Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Spravato, 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 (see section 5.1).
The decision to prescribe Spravato should be determined by a psychiatrist.
Spravato is intended to be self-administered by the patient under the direct supervision of a healthcare professional.
A treatment session consists of nasal administration of Spravato and a post-administration observation period. Both administration and post-administration observation of Spravato should be carried out in an appropriate clinical setting.
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 Spravato treatment should be considered (see section 4.4). Spravato 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, Spravato should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available (see section 4.4).
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 until the patient is considered clinically stable and ready to leave the healthcare setting (see section 4.4).
The dose recommendations for Spravato 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, Spravato dosing should be individualised to the lowest frequency to maintain remission/response.
Table 1. Recommended dosing for Spravato in adults <65 years:
| Induction phase | Maintenance 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 reexamined periodically. |
Table 2. Recommended dosing for Spravato in adults ≥65 years:
| Induction phase | Maintenance 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 reexamined periodically. |
After depressive symptoms improve, treatment is recommended for at least 6 months.
Since some patients may experience nausea and vomiting after administration of Spravato, 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).
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 Spravato administration.
In case one or two treatment sessions are missed, the next session should be scheduled when the next session was scheduled to occur based on current treatment frequency. If more than 2 treatment sessions have been missed, per clinical judgment, adjustment of the dose or frequency of Spravato may be clinically appropriate.
In elderly patients the initial Spravato dose 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.
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).
No dose adjustment is necessary in patients with mild to severe renal impairment. Patients on dialysis were not studied.
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: 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 reexamined periodically. |
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 in the indication for treatment-resistant depression.
Spravato 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.
If sneezing occurs immediately after administration, a replacement device should not be used.
If administration in the same nostril occurs, a replacement device should not be used.
Treatment discontinuation with Spravato does not require tapering off; based on data from clinical trials the risk of withdrawal symptoms is low.
The potential for overdose of Spravato by the patient is minimised due to the product’s design and the administration taking place under the supervision of a healthcare professional (see section 4.2).
The maximum single esketamine nasal spray dose tested in healthy volunteers was 112 mg which showed no evidence of toxicity and/or adverse clinical outcomes. However, compared to the recommended dose range, the 112-mg esketamine nasal spray dose was associated with higher rates of adverse reactions, including dizziness, hyperhidrosis, somnolence, hypoaesthesia, feeling abnormal, nausea and vomiting.
Life-threatening symptoms are expected based on experience with ketamine given at 25-fold the usual anaesthetic dose. Clinical symptoms are described as convulsions, cardiac arrhythmias, and respiratory arrest. Administration of a comparable supratherapeutic dose of esketamine by the intranasal route is unlikely to be feasible.
There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple medicinal products involvement should be considered. Management of Spravato overdose should consist of treating clinical symptoms and relevant monitoring. Close supervision and monitoring should continue until the patient recovers.
3 years.
This medicinal product does not require any special storage conditions.
Type-I glass vial with a chlorobutyl rubber stopper. The filled and stoppered vial is assembled into a manually-activated nasal spray device. The device dispenses two sprays.
Within each pack, each device is individually packaged in a sealed blister.
Pack sizes of 1, 2, 3, or 6 nasal spray devices.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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