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.

BRINEURA (BLA-761052)

(CERLIPONASE ALFA)

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

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07/24/2024 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions Including Anaphylaxis

Additions and/or revisions underlined:

Life-threatening hypersensitivity reactions including anaphylaxis have been reported in patients treated with enzyme replacement therapies, including BRINEURA. BRINEURA-treated patients have had these reactions occur in clinical studies and postmarketing use [see Adverse Reactions (6)]. In clinical Trial 1 and Trial 2 to 96 weeks, a total of 11 of 24 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. Patients in clinical trials were routinely pre- medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of BRINEURA. During postmarketing use, anaphylactic reactions occurred during or within several hours of BRINEURA infusion. Epinephrine was administered in these patients, and they received subsequent BRINEURA infusions without recurrence of anaphylaxis.

In Trial 3, hypersensitivity reactions were reported in 5 of 8 (63 %) patients less than 3 years of age at baseline as compared to 0 of 6 patients greater than or equal to 3 years of age at baseline [see Adverse Reactions (6.1)]. Of the reported hypersensitivity reactions, a single anaphylactic reaction occurred in a subject < 3 years of age.

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate BRINERUA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion.

Observe patients closely during and after the infusion. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue BRINEURA and immediately initiate appropriate medical treatment including use of epinephrine.

5.2 Meningitis and Other Intraventricular Access Device-Related Infections

Additions and/or revisions underlined:

Bacterial meningitis requiring antibiotic treatment and removal of the device was reported during postmarketing use of BRINEURA. Additionally, in clinical trials and during postmarketing use there were reports of other device-related clinical infections which were confirmed by positive CSF cultures, treated with antibiotics and removal of the entire intraventricular access device, and in which patients resumed treatment with BRINEURA after the device was replaced [see Adverse Reactions (6.1)]. In all cases, antibiotics were administered, the intraventricular access devices were removed and replaced, and patients resumed treatment with BRINEURA.

The signs and symptoms of infections may not be readily apparent in patients with CLN2 disease. To reduce the risk of infectious complications, BRINEURA should be administered by, or under the supervision of, a physician experienced in intraventricular administration.

…

5.4 Cardiovascular Adverse Reactions

Additions and/or revisions underlined:

…

In clinical Trial 1 and Trial 2 to 96 weeks, hypotension was reported in 2 of 24 (8%) patients, which occurred during or up to eight hours after BRINEURA infusion. Patients did not require alteration in treatment, and reactions resolved spontaneously or after intravenous fluid administration [see Adverse Reactions (6.1)].

5.5 Infusion-Associated Reactions

Newly added subsection:

Infusion-associated reactions (IARs) such as vomiting, seizure, rash, pyrexia, hypersensitivity, and anaphylactic reaction have been observed in patients treated with BRINEURA [see Adverse Reactions (6.1)].

Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor patients who have experienced IARs when re-administering BRINEURA.

In Trial 3, infusion-associated reactions were reported in 8 of 8 patients less than 3 years of age at baseline as compared to 4 of 6 patients greater than or equal to 3 years of age at baseline.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Infusion-Associated Reactions [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of BRINEURA have been established to slow the loss of ambulation in pediatric patients with CLN2 disease and the information on this use is discussed throughout the labeling.

BRINEURA is not recommended for use in patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) or those weighing less than 2.5 kg due to physiologic immaturity which may increase risk of serious and clinically significant adverse reactions observed with BRINEURA [see Warnings and Precautions (5)].

Patients less than 3 years of age may be at increased risk for developing hypersensitivity reactions with BRINEURA use compared to patients 3 years of age and older [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hypersensitivity Reactions Including Anaphylaxis and Infusion-Associated Reactions (IARs)

Advise patients and caregivers that life-threatening hypersensitivity reactions, including anaphylaxis, and IARs may occur with BRINEURA treatment.
Advise patients and caregivers that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.
Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and IARs and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1, 5.5)].

…

07/10/2024 (SUPPL-16)

Approved Drug Label (PDF)

Boxed Warning

Newly added section:

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS

Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

Initiate BRINEURA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue BRINEURA and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].

5 Warnings and Precautions

5.1 Hypersensitivity Reactions Including Anaphylaxis

Additions and/or revisions underlined:

Life-threatening hypersensitivity reactions including anaphylaxis have been reported in patients treated with enzyme replacement therapies, including BRINEURA. BRINEURA-treated patients have had these reactions occur in clinical studies and postmarketing use [see Adverse Reactions (6.1, 6.3)]. In clinical trials, a total of 11 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. Patients in clinical trials were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of BRINEURA. During postmarketing use, anaphylactic reactions occurred during or within several hours of BRINEURA infusion. Epinephrine was administered in one case. Patients received subsequent BRINEURA infusions without recurrence of anaphylaxis.

