esketamine

Absorption: 48% absorbed following nasal administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Primarily metabolized to noresketamine (active metabolite) in liver by CYP2B6 and CYP3A4 isoenzymes and to lesser extent by CYP2C9 and CYP2C19 isoenzymes. Primarily excreted in urine (≥78%; <1% as unchanged drug); ≤2% excreted in feces.

Half-Life: 7–12 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Intranasal	unknown	20–40 min	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity to esketamine or ketamine;
Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial and peripheral arterial vessels) or arteriovenous malformation;
History of intracerebral hemorrhage;
Severe hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

May ↑ risk of suicide attempt/ideation especially during early treatment or dose adjustment; this risk appears to be greater in adolescents or children
;
History of hypertensive encephalopathy;
Psychosis;
Substance use disorder
;
Moderate hepatic impairment;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: ↑BP, tachycardia

Derm: ↑sweating

EENT: nasal irritation, throat irritation

GI: nausea, vomiting, constipation, diarrhea, dry mouth

GU: urinary tract infection

Neuro: anxiety, depersonalization, derealization,

dissociative changes

, dizziness, dysgeusia, fatigue, headache, hypoesthesia,

sedation

, vertigo, cognitive impairment, insomnia, loss of consciousness, slurred/slow speech, SUICIDAL THOUGHTS/BEHAVIORS, tremor

Resp: RESPIRATORY DEPRESSION

Misc:

physical dependence

psychological dependence

, tolerance

Interactions ⬆ ⬇

Drug-drug:

Concurrent use with psychostimulants, including amphetamines, methylphenidate, modafanil, or armodafanil, as well as MAO inhibitors, may ↑ BP.
Use with opioids or other CNS depressants, including benzodiazepines, nonbenzodiazepine sedative/hypnotics, anxiolytics, general anesthetics, muscle relaxants, antipsychotics, and alcohol, may cause profound sedation.

Route/Dosage ⬆ ⬇

Treatment-Resistant Depression

(Adults ): Induction phase (Wk 1–4): 56 mg (2 sprays in each nostril) or 84 mg (3 sprays in each nostril) twice weekly. Maintenance phase (Wk 5–8): 56 mg (2 sprays in each nostril) or 84 mg (3 sprays in each nostril) once weekly. Maintenance phase (Wk 9 and beyond): 56 mg (2 sprays in each nostril) or 84 mg (3 sprays in each nostril) once weekly or every other wk (use least frequent dosing to maintain remission/response).

Depressive Symptoms in Patients With Major Depressive Disorder With Acute Suicidal Ideation or Behavior

(Adults ): 84 mg (3 sprays in each nostril) twice weekly for 4 wk; may ↓ dosage to 56 mg (2 sprays in each nostril) twice weekly based on tolerability. Reevaluate patient for continued need for treatment after 4 wk.

Availability ⬆ ⬇

Nasal spray: 28 mg/device (14 mg/spray)

Assessment ⬆ ⬇

Monitor patient for sedation and respiratory depression for ≥2 hr after each dose.
Monitor BP before and 40 min after each dose and then periodically for ≥2 hr after administration. If BP elevated before administration, may hold dose. If BP elevated following dose, continue monitoring.
Assess for history of psychosis and dissociative or perceptual changes (distortion of time, space, and illusions), derealization, and depersonalization at baseline and for ≥2 hr after each dose.
Monitor for worsening or emergence of suicidal thoughts and behaviors, especially during initial few months of therapy and with dose changes.
Monitor for urinary tract and bladder symptoms during therapy. If symptoms of ulcerative or interstitial cystitis occur, consult specialist as clinically indicated.
Assess for risk of abuse or misuse prior to administration, and monitor for these behaviors as well as drug-seeking behaviors and dependence during treatment.

Implementation ⬆ ⬇

Do not confuse Spravato with Steglatro.
REMS: Due to risks of serious adverse outcomes from sedation, dissociation, abuse, and misuse, esketamine is available only through a restricted program under Spravato REMS. Health care settings and pharmacies must be certified, and patients must be enrolled in REMS program. Esketamine is only administered in health care settings under direct observation of health care provider, and patients must be monitored for 2 hr after administration.
Advise patient to avoid food for ≥2 hr and liquids for 30 min prior to administration.
If nasal corticosteroid or nasal decongestant is administered on a dosing day, administer ≥1 hr before esketamine administration.
Esketamine may be given as monotherapy or in conjunction with an oral antidepressant.
Use 2 devices (for a 56-mg dose) or 3 devices (for an 84-mg dose), with a 5-min rest between use of each device. Do not prime device. Advise patient to gently blow nose before 1st dose. Check that indicator shows two or three green dots. Instruct patient to recline head back 45°, insert device into nostril until nose rest is between nostrils, close opposite nostril, and sniff gently after administering dose. After administration, confirm no green dots. Instruct patient to recline and rest for 5 min between doses and to not blow their nose. Repeat for each dose. Discard according to institution guidelines for Schedule III drugs. Observe patient for ≥2 hr after dose until stable for discharge.

Patient/Family Teaching ⬆ ⬇

REMS: Explain purpose of esketamine, administration procedure, and Spravato REMS program to patient. Advise patient to read Medication Guide before starting therapy. If a treatment session is missed and no worsening of depressive symptoms occurs, continue current dosing schedule. If depressive symptoms worsen, may return to previous dosing schedule.
Advise patient that esketamine is a controlled substance and can lead to dependence and has abuse potential.
Caution patient to avoid driving or activities requiring alertness until next day after a restful sleep.
Advise patient, family, and caregivers to look for changes in behavior and suicidality, especially during early therapy or dose changes. Notify health care provider immediately of thoughts about suicide or dying, suicide attempts, new or worse depression or anxiety, agitation or restlessness, panic attacks, insomnia, new or worse irritability, aggressiveness, acting on dangerous impulses, mania, or other changes in mood or behavior.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of Rx, OTC, and herbal products without consulting health care provider.
Rep: May cause fetal harm. Advise women of reproductive potential to use effective contraception during therapy and to avoid breastfeeding. Notify health care provider promptly if pregnancy is planned or suspected. Inform patients who become pregnant during therapy of pregnancy registry that monitors pregnancy outcomes. Enroll patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