REMS: FDA approved a REMS for esketamine to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of esketamine and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page ([Web]). |
Esketamine hydrochloride, the S -enantiomer of racemic ketamine, is an N -methyl-d-aspartate (NMDA) receptor antagonist and an antidepressant.1, 13, 35, 40
Esketamine is used intranasally in the management of depression.1 Esketamine has not demonstrated effectiveness in preventing suicide or in reducing suicidal thoughts and behaviors (suicidality).1 Esketamine use does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of esketamine.1 Esketamine nasal solution is not labeled for use as an anesthetic agent and the manufacturer states that the safety and efficacy of the drug for this use have not been established.1
Treatment-resistant Depression
Esketamine hydrochloride is used for the management of treatment-resistant depression in adults, as monotherapy or in conjunction with an oral antidepressant.1, 2, 3, 301, 316
Although there are various definitions of treatment-resistant depression, the condition often has been defined as the failure of at least 2 trials of first-line antidepressants given in an adequate dosage for an adequate duration of therapy.1, 2, 3, 301, 307, 309, 315
Efficacy of intranasal esketamine as monotherapy for treatment-resistant depression was established in a randomized, double-blind, placebo-controlled trial (NCT04599855) in adult patients.1, 316 Patients who met DSM-5 criteria for major depressive disorder and who were in a current depressive episode that had not responded adequately to at least 2 different antidepressants of adequate dosage and duration were randomized 1:1:2 to receive twice weekly doses of intranasal esketamine 56 mg, 84 mg, or placebo for 4 weeks.1, 316 Patients with suicidal or homicidal ideation with intent to act within the prior 6 months, suicidal behavior in the prior 12 months, or moderate or severe substance or alcohol use disorder (with the exception of caffeine or nicotine) within the prior 6 months were excluded.316 The primary efficacy end point was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score, a 10-item clinician-rated scale used to assess the degree of depressive symptomatology, at the end of the 4-week induction phase.1 Scores on the MADRS range from 0 to 60; higher scores indicate more severe depression.1 The median age of patients in this study was 46 years (range: 19 to 76 years); the majority were female (61%) and Caucasian (87%).1 At the end of 4 weeks of treatment, the mean MADRS total score was substantially lower in patients who received esketamine compared to placebo.1 This effect was noted at day 2 in patients receiving esketamine compared to placebo and remained through day 28.1
Efficacy of intranasal esketamine in conjunction with an oral antidepressant was established in 2 randomized controlled trials (one short-term trial of 4 weeks' duration and one maintenance trial) in adults younger than 65 years of age with treatment-resistant depression.1, 2, 3 Short-term efficacy of the drug was established in a double-blind, placebo-controlled, multicenter trial of 4 weeks' duration (TRANSFORM-2) in 223 patients who met DSM-5 criteria for major depressive disorder (without psychotic features) and who did not adequately respond to 2 separate trials of different antidepressants of adequate dosage and duration in their current episode.1, 2 Patients with suicidal ideation with intent to act or suicidal behavior within the past year were excluded from the study.2 The median age of patients in this study was 47 years (range: 19 to 64 years); 62% were female and 93% were Caucasian.1 After discontinuing all prior antidepressants, patients were randomized to receive either flexible-dose esketamine (initially 56 mg twice weekly and increased to 84 mg twice weekly based on tolerability and efficacy) or placebo intranasally in conjunction with open-label treatment with a newly initiated oral antidepressant (duloxetine, escitalopram, sertraline, or extended-release venlafaxine) chosen by the investigator based on the patient's treatment history.1, 2 The primary efficacy end point was the change from baseline in the MADRS total score.1, 2 After 4 weeks of treatment, the mean MADRS total score was substantially lower in patients who received esketamine compared with placebo.1, 2 Most of the treatment effect was evident by 24 hours after the first dose.1, 2 Between 24 hours and day 28, patients in both groups continued to improve; the difference between the groups remained generally the same but did not appear to increase during the 4-week treatment period.1 Of the patients randomized to receive esketamine, about 46% were receiving the 84-mg dosage by day 4 and about 67% were receiving the 84-mg dosage by the end of the treatment period.1, 2
In the longer-term maintenance study (SUSTAIN-1), continued treatment with intranasal esketamine was found to be effective in delaying the time to relapse compared with placebo in adult patients who had responded to at least 16 weeks of intranasal esketamine therapy.1, 3 In this study, patients (newly enrolled or recruited from short-term controlled trials) initially received at least 16 weeks of treatment with intranasal esketamine 56 or 84 mg (flexibly dosed) twice weekly for 4 weeks, followed by a fixed dose once weekly for 4 weeks, then weekly or every other week (based on depressive symptoms) in conjunction with a new oral antidepressant.1, 3 Patients who achieved stable remission (i.e., MADRS total score or 12 or less for at least 3 of the last 4 weeks) or stable response (i.e., at least 50% reduction in MADRS total score but MADRS score above 12 for at least 3 of the last 4 weeks and not in remission) were randomized to continue receiving intranasal esketamine (56 or 84 mg once weekly or every other week based on depressive symptoms) or to be switched to placebo for the maintenance phase and monitored