Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SPRAVATO (NDA-211243)

(ESKETAMINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/28/2025 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Cardiac disorders: bradycardia

…

01/17/2025 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Increase in Blood Pressure

Additions and/or revisions underlined:

…

Approximately 3% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo- treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. SPRAVATO is contraindicated in patients for whom an increase in BP or intracranial pressure poses a serious risk (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage) [see Contraindications (4)]. 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.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for additional information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the total number of patients in randomized, double-blind, placebo-controlled short-term clinical studies exposed to SPRAVATO, (N=2064), 238 (12%) were 65 years of age and older, and 29 (1%) were 75 years of age and older. No overall differences in the safety profile were observed between patients 65 years of age and older and patients younger than 65 years of age.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Additions and/or revisions underlined:

What is the most important information I should know about SPRAVATO?

…

Abuse and misuse. There is a risk for abuse and misuse with SPRAVATO, which may lead to physical and psychological dependence. Your healthcare provider should check you for signs of abuse, misuse, and dependence before and during treatment.
- 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 in drug addiction.

…

Tell your healthcare provider right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:

trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
other unusual changes in behavior
an extreme increase in activity and or mood talking (mania)

See “What are the possible side effects of SPRAVATO?” for more information about side effects.

What is SPRAVATO?

SPRAVATO is a prescription medicine used:with or without an antidepressant taken by mouth, to treat adults with treatment-resistant depression (TRD).
with an antidepressant taken by mouth, to treat depressive symptoms in adults with major depressive disorder (MDD) with suicidal thoughts or actions.

…

Before you take SPRAVATO, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. SPRAVATO may harm your unborn baby. You should not take SPRAVATO if you are pregnant.

…

What are the possible side effects of SPRAVATO? SPRAVATO may cause serious side effects, including:

See “What is the most important information I should know about SPRAVATO?”

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.

…

The most common side effects of SPRAVATO include:

…

headache

…

11/04/2024 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Cognitive Impairment

Additions and/or revisions underlined:

…

Long-Term Cognitive Impairment

Long-term cognitive and memory impairment have been reported with repeated ketamine misuse or abuse. In 1-year and 3-year, long-term, open-label clinical trials in adults, the effect of SPRAVATO on cognitive functioning remained stable over time as evaluated by the Cogstate computerized battery and Hopkins Verbal Learning Test-Revised.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Vascular disorders: hypotension

10/18/2023 (SUPPL-12)

Approved Drug Label (PDF)

Boxed Warning

Additions and revisions underlined:

WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE

AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS

Sedation

- Patients are at risk for sedation after administration of SPRAVATO [see Warnings and

Precautions (5.1)].

Dissociation

- Patients are at risk for dissociative or perceptual changes after administration of

SPRAVATO [see Warnings and Precautions (5.2)].

Respiratory Depression

- Respiratory depression has been observed in postmarketing experience [see Warnings

and Precautions (5.3)].

Because of the risks of sedation, dissociation, and respiratory depression, 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, 5.3)].

Abuse and Misuse

- 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

(5.4)].

Because of the risks of serious adverse outcomes resulting from sedation, dissociation,

respiratory depression, 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 (5.5)].

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 (5.6)].

5 Warnings and Precautions

5.1 Sedation

Newly added information:

SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing.

5.3 Respiratory Depression

Newly added subsection:

In post marketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest [see Adverse Reactions (6.2)].

Because of the risks of respiratory depression, patients must be monitored for changes in respiratory status by a healthcare provider for at least 2 hours (including pulse oximetry) 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 Dosage and Administration (2.5)].

SPRAVATO is available only through a restricted program under a REMS [see Warnings and Precautions (5.5)].

5.5 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)

Additions and revisions underlined:

SPRAVATO is available only through a restricted program under a REMS called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, respiratory depression, abuse and misuse [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

6 Adverse Reactions

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

Sedation [see Warnings and Precautions (5.1)]
Dissociation [see Warnings and Precautions (5.2)]
Respiratory Depression [see Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

Newly added subsection:

The following adverse reaction has been identified during postapproval use of SPRAVATO. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, thoracic and mediastinal disorders: respiratory depression (including respiratory arrest)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

SPRAVATO can cause serious side effects, including:

Sedation, dissociation, and respiratory depression. SPRAVATO may cause sleepiness (sedation), fainting, dizziness, spinning sensation, anxiety, or feeling disconnected from yourself, your thoughts, feelings, space and time (dissociation), and breathing problems (respiratory depression and respiratory arrest).

SPRAVATO Risk Evaluation and Mitigation Strategy (REMS). Because of the risks for sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program called the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) Program.

07/31/2020 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Sedation

Additions and/or revisions underlined:

In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified Observer’s Assessment of Alertness/Sedation scale (MOAA/S) [see Adverse Reactions (6.1)], and 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0).

5.2 Dissociation

Additions and/or revisions underlined:

The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO-treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale) [see Adverse Reactions (6.1)] …

5.1 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS)

Additions and/or revisions underlined:

… Important requirements of the SPRAVATO REMS include the following:

Healthcare settings must be certified in the program and ensure that SPRAVATO is:

Only dispensed and administered in healthcare settings.
Patients treated in outpatient settings (e.g. medical offices and clinics) must be enrolled in the program.

5.6 Increase in Blood Pressure

Additions and/or revisions underlined:

… Approximately 8% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… 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.

Newly added information following Table 3:

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 greater than or equal to5% 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 greater than or equal to2% 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 Newly added table; please refer to label for complete information.

Additions and/or revisions underlined:

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 greater than or equal to65 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 greater than or equal to65 Years of Age with TRD) Previously Table 4.

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 greater than or equal to65 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 greater than or equal to65 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 [see Warnings and Precautions (5.6)]. Table 7 presents increases in blood pressure in short-term trials with patients <65 years of age and greater than or equal to 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 greater than or equal to180 mmHg or greater than or equal to40 mmHg increases in SBP, and similar rates of increases to DBP greater than or equal to110 mmHg or greater than or equal to25 mmHg increases in DBP, compared to the TRD study results in Table 7.

Nausea and Vomiting

SPRAVATO can cause nausea and vomiting … 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

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. Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the program.
Increased risk of suicidal thoughts and actions. Antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. SPRAVATO is not for use in children.

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 and actions. These include people who have (or have a family history of) depression or a history of suicidal thoughts and actions.
How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
- 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 or your family member have any of the following symptoms, especially if they are new, worse, or worry you …

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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:

Patients treated in outpatient healthcare settings (e.g. medical offices and clinics) must be enrolled in the SPRAVATO REMS Program prior to administration.

05/09/2019 (SUPPL-1)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of SPRAVATO in pediatric patients have not been established. Clinical studies of SPRAVATO in pediatric patients have not been conducted.