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.

KANUMA (BLA-125561)

(SEBELIPASE ALFA)

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

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07/10/2024 (SUPPL-20)

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 KANUMA 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 KANUMA 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 KANUMA. These reactions in KANUMA- treated patients were based on application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis. In clinical trials, 3 (infants) of 106 (3%) patients treated with KANUMA experienced signs and symptoms consistent with anaphylaxis. These patients experienced reactions during infusion with signs and symptoms including chest discomfort, conjunctival injection, dyspnea, generalized and itchy rash, hyperemia, swelling of eyelids, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and urticaria.

…

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of KANUMA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate KANUMA 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.

The management of hypersensitivity reactions should be based on the severity of the reaction and may include temporarily interrupting the infusion, lowering the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue KANUMA and immediately initiate appropriate medical treatment, including use of epinephrine. If interrupted, the infusion may be resumed at a slower rate with increases as tolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions in those cases where symptomatic treatment was required.

Inform patients 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 anaphylaxismay occur with KANUMA 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)].

…

11/19/2021 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions Including Anaphylaxis

Additions and/or revisions underlined:

Hypersensitivity reactions, including anaphylaxis, have been reported in KANUMA-treated patients, based on application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis. In clinical trials, 3 (infants) of 106 (3%) patients treated with KANUMA experienced signs and symptoms consistent with anaphylaxis. These patients experienced reactions during infusion with signs and symptoms including chest discomfort, conjunctival injection, dyspnea, generalized and itchy rash, hyperemia, swelling of eyelids, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and urticaria. Anaphylaxis has occurred as early as the sixth infusion and as late as 1 year after treatment initiation.

In clinical trials, 21 of 106 (20%) KANUMA-treated patients, including 9 of 14 (64%) infants and 12 of 92 (13%) pediatric patients who were 4 years and older and adults, experienced signs and symptoms either consistent with or that may be related to a hypersensitivity reaction. Signs and symptoms of hypersensitivity reactions, occurring in two or more patients, included abdominal pain, agitation, fever, chills, diarrhea, eczema, edema, hypertension, irritability, laryngeal edema, nausea, pallor, pruritus, rash, and vomiting. The majority of reactions occurred during or within 4 hours of the completion of the infusion. Patients were not routinely pre- medicated prior to infusion of KANUMA in these clinical trials.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Other less common adverse reactions reported in patients with rapidly progressive disease presenting within the first 6 months of life who received KANUMA included hypotonia, decreased oxygen saturation, retching, sneezing, and tachycardia.

For infant patients within Study 1 and Study 3 (n = 19), the following additional adverse reactions were reported in greater than or equal to 30% of infants who received Kanuma since the time of marketing authorization, including patients who received an escalated dose to 5 mg/kg qw: hypersensitivity, respiratory distress, and tachycardia.

For pediatric and adult patients within Study 2 (n = 106), the following additional adverse reactions were reported in greater than or equal to 8% of pediatric and adult patients who received Kanuma since the time of marketing authorization, including patients who received an escalated dose to 3 mg/kg qw: hypersensitivity, diarrhea, abdominal pain, and dizziness.

6.2 Immunogenicity

Additions and/or revisions underlined:

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other sebelipase alfa products may be misleading.

Approximately 8% (9/106) of pediatric and adult patients with LAL deficiency developed antibodies to sebelipase alfa (anti-drug antibodies or ADA) following treatment with KANUMA across all clinical studies. Among the 9 patients who developed ADA, 2 patients were positive for neutralizing antibodies (NAb). Approximately 53% (10/19) of infants with rapidly progressive LAL deficiency developed ADA following treatment with KANUMA across all clinical studies. Among the 10 patients who developed ADA, 9 patients were positive for NAb.

Study 1: Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life

Seven of the 9 infants with rapidly progressive disease had at least one post-treatment ADA assessment, and 4 of these 7 (57%) patients developed ADA during treatment with KANUMA. All of the 4 ADA-positive patients were determined to be positive for neutralizing antibodies that inhibit in vitro enzyme activity and/or cellular uptake of the enzyme. At the time of initial ADA positivity, 3 patients were receiving a dosage of 1 mg/kg once weekly and 1 patient was receiving a dosage of 3 mg/kg once weekly. Three of the 4 ADA-positive patients had ADA titers monitored from the initiation of treatment and developed measurable ADA titers within the first 2 months of exposure. Persistent ADA was observed in all 4 patients.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data with KANUMA use in pregnant women are insufficient to identify a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproductive studies conducted with sebelipase alfa showed no evidence of embryolethality, fetotoxicity, teratogenicity, or abnormal early embryonic development at dosages up to 164 and 526 times the human dosage of 1 mg/kg every other week (based on AUC) in rats and rabbits, respectively.

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

17 PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hypersensitivity Reactions, including Anaphylaxis

Advise patients and caregivers that reactions related to administration and infusion may occur during and after KANUMA treatment, including anaphylactic reactions, life-threatening anaphylaxis and severe hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylactic reactions, anaphylaxis and hypersensitivity reactions, and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1)].

Hypersensitivity to Eggs or Egg Products

KANUMA is produced in the egg whites of genetically engineered chickens. Patients with a known history of egg allergies were excluded from the clinical trials. Consider the risks and benefits of treatment with KANUMA in patients with known systemic hypersensitivity reactions to eggs or egg products. [see Warnings and Precautions (5.2)].