for relapse (defined as MADRS total score of 22 or higher for 2 consecutive weeks or hospitalization for worsening depression or any other clinically relevant event indicative of relapse).1, 3 All patients continued to receive an oral antidepressant throughout the study.1, 3 Overall, 39 and 61% of patients who continued esketamine therapy received the 56- and 84-mg doses, respectively.1 Time to relapse of depressive symptoms in patients who achieved stable remission (the primary end point) was substantially longer in those receiving continued intranasal esketamine therapy plus an oral antidepressant compared with those who were switched to placebo plus an oral antidepressant.1, 3 Among patients who achieved stable remission and received continued esketamine therapy, 69% received every-other-week dosing and 23% received weekly dosing the majority of time during the maintenance phase.1, 3 In addition, time to relapse also was substantially longer in patients who achieved stable response and continued intranasal esketamine therapy compared with those who were switched to placebo.1, 3 Among patients who achieved stable response and received continued esketamine therapy, 34% received every-other-week dosing and 55% received weekly dosing the majority of time during the maintenance phase.1, 3
In a randomized, placebo-controlled, double-blind, multicenter study in 68 patients considered to be at imminent risk of suicide, patients receiving intranasal esketamine 84 mg twice weekly for 4 weeks in addition to comprehensive standard-of-care treatment had a substantially greater reduction in MADRS scores than those receiving placebo and comprehensive standard-of-care treatment at 4 hours and approximately 24 hours, but not at 25 days.14 The esketamine-treated patients in this study also demonstrated substantially greater improvement in suicidal thinking (as assessed by their score on the MADRS suicidal thoughts item) compared with those receiving placebo at 4 hours, but not at 24 hours or 25 days.14 These results suggest that, like ketamine, intranasal esketamine may potentially be effective in rapidly reducing symptoms of depression, including suicidal ideation, in depressed patients at imminent risk of suicide.14
A legacy practice guideline from the American Psychiatric Association (APA) provides treatment recommendations for major depressive disorder.317 For patients with treatment-resistant depression, these guidelines recommend switching to another antidepressant (e.g., from one selective serotonin-reuptake inhibitor [SSRI] to another or to a tricyclic antidepressant or monoamine oxidase [MAO] inhibitor), augmenting with a nonantidepressant medication (e.g., lithium, antipsychotics), adding or switching to depression-focused psychotherapy, or use of other nonpharmacologic treatments (e.g., transcranial magnetic stimulation, electroconvulsive therapy).317 Esketamine is not specifically addressed in these guidelines.317
The Department of Veterans Affairs and Department of Defense developed guidelines for the management of major depressive disorder.318 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAO inhibitors or tricyclic antidepressants), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.318 For patients not responsive to several adequate pharmacologic trials, esketamine can be considered as an option for augmentation.318
Depressive Symptoms in Major Depressive Disorder with Acute Suicidality
Esketamine is used in conjunction with an oral antidepressant for the treatment of depressive symptoms in adult patients with major depressive disorder with acute suicidal ideation or behavior.1
Efficacy of intranasal esketamine in conjunction with an oral antidepressant was established in 2 randomized placebo-controlled trials (ASPIRE I and ASPIRE II) in adults younger than 65 years of age with moderate-to-severe major depressive disorder and with active suicidal ideation and intent.1, 319, 320 Both studies were identical in design and consisted of a short-term (4 week) treatment period and a follow-up period through 90 days.1, 319, 320 Patients deemed to be in clinical need of acute inpatient psychiatric hospitalization and with a baseline MADRS total score >28 were randomized to receive either esketamine 84 mg or placebo intranasally twice weekly for 4 weeks.1, 319, 320 After the first dose, a one-time dosage reduction to 56 mg was allowed for patients unable to tolerate the 84 mg dose.1 Patients received treatment consistent with the standard of care, including hospitalization and optimized oral antidepressant therapy (either as monotherapy or in conjunction with augmentation therapy), as determined by study investigators.1, 319, 320 Patients with a concurrent psychiatric illness (e.g., bipolar disorder, obsessive compulsive disorder) and moderate-to-severe substance or alcohol use disorder within 6 months (12 months in some countries) prior to screening were excluded from the study.1, 319, 320 The primary efficacy end point was the change from baseline in the MADRS total score at 24 hours after the first dose.1, 319, 320
The baseline demographic and disease characteristics of the patients included in these studies were similar; the median age was 40 years (range: 18 to 64 years) and the majority were female (61%) and Caucasian (73%).1 Prior to study entry, most patients (92%) were receiving antidepressant therapy and 63% had at least one prior suicide attempt.1 During the study, 40% of patients received antidepressant monotherapy, 54% received antidepressant plus augmentation therapy, and 6% received both antidepressant monotherapy and antidepressant plus augmentation therapy.1 Approximately 19% of patients enrolled in the study required a dosage reduction in esketamine from 84 mg to 56 mg.1 At the follow-up assessment performed 24 hours after treatment, patients who received esketamine demonstrated a substantially lower MADRS total score than those who received placebo.1 This treatment difference was noted starting at 4 hours.1 Between 4 hours and day 25, both the esketamine and placebo groups continued to improve; the difference between groups generally remained but did not appear to increase over time through day 25.1
