Consumer medicine information

Spravato

Esketamine

BRAND INFORMATION

Brand name

Spravato

Active ingredient

Esketamine

Schedule

What is in this leaflet

This leaflet answers some common questions about SPRAVATO. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking SPRAVATO against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

What SPRAVATO is used for

SPRAVATO contains the active substance esketamine. This belongs to a group of medicines called antidepressants and is used to treat depression in adults.

SPRAVATO is a nasal spray used to reduce the broad range of symptoms of depression. This medicine can help improve the symptoms of your disease and reduce the chance of your symptoms coming back.

SPRAVATO is used in people who have tried other antidepressant medicines but have not benefitted from them.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you use SPRAVATO

When you must not take it

Do not take SPRAVATO if you have an allergy to:

any medicine containing esketamine or ketamine
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take SPRAVATO if you have, or have had, any of the following medical conditions:

an aneurysm, this is a weak spot in a blood vessel wall where it widens or bulges out.
bleeding in the brain.

This is because SPRAVATO can cause a temporary increase in blood pressure and in both these conditions, an increase in blood pressure can cause a serious medical condition.

Do not use SPRAVATO if you are pregnant. If you are pregnant, think you may be pregnant or are planning to have a baby, tell your doctor before using this medicine. Tell your doctor if you are trying to make your partner pregnant.

Using SPRAVATO during pregnancy has not been studied and it is not known if SPRAVATO will harm your unborn baby.

If you are able to become pregnant you must use highly effective contraception during treatment - and up to 6-weeks after the end of treatment. Talk with your doctor about methods of contraception to use.

Do not use SPRAVATO if you are breast-feeding. The active ingredient in SPRAVATO may pass into breast milk and there is a possibility that your baby may be affected.

Your doctor will only prescribe SPRAVATO for your self-administration based on its indicated usage.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, your doctor or other health care professional will arrange for its disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, or preservatives.

Tell your doctor if you have or have had any of the following medical conditions:

heart problems which are 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, a recent heart attack, heart valve disease or heart failure
slow or fast heartbeats causing shortness of breath, palpitations or chest discomfort, feeling light-headed or fainting
problems with the blood supply to your brain (such as a stroke)
a head injury or serious problems affecting the brain, particularly where there is increased pressure in the brain
problems with drug abuse – prescribed or illegal drugs - or a problem with alcohol
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)
you have ever had a condition called “bipolar disorder” or symptoms of mania – where you are being very over-active or over excited
an overactive thyroid that is not properly treated (hyperthyroidism)
lung problems causing breathing difficulty (pulmonary insufficiency)
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.

Tell your doctor if you are of Japanese or Chinese ancestry.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and SPRAVATO may interfere with each other. These include:

other nasal sprays. Do not use any other nasal spray within 1 hour of using SPRAVATO.
Central Nervous System (CNS) depressants (for example, benzodiazepines, opioids, medicines or beverages containing alcohol)
Psychostimulants (for example, amphetamines, methylphenidate, modafanil, armodafinil)
Monoamine oxidase inhibitors (MAOIs) medicines (for example, tranylcypromine, selegiline, phenelzine)

Some medicines may be affected by SPRAVATO or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor will have more information on medicines to be careful with or avoid while taking SPRAVATO.

How to take SPRAVATO

You will use the SPRAVATO nasal spray yourself - under the supervision of your doctor or other health care professional in the doctor’s office, clinic or hospital.

SPRAVATO is used together with another antidepressant.

Follow all directions given to you by your doctor or other health care professional carefully.

Your doctor or other health care professional will show you how to use the nasal spray device and you must also read the Instructions for Use leaflet provided in the SPRAVATO pack.

If you do not understand the instructions in the Instructions for Use leaflet, ask your doctor or other health care professional for help.

How much to take

One nasal spray device delivers two sprays (one spray per nostril).

Your doctor will decide how many nasal spray devices and how often you should come to the doctor’s office or clinic for the medicine.

SPRAVATO is taken twice a week for the first 4 weeks.
For some patients, after the first 4 weeks, SPRAVATO is usually taken once a week for a further 4 weeks.
For some patients, after this, SPRAVATO is usually taken either once a week or once every 2 weeks.

During and after each use of this medicine, you will be checked, and your doctor or other health care professional will decide how long to monitor you.

This medicine may cause a temporary increase in your blood pressure after taking a dose. Your blood pressure will be checked before and after taking this medicine. Tell the medical staff right away if you get chest pain, shortness of breath, sudden severe headache, change in vision, or seizures after taking this medicine.
This medicine may cause sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation) difficulty breathing (respiratory depression). Tell the medical staff right away if you feel like you cannot stay awake or if you feel like you are going to pass out.

How to take it

Step 1.

Your doctor or other health care professional will instruct you to blow your nose before using the first device only.

Step 2.

Your doctor or other health care professional will check the expiry date and remove the device from its blister and check that the indicator shows 2 green dots. They will then hand you the device.

