AHFS Class:

• NMDA Antagonists 28:16.04.06

Generic Name(s):

• Esketamine

• Esketamine Hydrochloride

Esketamine hydrochloride, the S -enantiomer of racemic ketamine, is an N -methyl-d-aspartate (NMDA) receptor antagonist and an antidepressant.1,13,35

Treatment-resistant Depression

Esketamine hydrochloride is used intranasally in conjunction with an oral antidepressant for the treatment of treatment-resistant depression.1,2,3,4 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 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.1,2,3,4 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; 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 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.1,2 Scores on the MADRS range from 0 to 60; higher scores indicate more severe depression.1 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.1,3,4 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.1,3,4 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).1,3,4 All patients continued to receive an oral antidepressant throughout the study.1,3,4 Overall, 39 or 61% of patients who continued esketamine therapy received the 56- or 86-mg dose, respectively.1 Time to relapse of depressive symptoms in patients who had 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.1,3,4 Of these patients (i.e., those who had achieved stable remission) who 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 had achieved stable response and continued intranasal esketamine therapy compared with those who were switched to placebo.1,3,4 Of these patients (i.e., those who had achieved stable response) who 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 preliminary 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 However, larger controlled studies are needed to more thoroughly evaluate the efficacy and safety of esketamine in such patients.14 (See Uses: Treatment-resistant Depression and Suicidality, in Ketamine Hydrochloride 28:04.)

Other Uses

Esketamine is the S -enantiomer of racemic ketamine, which is used as an anesthetic agent.1,35,40 (See Description.) However, 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

General

Because esketamine nasal spray can cause increases in systolic and/or diastolic blood pressure, blood pressure should be monitored prior to intranasal administration, approximately 40 minutes after administration (which corresponds to peak plasma concentrations of the drug), and as clinically indicated thereafter until blood pressure values decline.1 If baseline blood pressure is elevated (i.e., systolic or diastolic blood pressure exceeding 140 or 90 mm Hg, respectively), the risks of short-term increases in blood pressure and the benefit of esketamine treatment in patients with treatment-resistant depression should be considered.1 Esketamine should not be administered in patients in whom an increase in blood pressure or intracranial pressure would constitute a serious risk.1 If blood pressure is decreasing and the patient appears clinically stable for at least 2 hours, the patient may be discharged at the end of the post-dose monitoring period; if not, patient monitoring should continue.1 (See Cautions: Contraindications and see also Increases in Blood Pressure under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Because some patients may experience nausea and vomiting after administration of esketamine nasal spray, patients should be advised to avoid eating food for at least 2 hours before administration and avoid drinking liquids for at least 30 minutes prior to administration.1

Prior to administration, patients should be instructed not to engage in potentially hazardous activities (e.g., driving a motor vehicle, operating machinery) until the next day after a restful sleep.1 (See Impaired Ability to Drive or Operate Machinery under Warnings/Precautions: Other Warnings and Precautions, in Cautions and see also Advice to Patients.)

If use of an intranasal corticosteroid or intranasal decongestant is required on the same day as treatment with esketamine nasal solution, they should be administered at least 1 hour prior to esketamine.1 (See Drug Interactions: Intranasally administered Corticosteroids and Decongestants.)

Patients receiving esketamine therapy should be monitored for possible worsening of depression or emergence of suicidality, especially at the beginning of therapy or during periods of dosage adjustments.1 (See Suicidality under Warnings/Precautions: Warnings, in Cautions.)

Restricted Distribution Program

Because of the risks of serious adverse outcomes from sedation, dissociation, abuse, and misuse (see Cautions), esketamine nasal spray is available only through a restricted distribution program (Spravato^® REMS).1,10 Healthcare settings and pharmacies must be certified with the program before they can dispense and supervise patient self-administration of esketamine nasal solution; patients must be enrolled in the program to receive treatment.1,10 Esketamine nasal solution must be administered under the direct observation of a healthcare provider in a certified healthcare setting.1,10 (See Dosage and Administration: Administration.) Further information about the Spravato^® REMS program, including a list of certified pharmacies, is available at [Web] or at 855-382-6022.1,10

Administration

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 healthcare provider for at least 2 hours and then assessed for clinical stability and readiness to be discharged from the healthcare facility.1 (See Postadministration Observation under Dosage and Administration: Administration.) Patients should not drive after the treatment session.1 (See Impaired Ability to Drive or Operate Machinery under Warnings/Precautions: Other Warnings and Precautions, in Cautions and see also Advice to Patients.)