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate BRINERUA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. Observe patients closely during and after the infusion. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue BRINEURA and immediately initiate appropriate medical treatment including use of epinephrine.

Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur.

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hypersensitivity Reactions Including Anaphylaxis

Advise patients and caregivers that life-threatening hypersensitivity reactions, including anaphylaxis may occur with BRINEURA treatment.
Advise patients and caregivers that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy
Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1 )].

…

03/27/2020 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hypersensitivity Reactions Including Anaphylaxis

(additions underlined)

Hypersensitivity reactions including anaphylaxis have been reported in Brineura-treated patients during clinical studies and postmarketing use In clinical trials, a total of 11 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. Patients in clinical trials were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of Brineura. During postmarketing use, anaphylactic reactions occurred during or within several hours of Brineura infusion. Epinephrine was administered in one case. Patients received subsequent Brineura infusions without recurrence of anaphylaxis.

Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. Observe patients closely during and after the infusion. If a severe hypersensitivity reaction or anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Inform patients/caregivers of the signs and symptoms of hypersensitivity reactions and anaphylaxis and instruct them to seek immediate medical care should signs and symptoms occur.

The management of hypersensitivity reactions should be based on the severity of the reaction and may include temporarily interrupting the infusion, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. Consider the risks and benefits of readministration of Brineura following an anaphylactic reaction. If the decision is made to readminister Brineura after the occurrence of anaphylaxis, ensure appropriately trained personnel and equipment for emergency resuscitation (including epinephrine and other emergency medicines) are readily available during infusion. Initiate subsequent infusion at approximately one-half the initial infusion rate at which the anaphylactic reaction occurred.

6 Adverse Reactions

(addition underlined)

…

Hypersensitivity Reactions Including Anaphylaxis

6.3 Postmarketing Experience

(additions underlined)

…

Immune system disorders: Anaphylactic reaction characterized by acute pyrexia, respiratory distress (bronchospasm, hypoxemia, perioral cyanosis), tachycardia, hypotension, diarrhea, and rash.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

Hypersensitivity Reactions Including Anaphylaxis

Advise patients and caregivers that hypersensitivity reactions related to Brineura treatment, including anaphylaxis characterized by fever, respiratory distress and rash may occur. Inform patients and caregivers of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should signs and symptoms occur

12/11/2018 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

any sign or symptom of acute, unresolved localized infection on or around the device insertion site (e.g. cellulitis or abscess); or suspected or confirmed CNS infection (e.g. cloudy CSF or positive CSF gram stain, or meningitis).
any acute intraventricular access device-related complication (e.g., leakage, extravasation of fluid, or device failure)

5 Warnings and Precautions

Newly added subsection:

5.1 Meningitis and Other Intraventricular Access Device-Related Problems

Bacterial meningitis requiring antibiotic treatment and removal of the device was reported during postmarketing use of Brineura. Additionally, in clinical trials and during postmarketing use there were reports of other device-related clinical infections which were confirmed by positive CSF cultures, treated with antibiotics and removal of the device, and in which patients resumed treatment with Brineura after the device was replaced. In all cases, antibiotics were administered, the intraventricular access devices were removed and replaced, and patients resumed treatment with Brineura.

The signs and symptoms of infections may not be readily apparent in patients with CLN2 disease. To reduce the risk of infectious complications, Brineura should be administered by, or under the direction of, a physician experienced in intraventricular administration. Prior to each infusion of Brineura, and when clinically indicated, obtain a sample of CSF for cell count and culture. Do not administer Brineura if there are localized signs of infection on or around the device insertion site, such as erythema, tenderness, or discharge or suspected or confirmed CNS infection (e.g. cloudy CSF or positive CSF gram stain, or meningitis).

Healthcare providers should be vigilant for the development of signs and symptoms of infection, including meningitis, during treatment with Brineura and monitor the device insertion site for signs of infection.

5.2 Intraventricular Access Device-Related Complications

Extensively changed; please refer to label for complete information.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Meningitis and Other Intraventricular Access Device-Related Infections

Newly added subsection:

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Brineura. 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.

Infections and infestations: Bacterial meningitis

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Intraventricular Access Device-Related Infections

Advise patients and caregivers of the risk of device-related infections, including meningitis. Familiarize them with the signs and symptoms of these infections and instruct them to immediately contact their healthcare provider if an infection is suspected.