Other
Sedation
- Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1)].
- Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2)].
- SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.3)].
- The effectiveness of SPRAVATO in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated [see Clinical Studies (14.2)]. Use of SPRAVATO does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of SPRAVATO.
- SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established.
- Assess blood pressure prior to dosing with SPRAVATO [see Warnings and Precautions (5.6)].
- If baseline blood pressure is elevated (e.g., >140 mmHg systolic, >90 mmHg diastolic), consider the risks of short term increases in blood pressure and benefit of SPRAVATO treatment [see Warnings and Precautions (5.6)]. Do not administer SPRAVATO if an increase in blood pressure or intracranial pressure poses a serious risk [see Contraindications (4)].
- After dosing with SPRAVATO, reassess blood pressure at approximately 40 minutes (which corresponds with the Cmax) and subsequently as clinically warranted.
- If blood pressure is decreasing and the patient appears clinically stable for at least two hours, the patient may be discharged at the end of the post-dose monitoring period; if not, continue to monitor [see Warnings and Precautions (5.6)].
- Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the SPRAVATO REMS Program prior to administration.
- SPRAVATO must be administered under the direct observation of a healthcare provider.
- Patients must be monitored by a healthcare provider for at least 2 hours after administration of SPRAVATO.
Dissociation
Because of the risks of sedation and dissociation, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Warnings and Precautions (5.1, 5.2)].
Abuse and Misuse
Because of the risks of serious adverse outcomes resulting from sedation, dissociation, and abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.4)].
Suicidal Thoughts and Behaviors
Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.5)].
Limitations of Use:
Blood Pressure Assessment Before and After Treatment
Food and Liquid Intake Recommendations Prior to Administration
Because some patients may experience nausea and vomiting after administration of SPRAVATO [see Adverse Reactions (6.1)], advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration.
Nasal Corticosteroid or Nasal Decongestant
Patients who require a nasal corticosteroid or nasal decongestant on a dosing day should administer these medications at least 1 hour before SPRAVATO [see Clinical Pharmacology (12.3)].
Short-Term Cognitive Impairment
In a study in healthy volunteers, a single dose of SPRAVATO caused cognitive performance decline 40 minutes post-dose. Compared to placebo-treated subjects, SPRAVATO-treated subjects required a greater effort to complete cognitive tests at 40 minutes post-dose. Cognitive performance and mental effort were comparable between SPRAVATO and placebo at 2 hours post-dose. Sleepiness was comparable after 4 hours post-dose.
Long-Term Cognitive Impairment
Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. No adverse effects of SPRAVATO nasal spray on cognitive functioning were observed in a one-year open-label safety study; however, the long-term cognitive effects of SPRAVATO have not been evaluated beyond one year.
Treatment-Resistant Depression
SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14.1)] from five Phase 3 studies (3 short-term and 2 long-term studies) and one Phase 2 dose-ranging study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 479 (30%) received at least 6 months of treatment, and 178 (11%) received at least 12 months of treatment.
Adverse Reactions Leading to Discontinuation of Treatment
In short-term studies in adults <65 years old (Study 1 pooled with another 4-week study), the proportion of patients who discontinued treatment because of an adverse reaction was 4.6% in patients who received SPRAVATO plus oral AD compared to 1.4% for patients who received placebo nasal spray plus oral AD. For adults ≥65 years old, the proportions were 5.6% and 3.1%, respectively. In Study 2, a long-term maintenance study, the discontinuation rates because of an adverse reaction were similar for patients receiving SPRAVATO plus oral AD and placebo nasal spray plus oral AD in the maintenance phase, at 2.6% and 2.1%, respectively. Across all Phase 3 studies, adverse reactions leading to SPRAVATO discontinuation in more than 2 patients were (in order of frequency): anxiety (1.2%), depression (0.9%), blood pressure increased (0.6%), dizziness (0.6%), suicidal ideation (0.5%), dissociation (0.4%), nausea (0.4%), vomiting (0.4%), headache (0.3%), muscular weakness (0.3%), vertigo (0.2%), hypertension (0.2%), panic attack (0.2%) and sedation (0.2%).
Most Common Adverse Reactions
The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.
