Drug information of Esketamine

Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (NMDA is an ionotropic glutamate receptor).

The mechanism by which esketamine exerts its antidepressant effect is unknown.

Bioavailability: 48%

Peak plasma time: 20-40 minutes after last nasal spray of treatment session

Vd (IV): 709 L

Protein bound: 43-45%

Metabolism:Primarily metabolized to noresketamine by CYP2B and 3A4, and to a lesser extent by CYP2C9/2C19.

Noresketamine is metabolized by CYP-dependent pathways, and certain subsequent metabolites undergo glucuronidation.

Noresketamine demonstrated activity at the NMDA receptor with less affinity.

Half-life: 7-12 hr; 8 hr (noresketamine)

Clearance (IV): 89 L/hr

Excretion:

Urine: <1% unchanged; ≥78% metabolites

Feces: ≤2% metabolites

-Depression, treatment-resistant

-Major depressive disorder (unipolar) with suicidality

-Treatment-resistant Depression

Indicated in conjunction with an oral antidepressant for treatment-resistant depression (TRD)

1-Induction phase

-Weeks 1-4

   Administer intranasally twice per week

  Day 1 starting dose: 56 mg

  Subsequent doses: 56 mg or 84 mg

2-Maintenance phase

-Weeks 5-8

    Administer intranasally once weekly

    56 mg or 84 mg

-Week 9 and after

  Administer intranasally q2Week or once weekly; individualize dosing frequency to the          least frequent dosing to maintain remission/response

  56 mg or 84 mg

-Major Depressive Disorder

Administer intranasally in conjunction with an oral antidepressant

84 mg twice per week x 4 weeks

May reduce dose to 56 mg twice per week based on tolerability

After 4 weeks of treatment, evaluate evidence of therapeutic benefit determine need for continued treatment.

-Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation

-History of intracerebral hemorrhage

-Hypersensitivity to esketamine, ketamine, or any excipients

Dissociation ,Dizziness ,Nausea ,Vertigo ,Sedation ,Headache ,Dysgeusia ,Hypoesthesia ,Anxiety ,Lethargy ,Increased blood pressure,Vomiting ,Insomnia ,Diarrhea ,Nasal discomfort ,Throat irritation ,Dry mouth ,Feeling drunk ,Dysarthria ,Euphoric mood ,Hyperhidrosis ,Constipation ,Feeling abnormal ,Mental impairment ,Tremor ,Pollakiuria ,Oropharyngeal pain ,Tachycardia ,Intentional self-injury ,Toothache ,Felling of relaxation ,Myalgia ,Confusion ,Dysphoria , Loss of consciousness

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-Available only through a restricted access program (REMS)

-Sedation is likely to occur

-Dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization reported

-The most common psychological effects are dissociative or perceptual changes (including distortion of time, space, and illusions), derealization, and depersonalization; carefully assess patients with psychosis before administering to determine if benefit outweighs risk

-Esketamine is a schedule III controlled substance and may be subject to abuse and diversion; assess risk for each patient before prescribing

-Pooled analyses of placebo-controlled trials of antidepressant drugs have shown an increased risk for suicidality in patients aged ≤24 yr; monitor all patients receiving antidepressants, especially during the initial phase of treatment, for clinical worsening and emergence of suicidal thoughts and behaviors

-Ulcerative or interstitial cystitis reported with long-term, off-label use or misuse/abuse of ketamine; esketamine intranasal showed a higher rate of lower urinary tract symptoms compared with placebo; however, no cases of interstitial cystitis observed

-May cause fetal harm when administered to pregnant women.

-After single dose in healthy volunteers, esketamine caused cognitive performance decline 40 minutes postdose compared with placebo.Cognitive performance, mental effort, and sleepiness were comparable at 2 hr postdose.

-Coadministration with other CNS depressants may cause additive risk for sedation

-Coadministration with psychostimulants or MAOIs may add to risk of increased blood pressure

- Because of risk of sedation, dissociation, and increased blood pressure, patients must be monitored for at least 2 hr after each treatment session; carefully assess to determine if the patient is clinically stable and ready to leave the healthcare setting.

- Must be administered in healthcare facility under direct supervision.

- After 4 weeks of treatment, evaluate evidence of therapeutic benefit determine need for continued treatment.

- Hepatic impairment:

• Moderate :Higher AUC and half-life observed compared with normal hepatic function; may need to be monitored for longer period after dose administration
• Severe : Not studied, and therefore not recommended

- Effectiveness in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated; use of esketamine intranasal does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose.

-Assess blood pressure before administration.

-If baseline blood pressure is elevated (eg, >140 mm Hg systolic, >90 mm Hg diastolic), consider the risks of short-term increases in blood pressure and benefit of treatment.

-Do not administer if increased blood pressure or intracranial pressure poses serious risk.

-After dosing, reassess blood pressure at ~40 minutes (corresponds with peak plasma concentration) and subsequently as clinically warranted.

-If blood pressure is decreasing and patient appears clinically stable for at least 2 hr, may discharge patient at the end of the postdose monitoring period; if not, continue to monitor.

- Some patients may experience nausea and vomiting after administration.Because of this, advise patients to avoid food for at least 2 hr before administration and to avoid drinking liquids at least 30 minutes before.

- Administer nasal corticosteroid or decongestant at least 1 hr before esketamine.

-Use of adequate methods of contraception should be encouraged.

-Patients of pregnancy potential should consider pregnancy planning and prevention.

-If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential harm to the fetus.

- Animal studies have revealed evidence of delayed sensorimotor development, skeletal malformations, and neuronal apoptosis at intranasally administered doses 0.3 times the maximum recommended human dose. There are no controlled data in human pregnancy.