Treatment-resistant major depressive disorder

Active Ingredient: Esketamine

Indication for Esketamine

Population group: only adults (18 years old or older)
Therapeutic intent: Curative procedure

Esketamine, in combination with a SSRI or SNRI, is indicated for adults with treatment-resistant Major Depressive Disorder, who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode.

For this indication, competent medicine agencies globally authorize below treatments:

56 mg starting dose on Day 1, 56 or 84 mg twice a week for Weeks 1-4, once a week for Weeks 5-8 and then every 2 weeks or once a week

For:

Dosage regimens

Regimen A :

Nasal, 56 milligrams esketamine, one dose. Afterwards, nasal, between 56 milligrams esketamine and 84 milligrams esketamine, 2 times weekly, over the duration of 4 weeks. Afterwards, nasal, between 56 milligrams esketamine and 84 milligrams esketamine, once weekly, over the duration of 4 weeks. Afterwards, nasal, between 56 milligrams esketamine and 84 milligrams esketamine, once weekly.

Regimen B :

Nasal, 56 milligrams esketamine, one dose. Afterwards, nasal, between 56 milligrams esketamine and 84 milligrams esketamine, 2 times weekly, over the duration of 4 weeks. Afterwards, nasal, between 56 milligrams esketamine and 84 milligrams esketamine, once weekly, over the duration of 4 weeks. Afterwards, nasal, between 56 milligrams esketamine and 84 milligrams esketamine, once every 2 weeks.

Detailed description

Assessment before treatment

Prior to dosing with esketamine blood pressure should be assessed.

If baseline blood pressure is elevated the risks of short-term increases in blood pressure and benefit of esketamine treatment should be considered. Esketamine should not be administered if an increase in blood pressure or intracranial pressure poses a serious risk.

Patients with clinically significant or unstable cardiovascular or respiratory conditions require additional precautions. In these patients, esketamine should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available.

Post-administration observation

After dosing with esketamine, blood pressure should be reassessed at approximately 40 minutes and subsequently as clinically warranted.

Because of the possibility of sedation, dissociation and elevated blood pressure, patients must be monitored by a healthcare professional until the patient is considered clinically stable and ready to leave the healthcare setting.

Posology

The dose recommendations for esketamine are shown in the table below. It is recommended to maintain the dose the patient receives at the end of the induction phase in the maintenance phase. Dose adjustments should be made based on efficacy and tolerability to the previous dose. During the maintenance phase, esketamine dosing should be individualised to the lowest frequency to maintain remission/response.

Recommended dosing for esketamine in adults <65 years:

Induction phaseMaintenance phase
Weeks 1-4:
Starting day 1 dose: 56 mg
Subsequent doses: 56 mg or 84 mg twice a week
Weeks 5-8:
56 mg or 84 mg once weekly

From Week 9:
56 mg or 84 mg every 2 weeks or once
weekly
Evidence of therapeutic benefit should be evaluated
at the end of induction phase to determine need for
continued treatment.
The need for continued treatment should be
re-examined periodically.

After depressive symptoms improve, treatment is recommended for at least 6 months.

Food and liquid intake recommendations prior to administration

Since some patients may experience nausea and vomiting after administration of esketamine, patients should be advised not to eat for at least 2 hours before administration and not to drink liquids at least 30 minutes prior to administration.

Nasal corticosteroid or nasal decongestant

Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should be advised not to administer these medicinal products within 1 hour before esketamine administration.

Missed treatment session(s)

Patients who have missed treatment session(s) during the first 4 weeks of treatment should continue with their current dosing schedule.

For patients with treatment-resistant Major Depressive Disorder who miss treatment session(s) during maintenance phase and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule.

Dosage considerations

Sneezing after administration

If sneezing occurs immediately after administration, a replacement device should not be used.

Use of the same nostril for 2 consecutive sprays

If administration in the same nostril occurs, a replacement device should not be used.

Treatment discontinuation does not require tapering off; based on data from clinical trials the risk of withdrawal symptoms is low.

