Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Spravato has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo and anxiety during the clinical trials (see section 4.8). These effects may impair attention, judgment, thinking, reaction speed and motor skills. At each treatment session, patients should be monitored under the supervision of a healthcare professional to assess when the patient is considered stable based on clinical judgement (see section 4.7).
Respiratory depression may occur at high doses following rapid intravenous injection of esketamine or ketamine when used for anaesthesia. No case of respiratory depression was observed in clinical trials with esketamine nasal spray (Spravato); rare cases of deep sedation have been reported. Concomitant use of Spravato with CNS depressants may increase the risk for sedation (see section 4.5). Close monitoring is required for sedation and respiratory depression.
Spravato can cause transient increases in systolic and/or diastolic blood pressure which peak at approximately 40 minutes after administration of the medicinal product and last approximately 1-2 hours (see section 4.8). A substantial increase in blood pressure could occur after any treatment session. Spravato is contraindicated in patients for whom an increase in blood pressure or intracranial pressure poses a serious risk (see section 4.3). Before prescribing Spravato, patients with other cardiovascular and cerebrovascular conditions should be carefully assessed to determine whether the potential benefits of Spravato outweigh its risks.
In patients whose blood pressure prior to dose administration is judged to be elevated (as a general guide: >140/90 mmHg for patients <65 years of age and >150/90 mmHg for patients ≥65 years of age), it is appropriate to adjust lifestyle and/or pharmacologic therapies to reduce blood pressure before starting treatment with Spravato. If blood pressure is elevated prior to Spravato administration a decision to delay Spravato therapy should take into account the balance of benefit and risk in individual patients.
Blood pressure should be monitored after dose administration. Blood pressure should be measured around 40 minutes post-dose and subsequently as clinically warranted until values decline. If blood pressure remains elevated for a prolonged period of time, assistance should promptly be sought from practitioners experienced in blood pressure management. Patients who experience symptoms of a hypertensive crisis should be referred immediately for emergency care.
Only initiate treatment with Spravato in patients with clinically significant or unstable cardiovascular or respiratory conditions if the benefit outweighs the risk. In these patients, Spravato should be administered in a setting where appropriate resuscitation equipment and healthcare professionals with training in cardiopulmonary resuscitation are available. Examples of conditions which should be considered include, but are not limited to:
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs, therefore, patients should be closely monitored. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.
Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of Spravato. Prior to prescribing Spravato, each patient’s risk for abuse or misuse should be assessed and patients receiving esketamine should be monitored for the development of behaviours or conditions of abuse or misuse, including drug seeking behaviour, while on therapy.
Dependence and tolerance have been reported with prolonged use of ketamine. In individuals who were dependent on ketamine, withdrawal symptoms of cravings, anxiety, shaking, sweating and palpitations have been reported upon discontinuing ketamine.
Ketamine, the racemic mixture of arketamine and esketamine, is a medicinal product that has been reported to be abused. The potential for abuse, misuse and diversion of Spravato is minimised due to the administration taking place under the direct supervision of a healthcare professional. Spravato contains esketamine and may be subject to abuse and diversion.
Spravato should be used with caution in patients with the following conditions. These patients should be carefully assessed before prescribing Spravato and treatment initiated only if the benefit outweighs the risk:
Elderly patients treated with Spravato may have a greater risk of falling once mobilised, therefore, these patients should be carefully monitored.
Due to expected increase in exposure and lack of clinical experience, Spravato is not recommended in patients with Child-Pugh class C (severe) hepatic impairment.
Hepatotoxicity has been reported with chronic ketamine use, therefore, the potential for such an effect due to long-term use of Spravato cannot be excluded.
Urinary tract and bladder symptoms have been reported with Spravato use (see section 4.8). It is recommended to monitor for urinary tract and bladder symptoms during the course of treatment and refer to an appropriate healthcare provider when symptoms persist.
Concomitant use of Spravato with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation, which therefore should be closely monitored.
Blood pressure should be closely monitored when Spravato is used concomitantly with psychostimulants (e.g., amphetamines, methylphenidate, modafanil, armodafinil) or other medicinal products that may increase blood pressure (e.g. xanthine derivatives, ergometrine, thyroid hormones, vasopressin, or MAOIs, such as, tranylcypromine, selegiline, phenelzine).
Spravato is not recommended during pregnancy and in women of childbearing potential not using contraception.
