 1, starting dose, see 
Table 3). Subsequent doses should be increased in increments of 28 mg up to 56 mg or 84 mg, based 
on efficacy and tolerability.

Table 3: Recommended Dosing for Spravato in Adults of Japanese Ancestry
Induction phase Maintenance phase
Weeks 1-4:
Starting day 1 dose: 28 mg
Subsequent doses: 28 mg, 56 mg or 84 mg 

twice a week, all dose 
changes should be in 28 mg 
increments

Weeks 5-8:
28 mg, 56 mg or 84 mg once weekly, all 
dose changes should be in 28 mg increments

From week 9:
28 mg, 56 mg or 84 mg every 2 weeks or
once weekly, all dose changes should be in 
28 mg increments

Evidence of therapeutic benefit should be evaluated 
at the end of induction phase to determine need for 
continued treatment.

The need for continued treatment should be 
reexamined periodically. 

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.

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.



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

4.3 Contraindications

● Hypersensitivity to the active substance, ketamine, or to any of the excipients listed in 
section 6.1

● Patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (see 
section 4.8):
- 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).

4.4 Special warnings and precautions for use

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 section 4.8). 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 section 4.7).

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 section 4.5). 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 section 4.8). 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 section 4.3). 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.



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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.

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.



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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.

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.

Urinary tract symptoms

Urinary tract and bladder symptoms have been reported with Spravato use (see section 4.8). 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.

4.5 Interaction with other medicinal products and other forms of interaction

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).

4.6 Fertility, pregnancy and 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 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/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.



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4.7 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 section 4.8). 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 (see section 4.4).

4.8 Undesirable effects

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 below. 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).

System Organ Class Adverse Drug Reaction
Frequency

Very common Common Uncommon
Psychiatric disorders dissociation euphoric mood, agitation, 

anxiety, illusion, 
irritability, panic attack, 
time perception altered,
hallucination including 
visual hallucination, 
derealisation

Nervous system disorders dizziness, headache,
dysgeusia, somnolence,
hypoaesthesia

mental impairment, 
tremor, lethargy, 
dysarthria, paraesthesia, 
sedation

Eye disorders vision blurred 
Ear and labyrinth 
disorders

vertigo hyperacusis,
tinnitus 

Cardiac disorders tachycardia
Vascular disorders hypertension
Respiratory, thoracic and 
mediastinal disorders

nasal discomfort, nasal 
dryness including nasal 
crusting, nasal pruritus

Gastrointestinal disorders nausea, vomiting dry mouth, hypoaesthesia
oral

salivary 
hypersecretion

Skin and subcutaneous 
tissue disorders

hyperhidrosis

Renal and urinary 
disorders

pollakiuria, dysuria, 
micturition urgency

General disorders and 
administration site 
conditions

feeling abnormal, feeling 
drunk, feeling of body 
temperature change



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Investigations blood pressure increased

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 section 4.4). 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 
listed in Appendix V.

4.9 Overdose

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 section 4.2).

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

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.



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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 4.

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

Study TRD3002
(N=223)

Study TRD3001
(N=342)

Study TRD3005
(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 (for 
any reason), n/N (%)

30/227 (13.2%) 31/346 (9.0%) 16/138 (11.6%)

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 5), 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 5). In Study TRD3001, the 



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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 5). Subgroup analyses suggest limited efficacy in the population over 75 years old.

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

Study no. Treatment group§
Number of
patients

Mean
baseline score 
(SD)

LS mean
change from
baseline to
end of week 4 
(SE)

LS mean
difference
(95% CI)†

TRD3001

Spravato
56 mg + oral AD

115 37.4 (4.8) -18.9 (1.3)
-4.3

(-7.8, -0.8)#

Spravato
84 mg + oral AD

114 37.8 (5.6) -16.2 (1.3)
-1.2

(-4.7, 2.3)#

Oral AD + placebo 
nasal spray

113 37.5 (6.2) -14.7 (1.3)

TRD3002

Spravato (56 mg or 
84 mg) + oral AD

114 37.0 (5.7) -17.7 (1.3)
-3.5

(-6.7, -0.3)‡
Oral AD + placebo 
nasal spray

109 37.3 (5.7) -14.3 (1.3)

TRD3005
(≥ 65 years)

Spravato (28 mg, 
56 mg or 
84 mg) + oral AD

72 35.5 (5.9) -10.1 (1.7)
-2.9

(-6.5, 0.6)#

Oral AD + placebo 
nasal spray

65 34.8 (6.4) -6.8 (1.7)

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

Nasally administered esketamine or placebo; oral AD = a newly initiated AD (SNRI: duloxetine, venlafaxine extended 
release; 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 nasal 
spray), and 95% flexible confidence interval

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 6).