Table 3 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD at any dose and greater than patients treated with placebo nasal spray plus oral AD.
| SPRAVATO + Oral AD (N=346) | Placebo + Oral AD (N=222) | |
|---|---|---|
| Cardiac disorders | ||
| Tachycardia The following terms were combined: | 6 (2%) | 1 (0.5%) |
| Ear and labyrinth disorders | ||
| Vertigo | 78 (23%) | 6 (3%) |
| Gastrointestinal disorders | ||
| Nausea | 98 (28%) | 19 (9%) |
| Vomiting | 32 (9%) | 4 (2%) |
| Diarrhea | 23 (7%) | 13 (6%) |
| Dry mouth | 19 (5%) | 7 (3%) |
| Constipation | 11 (3%) | 3 (1%) |
| General disorders and administration site conditions | ||
| Feeling drunk | 19 (5%) | 1 (0.5%) |
| Feeling abnormal | 12 (3%) | 0 (0%) |
| Investigations | ||
| Blood pressure increased | 36 (10%) | 6 (3%) |
| Nervous system disorders | ||
| Dizziness | 101 (29%) | 17 (8%) |
| Sedation | 79 (23%) | 21 (9%) |
| Headache | 70 (20%) | 38 (17%) |
| Dysgeusia | 66 (19%) | 30 (14%) |
| Hypoesthesia | 63 (18%) | 5 (2%) |
| Lethargy | 37 (11%) | 12 (5%) |
| Dysarthria | 15 (4%) | 0 (0%) |
| Tremor | 12 (3%) | 2 (1%) |
| Mental impairment | 11 (3%) | 2 (1%) |
| Psychiatric disorders | ||
| Dissociation | 142 (41%) | 21 (9%) |
| Anxiety | 45 (13%) | 14 (6%) |
| Insomnia | 29 (8%) | 16 (7%) |
| Euphoric mood | 15 (4%) | 2 (1%) |
| Renal and urinary disorders | ||
| Pollakiuria | 11 (3%) | 1 (0.5%) |
| Respiratory, thoracic and mediastinal disorders | ||
| Nasal discomfort | 23 (7%) | 11 (5%) |
| Throat irritation | 23 (7%) | 9 (4%) |
| Oropharyngeal pain | 9 (3%) | 5 (2%) |
| Skin and subcutaneous tissue disorders | ||
| Hyperhidrosis | 14 (4%) | 5 (2%) |
Depressive Symptoms in Patients with Major Depressive Disorder with Acute Suicidal Ideation or Behavior
SPRAVATO was evaluated for safety in 262 adults for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior [see Clinical Studies (14.2)] from two Phase 3 studies (Study 3 and Study 4) and one Phase 2 study. Of all SPRAVATO-treated patients in the completed Phase 3 studies, 184 (81%) received all eight doses over a 4-week treatment period.
Adverse Reactions Leading to Discontinuation of Treatment
In short-term studies in adults (pooled Study 3 and Study 4), the proportion of patients who discontinued treatment because of an adverse reaction was 6.2% for patients who received SPRAVATO plus oral AD compared to 3.6% for patients who received placebo nasal spray plus oral AD. Adverse reactions leading to SPRAVATO discontinuation in more than 1 patient were (in order of frequency): dissociation-related events (2.6%), blood pressure increased (0.9%), dizziness-related events (0.9%), nausea (0.9%), and sedation-related events (0.9%).
Most Common Adverse Reactions
The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, sedation, blood pressure increased, hypoesthesia, vomiting, euphoric mood, and vertigo. Table 4 shows the incidence of adverse reactions that occurred in patients treated with SPRAVATO plus oral AD and greater than patients treated with placebo nasal spray plus oral AD.
| SPRAVATO + Oral AD (N=227) | Placebo + Oral AD (N=225) | |
|---|---|---|
| Cardiac disorders | ||
| Tachycardia The following terms were combined: | 8 (4%) | 2 (1%) |
| Ear and labyrinth disorders | ||
| Vertigo | 14 (6%) | 1 (0.4%) |
| Gastrointestinal disorders | ||
| Nausea | 61 (27%) | 31 (14%) |
| Vomiting | 26 (11%) | 12 (5%) |
| Constipation | 22 (10%) | 14 (6%) |
| Dry mouth | 8 (4%) | 6 (3%) |
| Toothache | 5 (2%) | 2 (1%) |
| General disorders and administration site conditions | ||
| Feeling drunk | 8 (4%) | 1 (0.4%) |
| Feeling of relaxation | 5 (2%) | 3 (1%) |
| Investigations | ||
| Blood pressure increased | 34 (15%) | 14 (6%) |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 5 (2%) | 1 (0.4%) |
| Nervous system disorders | ||
| Dizziness | 103 (45%) | 34 (15%) |
| Sedation | 66 (29%) | 27 (12%) |
| Dysgeusia | 46 (20%) | 29 (13%) |
| Hypoesthesia | 30 (13%) | 4 (2%) |
| Lethargy | 10 (4%) | 4 (2%) |
| Confusional state | 5 (2%) | 0 (0%) |
| Psychiatric disorders | ||
| Dissociation | 108 (48%) | 30 (13%) |
| Anxiety | 34 (15%) | 20 (9%) |
| Euphoric mood | 17 (7%) | 1 (0.4%) |
| Intentional self-injury | 7 (3%) | 3 (1%) |
| Dysphoria | 5 (2%) | 0 (0%) |
| Renal and urinary disorders | ||
| Pollakiuria | 5 (2%) | 2 (1%) |
| Respiratory, thoracic and mediastinal disorders | ||
| Oropharyngeal pain | 10 (4%) | 3 (1%) |
| Throat irritation | 9 (4%) | 5 (2%) |
| Skin and subcutaneous tissue disorders | ||
| Hyperhidrosis | 11 (5%) | 5 (2%) |
Sedation
Sedation was evaluated by adverse event reports and the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). In the MOAA/S, 5 means "responds readily to name spoken in normal tone" and 0 means "no response after painful trapezius squeeze." Any decrease in MOAA/S from pre-dose is considered to indicate the presence of sedation, and such a decrease occurred in a higher number of patients on SPRAVATO than placebo during the short-term TRD studies. Dose-related increases in the incidence of sedation (MOAA/S score <5) were observed in a fixed-dose TRD study [see Warnings and Precautions (5.1)]. Table 5 presents the incidence of sedation (MOAA/S score <5) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD.