Dispensing and Administration Precautions
Esketamine hydrochloride is administered intranasally using a nasal spray device.1 The drug is intended for patient self-administration under the direct supervision of a healthcare provider .1 A treatment session consists of intranasal administration of esketamine and post-administration observation under supervision.1 Patients should be instructed on use of the nasal spray device and advised to read the patient instructions for use provided by the manufacturer.1 Following administration of each dose, patients must be monitored at the healthcare facility by a provider for at least 2 hours and then assessed for clinical stability and readiness to be discharged.1 Patients should not drive after the treatment session.1
Esketamine nasal solution is commercially available in kits containing either 2 (56-mg dose kit) or 3 (84-mg dose kit) stoppered glass vials within a nasal spray device.1 Each nasal spray device delivers a total of 28 mg of esketamine and delivers 2 sprays containing 14 mg of esketamine per spray.1 Two devices should be used for a 56-mg dose and 3 devices should be used for an 84-mg dose.1 An indicator on the device displays one green dot for each spray remaining in the device.1 Prior to administration of esketamine nasal spray, a healthcare provider should confirm the number of nasal spray devices required for the dose and check that each device indicator displays 2 green dots.1 To prevent loss of the drug, esketamine nasal spray devices should not be primed before use.1
Patients should be instructed to blow the nose to clear the nasal passages before the initial spray from the first device at each treatment session.1 During administration, patients should recline their head to about 45 degrees to help keep the solution inside the nose.1
The patient should insert the tip of the device straight into one nostril; the nose rest should touch the skin between the nostrils.1 While holding the other nostril closed, the patient should concurrently inspire through the nose while pushing on the plunger to activate the spray.1 The patient should then sniff gently to keep the solution in the nose.1 This procedure should be repeated for the other nostril.1
The procedure should then be repeated for each device until the full dose of esketamine nasal spray has been administered.1 Following administration of esketamine in each device (i.e., 2 sprays), the patient should rest in a comfortable position (preferably semi-reclined) for 5 minutes to allow the drug to be absorbed.1 Following use, each device should be checked by the healthcare provider to ensure that both sprays have been delivered; if a green dot appears in the device indicator, the patient should spray again into the second nostril.1 If liquid drips out of the nostril, the nose should be dabbed with a tissue.1
Following use, esketamine nasal spray devices must be handled with adequate security and accountability, and disposal must be in accordance with the facility's procedures and federal, state, and local regulations for C-III drug products.1
Store esketamine nasal spray at 20—25°C; excursions permitted from 15-30°C.1
During and following administration of esketamine nasal spray at each treatment session, patients must be observed (i.e., for sedation, dissociation, respiratory status, and increased blood pressure).1 Patient observation should continue for at least 2 hours until the patient can safely leave the healthcare setting.1
Dosage of esketamine hydrochloride is expressed in terms of esketamine.1
Treatment-resistant Depression
For the management of treatment-resistant depression as monotherapy or in combination with an oral antidepressant in adults, the recommended intranasal dosage of esketamine during the induction phase (weeks 1-4) is 56 or 84 mg administered twice weekly.1 Dosage adjustments should be made based on efficacy and tolerability.1
The recommended dosage during the maintenance phase (weeks 5-8) is 56 or 84 mg administered once weekly followed by 56 or 84 mg administered every 2 weeks or once weekly during week 9 and the following weeks.1 Dosing frequency during week 9 and thereafter should be individualized to the least frequent dosing interval that maintains remission or response.1 In the short- and long-term efficacy trials of esketamine nasal spray, approximately one-third of patients received 56-mg doses of esketamine and two-thirds received 84-mg doses of the drug.1, 2, 3
The clinical benefit of esketamine should be assessed at the end of the induction phase (i.e., week 4) to determine the need for continued therapy.1
If a treatment session is missed and there is no worsening of depressive symptoms, patient should continue the current dosing schedule.1 If a treatment session is missed during the maintenance phase and worsening of depression occurs, the dosing frequency may be increased back to the patient's previous dosing schedule (i.e., every 2 weeks to once weekly, once weekly to twice weekly) based on clinical judgment.1
Depressive Symptoms in Major Depressive Disorder with Acute Suicidal Ideation or Behavior
For the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior in combination with an oral antidepressant, the recommended intranasal dosage of esketamine is 84 mg twice per week for 4 weeks.1 Dosage may be reduced to 56 mg twice per week based on tolerability.1
After 4 weeks of treatment with esketamine, evidence of therapeutic benefit should be evaluated to determine the need for continued treatment.1
The use of esketamine in combination with an oral antidepressant beyond 4 weeks has not been systematically evaluated in this patient population.1