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 6).



13

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

Study No.
Treatment 

group§

Number of patients (%)

Response rate† Remission 
rate‡

24 hours Week 1 Week 2 Week 3 Week 4 Week 4

TRD3001

Spravato
56 mg + oral 
AD

20
(17.4%)

21
(18.3%)

29
(25.2%)

52
(45.2%)

61
(53.0%)

40
(34.8%)

Spravato
84 mg + oral 
AD

17
(14.9%)#

16
(14.0%)

25
(21.9%)

33
(28.9%)

52
(45.6%)

38
(33.3%)

Oral AD + 
placebo nasal 
spray

8
(7.1%)

5
(4.4%)

15
(13.3%)

25
(22.1%)

42
(37.2%)

33
(29.2%)

TRD3002

Spravato
56 mg or
84 mg + oral 
AD

18
(15.8%)

15
(13.2%)

29
(25.4%)

54
(47.4%)

70
(61.4%)

53
(46.5%)

Oral AD + 
placebo nasal 
spray

11
(10.1%)

13
(11.9%)

23
(21.1%)

35
(32.1%)

52
(47.7%)

31
(28.4%)

TRD3005
(≥ 65 years)

Spravato
28 mg, 56 mg 
or 84 mg + 
oral AD

NA
4

(5.6%)
4

(5.6%)
9

(12.5%)
17

(23.6%)
11

(15.3%)

Oral AD + 
placebo nasal 
spray

NA
3

(4.6%)
8

(12.3%)
8

(12.3%)
8

(12.3%)
4

(6.2%)

AD = antidepressant; NA = not available
§

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, 
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



14

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.

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- 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).



15

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- 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 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

Spravato + 
Oral AD
(N=90)

Oral AD + 
Placebo Nasal 

Spray
(N=86)

Spravato + 
Oral AD
(N=62)

Oral AD + 
Placebo Nasal 

Spray
(N=59)

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



16

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%)

Paediatric population

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 paediatric 
population (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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 
section 4.2).

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.



17

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.



18

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 section 4.2).

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 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∞ 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 section 4.2 and 4.4).

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.

5.3 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 section 4.6).

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 



19

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid monohydrate
Disodium edetate
Sodium hydroxide (for pH adjustment)
Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Type-I glass vial with a chlorobutyl rubber stopper. The filled and stoppered vial is assembled into a 
manually-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.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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



20

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

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)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

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


21

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE 
AND EFFECTIVE USE OF THE MEDICINAL PRODUCT



22

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to special and restricted medical prescription (see Annex I: Summary of 
Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

 Additional risk minimisation measures

Prior to the launch of SPRAVATO in each Member State (MS), the Marketing Authorisation Holder 
(MAH) must agree about the content and format of the educational materials (EM) and the 
controlled access programme (CAP), including communication media, distribution modalities, and 
any other aspects of the programme, with the National Competent Authority (NCA). 

The MAH shall ensure that in each MS where SPRAVATO is marketed a CAP is implemented to 
prevent/minimise the important identified risk of Drug abuse. 

SPRAVATO is intended to be self-administered by the patient under direct Healthcare Professional 
(HCP) supervision, and should be dispensed to the healthcare settings where administration takes 
place, as agreed at the MS level, based on local legal requirements and/or local healthcare systems.
When the administration is intended for outpatients, it should only be reserved to an environment 
where the patient is appropriately followed-up.