| Patients <65 years | Patients ≥65 years | ||||
|---|---|---|---|---|---|
| Placebo + Oral AD | SPRAVATO + Oral AD | Placebo + Oral AD | SPRAVATO + Oral AD | ||
| 56 mg | 84 mg | 28 to 84 mg | |||
| Number of patients Patients who were evaluated with MOAA/S | N=112 | N=114 | N=114 | N=63 | N=72 |
| Sedation (MOAA/S score <5) | 11% | 50% | 61% | 19% | 49% |
In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, there was a higher incidence of sedation (MOAA/S score <5) in patients treated with SPRAVATO plus oral AD compared to patients treated with placebo plus oral AD, similar to the TRD study results in Table 5.
Dissociation/Perceptual Changes
SPRAVATO can cause dissociative symptoms (including derealization and depersonalization) and perceptual changes (including distortion of time and space, and illusions). In clinical trials, dissociation was transient and occurred on the day of dosing. Dissociation was evaluated by adverse event reports and the Clinician-Administered Dissociative States Scale (CADSS). A CADSS total score of more than 4 indicates the presence of dissociative symptoms, and such an increase to a score of 4 or more occurred in a higher number of patients on SPRAVATO compared to placebo during the short-term TRD studies. Dose-related increases in the incidence of dissociative symptoms (CADSS total score >4 and change >0) were observed in a fixed-dose TRD study [see Warnings and Precautions (5.2)]. Table 6 presents the incidence of dissociation (CADSS total score >4 and change >0) in a fixed-dose study with adult patients <65 years of age with TRD and a flexible-dose study with patients ≥65 years of age with TRD.
| Patients <65 years | Patients ≥65 years | ||||
|---|---|---|---|---|---|
| Placebo + Oral AD | SPRAVATO + Oral AD | Placebo + Oral AD | SPRAVATO + Oral AD | ||
| 56 mg | 84 mg | 28 to 84 mg | |||
| Number of patients Number of patients who were evaluated with CADSS | N=113 | N=113 | N=116 | N=65 | N=72 |
| CADSS total score >4 and change >0 | 5% | 61% | 69% | 12% | 75% |
In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral AD also demonstrated a higher number (84%) with dissociation (CADSS total score >4 and change >0) compared to patients treated with placebo plus oral AD (16%).
Increase in Blood Pressure
The mean placebo-adjusted 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 with TRD receiving SPRAVATO plus oral antidepressants [see Warnings and Precautions (5.6)]. Table 7 presents increases in blood pressure in short-term trials with patients <65 years of age and ≥65 years of age with TRD.
| Patients <65 years | Patients ≥65 years | |||
|---|---|---|---|---|
| SPRAVATO + Oral AD N=346 | Placebo + Oral AD N=222 | SPRAVATO + Oral AD N=72 | Placebo + Oral AD N=65 | |
| Systolic blood pressure | ||||
| ≥180 mmHg | 9 (3%) | --- | 2 (3%) | 1 (2%) |
| ≥40 mmHg increase | 29 (8%) | 1 (0.5%) | 12 (17%) | 1 (2%) |
| Diastolic blood pressure | ||||
| ≥110 mmHg | 13 (4%) | 1 (0.5%) | --- | --- |
| ≥25 mmHg increase | 46 (13%) | 6 (3%) | 10 (14%) | 2 (3%) |
In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients treated with SPRAVATO plus oral antidepressants demonstrated similar mean placebo-adjusted increases in SBP and DBP compared to patient with TRD, as well as similar rates of increases to SBP ≥180 mmHg or ≥40 mmHg increases in SBP, and similar rates of increases to DBP ≥110 mmHg or ≥25 mmHg increases in DBP, compared to the TRD study results in Table 7.
