Esketamine (Spravato) is an NMDA-receptor antagonist that is used in the treatment of treatment-resistant depression. It is available as an intranasal spray.

Esketamine (Spravato) Uses:

• Treatment-resistant Depression:

  • Used in conjunction with an oral antidepressant to treat individuals with treatment-resistant depression (TRD)
  • Restrictions on use: Not permitted to be used as an anaesthetic. Esketamine has not yet been proven to be a safe and efficient anaesthetic.

Esketamine (Spravato) Dose in Adults

Esketamine (Spravato) Dose in treatment-resistant  Depression:

Note:

• Combine with an oral antidepressant when administering.
• Patients must be monitored for side effects for at least two hours after receiving the medication under the direct supervision of a healthcare professional.
• Intranasal:
  • Induction:
    • After the initial dosage, the dose may be increased (up to 84 mg twice in a weak) according on reaction and tolerability.
    • Check for therapeutic benefit after 4 weeks to assess whether more treatment is necessary.
  • Maintenance:
    • Reduce the frequency of administration to once every two weeks starting in week 5 while continuing to use the previously prescribed dose (56 or 84 mg).
    • From week 9 on, reduce the dose frequency to every two weeks or keep it at once weekly in order to sustain remission or response.

• Missed treatment sessions or worsening of symptoms:

  • Think about going back to the patient's prior dose regimen (for example, every two weeks to once per week or weekly to twice per weak).

Use in Children:

Not indicated.

Esketamine (Spravato) Pregnancy Risk Category: N (Not assigned)

• Animal studies suggest that drugs that reduce gamma-aminobutyric acid (GABA) activity and/or block N-methyl-D-aspartate receptors (NMDA) may have an impact on brain development.
• For human foetuses, the third trimester may be the most delicate.
• The ACOG advises that therapy for depression during pregnancy be tailored to the individual
• The American Psychiatric Association states that medication treatment can have risks, but should be weighed against untreated depression and other options.
• Women who have stopped taking antidepressant medication during pregnancy or who are at high risk of postpartum depression can resume their medications after delivery.
• The ACOG and APA have developed treatment algorithms for women suffering from depression during pregnancy and before conception.
• Based on negative outcomes in animal reproduction tests, the manufacturer advises females with reproductive potential to consider pregnancy planning and prevention while undergoing esketamine medication.
• Women who are expecting should register with the National Pregnancy Registry for Antidepressants if they have been exposed to antidepressants while pregnant.

Use of esketamine during lactation

• It can be found in breast milk
• According to research in animals, drugs that obstruct NMDA receptors and/or reduce GABA action may have an effect on how the brain develops.
• Infants are most vulnerable in the first few months of their lives, and perhaps even up to three years old.
• The manufacturer does not recommend breastfeeding due to the possibility of adverse events in nursing infants.

Esketamine (Spravato) Dose in Kidney Disease:

Manufacturer labeling doesn't provide any dosage adjustment (has not been studied).

Esketamine (Spravato) Dose in Liver disease:

• Mild to moderate impairment (Child-Pugh classes A and B):

  • Manufacturer labeling doesn't provide any dosage adjustments (has not been studied);
  • Patients with mild impairment could require longer-term monitoring for negative consequences.

• Severe impairment (Child-Pugh class C):

  • Use is not recommended (has not been studied).

Common Side Effects of Esketamine (Spravato):

• Cardiovascular:

  • Increased Systolic Blood Pressure
  • Increased Diastolic Blood Pressure

• Central Nervous System:

  • Depersonalization
  • Derealization
  • Headache
  • Hypoesthesia
  • Anxiety
  • Dissociative Reaction
  • Sedated State
  • Dizzinessa
  • Vertigo
  • Lethargy

• Gastrointestinal:

  • Nausea
  • Dysgeusia
  • Vomiting

Less Common Side Effects Of Esketamine (Spravato):

• Cardiovascular:

  • Increased Blood Pressure
  • Tachycardia

• Central Nervous System:

  • Insomnia
  • Intoxicated Feeling
  • Euphoria
  • Feeling Abnormal
  • Mental Deficiency
  • Dysarthria

• Dermatologic:

  • Hyperhidrosis

• Gastrointestinal:

  • Diarrhea
  • Xerostomia
  • Constipation
  • Severe Nausea
  • Severe Vomiting

• Genitourinary:

  • Pollakiuria

• Neuromuscular & Skeletal:

  • Tremor

• Respiratory:

  • Nasal Discomfort
  • Throat Irritation
  • Oropharyngeal Pain

Side effects of Esketamine (Spravato) - Frequency Not Defined:

• Central Nervous System:

  • Cognitive Dysfunction
  • Drug Abuse

• Genitourinary:

  • Dysuria
  • Cystitis
  • Nocturia
  • Urinary Urgency

Contraindications to Esketamine (Spravato):

• Hypersensitivity to any ingredient in this formulation, including esketamine and ketamine
• Aneurysmal Vascular Disease (including intracranial and peripheral arterial vessels, thoracic, abdominal, and thoracic aorta) or Arteriovenous Malformation.
• History of intracerebral hemorhage

Warnings and precautions

• Missbrauch and abuse [US Boxed Warning]

  • Esketamine can be misused and abused.
  • Before providing esketamine to patients who are more likely to abuse it, weigh the advantages and disadvantages of doing so.
  • Keep an eye out for symptoms and indicators of abuse or usage.
  • Behaviors that lead to drug use can be treated
  • People who have a history of drug addiction or dependence are more vulnerable. Be cautious before beginning treatment. Observe abuse's warning signs and symptoms as well.

• CNS Depression: [US Boxed Warning]

  • After esketamine is administered, patients are at high risk of feeling sedated.
  • Patients must be closely monitored during treatment sessions due to the potential for sedation. After each session, a patient assessment is performed to determine if the patient is clinically stable and ready for discharge.
  • CNS depression can cause impairments in mental or physical abilities. Patients should be cautious about driving or operating machinery until they are able to sleep soundly the next day.
  • No negative effects of esketamine nasal spray on cognitive function were discovered during a one-year safety investigation.
  • However, frequent ketamine abuse has been connected to memory and cognitive deficits.
  • Patients should arrange transport home after treatment according to manufacturer labeling
  • Monitor closely the effects of sedation and concomitant CNS depressions.

• Dissociation: [US Boxed Warning]

  • After the administration of esketamine, patients are at high risk for perceptual or dissociative changes.
  • Patients must be closely monitored during treatment sessions to avoid dissociation. After that, a patient's clinical stability and readiness to leave the hospital setting should be determined.
  • It's critical to thoroughly analyse patients before giving them esketamine because it can lead to depersonalization and derealization in some individuals, as well as dissociative or perceptual abnormalities (including distortions of time, space, and illusions). Only begin treatment if the benefits are obvious.

• Blood pressure

  • All recommended doses have shown increases in systolic (or diastolic) blood pressure (BP), which can occur within 40 minutes and last 4 hours.
  • Even if the effects of previous administrations were less, significant BP increases can occur.
  • Patients who have a high risk of developing aneurysmal vascular disease or an increase in BP are advised to stop taking Esketamine.
  • Before esketamine is given to patients, it is important to assess whether there are any other cerebrovascular and cardiovascular conditions.
  • Check your blood pressure before starting treatment. If it is high (>140/90 mmHg), weigh the advantages and disadvantages of delaying treatment.
  • Within 40 minutes of administration, the blood pressure should be checked. After the last dose, the blood pressure should be monitored for at least two hours, or until it falls below that level.
  • Patients with hypertensive crisis symptoms, such as shortness of breath or chest pain, or hypertensive encephalopathy symptoms, such as abrupt, severe headaches, visual disturbances, seizures, decreased awareness or focal neurological deficits, should be referred to emergency care.
  • If you're using esketamine together with psychostimulants, monoamine oxidase inhibitors, or both, be sure to keep a close eye on your blood pressure.
  • Patients who have a history of hypertensive encephalopathy should receive closer monitoring, including more regular blood pressure checks and symptom evaluation. Even with slight BP increases in these patients, encephalopathy risk increases.