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 prior to use.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

Used nasal spray devices should be properly disposed of in accordance with the facility's procedures and federal, state, and local regulations for controlled substance disposal.1 (See Abuse and Misuse under Warnings/Precautions: Warnings, in Cautions.)

Post-administration Observation

During and following administration of esketamine nasal spray at each treatment session, patients must be observed (i.e., for sedation, dissociation, and increased blood pressure).1 Patient observation should continue for at least 2 hours until the patient can safely leave the healthcare setting.1 (See Cautions.)

Dosage

Dosage of esketamine hydrochloride is expressed in terms of esketamine.1

Treatment-resistant Depression

For the treatment of treatment-resistant depression in combination with an oral antidepressant in adults, the recommended intranasal dosage of esketamine during the induction phase (weeks 1-4) is 56 mg initially on day 1, followed by 56- or 84-mg doses 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 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

Special Populations

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 The drug is not recommended for use in patients with severe hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer makes no specific dosage recommendations for geriatric patients or patients with renal impairment.1,5 (See Specific Populations under Cautions: Warnings/Precautions.)

Contraindications

Esketamine in contraindicated in patients in whom an increase in blood pressure or intracranial pressure poses a serious risk such as in patients with aneurysmal vascular disease (including that affecting the thoracic and abdominal aorta and intracranial and peripheral arterial vessels) or arteriovenous malformation and those with a history of intracerebral hemorrhage.1 (See Increases in Blood Pressure under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Esketamine is also contraindicated in patients who are hypersensitive to esketamine, ketamine, or any excipient in the formulation.1

Warnings/Precautions

Warnings

Sedation

Esketamine can cause dose-related sedation and, rarely, loss of consciousness.1 Sedation (defined as any decrease from baseline in the Modified Observer's Alertness/Sedation scale [MOAA/s]) was reported in 49-61% of patients and loss of consciousness (MOAA/s score of 0) was reported in 0.3% 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 (See Post-administration Observation under Dosage and Administration: Administration.)

Patients concomitantly receiving esketamine and CNS depressants should be closely monitored.1 (See Drug Interactions: CNS Depressants.)

Dissociation

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 Dissociative (dissociation was defined as a Clinician-administered Dissociative States Scale [CADSS] total score of 4 or greater) or perceptual changes were reported in 61-75% 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 benefit outweighs 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 (See Post-administration Observation under Dosage and Administration: Administration.)

Abuse and Misuse

Esketamine is a schedule III (C-III) drug and has the potential to be abused or misused.1 Esketamine is the S -enantiomer of racemic ketamine, which is also a C-III drug with known abuse potential.1,40,41 For further information on abuse and misuse of ketamine, see Uses in Ketamine Hydrochloride 28:04.

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

Suicidality

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 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 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Other Warnings and Precautions

Increases in Blood Pressure

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 7-9 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 8-17% of patients receiving esketamine compared with 1-3% 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 (See Drug Interactions.)

Cognitive Impairment

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 (See Sedation under Warnings/Precautions: Warnings, in Cautions.)

Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse .1 Although no adverse cognitive effects of esketamine nasal spray were observed in a 1-year, open-label safety study, the long-term cognitive effects of the drug have not been evaluated beyond 1 year.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

Following treatment with esketamine, patients 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 their transportation home following each esketamine treatment session.1 (See Advice to Patients.)

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

For further information on the urinary effects of ketamine, see Cautions: Genitourinary Effects in Ketamine Hydrochloride 28:04.

Embryofetal Toxicity

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

For further information on the effects of ketamine during pregnancy, see Neurodevelopmental and Cognitive Effects under Cautions: Pediatric Precautions, in Ketamine Hydrochloride 28:04.