DO NOT PRIME THE DEVICE

Step 3.

Hold device as shown with the thumb gently supporting the plunger. Do not press the plunger.

Recline head at about 45 degrees during administration to keep medication inside the nose.

Step 4.

Insert tip straight into the first nostril. The nose rest should touch the skin between the nostrils.

Close opposite nostril.

Breathe in through nose while pushing plunger all the way up until it stops.

Sniff gently after spraying to keep medication inside nose.

Switch hands to insert tip into the second nostril.

Repeat Step 4 to deliver second spray.

Step 5

Your doctor or other health care professional will take the used device and check that the indicator shows no green dots. If there is a green dot they will have you spray again into the second nostril.

You will then rest in a semi-reclined position for 5 minutes after each device.

DO NOT BLOW NOSE.

If any liquid runs out, dab nose with a tissue.

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

It is important that you rest for 5 minutes after each device to allow the medication to absorb.

When to take it

You will be directed to use SPRAVATO by your doctor in the doctor’s office or clinic.

Some patients taking SPRAVATO may experience nausea or vomiting.

You should avoid eating 2 hours before and drinking liquids 30 minutes before using this medicine.

If you need steroid or decongestant medicines as a nasal spray, avoid using these medicines within 1 hour before your SPRAVATO treatment.

How long to take it

Continue using SPRAVATO for as long as your doctor tells you.

If you forget your appointment

It is important you make sure you come in for your scheduled appointments, so that this medicine is effective for you.

If you miss an appointment it is important that you contact your doctor as soon as possible to make a new appointment.

If you take too much (overdose)

This medicine will be given to you under the supervision of your doctor in the doctor’s office or clinic. Therefore, it is unlikely that you will be given too much.

However, if you experience any side effects after using SPRAVATO, tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital. You may need urgent medical attention.

While you are using SPRAVATO

Things you must do

Be sure to keep all your doctor's appointments so your progress can be checked. It is important to have your follow-up doses of SPRAVATO at the appropriate times to get the best effects from your treatment.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking SPRAVATO.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant or your partner becomes pregnant while taking this medicine, tell your doctor immediately.

Things to be careful of

Do not drive or operate machinery after taking SPRAVATO. SPRAVATO can make you feel sleepy, dizzy, and have other side effects that can temporarily affect your ability to drive motor vehicles or use other machines and do anything where you need 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.

If you think your depression getting worse. Tell your doctor or go to the nearest hospital straight away if you have suicidal thoughts or thoughts of harming yourself at any time. You may find it helpful to talk to a relative or 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 a short time (about 1 to 2 hours) – so you will have your blood pressure measured at various times. Your blood pressure will be measured before you start using SPRAVATO and after taking 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 increases significantly after using this medicine and remains elevated for more than a few hours after dosing, your doctor may send you to another doctor for evaluation.

Side effects

Like all medicines, SPRAVATO can cause side effects although not everybody gets them. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

feeling disconnected from yourself, your thoughts, feelings and things around you
feeling anxious
feeling confused
difficulty in paying attention
change in sense of taste
feeling dizzy
feeling sleepy
decreased feeling or sensitivity, including around the mouth area
headache
spinning sensation (“vertigo”)
vomiting
nausea
increased blood pressure
emotional distress, crying
feeling extremely happy (euphoria)
feeling unhappy or uneasy (dysphoria)
problems with thinking
muscle tremors
difficulty speaking
fast heartbeat
nasal discomfort
throat irritation or pain
dry mouth
excessive sweating, cold sweat
pain when passing urine
frequent need to pass urine
feeling abnormal
feeling drunk
feeling weak with low energy (asthenia)
problems walking
fast eye movements that you cannot control
making movements without purpose (psychomotor hyperactivity)
increased saliva
low blood pressure
difficulty breathing (respiratory depression)

The above list includes some side effects of your medicine.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using SPRAVATO

During and after each use of SPRAVATO, you will be checked by your doctor or other health care professional who will decide how long to monitor you.

After being treated with this medicine, do not drive or use other machines that require you to be completely alert until the next day following a restful sleep.

Storage

Your doctor or healthcare professional will store your SPRAVATO for your use.

SPRAVATO should be kept in its original packaging in a cool dry place, where the temperature stays below 25°C

Disposal

Your doctor or healthcare professional will arrange to dispose of the device(s) and any medicine that is left over.

Do not take this medicine away from the clinic.

You must never be in direct possession of this medicine outside of the treatment site.

Product description

What it looks like

SPRAVATO is a nasal spray solution. It is a clear, colourless, aqueous solution provided in a pre-filled nasal spray device. Each nasal spray device is individually packaged in a sealed blister pack.

SPRAVATO is available in pack sizes containing 1, 2, or 3 single use nasal spray devices.

Ingredients

SPRAVATO contains 32.3 mg of esketamine hydrochloride (equivalent to 28 mg esketamine) as the active ingredient.

