We will have limited operations from 15:00 Tuesday 24 December 2024 (AEDT) until Thursday 2 January 2025. Find out how to contact us during the holiday period.
Spravato
Sponsor
Device/Product name
Spravato
Active Ingredient
Esketamine hydrochloride
Date of decision
Published
Submission type
New chemical entity
ATC codes
N06AX27
Decision
Approved
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Spravato was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
| Description | Date |
|---|---|
| Submission dossier accepted and first round evaluation commenced | 2 January 2019 |
| First round evaluation completed | 11 July 2019 |
| Sponsor provides responses on questions raised in first round evaluation | 6 August 2019 |
| Second round evaluation completed | 12 September 2019 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 2 March 2020 |
| Sponsor's pre-Advisory Committee response | 13 March 2020 |
| Advisory Committee meeting | 2 and 3 April 2020 4 and 5 June 2020 |
| Registration decision (Outcome) | 10 September 2020 |
| Number of working days from submission dossier acceptance to registration decision* | 188 |
| Section 60 appeal decision (initial decision revoked) | 27 January 2021 |
| Registration decision (Section 60 - approval) | 5 March 2021 |
| Completion of administrative activities and registration on ARTG | 9 March 2021 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. This product will remain in the scheme for 5 years, starting on the date the product is first supplied in Australia.
Dose forms
Nasal spray solution
Strength
32.3 mg esketamine hydrochloride (equivalent to 28 mg of esketamine) per 2 actuations
Other ingredients
Citric acid monohydrate, disodium edetate, sodium hydroxide, water for injections
Containers
Vial assembled in nasal spray device
Pack sizes
1, 2 or 3 single-use nasal spray devices
Routes of administration
Nasal
Dosage
Spravato should be administered in conjunction with a newly initiated oral antidepressant (AD). During the Phase III clinical program patients were assigned a serotonin and norepinephrine reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) as the new oral antidepressant (see Section 5.1 Pharmacodynamic properties, clinical trials, in the Product Information).
Spravato will be provided by the supervising healthcare professional for the patient to self-administer under their direct supervision. A treatment session consists of nasal administration of Spravato and post administration observation under the supervision of a healthcare professional (see Section 4.4 Special warnings and precautions for use, in the Product Information).
Dosage - adults
The dosage recommendations for Spravato are shown in Table 1 of the Product Information. Recommended dosing consists of an induction phase (Weeks 1 to 4), followed by a maintenance phase (Week 5 onwards). Dose adjustments should be made based on efficacy and tolerability to the previous dose.
For further information refer to the Product Information.
Pregnancy category
B3Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Spravato (esketamine hydrochloride) was approved for the following therapeutic use:
Spravato is indicated for treatment resistant depression (Major Depressive Disorder in adults who have not responded adequately to at least two different antidepressants of adequate dose and duration to treat the current moderate to severe depressive episode).
Spravato is to be initiated in conjunction with a newly initiated oral antidepressant.
What is this medicine and how does it work
Esketamine, the S-enantiomer of racemic ketamine, is an antidepressant with a novel mechanism of action. It is a non-selective, non-competitive, antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.Putative aetiological contributors of depression, including stress and other conditions, are known to cause structural and functional impairment of synapses in brain regions involved with the regulation of mood and emotional behaviour. Evidence within the literature suggests that 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 that restore synaptic function in these brain regions. Unlike other antidepressant therapies, esketamine's primary antidepressant action does not directly involve monoamine, gamma-aminobutyric acid (GABA), or opioid receptors.
What post-market commitments will the sponsor undertake
- Spravato (esketamine hydrochloride) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Spravato must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date that the sponsor notifies the TGA of supply of the product.
- The Spravato European Union (EU)-risk management plan (RMP) (version 1.0 Succession 2, date 20 May 2019; data lock point 4 March 2018), with Australian specific Annex (version 0.2; date 27 June 2019), included with submission PM-2018-04814-1-1, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of risk management plans is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Unless agreed separately between the supplier who is the recipient of the approval and the TGA, the first report must be submitted to TGA no later than 15 calendar months after the date of the approval letter. The subsequent reports must be submitted no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of the approval letter. The annual submission may be made up of two PSURs each covering six months. If the sponsor wishes, the six monthly reports may be submitted separately as they become available.
If the product is approved in the EU during the three years period, reports can be provided in line with the published list of EU reference dates no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of the approval letter. The reports are to at least meet the requirements for PSURs as described in the European Medicines Agency's Guideline on Good Pharmacovigilance Practices (GVP) Module VII-periodic safety update report (Rev 1), Part VII.B Structures and processes. Note that submission of a PSUR does not constitute an application to vary the registration. Each report must have been prepared within ninety calendar days of the data lock point for that report.