28 mg starting dose on Day 1, 28 mg, 56 mg ή 84 mg twice a week for Weeks 1-4, once a week for Weeks 5-8 and then every 2 weeks or once a week

For:

Dosage regimens

Regimen A :

Nasal, 28 milligrams esketamine, one dose. Afterwards, nasal, between 28 milligrams esketamine and 84 milligrams esketamine, 2 times weekly, over the duration of 4 weeks. Afterwards, nasal, between 28 milligrams esketamine and 84 milligrams esketamine, once weekly, over the duration of 4 weeks. Afterwards, nasal, between 28 milligrams esketamine and 84 milligrams esketamine, once every 2 weeks.

Regimen B :

Nasal, 28 milligrams esketamine, one dose. Afterwards, nasal, between 28 milligrams esketamine and 84 milligrams esketamine, 2 times weekly, over the duration of 4 weeks. Afterwards, nasal, between 28 milligrams esketamine and 84 milligrams esketamine, once weekly, over the duration of 4 weeks. Afterwards, nasal, between 28 milligrams esketamine and 84 milligrams esketamine, once weekly.

Detailed description

Assessment before treatment

Prior to dosing with esketamine blood pressure should be assessed.

If baseline blood pressure is elevated the risks of short-term increases in blood pressure and benefit of esketamine treatment should be considered. Esketamine should not be administered if an increase in blood pressure or intracranial pressure poses a serious risk.

Patients with clinically significant or unstable cardiovascular or respiratory conditions require additional precautions. In these patients, esketamine should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available.

Post-administration observation

After dosing with esketamine, blood pressure should be reassessed at approximately 40 minutes and subsequently as clinically warranted.

Because of the possibility of sedation, dissociation and elevated blood pressure, patients must be monitored by a healthcare professional until the patient is considered clinically stable and ready to leave the healthcare setting.

Posology

The dose recommendations for esketamine are shown in the table below. It is recommended to maintain the dose the patient receives at the end of the induction phase in the maintenance phase. Dose adjustments should be made based on efficacy and tolerability to the previous dose. During the maintenance phase, esketamine dosing should be individualised to the lowest frequency to maintain remission/response.

Recommended dosing for esketamine in adults ≥65 years with treatment-resistant Major Depressive Disorder:

Induction phaseMaintenance phase
Weeks 1-4:
Starting day 1 dose: 28 mg
Subsequent doses: 28 mg, 56 mg or 84 mg
twice a week, all dose
changes should be in 28 mg
increments
Weeks 5-8:
28 mg, 56 mg or 84 mg once weekly, all
dose changes should be in 28 mg increments

From Week 9:
28 mg, 56 mg or 84 mg every 2 weeks or
once weekly, all dose changes should be in
28 mg increments
Evidence of therapeutic benefit should be evaluated
at the end of induction phase to determine need for
continued treatment.
The need for continued treatment should be
re-examined periodically.

After depressive symptoms improve, treatment is recommended for at least 6 months.

Food and liquid intake recommendations prior to administration

Since some patients may experience nausea and vomiting after administration of esketamine, patients should be advised not to eat for at least 2 hours before administration and not to drink liquids at least 30 minutes prior to administration.

Nasal corticosteroid or nasal decongestant

Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should be advised not to administer these medicinal products within 1 hour before esketamine administration.

Missed treatment session(s)

Patients who have missed treatment session(s) during the first 4 weeks of treatment should continue with their current dosing schedule.

For patients with treatment-resistant Major Depressive Disorder who miss treatment session(s) during maintenance phase and have worsening of depression symptoms, per clinical judgement, consider returning to the previous dosing schedule.

Dosage considerations

Sneezing after administration

If sneezing occurs immediately after administration, a replacement device should not be used.

Use of the same nostril for 2 consecutive sprays

If administration in the same nostril occurs, a replacement device should not be used.

Treatment discontinuation does not require tapering off; based on data from clinical trials the risk of withdrawal symptoms is low.

Active ingredient

Esketamine

Esketamine is the S-enantiomer of racemic ketamine. It is a non-selective, non-competitive, antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. Through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulation and subsequently to increases in neurotrophic signalling which may contribute to the restoration of synaptic function in these brain regions involved with the regulation of mood and emotional behaviour. Restoration of dopaminergic neurotransmission in brain regions involved in the reward and motivation, and decreased stimulation of brain regions involved in anhedonia, may contribute to the rapid response.

Read more about Esketamine

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