Nausea and Vomiting
SPRAVATO can cause nausea and vomiting. Most of these events occurred on the day of dosing and resolved the same day, with the median duration not exceeding 1 hour in most subjects across dosing sessions. Rates of reported nausea and vomiting decreased over time across dosing sessions from the first week of treatment in the short-term studies, as well as over time with long-term treatment. Table 8 presents the incidence and severity of nausea and vomiting in a short-term study with patients with TRD.
| Nausea | Vomiting | ||||
|---|---|---|---|---|---|
| Treatment (+ Oral AD) | |||||
| N | All | Severe | All | Severe | |
| SPRAVATO 56 mg | 115 | 31 (27%) | 0 | 7 (6%) | 0 |
| SPRAVATO 84 mg | 116 | 37 (32%) | 4 (3%) | 14 (12%) | 3 (3%) |
| Placebo Nasal Spray | 113 | 12 (11%) | 0 | 2 (2%) | 0 |
In studies for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, patients demonstrated similar incidence and severity of reported nausea and vomiting compared to the TRD study results described above.
Sense of Smell
Sense of smell was assessed over time; no difference was observed between patients treated with SPRAVATO plus oral AD and those treated with placebo nasal spray plus oral AD during the double-blind maintenance phase of Study 2 [see Clinical Studies (14.1)].
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Risk Summary
SPRAVATO is not recommended during pregnancy. There are insufficient data on SPRAVATO use in pregnant women to draw conclusions about any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on published findings from pregnant animals treated with ketamine, the racemic mixture of arketamine and esketamine, SPRAVATO may cause fetal harm when administered to pregnant women (see Data). Advise pregnant women of the potential risk to an infant exposed to SPRAVATO in utero. There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations). If a woman becomes pregnant while being treated with SPRAVATO, treatment with esketamine should be discontinued and the patient should be counseled about the potential risk to the fetus.
Published studies in pregnant primates demonstrate that the administration of drugs that block N-methyl-D-aspartate (NMDA) receptors during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [see Use in Specific Populations (8.2)].
In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted at maternally toxic doses when ketamine was intranasally administered with a No Observed Adverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at the maximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasal administration of esketamine to pregnant rats during pregnancy and lactation at exposures that were similar to those at the MRHD resulted in a delay in sensorimotor development in pups during the preweaning period and a decrease in motor activity in the post-weaning period.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo-Fetal Risk
A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Data
Animal Data
Based on published data, when female monkeys were treated intravenously with racemic ketamine at anesthetic dose levels in the third trimester of pregnancy, neuronal cell death was observed in the brains of their fetuses. This period of brain development translates into the third trimester of human pregnancy. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.
Racemic ketamine was administered intranasally to pregnant rats during the period of organogenesis at doses of 15, 50, and 150 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) for embryo-fetal toxicity in rats was the highest dose of 150 mg/kg/day. Estimating 50% of the exposure to be from esketamine, the NOAEL associated with esketamine plasma exposure (AUC) is 12-times the AUC exposure at the MRHD of 84 mg/day. In pregnant rabbits, racemic ketamine was administered intranasally from gestational day 6 to 18 at doses of 10, 30, and 100 mg/kg/day. The high dose was lowered from 100 to 50 mg/kg after 5 days of dosing due to excessive mortality in the pregnant rabbits. Skeletal malformations were observed at doses ≥ 30mg/kg/day, which were maternally toxic. The NOAEL for skeletal malformations was associated with a plasma esketamine exposure (AUC) that was 0.3 times the AUC exposure at MRHD of 84 mg/day.
Administration of esketamine to pregnant rats during pregnancy and lactation at intranasal doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat) produced AUC exposures 0.07, 0.5, and 0.7 times the MRHD of 84 mg/day, respectively. Maternal toxicity was observed at doses ≥ 15 mg/kg/day. In addition, a dose-dependent delay in the age of attainment of Preyer response reflex was observed in pups at all doses during the preweaning period. This sensory/motor developmental measure was tested starting on postnatal day (PND) 9, and the effect normalized by PND 19 in treatment groups as compared with PND 14 for the majority of the control animals. There is no NOAEL for this delay in sensory/motor response observed in pups during the preweaning period. During the postweaning period, a decrease in motor activity was observed at doses ≥ 15 mg/kg which is 0.5-times the human exposure at the MRHD of 84 mg/day. The NOAEL for maternal toxicity and decreased motor activity during the postweaning period was 4.5 mg/kg/day which was associated with a plasma exposure (AUC) that was 0.07-times the AUC exposure at MRHD of 84 mg/day.