23

SPRAVATO may induce transient sedation, dissociative and perception disorders and/or hypertension.
Patients must, therefore, be monitored by a HCP during and after each treatment session including an 
assessment to determine when the patient is considered clinically stable and ready to leave the 
healthcare setting. In patients with clinically significant or unstable cardiovascular or respiratory 
conditions, SPRAVATO should be administered in a setting where appropriate resuscitation
equipment and healthcare professionals with training in cardiopulmonary resuscitation are available. 

The following EM should be provided to HCPs (and acknowledgement of receipt recorded):

o The HCP guide, aiming at addressing the risks of Transient dissociative states and perception 
disorders, Drug abuse, Disturbances in consciousness, and Blood pressure increased, should 
incorporate adequate reference to patient’s safety, and highlight that:

 All patients must be monitored accordingly after SPRAVATO administration until 
considered clinically stable to leave the healthcare setting;

 In patients with clinically significant or unstable cardiovascular or respiratory conditions, 
SPRAVATO should be administered in a clinical setting where equipment for 
cardiopulmonary resuscitation and staff trained in cardiopulmonary resuscitation are 
available;

 Due to the potential risk of cardiac adverse events, the patient’s blood pressure should be 
carefully monitored before and after SPRAVATO intake.

o The “Readiness for a patient to leave the healthcare setting” checklist for HCPs (attached to the 
HCP guide): the objective of this EM is to aid HCPs in evaluating when, following 
SPRAVATO administration, a patient is deemed stable and safely allowed to leave the 
clinic/facility where SPRAVATO has been administered.

The following EM should be provided to patients:

o The guide for patients, aiming at addressing the risks of transient dissociative states and 
perception disorders, drug abuse, disturbances in consciousness and blood pressure increased. 
The objective of this EM is to detail:

 Which adverse effects to expect following SPRAVATO administration, and how to 
minimize those effects;

 Risk factors/groups/ signs of abuse and dependence, which should be regularly assessed 
and monitored;

 The procedure for SPRAVATO intranasal administration, including preparation (fasting 
for 2 hours, no drinking for 30 minutes) and patient’s monitoring;

The guide for patients also aims at increasing awareness about: 

 The steps for SPRAVATO self-administration under direct HCP supervision;

 Monitoring of blood pressure before and after SPRAVATO dosing;

 Requirements for HCP supervision and post-dose observation, until the HCP confirms the 
patient is clinically stable and is allowed to leave the clinic/facility where SPRAVATO 
has been administered;

 The influence of SPRAVATO on the patient’s ability to drive or operate machinery



24

ANNEX III

LABELLING AND PACKAGE LEAFLET



25

A. LABELLING



26

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (for 1 and 6 nasal spray devices)

1. NAME OF THE MEDICINAL PRODUCT

Spravato 28 mg nasal spray, solution
esketamine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: Citric acid monohydrate, disodium edetate, sodium hydroxide, water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution

1 nasal spray device
6 nasal spray devices

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Nasal use
Do not prime or test before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



27

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1410/001 (1 spray container)
EU/1/19/1410/004 (6 spray containers)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

spravato

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



28

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (for 2 and 3 nasal spray devices)

1. NAME OF THE MEDICINAL PRODUCT

Spravato 28 mg nasal spray, solution
esketamine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: Citric acid monohydrate, disodium edetate, sodium hydroxide, water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Nasal spray, solution

2 nasal spray devices
3 nasal spray devices

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
nasal use
Do not prime or test before use.

56 mg pack = 2 nasal spray devices
84 mg pack = 3 nasal spray devices

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP



29

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1410/002 (2 spray containers)
EU/1/19/1410/003 (3 spray containers)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

spravato

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



30

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Spravato 28 mg nasal spray, solution
esketamine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



31

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

NASAL SPRAY/DEVICE LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Spravato 28 mg nasal spray, solution
esketamine
nasal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

28 mg

6. OTHER



32

B. PACKAGE LEAFLET



33

Package leaflet: Information for the patient

Spravato 28 mg nasal spray, solution
esketamine

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
● Keep this leaflet. You may need to read it again.
● If you have any further questions, ask your doctor or pharmacist.
● If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Spravato is and what it is used for
2. What you need to know before you use Spravato
3. How to use Spravato
4. Possible side effects
5. How to store Spravato
6. Contents of the pack and other information

1. What Spravato is and what it is used for

What Spravato is
Spravato contains the active substance esketamine. This belongs to a group of medicines called 
anti-depressants and you have been given this medicine to treat your depression.