The manufacturer makes no specific dosage recommendations for esketamine in patients with mild hepatic impairment.1 Although no specific dosage adjustments are recommended for patients with moderate hepatic impairment, such patients may require prolonged monitoring for adverse effects.1, 6 The drug is not recommended for use in patients with severe hepatic impairment.1, 6
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1, 5
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Esketamine may cause sedation or loss of consciousness.1 The prescribing information for esketamine contains a boxed warning regarding this risk.1 Sedation (defined as any decrease from baseline in the Modified Observer's Alertness/Sedation scale [MOAA/S]) was reported in 48-61% of patients and loss of consciousness (MOAA/S score of 0) was reported in 0.3—0.4% of patients receiving esketamine nasal spray in conjunction with an oral antidepressant in clinical trials.1
Because of the possibility of delayed or prolonged sedation, patients receiving esketamine must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine if the patient is considered clinically stable and ready to leave the healthcare setting.1
Patients concomitantly receiving esketamine and CNS depressants should be closely monitored.1
Intranasal esketamine may cause dissociative effects (e.g., derealization, depersonalization) and perceptual changes (e.g., distortion of time and space and illusions); these adverse effects appear to be dose related.1 The prescribing information for esketamine contains a boxed warning regarding this risk.1 Dissociative (dissociation was defined as a Clinician-administered Dissociative States Scale [CADSS] total score of 4 or greater) or perceptual changes were reported in 61-84% of patients receiving esketamine nasal spray in clinical trials.1 In these trials, dissociation was transient and occurred on the day of intranasal esketamine administration.1
Because of the risk of dissociative effects, patients with psychosis should be carefully assessed prior to treatment with esketamine; therapy should be initiated in such patients only if the benefits outweigh the risks.1
In addition, patients receiving esketamine must be monitored by a healthcare provider for at least 2 hours at each treatment session, followed by an assessment to determine if the patient is considered clinically stable and ready to leave the healthcare setting.1
Respiratory depression, including respiratory arrest, has been reported in postmarketing experience with esketamine.1 The prescribing information for esketamine contains a boxed warning regarding this risk.1
Monitor respiratory status (including pulse oximetry) for at least 2 hours at each treatment session, then assess to determine when the patient is considered clinically stable and ready to leave the healthcare setting.1
Esketamine is a schedule III (C-III) drug and has the potential to be abused or misused.1 The prescribing information for esketamine contains a boxed warning regarding this risk.1 Esketamine is the S -enantiomer of racemic ketamine, which is also a C-III drug with known abuse potential.1, 40, 41
Intranasal esketamine may produce a variety of symptoms, including anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and feelings of floating, detachment, and being “spaced out”.1, 35 In a double-blind, crossover, abuse potential study in recreational polydrug users who had experience with perception-altering drugs, including ketamine, administration of single 84- and 112-mg intranasal doses of esketamine (the maximum recommended dose and 1.3 times the maximum recommended dose, respectively) produced scores for “drug liking at the moment” and “take drug again” that were similar to scores in patients receiving an IV infusion of ketamine (0.5 mg/kg).1 These scores were higher for both esketamine and ketamine compared with placebo.1
Physical dependence has been reported with prolonged use of ketamine, and withdrawal symptoms have been reported following the discontinuance of frequently used large doses of the drug when given for prolonged periods of time.1, 35, 40 The manufacturer of esketamine states that although withdrawal symptoms have not been observed after cessation of esketamine treatment, such withdrawal symptoms are likely to occur if esketamine is similarly abused.1 Tolerance has been reported with prolonged use of ketamine, and similar tolerance would be expected with prolonged use of esketamine.1
Each patient's risk for abuse or misuse should be assessed prior to prescribing esketamine, and all patients receiving the drug should be monitored for the development of these behaviors or conditions, including drug-seeking behavior, during therapy.1 Individuals with a history of drug abuse or dependence are at greater risk for abuse and misuse of esketamine.1 Therefore, the manufacturer states that careful consideration is advised prior to esketamine use in individuals with a history of substance use disorder, including alcohol.1 Patients receiving esketamine therapy should also be monitored for signs and symptoms of physical dependence following discontinuance of therapy.1
Following use, esketamine nasal spray devices must be handled with adequate security and accountability, and disposal must be in accordance with the facility's procedures and federal, state, and local regulations for C-III drug products.1
Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidal thoughts and behaviors (suicidality) in pediatric patients and young adults up to 24 years of age receiving antidepressants for major depressive disorder and other indications.1 The prescribing information for esketamine contains a boxed warning regarding this risk.1 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.1 It is not known whether the risk of suicidality in children, adolescents, and young adults extends to longer-term use (i.e., longer than 4 months) of antidepressants; however, substantial evidence from placebo-controlled maintenance studies in adults with major depressive disorder indicates that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidality.1
