SPRAVATO SIDE EFFECTS

Last updated on MDtodate: 10/6/2022

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 1 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 1: 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

	SPRAVATO + Oral AD (N=346)	Placebo + Oral AD (N=222)
Cardiac disorders
Tachycardia*	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%)
* The following terms were combined: Anxiety includes: agitation; anticipatory anxiety; anxiety; fear; feeling jittery; irritability; nervousness; panic attack; tension Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dissociation includes: delusional perception; depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; feeling of body temperature change; hallucination; hallucination, auditory; hallucination, visual; hyperacusis; illusion; ocular discomfort; oral dysesthesia; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred; visual impairment Dizziness includes: dizziness; dizziness exertional; dizziness postural; procedural dizziness Dysarthria includes: dysarthria; slow speech; speech disorder Dysgeusia includes: dysgeusia; hypogeusia Headache includes: headache; sinus headache Hypoesthesia includes: hypoesthesia; hypoesthesia oral, hypoesthesia teeth, pharyngeal hypoesthesia Lethargy includes: fatigue; lethargy Nasal discomfort includes: nasal crusting; nasal discomfort; nasal dryness; nasal pruritus Sedation includes: altered state of consciousness; hypersomnia; sedation; somnolence Tachycardia includes: extrasystoles; heart rate increased; tachycardia Vertigo includes: vertigo; vertigo positional

 

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 2: 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

	SPRAVATO + Oral AD (N=227)	Placebo + Oral AD (N=225)
Cardiac disorders
Tachycardia*	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%)
* The following terms were combined: Anxiety includes: agitation; anxiety; anxiety disorder; fear; irritability; nervousness; panic attack; psychomotor hyperactivity; tension Blood pressure increased includes: blood pressure diastolic increased; blood pressure increased; blood pressure systolic increased; hypertension Dissociation includes: depersonalization/derealization disorder; derealization; diplopia; dissociation; dysesthesia; feeling cold; feeling hot; hallucination; hallucination, auditory; hallucination, visual; hallucinations, mixed; hyperacusis; paresthesia; paresthesia oral; pharyngeal paresthesia; photophobia; time perception altered; tinnitus; vision blurred Dizziness includes: dizziness; dizziness exertional; dizziness postural Dysgeusia includes: dysgeusia; hypogeusia Hyperhidrosis includes: cold sweat; hyperhidrosis Hypoesthesia includes: hypoesthesia; hypoesthesia oral; intranasal hypoesthesia; pharyngeal hypoesthesia Lethargy includes: fatigue; lethargy; psychomotor retardation Pollakiuria includes: micturition urgency; pollakiuria Sedation includes: sedation; somnolence; stupor Tachycardia includes: heart rate increased; sinus tachycardia; tachycardia

 

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 3: 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)

	Patients <65 years			Patients ≥65 years
	Placebo + Oral AD	SPRAVATO + Oral AD		Placebo + Oral AD	SPRAVATO + Oral AD 28 to 84 mg
		56 mg	84 mg
Number of patients*/td>	N=112	N=114	N=114	N=63	N=72
Sedation (MOAA/S score <5)	11%	50%	61%	19%	49%
* Patients who were evaluated with MOAA/S

 

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 4: 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)

	Patients <65 years			Patients ≥65 years
	Placebo + Oral AD	SPRAVATO + Oral AD		Placebo + Oral AD	SPRAVATO + Oral AD 28 to 84 mg
		56 mg	84 mg
Number of patients*	N=113	N=113	N=116	N=65	N=72
CADSS total score >4 and change >0	5%	61%	69%	12%	75%
* Number of patients who were evaluated with CADSS

 

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 5: 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

	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 5.

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

Treatment (+ Oral AD)		Nausea		Vomiting
	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 .