Spravato

Antidepressant Augmentation Agents

Inhalation Administration Intranasal Administration

General Administration Instructions:
For nasal use only.
Each treatment must be administered under the direct supervision of a health care provider. Because of the risks of dissociation, the patient must be monitored by a health care provider during administration and for at least 2 hours after each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the health care setting.
Due to the potential for drug-induced nausea and vomiting, advise patients to avoid food for at least 2 hours before administration and avoid liquids at least 30 minutes before administration.
Patients requiring a nasal corticosteroid or nasal decongestant on dosing day should administer these medicines at least 1 hour before receiving esketamine.
Before each treatment, instruct patients not to engage in potentially hazardous activities (e.g., driving, operating heavy machinery) until the next day after the treatment and after a restful sleep.
Assess blood pressure before dosing. If baseline blood pressure is elevated (e.g., systolic BP more than 140 mmHg or diastolic BP more than 90 mmHg), consider risk of short-term increase in blood pressure versus benefit of esketamine. Do not administer esketamine if an increase in blood pressure or intracranial pressure poses a serious risk.
Reassess blood pressure about 40 minutes after dosing and subsequently as clinically indicated. 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, continue to monitor.
Missed doses: If a patient misses a treatment session, provided there is no worsening of their depressive symptoms, continue the current dosing schedule. If a patient misses treatment sessions and has worsening of depression symptoms, consider resuming treatment at the prior dosing schedule (e.g., if doses missed during weekly dosing, revert to twice weekly dosing).[63989]
 
Nasal Spray Administration:
Each device contains 2 sprays (1 spray for each nostril), for a total of 28 mg of esketamine. Use 2 devices for a 56 mg dose and 3 devices for an 84 mg dose with a 5-minute rest between use of each device.
Step 1: Instruct patient to blow nose before the first device use only. Confirm the required number of devices (56 mg = 2 devices; 84 mg = 3 devices).
Step 2: Check expiration date. Peel blister and remove device. To prevent loss of medication, do not prime the device before use. Ensure that the indicator on the device shows 2 green dots. Give device to patient.
Step 3: Instruct patient to hold device with thumb gently supporting but not pressing the plunger as shown in the product labeling. The patient should recline head at about 45 degrees during administration to keep medication in nose.
Step 4: Instruct patient as follows: insert tip straight into the first nostril; the nose rest should touch the skin between the nostrils; close the opposite nostril; breathe in through nose while pushing plunger all the way up until it stops; sniff gently after spraying to keep medication inside nose; switch hands to insert tip into the second nostril; repeat steps to deliver second spray.
Step 5: After administration is complete, take the device from the patient. Check that indicator on device shows no green dots. If green dot remains, have patient spray again into the second nostril. Instruct patient to rest comfortably (preferably semi-reclined) for 5 minutes after each device. If liquid drips out, dab nose with a tissue. DO NOT blow nose.
If a second device is required, ensure a 5-minute waiting period before using the second device to allow medication from the first device to be absorbed.
Disposal: Dispose of the used device per facility procedures and applicable local, state, or federal regulations for a controlled substance.
Refer to the 'Administration Instructions' section of the product labeling for detailed visual aids which accompany the written instructions.[63989]

Severe

suicidal ideation / Delayed / 0.5-0.5
hypertensive crisis / Early / Incidence not known

Moderate

dissociation / Early / 41.0-48.0
hypertension / Early / 1.0-17.0
constipation / Delayed / 3.0-10.0
euphoria / Early / 4.0-7.0
dysarthria / Delayed / 4.0-4.0
sinus tachycardia / Rapid / 2.0-4.0
dysphoria / Early / 2.0-2.0
confusion / Early / 2.0-2.0
loss of consciousness / Rapid / 0.3-0.4
impaired cognition / Early / Incidence not known
memory impairment / Delayed / Incidence not known
myasthenia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
depression / Delayed / Incidence not known
physiological dependence / Delayed / Incidence not known
psychological dependence / Delayed / Incidence not known
tolerance / Delayed / Incidence not known

