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.

ADUHELM (BLA-761178)

(ADUCANUMAB-AVWA)

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

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08/30/2023 (SUPPL-11)

Approved Drug Label (PDF)

Boxed Warning

WARNING: AMYLOID RELATED IMAGING ABNORMALITIES

(Newly added section)

Monoclonal antibodies directed against aggregated forms of beta amyloid, including ADUHELM, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H).

Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events rarely can occur. Serious intracerebral hemorrhages, some of which have been fatal, have been observed in patients treated with this class of medications [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

ApoE epsilon 4 Homozygotes

Patients who are apolipoprotein E epsilon 4 (ApoE epsilon 4) homozygotes (approximately 15% of Alzheimer’s disease patients) treated with this class of medications, including ADUHELM, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE epsilon 4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed they can still be treated with ADUHELM; however, it cannot be determined if they are ApoE epsilon 4 homozygotes and at higher risk for ARIA [see Warnings and Precautions (5.1)].

Consider the benefit of ADUHELM for the treatment of Alzheimer’s disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with ADUHELM [see Warnings and Precautions (5.1) and Clinical Studies (14)].

5 Warnings and Precautions

5.1 Amyloid Related Imaging Abnormalities

(Extensive changes; please refer to label for complete information)

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Amyloid Related Imaging Abnormalities

Inform patients that ADUHELM may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients to notify their healthcare provider if these symptoms occur. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking ADUHELM, and that the use of anticoagulant or thrombolytic medications while taking ADUHELM may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA [see Warnings and Precautions (5.1)].

Inform patients that although ARIA can occur in any patient treated with ADUHELM, there is an increased risk in patients who are ApoE epsilon 4 homozygotes, and that testing for ApoE epsilon 4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Inform patients that if testing is not performed, it cannot be determined if they are ApoE epsilon 4 homozygotes and at a higher risk for ARIA.

Patient Registry

Advise patients that the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease, including ADUHELM. Encourage patients to participate in the ALZ-NET registry [see Warnings and Precautions (5.1)]…

02/08/2023 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Amyloid Related Imaging Abnormalities

Extensive changes; please refer to label for complete information

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

Amyloid Related Imaging Abnormalities [see Warnings and Precautions (5.1)]
Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no data on the presence of aducanumab-avwa in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Published data from other monoclonal antibodies generally indicate low passage of monoclonal antibodies into human milk and limited systemic exposure in the breastfed infant. The effects of this limited exposure are unknown.

…

8.4 Pediatric Use

Safety and effectiveness of ADUHELM in pediatric patients have not been established.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Amyloid Related Imaging Abnormalities

Inform patients that ADUHELM may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients to notify their healthcare provider if these symptoms occur. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking ADUHELM, and that the use of antithrombotic or thrombolytic medications while taking ADUHELM may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA [see Warnings and Precautions (5.1)].

Inform patients that although ARIA can occur in any patient treated with ADUHELM, there is an increased risk in patients who are ApoE ?4 homozygotes, and that there is a test available to determine ApoE ?4 genotype.

Patient Registry

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Amyloid Related Imaging Abnormalities or “ARIA”. ARIA is a common side effect that does not usually cause any symptoms but can be serious. It is most commonly seen as temporary swelling in

areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain, and infrequently, larger areas of bleeding in the brain can occur. Most people with this type of swelling in the brain do not get symptoms, however some people may have symptoms, such as:

o headache

o nausea

o confusion

o difficulty walking

o Dizziness

o Vision changes

o seizures

Your healthcare provider will do magnetic resonance imaging (MRI) scans before and during your treatment with ADUHELM to check you for ARIA. Some people have a genetic risk factor (homozygous apolipoprotein E gene carriers) that may cause an increased risk for ARIA. Talk to your healthcare provider about testing to see if you have this risk factor.

…

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take medicines to reduce blood clots from forming (antithrombotic medicines, including aspirin). Ask your healthcare provider for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacists when you get a new medicine.

…

What are the possible side effects of ADUHELM?

…

These are not all the possible side effects of ADUHELM. For more information, ask your healthcare provider or pharmacist.

…

General Information about the safe and effective use of ADUHELM.

…

There is a registry that collects information on treatments for Alzheimer’s disease. The registry is named ALZ-NET (Alzheimer’s Network for Treatment and Diagnostics). Your healthcare provider can help you become enrolled in this registry.

04/29/2022 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Amyloid Related Imaging Abnormalities

Extensive additions and/or revisions, please refer to label for complete information

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

MEDICATION GUIDE

Additions underlined

… Although most people with swelling in areas of the brain do not have symptoms, some people may have symptoms, such as:

…

Seizure

…

PATIENT COUNSELING INFORMATION

Additions underlined

… Inform patients that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, or seizure.

…