Drug Safety-related Labeling Changes (SrLC)
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Guide
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.
INGREZZA (NDA-209241)
(VALBENAZINE TOSYLATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/18/2023 (SUPPL-26)
Boxed Warning
Newly added information; refer to label for complete information
5 Warnings and Precautions
5.1 Depression and Suicidal Ideation and Behavior in Patients with Huntington’s Disease
Newly added subsection:
Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors. VMAT2 inhibitors, including INGREZZA, can increase the risk for suicidal ideation and behaviors in patients with Huntington’s disease.
In a 14-week, double-blind, placebo-controlled trial [see Clinical Studies (14.2)], depression or depressed mood was reported in 4.7% of patients taking INGREZZA compared to 1.6% of patients who received placebo, and no patients taking INGREZZA reported suicidal ideation or behavior compared to 1 patient (1.6%) who received placebo. Patients with significant risk for suicidal behavior or with unstable psychiatric symptoms were excluded from this trial. Suicidal ideation (9 subjects; 7.2%) and suicide attempts (3 subjects; 2.4%) were reported in the longer open-label extension trial (N = 125).
When considering the use of INGREZZA, the risk of suicidal ideation and behaviors must be balanced against the need for treatment of chorea. All patients treated with INGREZZA should be observed for new or worsening depression, suicidal ideation or behaviors. If any of these reactions occur and do not resolve, consider discontinuing treatment with INGREZZA.
5.2 Hypersensitivity Reactions
Newly added subsection:
Hypersensitivity reactions, including cases of angioedema involving the larynx, glottis, lips, and eyelids, have been reported in the post-marketing setting in patients after taking the first or subsequent doses of INGREZZA [see Adverse Reactions (6.2)]. A case of angioedema involving the lips and face, with rash and shortness of breath was reported in a patient with Huntington’s disease taking INGREZZA during a clinical study. Urticaria and rash were also reported during a clinical study in patients with Huntington’s disease. Angioedema associated with laryngeal edema can be fatal. If any of these reactions occur, discontinue INGREZZA.
5.3 Somnolence and Sedation
Additions and/or revisions underlined:
INGREZZA can cause somnolence and sedation, which was the most common adverse reaction in placebo- controlled trials [see Adverse Reactions (6.1)]. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.
5.5 Neuroleptic Malignant Syndrome (NMS)
Newly added subsection:
A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. In the post-marketing setting, NMS has been reported in patients taking VMAT2 inhibitors, including INGREZZA. Clinicians should be alerted to the signs and symptoms associated with NMS. 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 creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include (1) immediate discontinuation of INGREZZA; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
Recurrence of NMS has been reported with resumption of drug therapy. If treatment with INGREZZA is needed after recovery from NMS, patients should be monitored for signs of recurrence.
5.6 Parkinsonism
Additions and/or revisions underlined:
…
In a placebo-controlled clinical study in patients with chorea associated with Huntington’s disease, the incidence of parkinson-like adverse events was 4.7% in patients treated with INGREZZA and 0% in placebo- treated patients. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington’s disease. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease.
Postmarketing safety reports have described parkinson-like symptoms in patients taking INGREZZA for tardive dyskinesia, some of which were severe and required hospitalization.
…
6 Adverse Reactions
Addition of the following to the bulleted line listing:
The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:
Depression and Suicidal Ideation and Behavior in Patients with Huntington’s Disease [see Boxed Warning and Warnings and Precautions (5.1)]
Hypersensitivity Reactions [see Contraindications (4) and Warning and Precautions (5.2)]
- Somnolence and Sedation [see Warnings and Precautions (5.3)]
…
6.1 Clinical Trials Experience
Extensive changes; please refer to label for complete information
7 Drug Interactions
7.1 Drugs Having Clinically Important Interactions with INGREZZA
Addition to MAOIs Prevention or Management section of table 3; please refer to label for complete information
8 Use in Specific Populations
8.5 Geriatric Use
Additions and/or revisions underlined:
No dose adjustment is required for elderly patients.
Tardive Dyskinesia
In 3 randomized, placebo-controlled studies of INGREZZA in patients with tardive dyskinesia, 16% of patients were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients.
Huntington’s Disease
In the randomized, placebo-controlled study of INGREZZA in 127 patients with chorea associated with Huntington’s disease, 15% were 65 years and older. This study did not include sufficient numbers of subjects aged 65 and older to determine whether they responded differently from younger subjects [see Clinical Studies (14.2)].
8.6 CYP2D6 Poor Metabolizers
Additions and/or revisions underlined:
Dosage reduction of INGREZZA is recommended for known CYP2D6 poor metabolizers [see Dosage and Administration (2.3)]. Increased exposure (Cmax and AUC) to valbenazine’s active metabolite was observed in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions [see Clinical Pharmacology (12.3, 12.5)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Depression and Suicidal Ideation and Behavior in Patients with Huntington’s Disease
Inform
patients, their caregivers, and families of the risks of depression, worsening
depression, and suicidal ideation
and behavior associated with INGREZZA, and instruct them to report behaviors of
concern promptly to the treating physician. Patients with Huntington’s disease
who express suicidal ideation should be evaluated immediately [see Warnings and Precautions (5.1)].
Hypersensitivity Reactions
Inform patients about the signs and symptoms of hypersensitivity reactions, such as angioedema, including difficulty breathing, swelling of the face, lips, eyelids, tongue or throat. Advise patients to discontinue INGREZZA immediately if any of these reactions occur and report to the emergency room if symptoms of angioedema occur [see Warnings and Precautions (5.2)].
Somnolence and Sedation
Inform patients that INGREZZA may cause somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to INGREZZA, they should be careful or avoid doing activities that require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions (5.3)].
…
Neuroleptic Malignant Syndrome (NMS)
Counsel patients about a potentially fatal adverse reaction – neuroleptic malignant syndrome (NMS) – that has been reported in association with administration of VMAT2 inhibitors, including INGREZZA. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS [see Warnings and Precautions (5.5)].
PATIENT INFORMATION
Extensive changes; please refer to label for complete information