Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most commonly observed adverse reactions in patients treated with Spravato were dizziness (31%), dissociation (27%), nausea (27%), headache (23%), somnolence (18%), dysgeusia (18%), vertigo (16%), hypoaesthesia (11%), vomiting (11%), and blood pressure increased (10%).

Tabulated list of adverse reactions

Adverse reactions reported with esketamine are listed in Table 4. 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).

Table 4:    List of adverse reactions
System Organ                                            Adverse Drug Reaction Class                                                           Frequency Very common                    Common                Uncommon                 Rare Psychiatric            dissociation            anxiety, euphoric mood,      psychomotor disorders                                      confusional state,           retardation, derealisation, irritability, emotional distress,
hallucination including      dysphoria visual hallucination,
agitation, illusion, panic attack, time perception altered


Nervous system          dizziness,              paraesthesia, sedation,      nystagmus, disorders               headache,               tremor, mental               psychomotor somnolence,             impairment, lethargy,        hyperactivity dysgeusia,              dysarthria, disturbance in hypoaesthesia           attention
Eye disorders                                   vision blurred
Ear and labyrinth       vertigo                 tinnitus, hyperacusis, disorders
Cardiac disorders                               tachycardia
Vascular disorders                              hypertension                 hypotension Respiratory,                                    nasal discomfort, throat                          respiratory thoracic and                                    irritation, oropharyngeal                         depression mediastinal                                     pain, nasal dryness disorders                                       including nasal crusting, nasal pruritus
Gastrointestinal        nausea, vomiting        hypoaesthesia oral, dry      salivary disorders                                       mouth                        hypersecretion Skin and                                        hyperhidrosis                cold sweat subcutaneous tissue disorders
Renal and urinary                               pollakiuria, dysuria, disorders                                       micturition urgency
General disorders                               feeling abnormal, feeling    gait disturbance and administration                              drunk, asthenia, crying, site conditions                                 feeling of body temperature change
Investigations          blood pressure increased

Long-term safety

Long-term safety was assessed in a Phase 3, multicentre, open-label extension study (TRD3008) in 1 148 adult patients with treatment-resistant Major Depressive Disorder representing 3 777 patient-years of exposure. Patients were treated with esketamine for a mean total duration of exposure of 42.9 months (up to 79 months) with 63% and 28% of patients receiving treatment at least 3 years and 5 years, respectively. The safety profile of esketamine was consistent with the known safety profile observed in the pivotal clinical trials. No new safety concerns were identified.

Description of selected adverse reactions

Dissociation
Dissociation (27%) was one of the most common psychological effects of esketamine. Other related terms included derealisation (2.2%), depersonalisation (2.2%), illusions (1.3%), 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.

Sedation/somnolence/respiratory depression
In clinical trials, adverse reactions of sedation (9.3%) and somnolence (18.2%) 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. During post-marketing use, rare cases of respiratory depression have been observed (see section 4.4).
Changes in blood pressure
In clinical trials, for treatment-resistant Major Depressive Disorder, 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
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, including a clinical trial with patients treated for a mean total duration of exposure of 42.9 months (up to 79 months), the effect of esketamine nasal spray on cognitive functioning was evaluated over time and performance remained stable.

Urinary tract symptoms
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. In a long-term clinical trial with patients treated for a mean total duration of exposure of 42.9 months (up to 79 months), no cases of interstitial cystitis were observed.


Reporting of suspected adverse reactions
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il