There are no or limited data on the use of esketamine in pregnant women. Animal studies have shown that ketamine, the racemic mixture of arketamine and esketamine, induces neurotoxicity in developing foetuses (see section 5.3). A similar risk with esketamine cannot be excluded.
If a woman becomes pregnant while being treated with Spravato, treatment should be discontinued, and the patient should be counselled about the potential risk to the foetus and clinical/therapeutic options as soon as possible.
It is unknown whether esketamine is excreted in human milk. Data in animals have shown excretion of esketamine in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Spravato therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Animal studies showed that fertility and reproductive capacities were not adversely affected by esketamine.
Spravato has a major influence on the ability to drive and use machines. In clinical studies, Spravato has been reported to cause somnolence, sedation, dissociative symptoms, perception disturbances, dizziness, vertigo and anxiety (see section 4.8). Before Spravato administration, patients should be instructed not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a vehicle or operating machinery, until the next day following a restful sleep (see section 4.4).
The most commonly observed adverse reactions in treatment-resistant depression patients treated with Spravato were dizziness (30%), nausea (27%), dissociation (26%), headache (24%), somnolence (18%), vertigo (18%), dysgeusia (17%), hypoaesthesia (11%), and vomiting (10%).
Adverse reactions reported with esketamine are listed in the table below. Within the designated system organ classes, adverse reactions are listed under headings of frequency, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Very common: dissociation
Common: euphoric mood, agitation, anxiety, illusion, irritability, panic attack, time perception altered, hallucination including visual hallucination, derealisation
Very common: dizziness, headache, dysgeusia, somnolence, hypoaesthesia
Common: mental impairment, tremor, lethargy, dysarthria, paraesthesia, sedation
Common: vision blurred
Very common: vertigo
Common: hyperacusis, tinnitus
Common: tachycardia
Common: hypertension
Common: nasal discomfort, nasal dryness including nasal crusting, nasal pruritus
Very common: nausea, vomiting
Common: dry mouth, hypoaesthesia oral
Uncommon: salivary hypersecretion
Common: hyperhidrosis
Common: pollakiuria, dysuria, micturition urgency
Common: feeling abnormal, feeling drunk, feeling of body temperature change
Common: blood pressure increased
Dissociation (26%) was one of the most common psychological effects of esketamine. Other related terms included derealisation (1.9%), depersonalisation (1.7%), illusions (1.5%), and distortion of time (1.2%). These adverse reactions were reported as transient and self-limited and occurred on the day of dosing. Dissociation was reported as severe in intensity at the incidence of less than 4% across studies. Dissociation symptoms typically resolved by 1.5 hours post-dose and the severity tended to reduce over time with repeated treatments.
Adverse reactions of sedation (9.1%) and somnolence (18.0%) were primarily mild or moderate in severity, occurred on the day of dosing and resolved spontaneously the same day. Sedative effects typically resolved by 1.5 hours post-dose. Rates of somnolence were relatively stable over time during long-term treatment. In the cases of sedation, no symptoms of respiratory distress were observed, and haemodynamic parameters (including vital signs and oxygen saturation) remained within normal ranges.
In clinical trials, increases in systolic and diastolic blood pressure (SBP and DBP) over time were about 7 to 9 mmHg in SBP and 4 to 6 mmHg in DBP at 40 minutes post-dose and 2 to 5 mmHg in SBP and 1 to 3 mmHg in DBP at 1.5 hours post-dose in patients receiving Spravato plus oral antidepressants (see section 4.4). The frequency of markedly abnormal blood pressure elevations of SBP (≥40 mmHg increase) ranged from 8% (<65 years) to 17% (≥65 years) and DBP (≥25 mmHg increase) ranged from 13% (<65 years) to 14% (≥65 years) in patients receiving esketamine plus oral antidepressant. The incidence of increased SBP (≥180 mmHg) was 3% and DBP (≥110 mmHg) was 4%.
Cognitive and memory impairment have been reported with long-term ketamine use or drug abuse. These effects did not increase over time and were reversible after discontinuing ketamine. In long-term clinical trials, the effect of esketamine nasal spray on cognitive functioning was evaluated over time and performance remained stable.
Cases of interstitial cystitis have been reported with daily and long-term ketamine use at high doses. In clinical studies with esketamine, there were no cases of interstitial cystitis, however a higher rate of lower urinary tract symptoms was observed (pollakiuria, dysuria, micturition urgency, nocturia, and cystitis) in esketamine-treated patients compared with placebo-treated patients.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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