All patients being treated with antidepressants should be monitored for clinical worsening and emergence of suicidality, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 Families and caregivers of patients being treated with antidepressants also should be advised to monitor patients for changes in behavior and to report such changes immediately to a health-care provider.1 Consideration should be given to changing the therapeutic regimen, including possible discontinuance of esketamine and/or the concomitant oral antidepressant, in patients whose depression is persistently worse or in patients experiencing emergent suicidality.1
Esketamine is not labeled for use in pediatric patients.1
Other Warnings and Precautions
Increases in systolic and/or diastolic blood pressure can occur following intranasal administration of esketamine at all recommended dosages.1 A substantial increase in blood pressure could occur after any intranasal dose of esketamine even if smaller blood pressure effects were observed with previous administration of the drug.1 Blood pressure increases peak approximately 40 minutes after intranasal administration of esketamine and last for approximately 4 hours.1 In short-term clinical trials, mean placebo-adjusted increases in systolic and diastolic blood pressure were approximately 7-10 and 4-6 mm Hg, respectively, at 40 minutes and 2-5 and 1-3 mm Hg, respectively, at 1.5 hours following intranasal administration of esketamine.1 Increases of more than 40 mm Hg in systolic blood pressure and/or 25 mm Hg in diastolic blood pressure in the first 1.5 hours after administration occurred at least once during the first 4 weeks of treatment in approximately 3-19% of patients receiving esketamine compared with 1-4% of placebo recipients.1
Blood pressure should be assessed prior to each esketamine treatment session, approximately 40 minutes after administration of each dose, and as clinically warranted until values decline for at least 2 hours following administration.1 If blood pressure is elevated prior to esketamine administration (i.e., systolic or diastolic blood pressure exceeding 140 or 90 mm Hg, respectively), a decision to delay therapy should be individualized and take into consideration the potential benefit and risk of esketamine in the patient.1
If blood pressure is decreasing following esketamine administration and the patient appears clinically stable for at least 2 hours, the patient may be discharged from the healthcare setting; otherwise, monitoring should be continued.1 If blood pressure remains elevated, clinicians experienced in blood pressure management should be consulted promptly.1 Patients experiencing symptoms of hypertensive crisis (e.g., chest pain, shortness of breath) or hypertensive encephalopathy (e.g., sudden severe headache, visual disturbances, seizures, diminished consciousness, focal neurologic deficits) should be immediately referred for emergency care.1
Patients with a history of hypertensive encephalopathy are at increased risk for developing encephalopathy with even small increases in blood pressure and should be monitored more intensively, including more frequent blood pressure monitoring and symptom assessment.1
Esketamine is contraindicated in patients in whom an increase in blood pressure or intracranial pressure would constitute a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage).1 Patients with other cardiovascular or cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of esketamine treatment outweigh the risks.1
Blood pressure should be closely monitored if esketamine is used concomitantly with psychostimulants or monoamine oxidase (MAO) inhibitors.1
Esketamine may cause short-term impairment in attention, judgment, thinking, reaction speed, and motor skills.1, 7 In a double-blind, placebo-controlled, crossover study in 24 healthy individuals, esketamine (given as a single 84-mg intranasal dose) was associated with a greater decline in cognitive function and greater mental effort was required to complete cognitive tests compared with placebo at 40 minutes post-dose.1, 7 Cognitive performance and mental effort were comparable between the esketamine and placebo groups at 2 hours post-dose.1, 7 Esketamine also was associated with increased sleepiness at 40 minutes and 2 hours post-dose, but was comparable to placebo by 4 hours post-dose.1, 7
Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse .1 In 1-year and 3-year, long-term, open-label clinical trials in adults, the cognitive effects of the drug remained stable over time as evaluated by the Cogstate computerized battery and Hopkins Verbal Learning Test-Revised.1
Impaired Ability to Drive or Operate Machinery
Esketamine may impair the ability to drive a motor vehicle or operate machinery.1 The effect of esketamine on driving performance was evaluated in 2 driving simulation studies; one study was conducted in adults with major depressive disorder and the other was conducted in healthy individuals.1 In a single-blind, placebo-controlled study in adults with major depressive disorder, next-day driving performance following a single 84-mg intranasal dose of esketamine was similar to that observed with placebo at 18 hours post-dose.1 Following twice-weekly dosing of intranasal esketamine in the same study, driving performance was evaluated once weekly on days 11, 18, and 25 and was found to be similar to that observed with placebo at 6 hours post-dose.1, 9
In a double-blind, placebo-controlled, crossover study in healthy adults, driving performance after administration of esketamine (single 84-mg intranasal dose) or placebo did not differ substantially when evaluated at 8 hours post-dose; however, 2 individuals in the study discontinued their driving tests prematurely after receiving intranasal esketamine because of a perceived inability to drive after experiencing post-dose adverse reactions.1, 8