Mild

drowsiness / Early / 23.0-61.0
dizziness / Early / 29.0-45.0
nausea / Early / 27.0-28.0
vertigo / Early / 6.0-23.0
dysgeusia / Early / 19.0-20.0
headache / Early / 20.0-20.0
hypoesthesia / Delayed / 13.0-18.0
anxiety / Delayed / 13.0-15.0
lethargy / Early / 4.0-11.0
vomiting / Early / 9.0-11.0
insomnia / Early / 8.0-8.0
diarrhea / Early / 7.0-7.0
throat irritation / Early / 4.0-7.0
xerostomia / Early / 4.0-5.0
hyperhidrosis / Delayed / 4.0-5.0
tremor / Early / 3.0-3.0
increased urinary frequency / Early / 2.0-3.0
dental pain / Delayed / 2.0-2.0
myalgia / Early / 2.0-2.0
psychomotor impairment / Early / Incidence not known
nasal dryness / Early / Incidence not known

Requires a specialized care setting

Esketamine is available only through the Spravato risk Evaluation and Mitigation Strategy (Spravato REMS) program because of the risks of serious adverse outcomes from sedation, dissociation, and potential for abuse. Esketamine administration requires a specialized care setting (i.e., healthcare settings must be certified in the REMS program). Additional requirements include the following: patients treated in outpatient settings (e.g., medical offices and clinics) must be enrolled in the Spravato REMS program, pharmacies must be certified in the REMS and must only dispense esketamine to healthcare settings that are certified in the program, esketamine is administered by patients under the direct observation of a healthcare provider, and patients must be monitored by a healthcare provider for at least 2 hours after esketamine administration. Following the post-treatment 2-hour observation period, an assessment should be performed to determine if the patient is clinically stable and ready to leave the healthcare setting. For further information, including a list of certified pharmacies, visit www.SPRAVATOrems.com or call 1-855-382-6022.

Children, suicidal ideation

The safety and effectiveness of esketamine nasal spray in has not been established in pediatric patients less than 18 years of age. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in children, adolescent, and young adult patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen, including discontinuation of esketamine and/or the concomitant oral antidepressant, may be necessary in patients with emerging suicidality or worsening depression.[63989]

Dissociation, psychosis, schizophrenia

During clinical trial evaluation of nasal esketamine, dissociative symptoms (e.g., derealization, depersonalization) and perceptual changes (e.g., distortion of time and space, illusions) were commonly reported psychological effects. Esketamine may also cause dysphoria, disorientation (confusion), and hallucinations. Because of the risks of dissociation, patients must be monitored by a healthcare provider for at least 2 hours after each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting. Due to the potential for esketamine to induce dissociative effects and psychotic symptoms, patients with psychosis (e.g., schizophrenia) should be carefully evaluated before receiving esketamine. Treatment should only be initiated if the benefit outweighs the risks in these patient populations.[63989]

Alcoholism, substance abuse

Esketamine is a controlled substance and has the potential for abuse, misuse, diversion, psychological dependence, and physiological dependence. Assess the risk of abuse or misuse prior to prescribing and monitor all patients for signs of abuse while on therapy. Esketamine may produce a variety of symptoms including euphoria, disorientation, flashbacks, hallucinations, feelings of floating, detachment, and being "spaced out". Use careful consideration prior to treatment with esketamine in patients with a known history of substance abuse, including alcoholism. If esketamine therapy is required in patients with a history of substance abuse or dependence, closely monitor for signs of abuse or dependence. Physical dependence has been reported with prolonged use of ketamine, a racemic compound containing esketamine. Reported withdrawal symptoms of ketamine include craving, fatigue, poor appetite, and anxiety. During clinical trial evaluation of esketamine, there were no withdrawal symptoms captured up to 4 weeks after cessation of treatment; however, patients should be monitored for signs and symptoms of physical dependence upon discontinuation of the drug. Tolerance has been reported with prolonged use of ketamine; a similar effect is possible during prolonged use of esketamine.