Risk Summary
Esketamine is present in human milk. There are no data on the effects of SPRAVATO on the breastfed infant or on milk production. Published studies in juvenile animals report neurotoxicity (see Data). Because of the potential for neurotoxicity, advise patients that breast-feeding is not recommended during treatment with SPRAVATO.
Data
Published juvenile animal studies demonstrate that the administration of drugs that block NMDA receptors, such as ketamine, during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but this window may extend out to approximately 3 years of age in humans.
Contraception
Based on published animal reproduction studies, SPRAVATO may cause embryo-fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. However, it is not clear how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential during treatment with SPRAVATO.
Abuse Potential Study
A cross-over, double-blind abuse potential study of SPRAVATO and ketamine was conducted in recreational polydrug users (n=34) who had experience with perception-altering drugs, including ketamine. Ketamine, the racemic mixture of arketamine and esketamine, is a Schedule III controlled substance and has known abuse potential. In this study, the mean "Drug Liking at the Moment" and "Take Drug Again" scores for single doses of intranasal SPRAVATO (84 mg and 112 mg – the maximum recommended dose and 1.3 times the maximum recommended dose, respectively) were similar to these scores in the intravenous ketamine (0.5 mg/kg infused over 40 minutes) control group. However, these scores were greater in the SPRAVATO and ketamine groups compared to the placebo group. The 112 mg dose of intranasal SPRAVATO was associated with significantly higher scores for "Hallucinating," "Floating," "Detached," and "Spaced Out" than the 84 mg dose of intranasal SPRAVATO and the intravenous ketamine dose.
Management of Overdosage
There is no specific antidote for esketamine overdose. In the case of overdose, the possibility of multiple drug involvement should be considered. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800-222-1222 or www.poison.org).
Cardiac Electrophysiology
The effect of SPRAVATO (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. A large increase in heart rate (i.e., >10 bpm) was observed in both intranasal and intravenous esketamine treatment groups. The totality of evidence from the nonclinical and clinical data indicates a lack of clinically relevant QTc prolongation at the therapeutic dose of esketamine.
Absorption
The mean absolute bioavailability is approximately 48% following nasal spray administration.
The time to reach maximum esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of a treatment session.
The inter-subject variability of esketamine ranges from 27% to 66% for Cmax and 18% to 45% for AUC∞. The intra-subject variability of esketamine is approximately 15% for Cmax and 10% for AUC∞.
Distribution
The mean steady-state volume of distribution of esketamine administered by the intravenous route is 709 L.
Protein binding of esketamine was approximately 43% to 45%.
The brain-to-plasma ratio of noresketamine is 4- to 6-times lower than that of esketamine.
Elimination
After Cmax was reached following intranasal administration, the decline in plasma esketamine concentrations was biphasic, with rapid decline for the initial 2 to 4 hours and a mean terminal half-life (t1/2) that ranged from 7 to 12 hours. The mean clearance of esketamine is approximately 89 L/hour following intravenous administration. The elimination of the major metabolite, noresketamine, from plasma is slower than esketamine. The decline of noresketamine plasma concentrations is biphasic, with rapid decline for the initial 4 hours and a mean terminal t1/2 of approximately 8 hours.
Metabolism
Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19. Noresketamine is metabolized via CYP-dependent pathways and certain subsequent metabolites undergo glucuronidation.
Excretion
Less than 1% of a dose of nasal esketamine is excreted as unchanged drug in urine. Following intravenous or oral administration, esketamine-derived metabolites were primarily recovered in urine (≥ 78% of a radiolabeled dose) and to a lesser extent in feces (≤ 2% of a radiolabeled dose).
Specific Populations
Exposures of esketamine in specific populations are summarized in Figure 1. No significant differences in the pharmacokinetics of SPRAVATO nasal spray were observed for sex and total body weight (>39 to 170 kg) based on population PK analysis. There is no clinical experience with SPRAVATO nasal spray in patients on renal dialysis or with severe (Child-Pugh class C) hepatic impairment.
Figure 1: Effect of Specific Populations on the Pharmacokinetics of Esketamine
Figure 1 (Spravato 10)
Drug Interaction Studies
The effect of other drugs on the exposures of intranasally administered esketamine are summarized in Figure 2. The effect of SPRAVATO on the exposures of other drugs are summarized in Figure 3. Based on these results, none of the drug-drug interactions are clinically significant.
Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Esketamine
Figure 2 (Spravato 11)
Figure 3: Effect of Esketamine on the Pharmacokinetics of Co-Administered Drugs
Figure 3 (Spravato 12)
In Vitro Studies
Enzyme Systems: Esketamine has modest induction effects on CYP2B6 and CYP3A4 in human hepatocytes. Esketamine and its major metabolites do not induce CYP1A2. Esketamine and its major circulating metabolites did not show inhibition potential against CYPs and UGTs, except for a weak reversible inhibition of noresketamine on CYP3A4.
Transporter Systems: Esketamine is not a substrate of transporters P-glycoprotein (P-gp; multidrug resistance protein 1), breast cancer resistance protein (BCRP), or organic anion transporter (OATP) 1B1, or OATP1B3. Esketamine and its major circulating metabolites do not inhibit these transporters or multi-drug and toxin extrusion 1 (MATE1) and MATE2-K, or organic cation transporter 2 (OCT2), OAT1, or OAT3.
Carcinogenesis
Once-daily intranasal administration of esketamine at doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat) did not increase the incidence of tumors in a 2-year rat carcinogenicity study. At the highest dose, the AUC exposure to esketamine was lower than the human exposure (AUC) at the maximum recommended human dose (MRHD) of 84 mg. Once-daily subcutaneous administration of esketamine up to 75 mg/kg/day (reduced to 40 mg/kg/day during week 17) did not increase the incidence of tumors in a 6-month study in transgenic (Tg.rasH2) mice.
Mutagenesis
Esketamine was not mutagenic with or without metabolic activation in the Ames test. Genotoxic effects with esketamine were seen in a screening in vitro micronucleus test in the presence of metabolic activation. However, intravenously-administered esketamine was devoid of genotoxic properties in an in vivo bone marrow micronucleus test in rats and an in vivo Comet assay in rat liver cells.
Impairment of Fertility
Esketamine was administered intranasally to both male and female rats before mating, throughout the mating period, and up to day 7 of gestation at doses equivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat), which are approximately 0.05, 0.3, and 0.6-times the maximum recommended human dose (MRHD) of 84 mg/day based on mean AUC exposures, respectively. Estrous cycle irregularities were observed at the high dose of 45 mg/kg/day and increased time to mate was observed at doses ≥ 15 mg/kg/day without an overall effect on mating or fertility indices. The No Observed Adverse Effect Level (NOAEL) for mating and fertility is 45 mg/kg/day which is 0.6 times the esketamine exposures at MRHD of 84 mg/day.
Neurotoxicity
In a single-dose neuronal toxicity study where esketamine was administered intranasally to adult female rats, there were no findings of neuronal vacuolation in the brain up to an estimated dose equivalent of 45 mg/kg for a 200-gram rat with a safety margin of 1.8 and 4.5 times the clinical exposures for AUC and Cmax, respectively, to the MRHD of 84 mg/day. In a second single-dose neurotoxicity study conducted with intranasally administered esketamine to adult female rats, there were no findings of neuronal necrosis up to a dose equivalent of 270 mg/kg for a 200-gram rat which has a safety margin of 18-fold and 23-fold, respectively, to AUC and Cmax exposures at the MRHD of 84 mg/day. Neuronal vacuolation was not examined in this study.
In a single-dose neuronal toxicity study in adult rats, subcutaneously administered racemic ketamine caused neuronal vacuolation in layer I of the retrosplenial cortex of the brain without neuronal necrosis at a dose of 60 mg/kg. The NOAEL for vacuolation in this study was 15 mg/kg. Estimating 50% of the exposure to be from esketamine, the NOAEL for neuronal vacuolation is 1.6-times and 4.5-times and the NOAEL for neuronal necrosis is 10-times and 16-times exposures, respectively, for AUC and Cmax to the clinical exposure at the MRHD of 84 mg/day. The relevance of these findings to humans is unknown.
Short-Term Study
SPRAVATO was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week), Phase 3 study (Study 1; NCT02418585) in adult patients 18 to <65 years old with treatment-resistant depression (TRD). Patients in Study 1 met DSM-5 criteria for major depressive disorder (MDD) and in the current depressive episode, had not responded adequately to at least two different antidepressants of adequate dose and duration. After discontinuing prior antidepressant treatments, patients in Study 1 were randomized to receive twice weekly doses of intranasal SPRAVATO (flexible dose; 56 mg or 84 mg) or intranasal placebo. All patients also received open-label concomitant treatment with a newly initiated daily oral antidepressant (AD) (duloxetine, escitalopram, sertraline, or extended-release venlafaxine as determined by the investigator based on patient's prior treatment history). SPRAVATO could be titrated up to 84 mg starting with the second dose based on investigator discretion.
