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.

NAGLAZYME (BLA-125117)

(GALSULFASE)

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

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09/12/2024 (SUPPL-132)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data from a pregnancy sub-study within the MPS VI Clinical Surveillance Program and case reports with NAGLAZYME use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, galsulfase administered intravenously to pregnant rats and rabbits during the period of organogenesis, showed no evidence of harm to the fetus at doses of about 0.5 and 0.97 times, respectively for rats and rabbits, the recommended human dose of 1 mg/kg based on body surface area (see Data).

…

Data

Human Data

Available data from a pregnancy sub-study within the MPS VI Clinical Surveillance Program and case reports with the use of NAGLAZYME during pregnancy have identified seventeen pregnancies. No major birth defects have been reported. Drug-associated adverse maternal and fetal outcomes have not been identified.

…

07/10/2024 (SUPPL-131)

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 NAGLAZYME 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 NAGLAZYME 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 observed in patients treated with enzyme replacement therapies, including NAGLAZYME. These reactions have occurred during and up to 24 hours after completion of the NAGLAZYME infusion. Some of the reactions included shock, respiratory distress, dyspnea, bronchospasm, laryngeal edema, and hypotension [see Adverse Reactions (6.1, 6.3)].

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of NAGLAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate NAGLAZYME 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 NAGLAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. In patients who have experienced anaphylaxis or other serious hypersensitivity reactions during infusion with NAGLAZYME, caution should be exercised upon rechallenge.

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 and Infusion Reactions

Advise the patient or caregiver that life-threatening hypersensitivity reactions, including anaphylaxis and infusion reactions, may occur with NAGLAZYME treatment.

Advise the patient or caregiver that anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

Inform the patient or caregiver of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and infusion reactions and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1, 5.5)].

…

12/17/2019 (SUPPL-129)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

Serious and/or clinically significant adverse reactions described elsewhere in labeling include:

Anaphylaxis and Hypersensitivity Reactions
Risk of Acute Cardiorespiratory Failure
Immune-Mediated Reactions
Acute Respiratory Complications Associated with Administration
Infusion Reactions
Spinal or Cervical Cord Compression

6.2 Immunogenicity

(Additions and/or revisions underlined)

As with all the therapeutic proteins, there is potential for immunogenicity. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including 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 galsulfase products may be misleading.

Ninety-eight percent (53/54) of patients treated with NAGLAZYME and evaluable for the presence of antibodies to galsulfase developed anti-galsulfase IgG antibodies within 4 to 8 weeks of treatment (in four clinical studies). In 19 patients treated with NAGLAZYME from the placebo-controlled study, serum samples were evaluated for a potential relationship of anti-galsulfase antibody development to clinical outcome measures. All 19 patients treated with NAGLAZYME developed antibodies specific to galsulfase; however, the analysis revealed no consistent predictive relationship between total antibody titer, neutralizing or IgE antibodies, and infusion-associated reactions, urinary glycosaminoglycan (GAG) levels, or endurance measures. Antibodies were assessed for the ability to inhibit enzymatic activity but not cellular uptake.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Risk Summary

Available data from case reports and postmarketing experience with NAGLAZYME use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, galsulfase administered intravenously to pregnant rats and rabbits during the period of organogenesis, showed no evidence of harm to the fetus at doses of about 0.5 and 0.97 times, respectively for rats and rabbits, the recommended human dose of 1 mg/kg based on body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse pregnancy outcomes for both mother and fetus.

Data

Animal Data

Reproduction studies have been performed with intravenous galsulfase during the period of organogenesis in pregnant rats at doses of galsulfase up to 3 mg/kg/day (about 0.5 times the recommended human dose of 1 mg/kg based on the body surface area) and in pregnant rabbits at doses up to 3 mg/kg/day (about 0.97 times the recommended human dose of 1 mg/kg based on the body surface area) and have revealed no evidence of harm to the fetus due to galsulfase.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Risk Summary

There are no data on the presence of galsulfase in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAGLAZYME and any potential adverse effects on the breastfed infant from NAGLAZYME or from the underlying maternal condition.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Anaphylaxis, Hypersensitivity and Infusion Reactions

Inform the patient or caregiver that hypersensitivity reactions, including life-threatening anaphylaxis, and infusion reactions may occur with NAGLAZYME treatment. Advise the patient or caregiver to report immediately to a healthcare provider if signs or symptoms of a hypersensitivity or infusion reaction occur during infusion of NAGLAZYME.

Respiratory Adverse Reactions

Advise the patient or caregiver to report immediately to a healthcare provider if signs or symptoms of cardiac or respiratory decompensation occur during or following an infusion. Inform patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep to have these treatments readily available during infusion or extreme drowsiness/sleep induced by antihistamine use.