CNS depression, coadministration with other CNS depressants, driving or operating machinery, loss of consciousness

Esketamine commonly causes sedation and CNS depression, which may be delayed or prolonged, and can impair attention, judgment, thinking, reaction speed, and motor skills. Loss of consciousness occurred infrequently during clinical trial evaluation. Short-term cognitive impairment has occurred following administration of a single therapeutic dose of nasal esketamine, and long-term cognitive and memory impairment has occurred after repeated misuse or abuse of ketamine, a racemic mixture containing esketamine. No adverse effects of esketamine nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, evaluations of cognitive effects beyond one year have not been conducted. Patients should be instructed to avoid driving or operating machinery or engaging in other potentially hazardous activities requiring complete mental alertness and motor coordination until the day following esketamine administration after a restful sleep. Arrangements for transportation home following treatment with esketamine nasal spray will need to be made by the patient. In cases of coadministration with other CNS depressants, patients should be closely monitored.[63989]

Spravato

Rx, schedule III

S-enantiomer of racemic ketamine; given as a nasal spray; patients must enroll, and prescribers, health care setting, pharmacies are certified in a monitoring registry
Used for treatment-resistant depression in adults or depressive symptoms in adults with major depression with acute suicidal ideation or behavior
Must be administered in a health care setting; patients monitored for at least 2 hours and must not drive on the day of treatment; potential for abuse; may cause psychotic episodes

For the treatment of depression in conjunction with an oral antidepressant. For the treatment of treatment-resistant depression. Nasal dosage Adults

56 mg intranasally on day 1, then 56 or 84 mg intranasally twice weekly for weeks 1 through 4, then 56 or 84 mg intranasally once weekly for weeks 5 through 8, and then 56 or 84 mg intranasally once weekly or every 2 weeks; individualize dosing frequency to the least frequent dosing to maintain remission. The effectiveness of this drug in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after the initial dose.[63989]

For the treatment of depressive symptoms in persons with major depressive disorder with acute suicidal ideation or behavior. Nasal dosage Adults

84 mg intranasally twice weekly for 4 weeks, initially. May reduce dose to 56 mg intranasally twice weekly as tolerated. Evaluate evidence of therapeutic benefit after 4 weeks to determine need for continued therapy. Use beyond 4 weeks has not been formally evaluated in these patients. The effectiveness of this drug in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after the initial dose.

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): No dosage adjustments are required.
Severe hepatic impairment (Child-Pugh class C): Use is not recommended because the drug has not been studied in this population.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
 
Intermittent hemodialysis
There is no clinical experience with esketamine nasal spray in patients on dialysis.