Prior to esketamine administration, advise patients that following treatment, they should not engage in potentially hazardous activities requiring full mental alertness and motor coordination, such as driving or operating machinery, until the next day after a restful sleep.1 Patients should also arrange for transportation home following each esketamine treatment session.1
Ulcerative or Interstitial Cystitis
Cases of ulcerative or interstitial cystitis have been reported with long-term, off-label use or misuse/abuse of ketamine.1, 35, 40 In clinical studies with esketamine nasal spray, a higher incidence of lower urinary tract symptoms, including pollakiuria, dysuria, urgency, nocturia, and cystitis, was observed in esketamine-treated patients compared with those receiving placebo.1 However, no cases of esketamine-associated interstitial cystitis were observed in any of these studies, which included treatment of up to 1 year's duration.1
Patients receiving esketamine should be monitored for urinary tract and bladder symptoms (e.g., dysuria, urinary frequency or urgency, nocturia) during treatment.1 If urinary symptoms occur, patients should be evaluated by an appropriate healthcare provider as clinically warranted.1
Based on published findings in pregnant animals exposed to ketamine, esketamine may cause fetal harm if administered to pregnant women.1 The clinical relevance of these findings to humans treated with esketamine nasal spray at the recommended dosage is not known.1
Skeletal malformations were observed with intranasal administration of ketamine to pregnant rabbits; the no observed adverse effect level (NOAEL) for these malformations was associated with a plasma esketamine exposure that was 0.3 times the exposure at the maximum recommended human dosage (MRHD) of 84 mg daily.1 Intranasal administration of esketamine to pregnant rats produced delays in sensorimotor development and decreased motor activity at dosages that are associated with exposures that are less than the MRHD.1
Studies in primates have demonstrated that use of anesthetic and sedation drugs that block N -methyl-d-aspartate (NMDA) receptors during the period of peak brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis in the developing brain of offspring.1, 40 This period of brain development in animals is thought to correlate with the third trimester of pregnancy through the first several months of life in humans, but may extend to approximately 3 years of age.1, 40 The clinical relevance of these findings to humans is not known; however, studies in juvenile animals suggest that neuroapoptosis results in long-term cognitive deficits.1 There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.1
Esketamine is not recommended for use during pregnancy.1 The manufacturer states that women of reproductive potential should consider pregnancy planning and contraception during therapy.1 If a woman becomes pregnant while receiving esketamine, the drug should be discontinued and the patient apprised of the potential risk to the fetus.1
Data on esketamine use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 However, based on published findings from pregnant animals exposed to ketamine, esketamine may cause fetal harm.1 Esketamine is not recommended for use during pregnancy.1 If a patient becomes pregnant while being treated with esketamine, treatment with esketamine should be discontinued and the patient should be counseled on the potential risk to the fetus.1
In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when esketamine was intranasally administered with a NOAEL at estimated esketamine exposures 0.3 times the exposures at the MRHD of 84 mg/day.1 Intranasal administration of esketamine to rats during pregnancy and lactation at exposures similar to the MRHD resulted in a delay in sensorimotor development in pups during the pre-weaning period and a decrease in motor activity in the post-weaning period.1
A pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to antidepressants, including esketamine.1 For more information, patients or their clinicians may contact the National Pregnancy Registry for Antidepressants at 844-405-6185 or visit [Web].1
Esketamine is distributed into milk in humans.1 It is not known if the drug has any effect on the nursing infant or on milk production.1
Studies in juvenile animals demonstrate that administration of drugs that block NMDA receptors (including ketamine) during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.1 The window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend to approximately 3 years of age in humans.1
Because of the potential for neurotoxicity in nursing infants, the manufacturer states that breast-feeding during esketamine therapy is not recommended.1
Females and Males of Reproductive Potential
Based on animal studies, esketamine may cause embryo-fetal harm when administered to a pregnant woman.1 However, it is not clear how these animal findings relate to females of reproductive potential treated with the recommended clinical dosage.1 Consider pregnancy planning and prevention for females of reproductive potential during treatment with esketamine.1
Safety and efficacy of esketamine nasal spray have not been established in pediatric patients.1
Increased risk of suicidality has been observed in children and adolescents receiving antidepressants for major depressive disorder and other indications in short-term studies.1
Results of animal studies indicate that repeated or prolonged use of drugs that block NMDA receptors, including ketamine and esketamine, in children younger than approximately 3 years of age potentially may adversely affect brain development.1, 40 The clinical relevance of these findings to humans treated with esketamine nasal solution at the recommended clinical dosage is not known.1