What Spravato is used for
Spravato is used in adults to reduce the symptoms of depression, such as, feeling sad, anxious, or 
worthless, sleeping difficulties, change in appetite, loss of interest in favourite activities, feeling of 
being slowed down. It is given, together with another antidepressant, if you have tried at least 2 other 
antidepressant medicines but they have not helped.

2. What you need to know before you use Spravato

Do not use Spravato
● if you are allergic to esketamine, a similar medicine called ketamine used for anaesthesia, or any

of the other ingredients of this medicine (listed in section 6).
● if you have ever had certain conditions such as:

- an aneurysm (a weak spot in a blood vessel wall where it widens or bulges out)
- bleeding in the brain

● if you recently had a heart attack (within 6 weeks)
This is because Spravato can cause a temporary increase in blood pressure that may lead to 
serious complications in these conditions.

Do not use Spravato if any of the above apply to you. If you are not sure, talk to your doctor before 
using Spravato - your doctor will decide whether or not you can use this medicine.

Warnings and precautions
Talk to your doctor before using Spravato if you have:
● a heart problem which is not well controlled such as: poor blood flow in the blood vessels of the 

heart frequently with chest pain (such as angina), high blood pressure, heart valve disease or 
heart failure



34

● ever had problems with the blood supply to your brain (such as a stroke)
● ever had problems with drug abuse – prescribed medicines or illegal drugs - or a problem with 

alcohol
● ever had a condition called psychosis - where you believe in things that are not true (delusions) 

or see, feel, or hear things that are not there (hallucinations)
● ever had a condition called bipolar disorder, or symptoms of mania (where you become very 

over-active or over excited)
● ever had an overactive thyroid that is not properly treated (hyperthyroidism)
● ever had lung problems causing breathing difficulty (pulmonary insufficiency), including 

Chronic Obstructive Pulmonary Disease (COPD)
● sleep apnoea and are extremely overweight
● ever had slow or fast heartbeats causing shortness of breath, palpitations or chest discomfort, 

feeling light-headed or fainting
● had a serious head injury or serious problems affecting the brain, particularly where there is 

increased pressure in the brain
● severe liver problems.
If any of the above apply to you (or you are not sure), talk to your doctor before using Spravato. Your 
doctor will decide whether you should use this medicine.

Depression getting worse
Tell your doctor or go to the nearest hospital straight away if you have thoughts of harming or killing 
yourself at any time. 

You may find it helpful to talk to a relative or a close friend if you are depressed and ask them if they 
think your depression is getting worse or if they are worried about your behaviour. You might ask 
them to read this leaflet.

Blood pressure
Spravato can increase your blood pressure for about 1 to 2 hours after you use it so your blood 
pressure will be measured before you start using Spravato and after using it.

If your blood pressure is high before using this medicine, your doctor will decide whether to start the 
medicine or wait until your blood pressure is lower. If your blood pressure goes up after using this 
medicine and stays high for more than a few hours, you may need to have some more tests.

This medicine may cause a temporary increase in your blood pressure after taking a dose. Your blood 
pressure will be checked before and after using this medicine. Tell the medical staff right away if you
get chest pain, shortness of breath, sudden severe headache, change in vision, or seizures (fits) after 
using this medicine.

Tell your doctor if you get any of the below while you are using Spravato
● difficulty with your attention, judgment and thinking (see also “Driving and using machines” 

and “Possible side effects”). During and after each use of this medicine, your doctor will check 
your condition and decide how long to monitor you.

● sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected 
from yourself, your thoughts, feelings, space and time (dissociation), difficulties in breathing 
(respiratory depression). Tell the medical staff right away if your feel like you cannot stay 
awake or if you feel like you are going to pass out.

● pain when urinating or seeing blood in your urine – these could be signs of bladder problems. 
These can occur with high doses of a similar medicine (called ketamine) used over a long 
period.

Tell your doctor if you get any of the above while you are taking Spravato.