Acetaminophen; Aspirin, ASA; Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Acetaminophen; Caffeine; Pyrilamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Acetaminophen; Chlorpheniramine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Closely monitor patients receiving esketamine and doxylamine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Diphenhydramine: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Alfentanil: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Alprazolam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Amitriptyline: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Amobarbital: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Amoxapine: (Major) Closely monitor patients receiving esketamine and amoxapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Amphetamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Amphetamine; Dextroamphetamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Amphetamines: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Apomorphine: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as apomorphine, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Aripiprazole: (Moderate) Closely monitor patients receiving esketamine and aripiprazole for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Armodafinil: (Major) Closely monitor blood pressure during concomitant use of esketamine and armodafinil. Coadministration of psychostimulants, such as armodafinil, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Asenapine: (Moderate) Closely monitor patients receiving esketamine and asenapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Aspirin, ASA; Butalbital; Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Aspirin, ASA; Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Aspirin, ASA; Carisoprodol: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep. (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Atropine: (Moderate) Closely monitor patients receiving esketamine and atropine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Atropine; Difenoxin: (Moderate) Closely monitor patients receiving esketamine and atropine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Azelastine: (Major) Closely monitor patients receiving esketamine and azelastine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Azelastine; Fluticasone: (Major) Closely monitor patients receiving esketamine and azelastine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Baclofen: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Barbiturates: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Belladonna; Opium: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Benzodiazepines: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Benzphetamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Brexpiprazole: (Major) Closely monitor patients receiving esketamine and brexpiprazole for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Brompheniramine: (Moderate) Closely monitor patients receiving esketamine and brompheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and brompheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Brompheniramine; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and brompheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Brompheniramine; Pseudoephedrine: (Moderate) Closely monitor patients receiving esketamine and brompheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Closely monitor patients receiving esketamine and brompheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Buprenorphine: (Major) Closely monitor patients receiving esketamine and buprenorphine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Buprenorphine; Naloxone: (Major) Closely monitor patients receiving esketamine and buprenorphine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Butabarbital: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Butalbital; Acetaminophen: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Butalbital; Acetaminophen; Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Butorphanol: (Major) Closely monitor patients receiving esketamine and butorphanol for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure. (Moderate) Patients who regularly consume caffeine-containing foods or beverages may need to limit caffeine intake during esketamine treatment. Blood pressure should be closely monitored in patients treated with esketamine who regularly consume caffeine. Esketamine can increase blood pressure at all recommended doses and caffeine is a stimulant that may cause additive effects on blood pressure when combined with esketamine.
Caffeine; Sodium Benzoate: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Closely monitor patients receiving esketamine and sodium oxybate for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Cannabidiol: (Moderate) Closely monitor patients receiving esketamine and cannabidiol for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Capsaicin; Metaxalone: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Carbidopa; Levodopa: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Carbidopa; Levodopa; Entacapone: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as entacapone, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Cariprazine: (Moderate) Closely monitor patients receiving esketamine and cariprazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Carisoprodol: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Celecoxib; Tramadol: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Cetirizine: (Moderate) Closely monitor patients receiving esketamine and cetirizine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Cetirizine; Pseudoephedrine: (Moderate) Closely monitor patients receiving esketamine and cetirizine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlordiazepoxide: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlordiazepoxide; Amitriptyline: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep. (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlordiazepoxide; Clidinium: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Dextromethorphan: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpheniramine; Pseudoephedrine: (Moderate) Closely monitor patients receiving esketamine and chlorpheniramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorpromazine: (Major) Closely monitor patients receiving esketamine and chlorpromazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorthalidone; Clonidine: (Major) Closely monitor patients receiving esketamine and clonidine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Chlorzoxazone: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Clemastine: (Moderate) Closely monitor patients receiving esketamine and clemastine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Clomipramine: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Clonazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Clonidine: (Major) Closely monitor patients receiving esketamine and clonidine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Clorazepate: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Clozapine: (Major) Closely monitor patients receiving esketamine and clozapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Codeine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Phenylephrine; Promethazine: (Major) Closely monitor patients receiving esketamine and promethazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Codeine; Promethazine: (Major) Closely monitor patients receiving esketamine and promethazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Cyclobenzaprine: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Cyproheptadine: (Moderate) Closely monitor patients receiving esketamine and cyproheptadine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Dantrolene: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Desipramine: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Deutetrabenazine: (Moderate) Closely monitor patients receiving esketamine and deutetrabenazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Dexmedetomidine: (Moderate) Closely monitor patients receiving esketamine and dexmedetomidine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Dextroamphetamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diethylpropion: (Major) Closely monitor blood pressure during concomitant use of esketamine and diethylpropion. Coadministration of psychostimulants, such as diethylpropion, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Dimenhydrinate: (Moderate) Closely monitor patients receiving esketamine and dimenhydrinate for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diphenhydramine: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diphenhydramine; Ibuprofen: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diphenhydramine; Naproxen: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diphenhydramine; Phenylephrine: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Diphenoxylate; Atropine: (Moderate) Closely monitor patients receiving esketamine and atropine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Doxepin: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Doxylamine: (Moderate) Closely monitor patients receiving esketamine and doxylamine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Doxylamine; Pyridoxine: (Moderate) Closely monitor patients receiving esketamine and doxylamine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Droperidol: (Major) Closely monitor patients receiving esketamine and droperidol for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day.
Entacapone: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as entacapone, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Ergotamine; Caffeine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Estazolam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Eszopiclone: (Major) Use of eszopiclone during treatment with esketamine may increase sedation and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Instruct patients to contact their provider immediately if these symptoms or behaviors occur and not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Major) It is advisable to avoid alcohol during treatment with esketamine. Concomitant use of alcohol and esketamine may enhance the sedative effects of esketamine. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Etomidate: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Fentanyl: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Flibanserin: (Moderate) Closely monitor patients receiving esketamine and flibanserin for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Fluphenazine: (Moderate) Closely monitor patients receiving esketamine and fluphenazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep after a restful sleep.
Flurazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Gabapentin: (Moderate) Closely monitor patients receiving esketamine and gabapentin for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
General anesthetics: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Guanfacine: (Moderate) Closely monitor patients receiving esketamine and guanfacine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Haloperidol: (Major) Closely monitor patients receiving esketamine and haloperidol for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Closely monitor patients receiving esketamine and methyldopa for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Hydrocodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Hydromorphone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Hydroxyzine: (Major) Closely monitor patients receiving esketamine and hydroxyzine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Iloperidone: (Moderate) Closely monitor patients receiving esketamine and iloperidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Imipramine: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Isocarboxazid: (Major) Closely monitor patients receiving esketamine and MAOIs for sedation and increased blood pressure, including the possibility of hypertensive crisis. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Isoflurane: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Ketamine: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Levocetirizine: (Moderate) Closely monitor patients receiving esketamine and cetirizine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Levodopa: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events ma

y occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Levorphanol: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Lisdexamfetamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Lofexidine: (Moderate) Closely monitor patients receiving esketamine and lofexidine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Lorazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Loxapine: (Moderate) Closely monitor patients receiving esketamine and loxapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Lurasidone: (Moderate) Closely monitor patients receiving esketamine and lurasidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Maprotiline: (Moderate) Closely monitor patients receiving esketamine and maprotiline for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Meclizine: (Moderate) Closely monitor patients receiving esketamine and meclizine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Melatonin: (Moderate) Closely monitor patients receiving esketamine and melatonin for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Meperidine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Meprobamate: (Moderate) Closely monitor patients receiving esketamine and meprobamate for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Metaxalone: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Methadone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Methamphetamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Methocarbamol: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Methohexital: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Methyldopa: (Moderate) Closely monitor patients receiving esketamine and methyldopa for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Methylphenidate Derivatives: (Major) Closely monitor blood pressure during concomitant use of esketamine and methylphenidate or its derivatives. Coadministration of psychostimulants, such as methylphenidates, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Metoclopramide: (Moderate) Closely monitor patients receiving esketamine and metoclopramide for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Midazolam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Mirtazapine: (Major) Closely monitor patients receiving esketamine and mirtazapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Modafinil: (Major) Closely monitor blood pressure during concomitant use of esketamine and modafinil. Coadministration of psychostimulants, such as modafinil, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
Molindone: (Major) Closely monitor patients receiving esketamine and molindone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Monoamine oxidase inhibitors: (Major) Closely monitor patients receiving esketamine and MAOIs for sedation and increased blood pressure, including the possibility of hypertensive crisis. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Morphine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Nalbuphine: (Major) Closely monitor patients receiving esketamine and nalbuphine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Nefazodone: (Major) Closely monitor patients receiving esketamine and nefazodone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Nortriptyline: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Olanzapine: (Major) Closely monitor patients receiving esketamine and olanzapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Olanzapine; Fluoxetine: (Major) Closely monitor patients receiving esketamine and olanzapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Olanzapine; Samidorphan: (Major) Closely monitor patients receiving esketamine and olanzapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Oliceridine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Opiate Agonists: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Orphenadrine: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Oxazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Oxycodone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Oxymorphone: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Paliperidone: (Moderate) Closely monitor patients receiving esketamine and paliperidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Pentazocine: (Major) Closely monitor patients receiving esketamine and pentazocine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Pentazocine; Naloxone: (Major) Closely monitor patients receiving esketamine and pentazocine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Pentobarbital: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Perampanel: (Moderate) Closely monitor patients receiving esketamine and perampanel for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Perphenazine: (Moderate) Closely monitor patients receiving esketamine and perphenazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Perphenazine; Amitriptyline: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep. (Moderate) Closely monitor patients receiving esketamine and perphenazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Phendimetrazine: (Major) Closely monitor blood pressure during concomitant use of esketamine and phendimetrazine. Coadministration of psychostimulants, such as phendimetrazine, with esketamine may increase blood pressure.
Phenelzine: (Major) Closely monitor patients receiving esketamine and MAOIs for sedation and increased blood pressure, including the possibility of hypertensive crisis. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Phenobarbital: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Moderate) Closely monitor patients receiving esketamine and atropine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Moderate) Closely monitor patients receiving esketamine and scopolamine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Phentermine: (Major) Closely monitor blood pressure during concomitant use of esketamine and phentermine. Coadministration of psychostimulants, such as phentermine, with esketamine may increase blood pressure.
Phentermine; Topiramate: (Major) Closely monitor blood pressure during concomitant use of esketamine and phentermine. Coadministration of psychostimulants, such as phentermine, with esketamine may increase blood pressure.