SPRAVATO also contains:

Citric acid monohydrate
Disodium edetate
Sodium hydroxide
Water for injections

SPRAVATO does not contain any preservatives, lactose, sucrose, gluten, tartrazine or any other azo dyes.

SPONSOR

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: 0800 800 806

Registration numbers

SPRAVATO 28 mg per 2 actuations
(AUST R 311827)

This leaflet was prepared in June 2024.

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Spravato

Active ingredient

Esketamine

Schedule

1 Name of Medicine

Esketamine hydrochloride.

2 Qualitative and Quantitative Composition

Spravato is a single use nasal spray device containing an intranasal solution inside the device. The solution contains esketamine hydrochloride equivalent to esketamine 28 mg/0.2 mL as the active ingredient.
Each nasal spray device delivers two actuations, one into each nostril containing a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

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

4 Clinical Particulars

4.1 Therapeutic Indications

Spravato is indicated for treatment resistant depression (major depressive disorder in adults who have not responded adequately to at least two different antidepressants of adequate dose and duration to treat the current moderate to severe depressive episode).
Spravato is to be initiated in conjunction with a newly initiated oral antidepressant.

4.2 Dose and Method of Administration

Spravato should be administered in conjunction with a newly initiated oral antidepressant (AD). During the phase III clinical program patients were assigned SNRI or SSRI as the new oral antidepressant (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Spravato will be provided by the supervising healthcare professional for the patient to self administer under their direct supervision. A treatment session consists of nasal administration of Spravato and post administration observation under the supervision of a healthcare professional (see Section 4.4 Special Warnings and Precautions for Use).

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 actuations (one actuation per nostril). To prevent loss of medication, 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.

Blood pressure assessment before and after treatment.

Assess blood pressure prior to dosing with Spravato (see Section 4.4 Special Warnings and Precautions for Use).
If baseline blood pressure is elevated (e.g. > 140 mmHg systolic, > 90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of Spravato treatment in patients with TRD (see Section 4.4 Special Warnings and Precautions for Use). Do not administer Spravato if an increase in blood pressure or intracranial pressure poses a serious risk (see Section 4.3 Contraindications).
After dosing with Spravato, reassess blood pressure at approximately 40 minutes and subsequently as clinically warranted.
If blood pressure is decreasing and the patient appears clinically stable, the patient may leave at the end of the post-dose monitoring period; if not, continue to monitor (see Section 4.4 Special Warnings and Precautions for Use).
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 Adverse Effects (Undesirable Effects), Nausea and vomiting).
Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should be advised not to administer these medications within 1 hour before administration of Spravato.
For instructions to prepare the patient and for use of the nasal spray device, see also the Consumer Medicine Information and the "Instructions for Use" leaflet provided separately in the carton.

Dosage - adults.

The dosage recommendations for Spravato are shown in Table 1. Dose adjustments should be made based on efficacy and tolerability to the previous dose.

After depressive symptoms improve, treatment should continue for at least 6 months.

Post administration observation.

During and after Spravato administration at each treatment session, patients should be monitored until the patient is stable based on clinical judgment.
Before Spravato administration, patients' blood pressure should be assessed and patients instructed not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery until the next day after a restful sleep (see Section 4.4 Special Warnings and Precautions for Use, Effect on blood pressure, Potential for cognitive and motor impairment, Effect on driving).
After administration with Spravato, blood pressure should be reassessed at approximately 40 minutes and subsequently as clinically warranted (see Section 4.4 Special Warnings and Precautions for Use, Effect on blood pressure, Potential for cognitive and motor impairment, Effect on driving).
Due to 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 Special Warnings and Precautions for Use, Effect on blood pressure, Potential for cognitive and motor impairment, Effect on driving).

Missed treatment session(s).

In case one or two treatment sessions are missed, schedule the next session when the next dosage session was scheduled to occur based on current treatment frequency. If more than 2 treatment sessions have been missed, per clinical judgement, adjustment of the dose or frequency of Spravato may be clinically appropriate.

Special populations.

Paediatrics (17 years of age and younger).

The safety and efficacy of Spravato have not been established in patients aged 17 years and younger.

Elderly (65 years of age and older).

In elderly patients the initial Spravato dose is 28 mg (Day 1, Starting Dose, see Table 1). 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 dosage adjustment is necessary in patients with mild (Child Pugh class A) or moderate (Child Pugh class B) 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 Section 5.2 Pharmacokinetic Properties).

Renal impairment.

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

Japanese and Chinese patients with treatment-resistant depression.

Efficacy of Spravato in Japanese and Chinese patients has been studied, but not established.

4.3 Contraindications

Spravato is contraindicated in patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (see Section 4.4 Special Warnings and Precautions for Use):
Patients with known aneurysmal vascular disease (including intracranial, thoracic, or abdominal aorta, or peripheral arterial vessels).
Patients with known history of intracerebral haemorrhage.
Spravato is contraindicated in patients with a known hypersensitivity to esketamine, ketamine, or to any of the excipients.

4.4 Special Warnings and Precautions for Use

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.

Effect on blood pressure.

Spravato can cause transient increases in systolic and/or diastolic blood pressure which peak at approximately 40 minutes after drug administration and last approximately 1-2 hours (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with cardiovascular and cerebrovascular conditions should be carefully assessed before prescribing Spravato and treatment initiated only if the benefit outweighs the risk (see Section 4.3 Contraindications). Examples of conditions which should be carefully considered include:
Unstable or poorly controlled hypertension.
History (within 6 weeks) of cardiovascular event, including myocardial infarction (MI). Patients with a history of an MI should be clinically stable and cardiac symptom free prior to dosage administration.
History (within 6 months) of ischemic stroke or transient ischemic attack.
Haemodynamically significant valvular heart disease such as mitral regurgitation, aortic stenosis, or aortic regurgitation.
New York Heart Association (NYHA) Class III IV heart failure of any aetiology.
Administration of Spravato can temporarily raise blood pressure lasting approximately 1-2 hours. Blood pressure should be assessed prior to dosing with Spravato. In patients whose blood pressures prior to dose administration are 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 consider lifestyle and/or pharmacologic therapies to reduce blood pressure before starting treatment with Spravato. The decision whether or not 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 until blood pressure returns to acceptable levels. If blood pressure remains too high, 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.
Closely monitor blood pressure with concomitant use of Spravato with psychostimulants or monoamine oxidase inhibitors (MAOIs) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Respiratory depression.

During post-marketing use, rare cases of respiratory depression have been observed (see Section 4.8 Adverse Effects (Undesirable Effects)). The majority of these cases have been reported with the use of Spravato in combination with other CNS depressants and/or in patients with comorbidities such as obesity, anxiety, cardiovascular and respiratory conditions. These events were transient in nature and resolved after verbal/tactile stimulation or supplemental oxygen. Patients should be monitored for respiratory depression.

Potential for cognitive and motor impairment.

Spravato has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo and anxiety during the clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). These effects may impair attention, judgment, thinking, reaction speed and motor skills. Tolerance to above effects may develop after a few treatment sessions. At each treatment session, patients should be monitored under the supervision of a healthcare professional to assess when the patient is considered clinically stable (see Section 4.2 Dose and Method of Administration).

Short-term cognitive impairment.

In a study in healthy volunteers, a single dose of Spravato caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, Spravato-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between Spravato and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.

Long-term cognitive impairment.

Long term 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 the clinical trials, the effect of esketamine nasal spray on cognitive functioning was evaluated over time and performance remained stable.

Effect on driving.

Two studies were conducted to assess the effects of Spravato on the ability to drive (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Effect on driving). Before Spravato administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor co-ordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep (see Section 4.4 Special Warnings and Precautions for Use, Potential for cognitive and motor impairment).

Bladder effects.

Cases of interstitial cystitis have been reported in subjects using ketamine for recreational use or for treatment of chronic pain at high doses with long-term use. In clinical studies with esketamine nasal spray, subjects were assessed for symptoms of cystitis, bladder pain and interstitial cystitis. No cases of esketamine related interstitial cystitis were observed in any of the studies, which involved treatment for up to a year (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Drug abuse and dependence.

Abuse.

Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of Spravato. Careful consideration is advised prior to treatment of individuals with a history of substance use disorder, including alcohol. Monitoring for signs of abuse or dependence is recommended.
The potential for abuse, misuse and diversion of Spravato is minimised due to the product's design and the administration taking place under the supervision by a healthcare professional.
Ketamine, the racemic mixture of arketamine and esketamine, has been reported as a drug of abuse. 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.

Dependence.

Dependence and tolerance have been reported with prolonged use of ketamine. Individuals who were dependent on ketamine reported withdrawal symptoms of cravings, anxiety, shaking, sweating and palpitations. Monitoring for signs of dependence is recommended.

Use in the elderly.

Of the total number (N = 1601) of patients in Phase 3 clinical studies exposed to Spravato, n = 194 (12.1%) were 65 years of age and older, while n = 25 (1.6%) were 75 years of age and older. No overall differences in the safety profile were observed between these patients and patients younger than 65 years of age, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetic analysis showed that mean esketamine C_max and AUC values were higher in elderly patients compared with younger adult patients (see Section 5.2 Pharmacokinetic Properties, Special populations, Elderly (65 years of age and older)). Therefore, the recommended initial dose of Spravato in elderly patients is lower than that for younger adults (see Section 4.2 Dose and Method of Administration, Special populations, Elderly (65 years of age and older)).
Evidence of efficacy has been observed in patients 65 and older (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Paediatric use.

The safety and efficacy of Spravato have not been established in patients aged 17 years and younger.

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;
Significant pulmonary insufficiency;
Patients with known uncontrolled bradyarrhythmias or tachyarrhythmias that lead to haemodynamic instability;
History of brain injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other condition associated with increased intracranial pressure.

Effects on laboratory tests.

Spravato has not been associated with any clinically important changes to laboratory parameters in serum chemistry, haematology, or urinalysis. However due to the potential for hepatotoxicity, periodic monitoring of liver function should be considered.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Concomitant use with CNS depressants (e.g. benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation with concomitant use of Spravato with CNS depressants.
Concomitant use with psychostimulants (e.g. amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure. Closely monitor blood pressure with concomitant use of Spravato with psychostimulants.
Concomitant use with monoamine oxidase inhibitors (MAOIs) (e.g. tranylcypromine, selegiline, phenelzine) may increase blood pressure. Closely monitor blood pressure with concomitant use of Spravato with MAOIs.
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 (see Section 5.2 Pharmacokinetic Properties).

Effect of other drugs 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 maximum plasma concentration (C_max) of esketamine administered as a nasal spray. The area under the plasma concentration time curve (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 C_max 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 C_max and AUC_∞ values of esketamine administered as a nasal spray by approximately 17% and 28%, respectively.

Other nasal spray products.

Concomitant use of Spravato with other nasally administered medicinal products has been evaluated in the following pharmacokinetic interaction studies. Pre-treatment of subjects with history of allergic rhinitis and pre-exposed to grass pollen with oxymetazoline administered as a nasal spray (2 actuations 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. (see Section 4.2 Dose and Method of Administration, Method of administration).

Effect of esketamine on other drugs.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal studies showed that fertility and reproductive capacities were not adversely affected by esketamine at clinically relevant doses. In a fertility and early embryonic developmental toxicity study, esketamine nasally administered to rats at 0.9, 3, or 9 mg/day caused maternal and paternal toxicity at 3 and 9 mg/day. Fertility and reproductive capacities were not adversely affected at any dose.
(Category B3)
Spravato should not be used during pregnancy. The risks of Spravato during pregnancy have not been studied. Human data in pregnant women during clinical trials with esketamine exposure are too limited to be conclusive.
In an embryo fetal developmental toxicity study with nasally administered ketamine in rats, the offspring was not adversely affected in the presence of maternal toxicity at doses up to 150 mg/kg/day. In rats, the C_max- and AUC-based safety margin estimated for esketamine at the 150 mg/kg/day dose of ketamine was 80- and 12-fold compared to the maximum recommended human dose (MRHD) of esketamine of 84 mg. In an embryo fetal developmental toxicity study with nasally administered ketamine in rabbits, fetal body weight was reduced at a clinically relevant maternally toxic dose of 30 mg/kg/day. Skeletal malformations were found in the offspring of rabbits nasally treated with ketamine at maternally toxic doses. In rabbits, the estimated exposure to esketamine at the 10 mg/kg/day no effect dose of ketamine was below the maximum exposure to esketamine at 84 mg in humans.
Animal studies with ketamine showed evidence of developmental neurotoxicity. Ketamine administered intravenously at high anaesthetic dose levels to female rats on gestation day 14 caused neuronal cell abnormalities in the brains of their offspring which showed behavioural changes and impaired memory up to young adult age. When female monkeys were treated intravenously with ketamine at high anaesthetic dose levels on gestation day 123 of pregnancy, neuronal cell death was observed in the brains of their fetuses. Ketamine induced neuronal cell death was also observed with early postnatal (postnatal days 7-11 in mice and days 7-8 in rats) intraperitoneal or subcutaneous treatment of rat and mice pups, during a period of rapid brain growth. This period of brain development translates into the third trimester of human pregnancy. The potential for esketamine to have neurotoxic effects on developing fetuses cannot be excluded.
In a pre- and postnatal developmental toxicity study with nasally-administered esketamine up to 9 mg/day in rats, no adverse effects occurred in the dams nor their offspring at this clinically relevant dose.
To avoid exposing the fetus to esketamine, women of reproductive potential should be advised to use highly effective contraception during and up to 6 weeks after the last treatment with Spravato. If a woman becomes pregnant while being treated with Spravato, treatment with esketamine should be discontinued and the patient should be counselled about the potential risk to the fetus and clinical/therapeutic options as soon as possible.
Spravato should not be used in women who are breast feeding. The risks of Spravato during breast feeding have not been studied in humans. There are no data available to assess the effects of esketamine on human milk production, its presence in human milk, or effects on the breastfed infant. Esketamine is expected to be excreted to human milk based on published data showing presence of ketamine in cow's milk in cows exposed to intravenously administered ketamine. Advise patients either not to undergo therapy with Spravato while breast feeding or discontinue breast feeding if treatment with Spravato is initiated, taking into account the importance of the drug to the mother.

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 Adverse Effects (Undesirable Effects)). Before Spravato administration, instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Effect on driving).

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Summary of the safety profile.

Spravato was evaluated for safety in 1709 patients diagnosed with TRD (patients with MDD and were non-responders to at least two oral antidepressants (ADs), of adequate dosage and duration, in the current major depressive episode) from five Phase 3 studies (3 short term and 2 long term studies) and one Phase 2 dose ranging study. Of all esketamine-treated patients in the completed Phase 3 studies, 479 (29.9%) received at least 6 months of treatment exposure, and 178 (11.1%) received at least 12 months of exposure.
The most commonly observed adverse reactions in TRD patients treated with Spravato (incidence ≥ 10% and greater than oral AD plus placebo nasal spray) were dissociation, dizziness, nausea, sedation, headache, vertigo, dysgeusia, hypoaesthesia, blood pressure increased, anxiety and vomiting. Most of these adverse reactions were mild or moderate in severity, reported post dose on the day of administration and resolved the same day.
Table 2 shows the incidence of adverse reactions that occurred in TRD patients treated with Spravato plus oral AD at any dose and greater than patients treated with oral AD plus placebo nasal spray. No differences in adverse reaction type or frequency were observed between younger and older-aged patients nor between induction and maintenance treatments.

Table 3 shows the adverse reactions that occurred in TRD patients treated with Spravato plus oral AD at any dose and greater than patients treated with oral AD plus placebo nasal spray from the five Phase 3 studies (3 short term and 2 long term studies) and one Phase 2 dose ranging study. 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).

The following additional adverse reactions were observed for esketamine when the safety dataset from the TRD studies was pooled with the safety dataset from two Phase 3 studies and one Phase 2 study for 262 patients diagnosed with Major Depressive Disorder with suicidal ideation and intent (Spravato is not approved for use in this indication).

Psychiatric disorders.

Common: confusional state.
Uncommon: psychomotor retardation, emotional distress, dysphoria.

Nervous system disorders.

Common: disturbance in attention.
Uncommon: nystagmus, psychomotor hyperactivity.

Respiratory, thoracic and mediastinal disorders.

Common: throat irritation, oropharyngeal pain.

Skin and subcutaneous tissue disorders.

Uncommon: cold sweat.

Renal and urinary disorders.

Common: dysuria, micturition urgency.

General disorders and administration site conditions.

Common: asthenia, crying.
Uncommon: gait disturbance.

Description of selected adverse reactions.

Dissociation/perceptual changes.

The most common psychological effects of esketamine have been dissociative/perceptual changes (including distortion of time and space and illusions), derealisation and depersonalisation. 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 and somnolence 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.

Impaired cognition.

In the short-term studies, treatment with Spravato plus oral AD did not influence any aspect of cognition studied in adult patients with TRD and was not associated with any systematic changes in cognition in the elderly patients. Consistently, in long term studies, performance on each of the cognitive tests relative to baseline showed slight improvement or remained stable in each treatment phase. In the elderly subgroup (≥ 65 years of age) slowing of reaction time starting at Week 20 and through the end of the study was observed, however, performance on other cognitive tests remained stable.

Changes 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 receiving Spravato plus oral antidepressants (Table 4).

Nausea and vomiting.

Spravato can cause nausea and vomiting (Table 5). 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 5).

Nasal tolerability and sense of smell.

Across studies, the vast majority of esketamine treated patients had no findings on nasal examination. For the patients who had nasal findings (including nasal discharge, nasal crust, or nasal erythema) all events were of mild severity with the exception of a few moderate findings. The most frequently reported post dose nasal symptoms of moderate or severe intensity (reported in at least 5% of patients) in the Phase 3 studies were post nasal drip, taste disturbance and stuffy nose. Other nasal symptoms of moderate or severe intensity included: runny nose, cough, dryness inside nose and sneezing. In addition, sense of smell was assessed over time; no difference was observed between patients treated with Spravato plus oral AD and those treated with oral AD plus placebo nasal spray during the double-blind maintenance phase of TRD3003.

Body weight.

Spravato had no clinically meaningful effect on body weight over short- or long-term administration. In the double-blind maintenance phase of TRD3003, the proportion of patients with an increase in body weight of ≥ 7% was comparable for the Spravato plus oral AD vs. oral AD plus placebo nasal spray groups (13.9% and 13.3%). In the open label, long term study TRD3004, a similar percentage of patients exhibited an increase or decrease in body weight of ≥ 7% (7.4% and 9.1%, respectively). In TRD3004, mean body weight remained stable during treatment with Spravato plus oral AD both in the induction phase and maintenance phase (mean change from baseline ± standard deviation of -0.29±2.15 kg at Day 28 and 0.44±5.83 kg at Week 48).

Hepatotoxicity.

Hepatotoxicity has been reported with chronic ketamine use, ketamine is a racemic mixture containing esketamine therefore, the potential for such an effect due to long term use of Spravato cannot be excluded.

Post-marketing data.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during post-marketing experience (Table 6). In the table, the frequencies are provided according to the following convention: very common: ≥ 1/10 (≥ 10%); common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%); uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%); rare: ≥ 1/10000 and < 1/1000 (≥ 0.01 and < 0.1%); very rare: < 1/10000, including isolated reports (< 0.01%); not known: cannot be estimated from the available data.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

No cases of overdose were reported in clinical studies with Spravato. 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 Dose and Method of Administration).

Symptoms.

There is limited clinical trial experience with esketamine nasal spray doses higher than the maximum recommended dose of 84 mg. 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.

Management of overdose.

There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug 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

Mechanism of action.

Esketamine, the S-enantiomer of racemic ketamine, is an antidepressant with a novel mechanism of action. It is a non selective, non-competitive, antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.
Putative aetiological contributors of depression, including stress and other conditions, are known to cause structural and functional impairment of synapses in brain regions involved with the regulation of mood and emotional behaviour. Evidence within the literature suggests that 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 that restore synaptic function in these brain regions. Unlike other antidepressant therapies, esketamine's primary antidepressant action does not directly involve monoamine, GABA, or opioid receptors.

Pharmacodynamic effects.

Effect on driving.

Two studies were conducted to assess the effects of Spravato on driving skills.
In a controlled study in 25 adult subjects with major depressive disorder, driving performance was assessed the day after administration of a single 84 mg dose. Treatment with esketamine nasal spray at this dose did not affect driving performance in a standard driving test.
In a healthy volunteer study (N = 23 subjects), driving performance was assessed 8 hours after administration of a single dose of 84 mg of esketamine nasal spray, mirtazapine, or placebo. The effect of esketamine nasal spray administration on driving was similar to placebo. However, two subjects discontinued the driving test after receiving esketamine because of a perceived inability to drive.

Effect on QT/QTc interval and cardiac electrophysiology.

Esketamine did not prolong the QT/QTc interval when nasally administered as an 84 mg dose or when intravenously infused as a 0.8 mg/kg dose over 40 minutes.

Clinical trials.

The efficacy and safety of Spravato nasal spray was evaluated 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. 1833 adult patients were enrolled, of which 1601 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, multicentre, 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 and Spravato dosages were then maintained on 56 mg or titrated to 84 mg 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) which was maintained or titrated to 56 mg or 84 mg dose administered twice-weekly during a 4 week double blind induction phase. 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.
The baseline demographic and disease characteristics of patients in TRD3001 and TRD3002 studies were similar between the Spravato plus oral AD and oral AD plus placebo nasal spray groups. The median subject age was 47 years (range 18 to 64 years), 67% were female; 83% Caucasian and 5% of African descent and mean duration of prior AD treatment was approximately 425 days. At the time of screening, the mean duration of the current episode of depression was 168 weeks. At the time of screening, 90% of patients had non-response to ≥ 2 oral ADs with the remainder requiring confirmation of non-response to the second AD during the 4-week screening prospective phase. The new open label oral AD initiated during the 4-week double blind induction phase was an SSRI in 38% of patients and an SNRI in 62% of patients. In TRD3005, the median subject age was 69 years (range 65 to 86 years) of which, 85% of patients were 65-74 years of age, 62% were female and 95% were Caucasian and mean duration of prior AD treatment was approximately 727 days. At the time of screening, the mean duration of the current episode of depression was 216 weeks in TRD3005. At the time of screening, 85% of patients had non-response to ≥ 2 oral ADs with the remainder requiring confirmation of non-response to the second AD during the 4-week screening prospective phase. The new open label AD initiated during the 4-week double blind induction phase was an SSRI in 55% of patients and an SNRI in 45% of patients.
The primary efficacy measure was change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score at the end of the 4-week double blind induction phase. The MADRS is a ten-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression.
In the flexible dose study TRD3002, for the primary efficacy measure of improvement in depressive symptoms (change in MADRS total scores from baseline at the end of the 4-week induction phase), Spravato plus a newly initiated oral AD demonstrated clinically meaningful and statistical superiority compared to standard of care (newly initiated oral AD) plus placebo nasal spray. In studies TRD3001 and TRD3005, 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 standard of care (newly initiated oral AD) plus placebo nasal spray (Table 7). In TRD3002, improvements in the Sheehan Disability Scale (SDS) total score assessing global functional impairment and Patient Health Questionnaire 9 (PHQ 9) total score assessing symptoms of depression numerically favoured Spravato plus a newly initiated oral AD compared to standard of care (newly initiated oral AD) plus placebo nasal spray.

Time course of treatment response.

In Study TRD3002, an effect of Spravato on symptom reduction was observed as early as 24 hours post-dose and increased in subsequent weeks with the full antidepressant effect of Spravato seen by Day 28. Throughout the 4-week double blind induction phase of Study TRD3002, the mean change in MADRS total score for flexibly dosed Spravato (56 mg or 84 mg) plus oral AD was greater than for oral AD plus nasally-administered placebo. At Day 28, 67% of the patients randomised to Spravato were on 84 mg. Figure 1 depicts time course of response in the primary efficacy measure (MADRS) in Study TRD3002. A consistent treatment effect was observed in Studies TRD3001 and TRD3005.

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 8).
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 8).

Treatment resistant depression - long term studies.

Relapse prevention study.

Study SUSTAIN 1 (TRD3003) was a long term randomised, double blind, parallel group, active controlled, multicentre, relapse prevention study. 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. Patients who were responders (MADRS total score reduction ≥ 50% from baseline), continued receiving treatment with Spravato plus oral AD in a 12 week optimisation 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). Four hundred fifty five (455) esketamine treated patients entered the optimisation phase, patients in stable remission or stable response were randomised to continue with Spravato or stop Spravato and switch to placebo nasal spray. After an initial 16 weeks of treatment with Spravato plus oral AD, 176 (39%) patients were in stable remission and 121 (27%) patients were in stable response (but not in stable remission). 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.
The baseline demographic and disease characteristics of the patients randomised to the double blind maintenance phase were similar between the Spravato plus oral AD and oral AD plus placebo groups, median patient age was 48 years (range 19 to 64 years), 66% were female; 90% Caucasian and 4% of African descent.

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 standard of care (oral AD) plus placebo nasal spray (Figure 2). 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 standard of care (oral AD) 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.

For patients in stable remission, the estimated hazard ratio (95% CI) of Spravato plus oral AD relative to standard of care (oral AD) plus placebo nasal spray based on weighted estimates was 0.49 (95% CI: 0.29, 0.84), indicating that, patients who were in stable remission and continued treatment with Spravato plus oral AD group were on average 51% less likely to relapse than patients who switched to standard of care (oral AD) plus placebo nasal spray.

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 standard of care (oral AD) plus placebo nasal spray (Figure 3). The median time to relapse for standard of care (oral AD) plus placebo nasal spray group (88 days) was shorter compared to Spravato plus oral AD group (635 days).

For patients in stable response, the estimated hazard ratio (95% CI) of Spravato plus oral AD relative to standard of care (oral AD) plus placebo nasal spray based on Cox proportional hazards model was 0.30 (95% CI: 0.16, 0.55), indicating that, patients who were stable responders and continued treatment with Spravato plus oral AD group were on average 70% less likely to have a relapse than patients who switched to standard of care (oral AD) plus placebo nasal spray.
Enrolment 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.

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. The dosing frequency used the majority of the time during the maintenance phase is shown in Table 9. Of the patients randomised to Spravato, 60% received 84 mg and 40% received 56 mg dose.

Open label long term safety and efficacy study.

Study SUSTAIN 2 (TRD3004) was an open label, long term study of Spravato plus oral AD in patients with TRD.
The primary objective was to evaluate the long term (up to 52 weeks) safety and efficacy of Spravato. Spravato was not associated with effects on cognitive function or treatment emergent symptoms of interstitial cystitis. In the elderly subgroup (≥ 65 years of age) slowing of reaction time starting at Week 20 and through the end of the study was observed, however, performance on other cognitive tests remained stable.
In addition, there was no evidence of withdrawal and/or rebound symptoms following cessation of Spravato treatment. No cases of respiratory depression were reported and there was no evidence of treatment related changes in lab parameters.
Mean body weight remained stable during treatment with Spravato plus oral AD both in the induction phase and maintenance phase (mean change from baseline ± standard deviation of -0.29±2.15 kg at Day 28 and 0.44±5.83 kg at Week 48).
TRD3004 also evaluated long term efficacy, including effects on depressive symptoms. At the end of the 4 week induction phase, the response rate (≥ 50% improvement from Baseline in the MADRS total score) was 78.4% (593/756) and remission rate (MADRS total score ≤ 12) was 47.2% (357/756); of the responders proceeding to the maintenance phase, 76.5% (461/603) were in response and 58.2% (351/603) were in remission at endpoint.
Dose-response study in treatment resistant depression. A Phase 2 adjunctive, doubly randomised, double blind, placebo controlled, dose ranging study, enrolled 108 adult patients with TRD. Adjunctive to continued oral AD therapy, patients were treated with esketamine 14 mg, 28 mg, 56 mg or 84 mg or placebo administered nasally twice a week for 2 weeks. Treatment with the 28 mg, 56 mg and 84 mg doses of Spravato significantly improved depressive symptoms in patients with TRD as demonstrated by the change in MADRS total score after 1 week. While Spravato doses of 28 mg, 56 mg and 84 mg were efficacious in TRD treatment, the duration of the efficacy of the 28 mg dose was shorter.
Response rates at Day 8 of Period 1 for the double blind phase are shown in Table 10.

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 (t_max) is typically 20 to 40 minutes after the last nasal actuation of a treatment session (see Section 4.2 Dose and Method of Administration).
Dose dependent, linear increases in the plasma C_max and 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.

Metabolism.

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 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.

Excretion.

The mean clearance of esketamine administered by the intravenous route was approximately 89 L/hour. After C_max 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.