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.

REXULTI (NDA-205422)

(BREXPIPRAZOLE)

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

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05/10/2023 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Additions and/or revisions underlined:

…REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease [see Boxed Warning, Warnings and Precautions (5.3)].

5.14 Potential for Cognitive and Motor Impairment

Additions and/or revisions underlined:

…

In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer’s disease, somnolence (including sedation) was reported in 3% of patients treated with REXULTI compared to 1% of patients treated with placebo.

…

5.3 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia- Related Psychosis

Additions and or revisions underlined:

In placebo-controlled trials in elderly patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease [see Boxed Warning, Warnings and Precautions (5.1)].

5.4 Neuroleptic Malignant Syndrome (NMS)

Additions and/or revisions underlined:

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including REXULTI.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia

Additions and/or revisions underlined:

…

The risk of tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the cumulative dose increases. The syndrome can develop after relatively brief treatment periods, at low doses. It may also occur after discontinuation of treatment.

…

5.6 Metabolic Changes

Extensive additions and/or revisions, please refer to label.

5.9 Orthostatic Hypotension and Syncope

Additions and/or revisions underlined

Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of REXULTI plus ADT in adult patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in REXULTI plus ADT-treated patients compared to placebo plus ADT-treated patients included: dizziness (2% versus 2%) and orthostatic hypotension (0.1% versus 0%). In the short-term, placebo-controlled clinical studies of REXULTI in adult patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patients included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). In 12-week, placebo- controlled clinical studies of REXULTI in patients with agitation associated with dementia due to Alzheimer’s disease, the incidence of orthostatic hypotension-related adverse reactions in patients treated with REXULTI compared to patients treated with placebo included: dizziness (3% versus 3%), orthostatic hypotension (1% versus 1%), and syncope (0.2% versus 0.8%).

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and/or revisions, please refer to label.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)].

Adjunctive Treatment of Major Depressive Disorder (MDD) and Schizophrenia

Of the total number of REXULTI-treated patients in the clinical studies for the adjunctive therapy to antidepressants for MDD and for schizophrenia, 248 (3%) were 65 years of age and older (which included 45 (18%) patients who were 75 years of age and older). Clinical studies of REXULTI in these patients did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. In general, dosage selection for the treatment of MDD or schizophrenia in a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.

Agitation Associated with Dementia Due to Alzheimer’s Disease

The total number of REXULTI-treated patients 65 years of age and older in the clinical studies for agitation associated with dementia due to Alzheimer’s disease (Studies 6 and 7) was 448 (86%) including 170 (33%) patients 65 to 74 years of age, 228 (44%) patients 75 to 84 years of age, and 50 (10%) patients 85 years of age and older [see Clinical Studies (14.3)

In clinical studies of REXULTI for the treatment of agitation associated with dementia due to Alzheimer’s disease did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

The maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score greater than or equal to 7) is lower than those with mild hepatic impairment and those with normal hepatic function [see Dosage and Administration (2.4)]. Patients with moderate to severe hepatic impairment generally had higher exposure to brexpiprazole than patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Greater exposure may increase the risk of REXULTI-associated adverse reactions

12/27/2021 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Metabolic Changes

Extensive changes; please refer to label

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Other Adverse Reactions Observed during the Premarketing Evaluation of REXULTI

Other adverse reactions (greater than or equal to 1% frequency and greater than placebo) within the short-term, placebo-controlled trials in adult patients with MDD and schizophrenia are shown below. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.

Eye Disorders: Vision Blurred

Gastrointestinal Disorders: Nausea, Dry Mouth, Salivary Hypersecretion, Abdominal Pain, Flatulence

Infections and Infestations: Urinary Tract Infection

Investigations: Blood Prolactin Increased

Musculoskeletal and Connective Tissue Disorders: Myalgia

Psychiatric Disorders: Abnormal Dreams, Insomnia

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis Pediatric Patients (13 to 17 years of age)

In an on-going, 2 year, open-label study in pediatric patients 13 to 17 years of age with schizophrenia, in which safety was assessed in 194 patients of which 140 received REXULTI for at least 6 months. Adverse reactions reported in clinical studies for this age group were generally similar to those observed in adult patients.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Schizophrenia

Safety and effectiveness of REXULTI for treatment of schizophrenia have been established in pediatric patients 13 years of age and older. Use of REXULTI in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Clinical Pharmacology (12.3)].Major Depressive Disorder

Safety and effectiveness in pediatric patients with major depressive disorder have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.2)].

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

MEDICATION GUIDE

Extensive changes; please refer to label

06/17/2020 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

Neuroleptic Malignant Syndrome (NMS)

(Additions and/or revisions underlined)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including REXULTI.

Tardive Dyskinesia

(Additions and/or revisions underlined)

The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.

6 Adverse Reactions

Postmarketing Experience

(Newly added section)

The following adverse reaction has been identified during post-approval use of REXULTI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System disorders: Neuroleptic Malignant Syndrome

02/09/2018 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Pathological Gambling and Other Compulsive Behaviors

Newly added subsection:

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking REXULTI. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with REXULTI. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

6 Adverse Reactions

Addition of the following:

Pathological Gambling and Other Compulsive Behaviors

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Pathological Gambling and Other Compulsive Behaviors

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking REXULTI. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped.

02/23/2017 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Falls

(Newly added subsection)

Antipsychotics, including REXULTI, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

09/23/2016 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Body Temperature Dysregulation

Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use REXULTI with caution in patients who may experience these conditions. (revised)

5.12 Potential for Cognitive and Motor Impairment

REXULTI, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week, placebo controlled clinical trials in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% for REXULTI+ADT-treated patients compared to 1% of placebo+ADT patients.
In 6-week, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.

5.3 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis. (revised)

5.4 Neuroleptic Malignant Syndrome (NMS)

If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring. (revised)

5.6 Metabolic Changes

Hyperglycemia and Diabetes Mellitus

There have been reports of hyperglycemia in patients treated with REXULTI…Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. (revision is underlined)

Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. (revised)

Major Depressive Disorder

In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL

cholesterol) of patients taking REXULTI… (revision underlined)

Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter. (revision underlined)

5.7 Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this class. (revised)
In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. (revision underlined)

5.8 Orthostatic Hypotension and Syncope

Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of REXULTI+ADT… revision underlined)
Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication, patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. REXULTI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. (revised)

5.9 Seizures

Like other antipsychotic drugs, REXULTI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. (revised)