esketamine: prescribing information – dosing, contraindications, interactions, side effects

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.
Spravato, 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.
See section 5.1 for a description of the populations studied.

The decision to prescribe this medicinal product should be determined by a psychiatrist.
It is intended to be self-administered by the patient under the direct supervision of a healthcare professional.
A treatment session consists of nasal administration and a post-administration observation period.
Both administration and post-administration observation should be carried out in an 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 the treatment should be considered (see section 4.4). The medicinal product 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, the medicinal product 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).
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
Treatment-resistant Major Depressive Disorder
The dose recommendations for treatment-resistant Major Depressive Disorder 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, dosing should be individualised to the lowest frequency to maintain remission/response.
Table 1:
Recommended dosing for Spravato in adults <65 years with treatment-resistant
Major Depressive Disorder
Induction phase
Maintenance phase
Weeks 1-4:
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 re-examined periodically.
Table 2:
Recommended dosing for Spravato in adults ≥65 years with treatment-resistant
Major Depressive Disorder
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 re-examined periodically.
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 with Spravato, the oral antidepressant (AD) therapy should be continued, per clinical judgement.
In these patients, treatment with Spravato should be part of the comprehensive clinical care plan.

Food and liquid intake recommendations prior to administration
Since some patients may experience nausea and vomiting after administration of the medicinal product, 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 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 (see Tables 1 and 2).
Special populations
Elderly (65 years of age and older)
In elderly patients the initial Spravato dose for treatment-resistant Major Depressive Disorder 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.
Spravato 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.
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.
Paediatric population
The safety and efficacy of Spravato in paediatric patients aged 17 years and younger have not been established. There is no relevant use of Spravato in children less than 7 years of age.
Method of administration
This medicinal product is for nasal use only. The nasal spray device is a single-use device that delivers a total of 28 mg of esketamine, in two sprays (one spray per nostril). To prevent loss of medicinal product, the device should not be primed before use. It is intended for administration by the patient under the supervision of a healthcare professional, using 1 device (for a 28 mg dose), 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device.
Sneezing after administration
If sneezing occurs immediately after administration, a replacement device should not be used.
Use of the same nostril for 2 consecutive sprays
If administration in the same nostril occurs, a replacement device should not be used.

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


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).

Summary of the safety profile
The most commonly observed adverse reactions in patients treated with Spravato were dizziness (31%), dissociation (27%), nausea (27%), headache (23%), somnolence (18%), dysgeusia (18%), vertigo (16%), hypoaesthesia (11%), vomiting (11%), and blood pressure increased (10%).
Tabulated list of adverse reactions
Adverse reactions reported with esketamine are listed in Table 3. 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).
Table 3:
List of adverse reactions
System Organ Class
Adverse Drug Reaction
Frequency
Very common
Common
Uncommon
Rare
Psychiatric disorders dissociation anxiety, euphoric mood, confusional state, derealisation, irritability, hallucination including visual hallucination, agitation, illusion, panic attack, time perception altered psychomotor retardation, emotional distress, dysphoria

Nervous system disorders dizziness, headache, somnolence, dysgeusia, hypoaesthesia paraesthesia, sedation, tremor, mental impairment, lethargy, dysarthria, disturbance in attention nystagmus, psychomotor hyperactivity seizure Eye disorders vision blurred Ear and labyrinth disorders vertigo tinnitus, hyperacusis Cardiac disorders tachycardia bradycardia Vascular disorders hypertension hypotension Respiratory, thoracic and mediastinal disorders nasal discomfort, throat irritation, oropharyngeal pain, nasal dryness including nasal crusting, nasal pruritus respiratory depression Gastrointestinal disorders nausea, vomiting hypoaesthesia oral, dry mouth salivary hypersecretion Skin and subcutaneous tissue disorders hyperhidrosis cold sweat Renal and urinary disorders pollakiuria, dysuria, micturition urgency General disorders and administration site conditions feeling abnormal, feeling drunk, asthenia, crying, feeling of body temperature change gait disturbance Investigations blood pressure increased Long-term safety Long-term safety was assessed in a Phase 3, multicentre, open-label extension study (TRD3008) in 1 148 adult patients with treatment-resistant Major Depressive Disorder representing 3 777 patient-years of exposure. Patients were treated with esketamine for a mean total duration of exposure of 42.9 months (up to 79 months) with 63% and 28% of patients receiving treatment at least 3 years and 5 years, respectively. The safety profile of esketamine was consistent with the known safety profile observed in the pivotal clinical trials. No new safety concerns were identified.
Description of selected adverse reactions
Dissociation
Dissociation (27%) was one of the most common psychological effects of esketamine. Other related terms included derealisation (2.2%), depersonalisation (2.2%), illusions (1.3%), and distortion of time (1.2%). These adverse reactions were reported as transient and self-limited and occurred on the day 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/respiratory depression
In clinical trials, adverse reactions of sedation (9.3%) and somnolence (18.2%) 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. During post-marketing use, rare cases of respiratory depression have been observed (see section 4.4).
Changes in blood pressure
In clinical trials for treatment-resistant Major Depressive Disorder, 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, including a clinical trial with patients treated for a mean total duration of exposure of 42.9 months (up to 79 months), 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. In a long-term clinical trial with patients treated for a mean total duration of exposure of 42.9 months (up to 79 months), no cases of interstitial cystitis were observed.
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.

Suicide/suicidal thoughts or clinical worsening
The effectiveness of esketamine in preventing suicide or in reducing suicidal ideation or behaviour has not been demonstrated (see section 5.1). Use of esketamine does not preclude the need for hospitalisation if clinically warranted, even if patients experience improvement after an initial dose of esketamine.
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
Esketamine 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. Rare cases of deep sedation have been reported. Concomitant use of esketamine with CNS depressants may increase the risk for sedation (see section 4.5). During post- marketing use, rare cases of respiratory depression have been observed. The majority of these cases have been reported with concomitant use of 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. Close monitoring is required for sedation and respiratory depression.

Effect on blood pressure
Esketamine 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. Esketamine is contraindicated in patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (see section 4.3). Before prescribing esketamine, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of esketamine 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 esketamine. 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 with esketamine in patients with clinically significant or unstable cardiovascular or respiratory conditions if the benefit outweighs the risk. In these patients, esketamine 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 of esketamine. Prior to prescribing esketamine, 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 esketamine 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.
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. In a long-term clinical trial with patients treated for a mean total duration of exposure of 42.9 months (up to 79 months), no evidence of hepatotoxicity was observed.
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.

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, 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).

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.

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).

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).
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

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 esketamine nasal spray was investigated in five Phase 3 clinical studies (TRD3001, TRD3002, TRD3003, TRD3004, and TRD3005) 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 esketamine. Additionally, 202 patients were randomised (122 patients received esketamine) in Phase 2 study TRD2005 in Japan, 252 patients were randomised (126 patients received esketamine) in Phase 3 study TRD3006 primarily in China, and 676 patients were randomised (334 patients received esketamine) in Phase 3 study TRD3013.
The efficacy and safety of esketamine nasal spray was investigated in two Phase 3 clinical studies in adult patients (18 to 64 years) with moderate to severe MDD (MADRS total score >28) who had affirmative responses to Mini International Neuropsychiatric Interview (MINI) questions B3 (“Think [even momentarily] about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide [i.e., about killing yourself]?”) and B10 (“Intend to act on thoughts of killing yourself in the past 24 hours?”). 456 adult patients were enrolled, of which 227 patients were exposed to Spravato.

Treatment-resistant depression – Short-term studies

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