Esketamine is not recommended for use during pregnancy.1 The manufacturer states that women of reproductive potential should consider pregnancy planning and contraception during esketamine therapy.1 If a woman becomes pregnant while receiving esketamine therapy, the drug should be discontinued and the patient apprised of the potential risk to the fetus.1

Specific Populations

Pregnancy

Data on esketamine use in pregnant women are insufficient to inform a drug-associated risk.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 (See Embryofetal Toxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

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

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, clinicians may consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at [Web]).15

Lactation

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

Because of the potential for neurotoxicity in nursing infants (see Embryofetal Toxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions), the manufacturer states that breast-feeding during esketamine therapy is not recommended.1

Pediatric Use

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 (See Suicidality under Warnings/Precautions: Warnings, in Cautions.)

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 (See Embryofetal Toxicity under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

For further information on the effects of ketamine during pregnancy, see Pediatric Neurotoxicity under Cautions, in Ketamine Hydrochloride 28:04.

Geriatric Use

In phase 3 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 2% 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

Hepatic Impairment

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

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

Renal Impairment

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

Common Adverse Effects

Adverse effects reported in at least 2% of patients with treatment-resistant depression receiving intranasal esketamine and an oral antidepressant and at a higher incidence than reported with placebo and an oral antidepressant in controlled trials include dissociation (including derealization and depersonalization) and perceptual changes (including distortion of time and space and illusions),1,2 dizziness,1,2 nausea,1,2 sedation,1 vertigo,1,2 headache,1,2 dysgeusia,1,2 hypoesthesia,1,2 anxiety,1,2 lethargy,1 increased blood pressure,1,2 vomiting,1,2 insomnia,1,2 diarrhea,1 nasal discomfort,1,2 throat irritation,1,2 dry mouth,1,2 feeling drunk,1,2 dysarthria,1 euphoric mood,1 hyperhidrosis,1 constipation,1 abnormal feeling,1 mental impairment,1 tremor,1 pollakiuria,1 oropharyngeal pain,1 and tachycardia.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 potent CYP inducer), ticlopidine (a CYP2B6 inhibitor), or clarithromycin (a potent 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

Clarithromycin

Concomitant administration of the potent 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

Rifampin

Concomitant administration of the potent 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

Ticlopidine

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

Substrates of CYP2B6 or CYP3A

Esketamine did not have any clinically important effect on the pharmacokinetics of oral bupropion (a CYP2B6 substrate) and its metabolite hydroxybupropion or oral midazolam (a CYP3A substrate).1,12

CNS Depressants

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

Hormonal Contraceptives

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

Intranasally administered 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 nasal decongestant on an esketamine dosing day should administer these drugs at least 1 hour prior to intranasal esketamine.1,12

Psychostimulants

Concomitant use of esketamine with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may result in increased blood pressure.1 Blood pressure should therefore be closely monitored if esketamine is used concurrently with psychostimulants.1 (See Increases in Blood Pressure under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Monoamine Oxidase Inhibitors

Concomitant use of esketamine with monoamine oxidase (MAO) inhibitors may result in increased blood pressure.1 Blood pressure should therefore be closely monitored if esketamine is used concurrently with MAO inhibitors.1 (See Increases in Blood Pressure under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Description

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

For detailed information on the pharmacologic effects of ketamine, see Description in Ketamine Hydrochloride 28:04.

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 area under the concentration-time curve (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

Advice to Patients

Importance of advising patients to read the manufacturer's medication guide and instructions for use.1

Esketamine nasal spray is only available through the Spravato^® REMS program.1,10 Importance of informing patients that they must be enrolled in the REMS program prior to drug administration.1,10 Importance of also informing patients that esketamine treatment must be administered under the direct supervision of a healthcare provider and that patients must be monitored by a healthcare provider for at least 2 hours following intranasal administration of the drug.1,10

Risk of sedation, dissociative symptoms, disturbances in perception, dizziness, vertigo, and/or anxiety.1 Importance of advising patients to notify a healthcare provider immediately if they feel like they cannot stay awake or feel like they may lose consciousness.1 Importance of informing patients that they will be monitored by a healthcare provider until these potential adverse effects resolve.1

Importance of advising patients that esketamine is a federally controlled substance because of its potential for abuse, misuse, and dependence.1

Risk of suicidal thoughts and behaviors (suicidality); importance of patients and caregivers being alert to emergence of suicidality, especially early during therapy or during periods of dosage adjustments.1 (See Suicidality under Warnings/Precautions: Warnings, in Cautions.)