The demographic and baseline disease characteristics of patients in Study 1 were similar for the SPRAVATO and placebo nasal spray groups. Patients had a median age of 47 years (range 19 to 64 years) and were 62% female, 93% Caucasian, and 5% Black. The newly initiated oral AD was an SSRI in 32% of patients and an SNRI in 68% of patients.
In Study 1, the primary efficacy measure was change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at the end of the 4-week double-blind induction phase. The MADRS is a ten-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression. SPRAVATO plus a newly initiated oral AD demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus a newly initiated oral AD (see Table 9).
| Treatment Group | Number of Patients | Mean Baseline Score (SD) | LS Mean (SE) Change from Baseline to end of Week 4 | LS Mean Difference (95% CI) Difference (SPRAVATO + Oral AD minus Placebo nasal spray + Oral AD) in least-squares mean change from baseline |
|---|---|---|---|---|
| SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval; AD=antidepressant | ||||
| SPRAVATO (56 mg or 84 mg) + Oral AD SPRAVATO + Oral AD was statistically significantly superior to placebo nasal spray + oral AD | 114 | 37.0 (5.7) | -19.8 (1.3) | -4.0 (-7.3; -0.6) |
| Placebo nasal spray + Oral AD | 109 | 37.3 (5.7) | -15.8 (1.3) | - |
Time Course of Treatment Response
Figure 4 shows the time course of response for the primary efficacy measure (MADRS) in Study 1. Most of SPRAVATO's treatment difference compared to placebo was observed at 24 hours. Between 24 hours and Day 28, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 28. At Day 28, 67% of the patients randomized to SPRAVATO were receiving 84 mg twice weekly.
| Figure 4: Least Squares Mean Change from Baseline in MADRS Total Score Over Time in Patients with TRD in Study 1 Note: In this flexible-dose study, dosing was individualized based on efficacy and tolerability. Few subjects (<10%) had reduction in SPRAVATO dosage from 84 mg to 56 mg twice weekly. (Full Analysis Set) |
 Figure 4 (Spravato 13) |
Treatment-Resistant Depression – Long-term Study
Study 2 (NCT02493868) was a long-term randomized, double-blind, parallel-group, multicenter maintenance-of-effect study in adults 18 to <65 years of age who were known remitters and responders to SPRAVATO. Patients in this study were responders in one of two short-term controlled trials (Study 1 and another 4-week study) or in an open-label direct-enrollment study in which they received flexibly-dosed SPRAVATO (56 mg or 84 mg twice weekly) plus daily oral AD in an initial 4-week phase.
Stable remission was defined as a MADRS total score ≤ 12 for at least 3 of the last 4 weeks. Stable response was defined as a MADRS total score reduction ≥ 50% for the last 2 weeks of optimization and not in remission. After at least 16 initial weeks of treatment with SPRAVATO and an oral AD, stable remitters and stable responders were randomized separately to continue intranasal treatment with SPRAVATO or switch to placebo nasal spray, in both cases with continuation of their oral AD. The primary study endpoint was time to relapse in the stable remitter group. Relapse was defined as a MADRS total score ≥22 for 2 consecutive weeks or hospitalization for worsening depression or any other clinically relevant event indicative of relapse.
The demographic and baseline disease characteristics of the two groups were similar. Patients had a median age of 48 years (range 19 to 64 years) and were 66% female, 90% Caucasian, and 4% Black.
Patients in stable remission who continued treatment with SPRAVATO plus oral AD experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on placebo nasal spray plus an oral AD (see Figure 5).
| Figure 5: Time to Relapse in Patients with TRD in Stable Remission in Study 2 Note: The estimated hazard ratio (95% CI) of SPRAVATO + Oral AD relative to Placebo nasal spray + Oral AD based on weighted estimates was 0.49 (95% CI: 0.29, 0.84). However, the hazard ratio did not appear constant throughout the trial. (Full Analysis Set) |
 Figure 5 (Spravato 14) |
Time to relapse was also significantly delayed in the stable responder population. These patients experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus oral AD (see Figure 6).
| Figure 6: Time to Relapse in Patients in Stable Response in Patients with TRD in Study 2 Note: The estimated hazard ratio (95% CI) of SPRAVATO + Oral AD relative to Placebo nasal spray + Oral AD based on Cox proportional hazards model was 0.30 (95% CI: 0.16, 0.55). (Full Analysis Set) |
 Figure 6 (Spravato 15) |
In Study 2, based on depressive symptomatology, the majority of stable remitters (69%) received every-other-week dosing for the majority of time during the maintenance phase; 23% of stable remitters received weekly dosing. Among stable responders, 34% received every-other-week dosing and 55% received weekly dosing the majority of time during the maintenance phase. Of the patients randomized to SPRAVATO, 39% received the 56 mg dose and 61% received the 84 mg dose.