Pimavanserin: (Moderate) Closely monitor patients receiving esketamine and pimavanserin for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Pimozide: (Major) Closely monitor patients receiving esketamine and pimozide for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Pramipexole: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as pramipexole, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Pregabalin: (Moderate) Closely monitor patients receiving esketamine and pregabalin for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Primidone: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Prochlorperazine: (Moderate) Closely monitor patients receiving esketamine and prochlorperazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Promethazine: (Major) Closely monitor patients receiving esketamine and promethazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Promethazine; Dextromethorphan: (Major) Closely monitor patients receiving esketamine and promethazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Promethazine; Phenylephrine: (Major) Closely monitor patients receiving esketamine and promethazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Propofol: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Protriptyline: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Quazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Quetiapine: (Major) Closely monitor patients receiving esketamine and quetiapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Ramelteon: (Moderate) Closely monitor patients receiving esketamine and ramelteon for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Rasagiline: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as rasagiline, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Remifentanil: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Remimazolam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Risperidone: (Major) Closely monitor patients receiving esketamine and risperidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Ropinirole: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as ropinirole, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Rotigotine: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as rotigotine, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Safinamide: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as safinamide, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Scopolamine: (Moderate) Closely monitor patients receiving esketamine and scopolamine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Secobarbital: (Major) Closely monitor patients receiving esketamine and barbiturates for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Selegiline: (Moderate) Closely monitor patients receiving esketamine and selegiline for sedation and increased blood pressure, including the possibility of hypertensive crisis.
Sevoflurane: (Major) Although CNS depression is a desired effect of general anesthetics, patients also receiving esketamine should be closely monitored for additive effects that may prolong recovery after administration of a general anesthetic. If possible, avoid scheduling a treatment session with esketamine on the same day that general anesthesia is required. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Skeletal Muscle Relaxants: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Sodium Oxybate: (Major) Closely monitor patients receiving esketamine and sodium oxybate for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and esketamine. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
Stiripentol: (Moderate) Closely monitor patients receiving esketamine and stiripentol for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Sufentanil: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Suvorexant: (Moderate) Closely monitor patients receiving esketamine and suvorexant for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Tapentadol: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Tasimelteon: (Moderate) Closely monitor patients receiving esketamine and tasimelteon for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Temazepam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Tetrabenazine: (Moderate) Closely monitor patients receiving esketamine and tetrabenazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Thalidomide: (Major) Closely monitor patients receiving esketamine and thalidomide for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Thioridazine: (Major) Closely monitor patients receiving esketamine and thioridazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Thiothixene: (Moderate) Closely monitor patients receiving esketamine and thiothixene for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Tizanidine: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Tolcapone: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as tolcapone, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
Tramadol: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Tramadol; Acetaminophen: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
Tranylcypromine: (Major) Closely monitor patients receiving esketamine and MAOIs for sedation and increased blood pressure, including the possibility of hypertensive crisis. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Trazodone: (Major) Closely monitor patients receiving esketamine and trazodone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Triazolam: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Tricyclic antidepressants: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Trifluoperazine: (Moderate) Closely monitor patients receiving esketamine and trifluoperazine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Trimipramine: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
Valerian, Valeriana officinalis: (Moderate) Closely monitor patients receiving esketamine and valerian for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Valproic Acid, Divalproex Sodium: (Moderate) Closely monitor patients receiving esketamine and valproic acid for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Zaleplon: (Major) Use of zaleplon during treatment with esketamine may increase sedation and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Instruct patients to contact their provider immediately if these symptoms or behaviors occur and not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Ziprasidone: (Moderate) Closely monitor patients receiving esketamine and ziprasidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Zolpidem: (Major) Use of zolpidem during treatment with esketamine may increase sedation and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Instruct patients to contact their provider immediately if these symptoms or behaviors occur and not to drive or engage in other activities requiring alertness until the next day after a restful sleep.