In short-term trials in the clinical development program for esketamine nasal spray in treatment-resistant depression, 12% of patients were 65 years of age or older and 1% were 75 years of age or older.1 No overall differences in the safety profile of esketamine were observed between geriatric patients and younger adults.1
Higher peak plasma concentrations and systemic exposure of esketamine have been observed in geriatric patients compared with younger adults.1
In a double-blind, placebo-controlled trial of 4 weeks' duration in patients 65 years of age or older with treatment-resistant depression, a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) total score was observed with esketamine treatment (initial dosage of 28 mg intranasally twice weekly then titrated to 56 or 84 mg twice weekly) in conjunction with a newly initiated oral antidepressant at the end of 4 weeks.1, 11 However, the difference in the reduction in the MADRS total score between the esketamine and placebo groups did not achieve statistical significance in this study.11
In a pharmacokinetic study of esketamine nasal spray, systemic exposure to esketamine was higher and the elimination half-life of the drug was longer in individuals with moderate hepatic impairment (Child-Pugh class B) compared with individuals with normal hepatic function.1, 6 Although the manufacturer provides no specific dosage recommendations for patients with moderate hepatic impairment, the manufacturer states that such patients may require prolonged monitoring for possible adverse effects.1, 6
Peak plasma concentrations and exposure to esketamine were slightly increased in patients with mild hepatic impairment (Child-Pugh class A); these changes were not considered clinically important.1, 6
Esketamine has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and is not recommended for use in such patients.1, 6
In a single-dose pharmacokinetic study, systemic exposure to esketamine was slightly higher in individuals with mild to severe renal impairment (creatinine clearance of 5-77 mL/minute; not requiring dialysis) compared with individuals with normal renal function; this difference was not considered clinically important.1, 5
Esketamine has not been studied in patients requiring dialysis to date.1, 5
Adverse effects reported in at least 5% of patients with treatment-resistant depression receiving intranasal esketamine and at an incidence at least twice that of placebo include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, drunk feeling, and headache.1
Adverse effects reported in at least 5% of patients (and at least twice that of placebo) with major depressive disorder receiving esketamine for the treatment of depressive symptoms with acute suicidal ideation or behavior include dissociation, dizziness, sedation, increased blood pressure, hypoesthesia, vomiting, euphoric mood, and vertigo.1
Esketamine is metabolized principally by cytochrome P-450 (CYP) isoenzymes 2B6 and 3A4 and, to a lesser extent, by CYP2C9 and CYP2C19.1 The drug's major active metabolite, noresketamine, also is metabolized via CYP-mediated pathways.1
In vitro, esketamine is a modest inducer of CYP2B6 and CYP3A4 and noresketamine weakly and reversibly inhibits CYP3A4.1 Esketamine and its major metabolites are unlikely to substantially inhibit other CYP isoenzymes or uridine diphosphate-glucuronosyltransferases (UGTs).1 Esketamine and its major metabolites do not induce CYP1A2 in vitro.1
Esketamine is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3 in vitro.1 The drug and its principal metabolites do not inhibit P-gp, BCRP, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE2K, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, or OAT3.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Inhibitors or Inducers of CYP2B6 or CYP3A
No clinically important pharmacokinetic interactions occurred when intranasal esketamine was administered concomitantly with rifampin (a strong CYP inducer), ticlopidine (a CYP2B6 inhibitor), or clarithromycin (a strong CYP3A inhibitor).1, 12
The manufacturer states that dosage adjustment of esketamine is not necessary in patients concurrently receiving inhibitors or inducers of CYP2B6 or CYP3A4.12
Concomitant administration of the strong CYP3A4 inhibitor clarithromycin (500 mg orally twice daily) with esketamine (84 mg intranasally) increased peak plasma concentrations and systemic exposure to esketamine by 11 and 4%, respectively; this pharmacokinetic interaction was not considered clinically important.1, 12
Concomitant administration of the strong CYP inducer rifampin (600 mg daily orally) with esketamine (56 mg intranasally) decreased peak plasma concentrations and systemic exposure to esketamine by 17 and 28%, respectively; this pharmacokinetic interaction was not considered clinically important.1, 12
Concomitant administration of the CYP2B6 inhibitor ticlopidine (250 mg orally twice daily) with esketamine (56 mg intranasally) increased peak plasma concentrations and systemic exposure to esketamine by 2 and 29%, respectively; this pharmacokinetic interaction was not considered clinically important.1, 12
Concomitant administration of the CYP2B6 substrate bupropion (150 mg orally daily) with esketamine (84 mg intranasally) did not impact the pharmacokinetics of bupropion.1, 12
Concomitant administration of the CYP3A4 substrate midazolam (6 mg orally) and esketamine (84 mg intranasally) decreased peak plasma midazolam concentrations and systemic exposure to midazolam by 11 and 16%, respectively; systemic exposure to 1-hydroxymidazolam was reduced by 14% but the peak plasma concentration was unaffected.1, 12 This pharmacokinetic interaction was not considered clinically important.1
Concomitant use of esketamine with other CNS depressants (e.g., alcohol, benzodiazepines, opiates) may increase the risk of CNS depression.1 Patients should be closely monitored for sedation if esketamine is used concurrently with other CNS depressants.1
Based on physiologically based pharmacokinetic modeling, multiple dosing of esketamine is not expected to affect systemic exposure to ethinyl estradiol in combination oral contraceptives.12
Intranasal Corticosteroids and Decongestants
The pharmacokinetics of esketamine were not substantially altered when an intranasal corticosteroid (mometasone furoate administered daily) or intranasal decongestant (oxymetazoline hydrochloride) was administered intranasally 1 hour prior to intranasal administration of esketamine.1, 12
The manufacturer states that esketamine dosage adjustment is not necessary in patients concurrently receiving intranasal corticosteroids or decongestants.12 However, patients who require a nasal corticosteroid or decongestant on an esketamine dosing day should administer these drugs at least 1 hour prior to intranasal esketamine.1, 12
Concomitant use of esketamine with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may result in increased blood pressure.1 Blood pressure should be closely monitored if esketamine is used concurrently with psychostimulants.1
Concomitant use of esketamine with monoamine oxidase (MAO) inhibitors may result in increased blood pressure.1 Blood pressure should be closely monitored if esketamine is used concurrently with MAO inhibitors.1
Esketamine is the S -enantiomer of racemic ketamine, which is a derivative of phencyclidine (PCP).1, 35 The drug is a nonselective, noncompetitive antagonist of the N -methyl-d-aspartate (NMDA) receptor, which is an inotropic glutamate receptor.1, 13, 35 Esketamine has a higher affinity for the NMDA receptor than the R -enantiomer of racemic ketamine.2 The precise mechanism of action of esketamine in major depressive disorder has not been fully elucidated;1, 13 however, the drug is thought to preferentially block NMDA receptors on inhibitory γ-aminobutyric acid (GABA)-ergic interneurons and transiently enhance the activity of glutamatergic neurons, leading to improved synaptic connectivity.13 The mechanism of antidepressant activity of esketamine is thought to be similar to that of ketamine and is not thought to directly involve serotonin, norepinephrine, or dopamine reuptake, nor is it believed to directly involve µ opiate receptor stimulation.13
Esketamine is rapidly absorbed following intranasal administration.1 The mean absolute bioavailability of the drug is approximately 48% and peak plasma concentrations occur in 20-40 minutes following the last nasal spray of a treatment session.1 The pharmacokinetics of esketamine increase in a less than dose-proportional manner over an intranasal dosage range of 28-84 mg; however, between 56-84 mg, the pharmacokinetics are approximately dose proportional.1 Interpatient variation in peak plasma concentration and AUC ranges from 27-66 and 18-45%, respectively.1 The intrapatient variation in peak plasma concentration and AUC is 15 and 10%, respectively.1 Esketamine is approximately 43-45% bound to plasma proteins.1 The drug distributes into the brain; the brain-to-plasma ratio of noresketamine (the principal active metabolite of esketamine) is 4-6 times lower than that of esketamine.1 Esketamine is metabolized principally by CYP2B6 and CYP3A4 and, to a lesser extent, by CYP2C9 and CYP2C19 to its principal active metabolite noresketamine.1 Noresketamine has demonstrated activity at the same NMDA receptor as its parent drug but with less affinity.1 Noresketamine also is metabolized via CYP-mediated pathways.1 Plasma esketamine and noresketamine concentrations decline in a biphasic manner, with a rapid initial phase (2-4 or 4 hours for esketamine or noresketamine, respectively) and a longer elimination phase (mean terminal half-life of 7-12 or 8 hours for esketamine or noresketamine, respectively).1 Following IV or oral administration of radiolabeled esketamine, metabolites were mainly recovered in the urine (over 78% of the dose) and, to a lesser extent, in feces (less than 2%).1 Less than 1% of the dose is excreted unchanged in urine.1 The pharmacokinetics of esketamine are not impacted by sex or total body weight (>39 to 170 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Esketamine is subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.1
Distribution of esketamine is restricted. Further information about the Spravato® REMS program, including a list of certified pharmacies, is available at [Web] or at 855-382-6022.1, 10
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Nasal | Solution | 14 mg (of esketamine) per metered spray (14 mg/0.1 mL) | Spravato® 56 mg Dose Kit (C-III; contains two 28-mg nasal spray devices) | |
Spravato® 84 mg Dose Kit (C-III; contains three 28-mg nasal spray devices) | Janssen |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions July 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Janssen Pharmaceuticals, Inc. Spravato® (esketamine hydrochloride) nasal spray prescribing information. Titusville, NJ; 2025 Jan.
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9. US National Institutes of Health. A study to evaluate the effects of a single-dose and repeat-administration of intranasal esketamine on on-road driving in participants with major depressive disorder (DriveSaFe2). NCT02919579. From ClinicalTrials.gov website. Accessed 2019 May 3. [Web]
10. Janssen Pharmaceuticals, Inc. Spravato® REMS Program Overview. Titusville, NJ; 2020 Aug. From Spravato REMS website. Accessed 2025 Apr 1. [Web]
11. Janssen Scientific Affairs, LLC. Spravato® (esketamine) use in elderly patients with treatment-resistant depression. From J&J Medical Connect website. Accessed 2025 Apr 1. [Web]
12. Janssen Scientific Affairs, LLC. Spravato® (esketamine) drug interactions - general. From J&J Medical Connect website. Accessed 2025 Apr 1. [Web]
13. Janssen Scientific Affairs, LLC. Spravato® (esketamine) mechanism of action. From J&J Medical Connect website. Accessed 2025 Apr 1. [Web]
14. Canuso CM, Singh JB, Fedgchin M et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry . 2018; 175:620-630. [PubMed 29656663]
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