• Suicidal thoughts, behaviors and behavior: [US Boxed Warn]

  • In short-term studies, antidepressants were associated with an increase in suicidal behavior and thoughts in young adults and children.
  • Studies conducted over a short period of time did not indicate an increase in risk for patients above the age of 24. The danger was lower for people 65 and older, though.
  • All patients should be cautiously watched for indications of clinical deterioration, suicidality, or odd conduct.
  • The patient's caretaker or family should give specific instructions to the patient's loved ones about how to closely watch the patient and talk to the doctor about their condition.
  • Drug therapy may need to be modified or discontinued if there are signs and symptoms such as severe suicidality and worsening depression.
  • Major depression can lead to suicide attempts. This possibility may continue until remission.
  • Pediatric patients are not recommended to use Esketamine.

• Interstitial or ulcerative cystitis

  • Individuals who have long-term ketamine misuse/abuse or off-label usage of ketamine have been known to develop interstitial or ulcerative cystitis.
  • Clinical trials showed that patients who were given esketamine for at least one year had lower rates of symptoms of the urinary tract (nocturia and pollakiuria; dysuria; micturition urgency and cystitis); however, there was no evidence of interstitial cystitis.
  • Observe for symptoms in the bladder and urinary tract during treatment. If necessary, refer to a qualified health care provider.

• Hepatic impairment

  • Esketamine should not be taken by patients who have significant hepatic impairment.
  • Patients who have modest hepatic impairment may need to be watched more closely for any negative effects.

Esketamine (intranasal): Drug Interaction

Monitoring parameters:

• After the last dose, all patients should be thoroughly watched in a medical setting for no more than two hours to look out for any side effects

• Blood pressure (prior and after dose); repeat for at most 40 minutes, then for as long as is clinically necessary for at least two hours.

• Suicidal ideation, particularly in the early stages of therapy and when dosages are changed
• Before administering medication, evaluate patient risk for misuse or abuse, psychosis, cardiovascular and cerebrovascular problems, and psychosis.
• Monitor all patients closely for signs of depression or suicidal thoughts or behaviors. This is especially important during the first few months of therapy.
• At the end of the induction phase, you should evaluate the therapeutic benefit evidence to decide whether further treatment is required.
• Patients should be constantly watched during therapy for any indications of abuse or misuse, and sedation should be watched out for when taking concurrent CNS depressants.

How to administer Esketamine (Spravato) Intranasal?

Intranasal:

• Avoid eating for at least two hours prior to administering medication and drink liquids no more than 30 minutes before administering. This will reduce the chance of nausea and vomiting.
• Dosing day: If the patient needs a nasal corticosteroid, or nasal decongestant, it should be administered at least one hour before esketamine is given.
• To avoid medication loss, do not prime the device before you use it. Each nasal spray device has 2 sprays (one for each nostril), and delivers 28 mg. Only one spray per nostril.
• To ensure absorption, you should use 2 or 3 devices to administer 56 mg of the dose.
• Gently blow your nose to clear the nostrils. Use only the schedule III drug procedure and comply with all federal, state and local regulations to dispose of any used devices.

Mechanism of action of Esketamine (Spravato):

• Esketamine (Selective, Noncompetitive Nmethyl-D-aspartate) receptor antagonist is known as Esketamine.
• It is not known how it works. Noresketamine, the major circulating metabolite, demonstrated similar activity but with less affinity.

Protein binding:

• ~43 percent  to 45 percent

Metabolism:

• Primarily metabolised by the cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4, and to a lesser amount by CYP2C9 and CYP2C19, to the active metabolite noresketamine.
• Through CYP-dependent pathways, noresketamine is metabolised, and some of the byproducts proceed through glucuronidation.

Bioavailability:

• ~48 percent

Half-life elimination:

• Esketamine: 7 to 12 hours;
• Noresketamine (active metabolite): ~8 hours

Time to peak, plasma:

• 20 to 40 minutes

Excretion:

• Urine (less than 1 percent  as unchanged drug)

International Brand Names of Esketamine Intranasal:

• Spravato (56 MG Dose)
• Esketiv
• Ketanest
• Ketanest S
• Ketanest-S
• Spravato (84 MG Dose)
• Vesierra

Intranasal Esketamine Brand Names in Pakistan:

There is no brand available in Pakistan.