Elderly (>65 years)
If you are elderly (>65 years), you will be carefully monitored as you may be at increased risk of 
falling when you start moving around after treatment.



35

Children and adolescents
Do not give this medicine to children and adolescents younger than 18 years of age. This is because 
Spravato has not been studied for treatment-resistant depression in this age group.

Other medicines and Spravato
Tell your doctor if you are taking, have recently taken or might take any other medicines.

Using Spravato with certain medicines may cause side effects. Especially tell your doctor if you take:
● Medicines used to treat nervous disorders or severe pain (for example, benzodiazepines,

opioids), or medicines or beverages containing alcohol
● Stimulants such as those used for conditions such as narcolepsy or medicines for ADHD (for 

example, amphetamines, methylphenidate, modafanil, armodafinil)
● Medicines that can increase your blood pressure, such as, thyroid hormones, asthma 

medications such as xanthine derivatives, medications for child birth bleeding (ergometrine) and 
heart medication such as vasopressin.

● Medicines for depression or Parkinson’s disease known as monoamine oxidase inhibitors 
(MAOIs) (for example, tranylcypromine, selegiline, phenelzine).

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor for advice before using this medicine.

Contraception
If you are able to become pregnant you must use contraception during treatment. Talk with your 
doctor about suitable methods of contraception.

Pregnancy
Do not use Spravato if you are pregnant.

If you become pregnant while being treated with Spravato, talk to your doctor straight away – to 
decide whether to stop treatment and to learn about other options for treatment.

Breast-feeding
Do not use Spravato if you are breast-feeding. Talk to your doctor before using Spravato if you are 
breast-feeding. Your doctor will discuss with you whether to stop breast-feeding or stop using this 
medicine. Your doctor will take into account the benefit of breast-feeding for you and your child, and 
the benefit of treatment for you.

Driving and using machines
Spravato can make you feel sleepy, dizzy, and have other side effects that can temporarily affect your 
ability to drive vehicles or use machines and do activities that need you to be completely alert. After 
being treated with this medicine, do not take part in these activities until the next day following a 
restful sleep.

3. How to use Spravato

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.

You will use the Spravato nasal spray yourself - under the supervision of your doctor or other 
healthcare professional in a healthcare setting, such as, the doctor’s office or clinic.

Your doctor or other healthcare professional will show you how to use the nasal spray device (see also
Instructions for use).



36

How much to use
Your doctor will decide if you need 1, 2 or 3 nasal spray devices and how often you should go to the 
doctor’s office or clinic for the medicine.
● One nasal spray device delivers two sprays (one spray per nostril)
● Spravato is usually used twice a week for the first 4 weeks
● After the first 4 weeks, Spravato is usually used once a week
● After this, Spravato is usually used either once a week or once every 2 weeks.
During and after each use of this medicine, your doctor will check you and decide how long to 
monitor you.

Food and drink
Some patients using Spravato may experience nausea or vomiting. You should avoid eating for 
2 hours before treatment and not drinking liquids for 30 minutes before using this medicine.

Nasal sprays
If you need steroid or decongestant medicines as a nasal spray, avoid using them during the hour
before your Spravato treatment.

If you use more Spravato than you should
You will use this medicine under the supervision of your doctor in the doctor’s office or clinic. 
Therefore, it is unlikely that you will use too much.

If you use too much Spravato, you are more likely to get side effects (see “Possible side effects”).

If you stop using Spravato
It is important to make sure you come in for your scheduled appointments, so that this medicine is 
effective for you.

If you have any further questions on the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you notice any of the following side effects.

Very common (may affect more than 1 in 10 people)
● feeling disconnected from yourself, your thoughts, feelings and things around you
● feeling dizzy
● headache
● change in sense of taste
● feeling sleepy
● decreased feeling or sensitivity, including around the mouth area
● spinning sensation (“vertigo”)
● vomiting
● nausea

