Posology : מינונים

4.2    Posology and method of administration
The decision to prescribe this medicinal product should be determined by a psychiatrist.
It is intended to be self-administered by the patient under the direct supervision of a healthcare professional.

A treatment session consists of nasal administration and a post-administration observation period.
Both administration and post-administration observation should be carried out in an appropriate clinical setting.

Assessment before treatment
Prior to dosing with Spravato blood pressure should be assessed.

If baseline blood pressure is elevated the risks of short-term increases in blood pressure and benefit of the treatment should be considered (see section 4.4). The medicinal product should not be administered if an increase in blood pressure or intracranial pressure poses a serious risk (see section 4.3).

Patients with clinically significant or unstable cardiovascular or respiratory conditions require additional precautions. In these patients, the medicinal product should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available (see section 4.4).

Post-administration observation
After dosing with Spravato, blood pressure should be reassessed at approximately 40 minutes and subsequently as clinically warranted (see section 4.4).

Because of the possibility of sedation, dissociation and elevated blood pressure, patients must be monitored by a healthcare professional for at least 2 hours at each treatment session and until the patient is considered clinically stable and ready to leave the healthcare setting (see section 4.4).

Posology

Treatment-resistant Major Depressive Disorder
The dose recommendations for treatment-resistant Major Depressive Disorder are shown in Table 1 and Table 2 (adults ≥65 years). 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, dosing should be individualised to the lowest frequency to maintain remission/response.

Table 1:      Recommended dosing for Spravato in adults <65 years with treatment-resistant Major Depressive Disorder
Induction phase                                                 Maintenance phase Weeks 1-4:                                          Weeks 5-8:
Starting day 1 dose: 56 mg                          56 mg or 84 mg once weekly Subsequent doses:      56 mg or 84 mg twice a week
From Week 9:
56 mg or 84 mg every 2 weeks or once weekly
Evidence of therapeutic benefit should be evaluated The need for continued treatment should be at the end of induction phase to determine need for re-examined periodically.
continued treatment.


Table 2:      Recommended dosing for Spravato in adults ≥65 years with treatment-resistant Major Depressive Disorder
Induction phase                                                 Maintenance phase Weeks 1-4:                                          Weeks 5-8:
Starting day 1 dose: 28 mg                          28 mg, 56 mg or 84 mg once weekly, all Subsequent doses:      28 mg, 56 mg or 84 mg        dose changes should be in 28 mg increments twice a week, all dose changes should be in 28 mg   From Week 9: increments                   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 The need for continued treatment should be at the end of induction phase to determine need for re-examined periodically.
continued treatment.

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

Acute short-term treatment of psychiatric emergency due to Major Depressive Disorder The recommended dosage for adult patients (<65 years) is 84 mg twice per week for 4 weeks. Dosage reduction to 56 mg should be made based on tolerability. After 4 weeks of treatment with Spravato, the oral antidepressant (AD) therapy should be continued, per clinical judgement.

In these patients, treatment with Spravato should be part of the comprehensive clinical care plan.

There is limited data on the use of esketamine in patients between 18 to 24 years.
A subgroup analysis of patients with or without at least one previous suicidal experience for the primary endpoint "Change from baseline (day 1, predose) to 24 hours after the first dose (day 2) in MADRS" of the pivotal studies, demonstrated no statistically significant efficacy for the group of patients without at least one previous suicidal experience (See section 5.1).

Food and liquid intake recommendations prior to administration
Since some patients may experience nausea and vomiting after administration of the medicinal product, 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 (see section 4.8).

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 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 (see Tables 1 and 2).

Special populations

Elderly (65 years of age and older)
In elderly patients the initial Spravato dose for treatment-resistant Major Depressive Disorder is 28 mg esketamine (day 1, starting dose, see Table 2 above). Subsequent doses should be increased in increments of 28 mg up to 56 mg or 84 mg, based on efficacy and tolerability.

Spravato has not been studied in elderly patients as acute short-term treatment of psychiatric emergency due to Major Depressive Disorder.

Hepatic impairment
No dose adjustment is necessary in patients with mild (Child Pugh class A) or moderate (Child Pugh class B) hepatic impairment. However, the maximum dose of 84 mg should be used with caution in patients with moderate hepatic impairment.

Spravato has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Use in this population is not recommended (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is necessary in patients with mild to severe renal impairment. Patients on dialysis were not studied.

Race
For patients of Japanese ancestry, initial Spravato dose is 28 mg esketamine (day 1, starting dose, see Table 3). Subsequent doses should be increased in increments of 28 mg up to 56 mg or 84 mg, based on efficacy and tolerability.

Table 3:      Recommended Dosing for Spravato in Adults of Japanese Ancestry Induction phase                                                 Maintenance phase Weeks 1-4:                                          Weeks 5-8:
Starting day 1 dose: 28 mg                          28 mg, 56 mg or 84 mg once weekly, all Subsequent doses:      28 mg, 56 mg or 84 mg        dose changes should be in 28 mg increments twice a week, all dose changes should be in 28 mg   From week 9: increments                   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 The need for continued treatment should be at the end of induction phase to determine need for reexamined periodically.
continued treatment.

Paediatric population
The safety and efficacy of Spravato in paediatric patients aged 17 years and younger have not been established. No data are available. There is no relevant use of Spravato in children less than 7 years of age.

Method of administration

This medicinal product is for nasal use only. The nasal spray device is a single-use device that delivers a total of 28 mg of esketamine, in two sprays (one spray per nostril). To prevent loss of medicinal product, the device should not be primed before use. It is intended for administration by the patient under the supervision of a healthcare professional, using 1 device (for a 28 mg dose), 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between use of each device.

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.