Side Effects of Spravato (esketamine)

Spravato (esketamine) is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults. 

Common side effects of Spravato include

• nausea,
• reduced sense of touch and sensation,
• anxiety,
• lack of energy,
• vomiting, and
• feeling drunk.

Serious side effects of Spravato include

• sleepiness (sedation),
• fainting,
• dizziness,
• spinning sensation (vertigo),
• anxiety;
• feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation);
• increased risk of suicidal thoughts or actions,
• increased blood pressure,
• problems thinking clearly, and
• bladder problems. 

There is a risk for abuse and physical and psychological dependence with Spravato treatment. 

Drug interactions of Spravato include central nervous system depressants (e.g., benzodiazepines, opioids, alcohol), which may increase sedation. Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure. Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure.

Spravato is not recommended during pregnancy. Spravato may cause fetal harm when administered to pregnant women. If a woman becomes pregnant while being treated with Spravato, treatment with Spravato should be discontinued and the patient should be counseled about the potential risk to the fetus. 

Spravato is present in breastmilk. Because of the potential for neurotoxicity, breastfeeding is not recommended during treatment with Spravato.

WARNING:

Spravato can cause serious side effects including:

• Sedation and dissociation. Spravato may cause sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation).
  • Tell your healthcare provider right away if your feel like you cannot stay awake or if you feel like you are going to pass out.
  • Your healthcare provider must monitor you for serious side effects for at least 2 hours after taking Spravato. Your healthcare provider will decide when you are ready to leave the healthcare setting.
• Abuse and misuse. There is a risk for abuse and physical and psychological dependence with Spravato treatment. Your healthcare provider should check you for signs of abuse and dependence before and during treatment with Spravato.
  • Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs.
  • Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.
• Spravato Risk Evaluation and Mitigation Strategy (REMS). Because of the risks for sedation, dissociation, and abuse and misuse, Spravato is only available through a restricted program called the Spravato Risk Evaluation and Mitigation Strategy (REMS) Program. Spravato can only be administered at healthcare settings certified in the Spravato REMS Program and to patients enrolled in the program.
• Increased risk of suicidal thoughts or actions. Spravato may cause worsening of depression and suicidal thoughts and behaviors, especially during the first few months of treatment and when the dose is changed. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression or a history of suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions?
  • Pay close attention to any changes, especially sudden changes, in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions.
  • Tell your healthcare provider right away if you have any new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Tell your healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:
    • attempts to commit suicide
    • worsening depression
    • thoughts about suicide or dying
    • other unusual changes in behavior or mood
• Increased blood pressure. Spravato can cause a temporary increase in your blood pressure that may last for about 4 hours after taking a dose. Your healthcare provider will check your blood pressure before taking Spravato and for at least 2 hours after you take Spravato. Tell your healthcare provider right away if you get chest pain, shortness of breath, sudden severe headache, change in vision, or seizures after taking Spravato.
• Problems with thinking clearly. Tell your healthcare provider if you have problems thinking or remembering.
• Bladder problems. Tell your healthcare provider if you develop trouble urinating, such as a frequent or urgent need to urinate, pain when urinating, or urinating frequently at night.

The most common side effects of Spravato when used along with an antidepressant taken by mouth include:

• dissociation
• dizziness
• nausea
• sedation
• reduced sense of touch and sensation
• anxiety
• lack of energy
• increased blood pressure
• spinning sensation
• vomiting
• feeling drunk

If these common side effects occur, they usually happen right after taking Spravato and go away the same day. These are not all the possible side effects of Spravato. Call your doctor for medical advice about side effects.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Sedation
• Dissociation
• Increase in Blood Pressure
• Cognitive Impairment
• Impaired Ability to Drive and Operate Machinery
• Ulcerative or Interstitial Cystitis
• Embryo-fetal Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Treatment-Resistant Depression

Spravato was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) 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.

Table 3: Adverse Reactions Occurring in ≥2% of Adult TRD Patients Treated with Spravato + Oral AD at Any Dose and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD

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 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.

Table 4: Adverse Reactions Occurring in ≥2% of Adult Patients with MDD and Acute Suicidal Ideation or Behavior Treated with Spravato + Oral AD and at a Greater Rate than Patients Treated with Placebo Nasal Spray + Oral AD

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.

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.

Table 5: Incidence of Sedation (MOAA/S Score <5) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study with Adult Patients <65 Years of Age with TRD and Flexible-Dose Study with Patients ≥65 Years of Age with TRD)

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.
• 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.

Table 6: Incidence of Dissociation (CADSS Total Score >4 and Change >0) in Double-Blind, Randomized, Placebo-Controlled Studies (Fixed-Dose Study with Adult Patients <65 Years of Age with TRD and Flexible-Dose Study with Patients ≥65 Years of Age with TRD)

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. Table 7 presents increases in blood pressure in short-term trials with patients <65 years of age and ≥65 years of age with TRD.

Table 7: Increases in Blood Pressure in Double-blind, Randomized, Placebo-Controlled, Short-Term Trials of Spravato + Oral AD Compared to Placebo Nasal Spray + Oral AD in the Treatment of TRD in Adult Patients

• 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.

Table 8: Incidence and Severity of Nausea and Vomiting in a Double-blind, Randomized, Placebo-Controlled, Fixed-Dose Study in Adult Patients with TRD

• 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.

Central Nervous System Depressants

• Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation with concomitant use of Spravato with CNS depressants.

Psychostimulants

• Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure. Closely monitor blood pressure with concomitant use of Spravato with psychostimulants.

Monoamine Oxidase Inhibitors (MAOIs)

• Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure. Closely monitor blood pressure with concomitant use of Spravato with MAOIs.

Drug Abuse And Dependence

Controlled Substance

• Spravato contains esketamine hydrochloride, the (S)-enantiomer of ketamine and a Schedule III controlled substance under the Controlled Substances Act.

Abuse

• Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of Spravato.
• Abuse is the intentional, non-therapeutic use of a drug, even once, for its psychological or physiological effects.
• Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.
• Careful consideration is advised prior to use of individuals with a history of substance use disorder, including alcohol.
• Spravato may produce a variety of symptoms including anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations, and feelings of floating, detachment and to be “spaced out”. Monitoring for signs of abuse and misuse is recommended.

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.

Dependence

• Physical dependence has been reported with prolonged use of ketamine.
• Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dosage reduction of a drug.
• There were no withdrawal symptoms captured up to 4 weeks after cessation of esketamine treatment. Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly) large doses of ketamine for long periods of time.
• Such withdrawal symptoms are likely to occur if esketamine were similarly abused. Reported symptoms of withdrawal associated with daily intake of large doses of ketamine include craving, fatigue, poor appetite, and anxiety.
• Therefore, monitor Spravato-treated patients for symptoms and signs of physical dependence upon the discontinuation of the drug.
• Tolerance has been reported with prolonged use of ketamine. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Similar tolerance would be expected with prolonged use of esketamine.