Time Course of Treatment Response
In both Study 3 and Study 4, SPRAVATO's treatment difference compared to placebo was observed starting at 4 hours. Between 4 hours and Day 25, both the SPRAVATO and placebo groups continued to improve; the difference between the groups generally remained but did not appear to increase over time through Day 25. Figure 7 depicts time course of the primary efficacy measure of change in MADRS total score from Study 3.
Figure 7: Least Squares Mean Change from Baseline in MADRS Total Score Over Time in Study 3 (Full Analysis Set)
Figure 7 (Spravato 15a)
* Note: In Study 3, after the first dose, a one-time dose reduction to SPRAVATO 56 mg was allowed for patients unable to tolerate the 84 mg dose. Approximately 19% of patients had reduction in SPRAVATO dosage from 84 mg to 56 mg twice weekly.
Effects on Driving
Two studies were conducted to assess the effects of SPRAVATO on driving skills; one study in adult patients with major depressive disorder (Study 5) and one study in healthy subjects (Study 6). On-road driving performance was assessed by the mean standard deviation of the lateral position (SDLP), a measure of driving impairment.
A single-blind, placebo-controlled study in 25 adult patients with major depressive disorder evaluated the effects of a single 84 mg dose of intranasal SPRAVATO on next day driving and the effect of repeated administration of 84 mg of intranasal SPRAVATO on same-day driving performance (Study 5). For the single dose treatment phase, an ethanol-containing beverage was used as a positive control. The SDLP after administration of single 84 mg dose of SPRAVATO nasal spray was similar to placebo 18 hours post-dose. For the multiple dose treatment phase, the SDLP after repeated administration of 84 mg intranasal SPRAVATO was similar to placebo 6 hours post-dose on Day 11, Day 18, and Day 25.
A randomized, double-blind, cross-over, placebo-controlled study in 23 healthy subjects evaluated the effects of a single 84-mg dose of esketamine nasal spray on driving (Study 6). Mirtazapine (30 mg) was used as a positive control. Driving performance was assessed at 8 hours after SPRAVATO or mirtazapine administration. The SDLP 8 hours after SPRAVATO nasal spray administration was similar to placebo. Two subjects discontinued the driving test after receiving SPRAVATO because of a perceived inability to drive after experiencing post-dose adverse reactions; one subject reported pressure behind the eyes and paresthesia of the hands and feet, the other reported headache with light sensitivity and anxiety.
Disposal
SPRAVATO nasal spray devices must be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.
Sedation and Dissociation
Inform patients that SPRAVATO has potential to cause sedation, dissociative symptoms, perception disturbances, dizziness, vertigo, and anxiety. Advise patients that they will need to be observed by a healthcare provider until these effects resolve [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].
Potential for Abuse, Misuse, and Dependence
Advise patients that SPRAVATO is a federally controlled substance because it can be abused or lead to dependence [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9)].
SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)
SPRAVATO is available only through a restricted program called the SPRAVATO REMS [see Warnings and Precautions (5.4)]. Inform the patient of the following notable requirements:
Suicidal Thoughts and Behaviors
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted [see Boxed Warning and Warnings and Precautions (5.5)].
Increases in Blood Pressure
Advise patients that SPRAVATO can cause increases in blood pressure. Inform patients that after treatment sessions they should be advised that they may need to be observed by a healthcare provider until these effects resolve [see Warnings and Precautions (5.6)].
Impaired Ability to Drive and Operate Machinery
Caution patients that SPRAVATO may impair their ability to drive or operate machinery. Instruct patients not to engage in potentially hazardous activities requiring complete mental alertness and motor coordination such as driving a motor vehicle or operating machinery until the next day after a restful sleep. Advise patients that they will need someone to drive them home after each treatment session [see Warnings and Precautions (5.8)].
Pregnancy
Advise pregnant women and women of reproductive potential of the potential risk to a fetus. Advise patients to notify their healthcare provider if they are pregnant or intend to become pregnant during treatment with SPRAVATO. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SPRAVATO during pregnancy. [See Use in Specific Populations (8.1)].
Lactation
Advise women not to breastfeed during treatment with SPRAVATO [see Use in Specific Populations (8.2)].
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
© 2019 Janssen Pharmaceutical Companies