Common (may affect up to 1 in 10 people)
● feeling extremely happy (“euphoria”)
● feeling agitated
● feeling anxious
● eyes, ears, or sense of touch are deceived or tricked in some way (something is not what it 

seems to be)
● feeling irritable
● panic attacks
● change in perception of time



37

● seeing, feeling, hearing or smelling things that are not there (hallucinations)
● feeling detached from reality
● problems with thinking
● muscle tremors
● feeling very sleepy with low energy
● difficulty speaking
● unusual feeling in the mouth (such as tingling or a crawling feeling)
● increased sensitivity to noise or sounds
● persistent ringing in the ears (tinnitus)
● blurred vision
● fast heartbeat
● nasal discomfort
● nasal dryness including dry crusts in the nose
● itchy nose
● dry mouth
● decreased feeling or sensitivity in the mouth
● excessive sweating
● frequent need to pass urine
● pain when passing urine
● urgent need to pass urine
● feeling abnormal
● feeling drunk
● feeling of body temperature change
● high blood pressure
● increased blood pressure

Uncommon (may affect up to 1 in 100 people)
● increased saliva

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Spravato

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the label. The expiry 
date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What Spravato contains
The active substance is esketamine.
Each nasal spray device contains esketamine hydrochloride corresponding to 28 mg esketamine.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


38

The other ingredients are:

Citric acid monohydrate
Disodium edetate
Sodium hydroxide (for pH adjustment)
Water for injections

What Spravato looks like and contents of the pack
Spravato is a nasal spray solution. This medicine is a clear, colourless solution, provided in a 
single-use nasal spray device.

Spravato is available in pack sizes containing 1, 2, 3, or 6 nasal spray devices.

Each nasal spray device is individually packaged in a sealed blister.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

Manufacturer
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com



39

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY} OR {month YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/.

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


40

The following information is intended for healthcare professionals only:

Instructions for Use
SPRAVATO
(esketamine)

Nasal Spray Device

28 mg per device
Each nasal spray device delivers
28 mg esketamine as two sprays.

Important
This device is intended for administration by the patient, under supervision of a healthcare 
professional. Read these Instructions for Use in full before training and supervising patient.

Need help?
For additional assistance or to share your feedback refer to the Package Leaflet for the contact 
information of the local representative of the Marketing Authorisation Holder.



41

Tip

Nose rest

Indicator

Finger rest

Plunger

Device full

One spray 
delivered

Nasal Spray Device

Each nasal spray device delivers 28 mg esketamine
as two sprays.

Indicator

One device contains 2 sprays
(1 spray for each nostril)
____________________

2 green dots (0 mg delivered)

____________________

1 green dot

____________________

No green dots
Two sprays (28 mg) delivered

Device empty



42

28 mg = 1 device

56 mg = 2 devices

84 mg = 3 devices

Before first device only:

Instruct patient to blow nose before first device only.

Confirm required number of devices.

Get readyStep 1



43

● Check expiration date (‘EXP’). If expired, get a new device.
● Peel blister and remove device.

● Do not prime device. This will result in a loss of medicine.
● Check that indicator shows 2 green dots. If not, dispose of device and get a new one.
● Hand device to patient.

Prepare deviceStep 2



44

Instruct the patient to:
● Hold device as shown with the thumb gently supporting the plunger.
● Do not press the plunger.

Instruct the patient to:
● Recline head at about 45 degrees during administration to keep medicine inside the nose.

Prepare patientStep 3

About 
45°



45

Instruct the patient to:
● Insert tip straight into the first nostril.
● Nose rest should touch the skin between the nostrils.

Instruct the patient to:
● Close opposite nostril.
● Breathe in through nose while pushing plunger all the way up until it stops.

Instruct the patient to:
● Sniff gently after spraying to keep medicine inside nose.

Patient sprays once into each nostrilStep 4



46

Instruct the patient to:
● Switch hands to insert tip into the second nostril.
● Repeat Step 4 to deliver second spray.



47

● 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.

Instruct the patient to:
● Rest in a comfortable position (preferably, semi-reclined) for 5 minutes after each device.
● If liquid drips out, dab nose with a tissue.

Do not blow nose.

Confirm delivery and restStep 5

5
MIN

REST



48

● Repeat Steps 2-5 if more than one device is required.

IMPORTANT: Ensure that patient waits 5 minutes after each device to allow medicine to absorb.

Disposal

Dispose of used device(s) in accordance with local requirements.

Revised: {month YYYY}

Next device (if required)


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET