Spravato

/ J-C Health Care Ltd., Israel

Treatment-resistant Major Depressive Disorder
The dose recommendations for treatment-resistant Major Depressive Disorder are shown in the prescribing information (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, the dosing should be individualised to the lowest frequency to maintain remission/response.
After depressive symptoms improve, treatment is recommended for at least 6 months.
Acute short-term treatment of psychiatric emergency due to Major Depressive Disorder
The recommended dosage for adult patients (<65 years) is 84 mg twice per week for 4 weeks. Dosage reduction to 56 mg should be made based on tolerability. After 4 weeks of treatment, the oral antidepressant (AD) therapy should be continued, per clinical judgement.
In these patients, treatment with this drug should be part of the comprehensive clinical care plan.
There is limited data on the use of esketamine in patients between 18 to 24 years.
A subgroup analysis of patients with or without at least one previous suicidal experience for the primary endpoint “Change from baseline (day 1, predose) to 24 hours after the first dose (day 2) in MARDS” of the pivotal studies, demonstrated no statistically significant efficacy for the group of patients without at least one previous suicidal experience.
Food and liquid intake recommendations prior to administration
Since some patients may experience nausea and vomiting after administration of this drug, 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.
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 administration.
Missed treatment session(s)
Patients who have missed treatment session(s) during the first 4 weeks of treatment should continue with their current dosing schedule.
For patients with treatment-resistant Major Depressive Disorder who miss treatment session(s) during maintenance phase and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule.
Elderly (65 years of age and older)
In elderly patients the initial dose for treatment-resistant Major Depressive Disorder is 28 mg esketamine (day 1, starting dose). Subsequent doses should be increased in increments of 28 mg up to 56 mg or 84 mg, based on efficacy and tolerability.
This drug has not been studied in elderly patients as acute short-term treatment of psychiatric emergency due to Major Depressive Disorder.
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.
This drug has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended.
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 dose is 28 mg esketamine (day 1, starting dose). Subsequent doses should be increased in increments of 28 mg up to 56 mg or 84 mg, based on efficacy and tolerability.
Paediatric population
The safety and efficacy in paediatric patients aged 17 years and younger have not been established. No data are available. There is no relevant use in children less than 7 years of age.
See prescribing information for full details.

This medicinal product, 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.
This medicinal product, co-administered with oral antidepressant therapy, is indicated in adults with a moderate to severe episode of Major Depressive Disorder, as acute short-term treatment, for the rapid reduction of depressive symptoms, which according to clinical judgement constitute a psychiatric emergency.
Limitations of Use: The effectiveness in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of this drug does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of this drug.

● Hypersensitivity to the active substance, ketamine, or to any of the excipients.
● Patients for whom an increase in blood pressure or intracranial pressure poses a serious risk:
– 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).

Suicide/suicidal thoughts or clinical worsening
The effectiveness in preventing suicide or in reducing suicidal ideation or behaviour has not been demonstrated. Use does not preclude the need for hospitalisation if clinically warranted, even if patients experience improvement after an initial dose of this drug.
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.
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.
Neuropsychiatric and motor impairments
This drug has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo and anxiety during the clinical trials. 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.
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; rare cases of deep sedation have been reported. Concomitant use with CNS depressants may increase the risk for sedation. During post-marketing use, rare cases of respiratory depression have been observed. The majority of these cases have been reported with concomitant use of CNS depressants 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. Close monitoring is required for sedation and respiratory depression.
Effect on blood pressure
This drug 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. A substantial increase in blood pressure could occur after any treatment session. This medicinal product is contraindicated in patients for whom an increase in blood pressure or intracranial pressure poses a serious risk. Before prescribing this drug, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits 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 this drug. If blood pressure is elevated prior to esketamine administration a decision to delay esketamine therapy should take into account the balance of benefit and risk in individual patients.
Blood pressure should be monitored after dose administration. Blood pressure should be measured around 40 minutes post-dose and subsequently as clinically warranted until values decline. If blood pressure remains elevated for a prolonged period of time, assistance should promptly be sought from practitioners experienced in blood pressure management. Patients who experience symptoms of a hypertensive crisis should be referred immediately for emergency care.
Patients with clinically significant or unstable cardiovascular or respiratory conditions
Only initiate treatment in patients with clinically significant or unstable cardiovascular or respiratory conditions if the benefit outweighs the risk. In these patients, this drug 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).
Drug abuse, dependence, withdrawal
Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse. Prior to prescribing this drug, 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 is minimised due to the administration taking place under the direct supervision of a healthcare professional. This medicinal product contains esketamine and may be subject to abuse and diversion.
Other populations at risk
This drug should be used with caution in patients with the following conditions. These patients should be carefully assessed before prescribing this drug 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.
Elderly (65 years of age and older)
Elderly patients treated with this drug 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, this drug 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 cannot be excluded.
Urinary tract symptoms
Urinary tract and bladder symptoms have been reported. 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.
See prescribing information for full details.

Very common: Dissociation, dizziness, headache, somnolence, dysgeusia, hypoaesthesia, vertigo, nausea, vomiting, blood pressure increased.
Common: Anxiety, euphoric mood, confusional state, derealisation, irritability, hallucination including visual hallucination, agitation, illusion, panic attack, time perception altered, paraesthesia, sedation, tremor, mental impairment, lethargy, dysarthria, disturbance in attention, vision blurred, tinnitus, hyperacusis, tachycardia, hypertension, nasal discomfort, throat irritation, oropharyngeal pain, nasal dryness including nasal crusting, nasal pruritus, hypoaesthesia oral, dry mouth, hyperhidrosis , pollakiuria, dysuria, micturition urgency, feeling abnormal, feeling drunk, asthenia, crying, feeling of body temperature change.
See prescribing information for full details.

Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation, which therefore should be closely monitored.
Blood pressure should be closely monitored when this drug is used concomitantly with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, 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).

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. A similar risk with esketamine cannot be excluded. If a woman becomes pregnant while being treated with this drug, 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.
Lactation:
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 therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

The potential for overdose by the patient is minimised due to the product’s design and the administration taking place under the supervision of a healthcare professional.
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 overdose should consist of treating clinical symptoms and relevant monitoring. Close supervision and monitoring should continue until the patient recovers.