Risk of blood pressure increases.1 Importance of informing patients that they may require observation by a healthcare provider until the blood pressure elevation resolves.1 Importance of advising patients to notify a healthcare provider immediately if they experience chest pain, shortness of breath, sudden severe headache, changes in vision, or seizures after intranasal administration of esketamine.1

Nausea and vomiting may occur in some patients.1 Importance of advising patients not to eat for at least 2 hours before administering esketamine nasal spray and to avoid drinking liquids for at least 30 minutes before administering the drug.1

Importance of informing patients that esketamine may impair their ability to drive or operate machinery.1 Following a treatment session, importance of advising patients not to drive, operate machinery, or engage in potentially hazardous activities requiring full mental alertness and motor coordination until the next day after a restful sleep.1 Patients should be advised that they will need someone to drive them home after each treatment session.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of advising women to avoid breast-feeding during esketamine therapy.1 Importance of informing patients about the potential fetal risk and informing women who become pregnant while taking esketamine about the existence of the national pregnancy registry for antidepressants.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription, OTC, and recreational drugs and dietary or herbal supplements (see Drug Interactions), as well as any concomitant or past illnesses (e.g., cardiovascular or cerebrovascular disease, hepatic disease, psychosis, substance abuse or dependence).1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

1. Janssen Pharmaceuticals, Inc. Spravato^® (esketamine hydrochloride) nasal spray prescribing information. Titusville, NJ; 2019 May.

2. Popova V, Daly EJ, Trivedi M et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry . 2019; :appiajp201919020172. [PubMed 31109201]

3. Daly EJ, Trivedi MH, Janik A et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry . 2019; [PubMed 31166571]

4. Janssen Scientific Affairs, LLC. Spravato^® (esketamine) clinical overview in treatment-resistant depression. From JanssenMD website. Accessed 29 May 2019. [Web]

5. Janssen Scientific Affairs, LLC. Spravato^® (esketamine) use in patients with renal impairment. From JanssenMD website. Accessed 9 May 2019. [Web]

6. Janssen Scientific Affairs, LLC. Spravato^® (esketamine) use in patients with hepatic impairment. From JanssenMD website. Accessed 9 May 2019.

7. Morrison RL, Fedgchin M, Singh J et al. Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology (Berl) . 2018; 235:1107-1119. [PubMed 29392371]

8. van de Loo AJAE, Bervoets AC, Mooren L et al. The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study. Psychopharmacology (Berl) . 2017; 234:3175-3183. [PubMed 28755104]

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 fact sheet. Titusville, NJ; 2019 Mar. From Spravato REMS website. Accessed 2019 Apr 30. [Web]

11. Janssen Scientific Affairs, LLC. Spravato^® (esketamine) use in elderly patients with treatment-resistant depression. From JanssenMD website. Accessed 9 May 2019. [Web]

12. Janssen Scientific Affairs, LLC. Spravato^® (esketamine) drug interactions - general. From JanssenMD website. Accessed 9 May 2019. [Web]

13. Janssen Scientific Affairs, LLC. Spravato^® (esketamine) mechanism of action. From JanssenMD website. Accessed 9 May 2019. [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]

15. Yonkers KA, Wisner KL, Stewart DE et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol . 2009; 114:703-713. [PubMed 19701065]

35. Zanos P, Moaddel R, Morris PJ et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev . 2018; 70:621-660. [PubMed 29945898]

40. Par Pharmaceutical, Inc. Ketalar^® (ketamine hydrochloride) injection prescribing information. Chestnut Ridge, NY; 2018 Jul.

41. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of ketamine into schedule III. 21 CFR Part 1308. Final Rule. DEA-183F] Fed Regist. 1999; 64:37673-5. [Web]

301. Feifel D, Malcolm B, Boggie D et al. Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. J Affect Dis . 2017; 221:283-8. [PubMed 28666206]

307. Murrough JW, Perez AM, Pillemer S et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry . 2013; 74:250-6. [PubMed 22840761]

309. Hu YD, Xiang YT, Fang JX et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med . 2016; 46:623-35. [PubMed 26478208]

315. Shiroma PR, Johns B, Kuskowski M et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord . 2014; 155:123-9. [PubMed 24268616]