Esketamine/SPRAVATO Nasal Spray: 28mg

Adults

84 mg intranasally twice per week during the induction phase; 84 mg intranasally once per week during the maintenance phase.

Geriatric

84 mg intranasally twice per week during the induction phase; 84 mg intranasally once per week during the maintenance phase.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Use not indicated.

Esketamine non-selectively blocks the N-methyl-D-aspartate (NMDA) receptor, which is an ionotropic glutamate receptor. Esketamine is the S-enantiomer of ketamine, which is primarily used for its anesthetic properties. The mechanism by which esketamine exerts its antidepressant effect is unknown; however, the activity on NMDA receptors may be responsible for both the therapeutic and the adverse psychiatric effects of esketamine, including dissociative symptoms and abuse. Ketamine, a racemic mixture containing esketamine, has sympathomimetic activity resulting in adverse cardiac effects including tachycardia, hypertension, and increased intracranial and intraocular pressure. Similar effects have occurred with esketamine. The major metabolite of esketamine, noresketamine, has demonstrated activity at the NMDA receptor with less affinity.[43431] [56732] [63989]

Esketamine is available as a nasal spray. No accumulation of esketamine in plasma was observed following twice a week administration. Protein binding is clinically insignificant. Esketamine is primarily metabolized to noresketamine, the active metabolite of esketamine, by CYP2B6 and CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Noresketamine is metabolized by CYP-dependent pathways and subsequent metabolism occurs through glucuronidation. Noresketamine has a brain-to-plasma ratio that is 4 to 6 times lower than esketamine. Elimination of esketamine is biphasic, with a rapid decline for the initial 2 to 4 hours and a mean terminal half-life that ranged from 7 to 12 hours. The elimination of noresketamine is also biphasic, with a rapid decline for the initial 4 hours and a mean terminal half-life of about 8 hours. Less than 1% of a dose is excreted as the parent compound. Following intravenous or oral administration, esketamine-derived metabolites were primarily recovered in urine (78% or more of a dose) and feces (2% or less of a dose).[63989]
 
Affected cytochrome P450 isoenzymes: CYP2B6, CYP3A4, CYP2C9, CYP2C19
Esketamine is primarily metabolized to noresketamine by CYP2B6 and CYP3A4 and a lesser extent by CYP2C9 and CYP2C19. Esketamine has modest induction effects on CYP2B6 and CYP3A4 in human hepatocytes. Esketamine and its major metabolites do not induce CYP1A2, or inhibit CYPs, transporter systems, or UGTs, except for a weak reversible inhibition of noresketamine on CYP3A4. Esketamine is not a substrate for P-gP, BCRP, OATP1B1, or OATP1B3. Noresketamine is metabolized by CYP-dependent pathways and subsequent metabolism occurs through glucuronidation.[63989]

Other Route(s)

Following nasal spray administration, the mean absolute bioavailability is about 48%. The time to reach maximum esketamine plasma concentrations (Cmax) is 20 to 40 minutes after the last nasal spray of a treatment session. Esketamine exposure increases with dose from 28 mg to 84 mg. The inter-subject variability of esketamine ranges from 27% to 66% for Cmax and 18% to 45% for AUC. The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC.[63989]

Pregnancy

Esketamine nasal spray is not recommended for use during pregnancy. There are insufficient human data regarding the use of esketamine during pregnancy to inform of any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, esketamine may cause fetal harm. If pregnancy occurs, esketamine nasal spray should be discontinued and the patient advised of the potential reproductive risk to the fetus. Pregnancy planning is recommended for individuals receiving esketamine who may become pregnant; specific contraception requirements have not been recommended but should be individualized to the patient. Published studies in pregnant primates demonstrate that the administration of drugs that block N-methyl-D-aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis (cell death) in the developing brain of the offspring. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans. In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the post-weaning period. It is not clear how these animal findings relate to females of reproductive potential receiving esketamine at the recommended dose. There is a pregnancy registry that monitors pregnancy outcomes related to antidepressant exposures, including esketamine nasal spray. Health care providers are encouraged to assist patients to register by contacting the National Pregnancy Registry for Antidepressants online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ or by calling 1-866-961-2388.[63989]