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.

FABRAZYME (BLA-103979)

(AGALSIDASE BETA)

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

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07/10/2024 (SUPPL-5313)

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 FABRAZYME 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 FABRAZYME 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 FABRAZYME.

…

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of FABRAZYME should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Initiate FABRAZYME 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 FABRAZYME and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering FABRAZYME following severe hypersensitivity reactions (including anaphylaxis). 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-Associated Reactions (IARs)

Advise the patient and caregiver that life-threatening hypersensitivity reactions, including anaphylaxis, and IARs may occur with FABRAZYME 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 and caregiver 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, 5.2)].

02/06/2024 (SUPPL-5312)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions Including Anaphylaxis

Subsection title revised

Additions and/or revisions underlined:

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in FABRAZYME-treated patients. In clinical trials and postmarketing safety experience with FABRAZYME, approximately 1% of patients developed anaphylaxis or severe hypersensitivity reactions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion.

In clinical trials with FABRAZYME, 10 of 238 patients developed IgE antibodies or skin test reactivity specific to FABRAZYME. Two of six patients in the rechallenge study discontinued treatment with FABRAZYME prematurely due to recurrent infusion-associated reactions. Four serious infusion-associated reactions occurred in three patients during FABRAZYME infusions, including bronchospasm, urticaria, hypotension, and development of FABRAZYME-specific antibodies. Other infusion-associated reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus.

Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-FABRAZYME antibodies and in adult patients with high antibody titer compared to that in antibody-negative adult patients [see Adverse Reactions (6.2)].

Prior to FABRAZYME administration, consider pretreating with antihistamines, antipyretics, and/or corticosteroids. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily available during FABRAZYME administration.

· If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue FABRAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re- administering FABRAZYME following severe hypersensitivity reactions (including anaphylaxis).

Consider testing for IgE antibodies in FABRAZYME-treated patients who experienced severe hypersensitivity reactions, including anaphylaxis and consider the risks and benefits of continued treatment in patients with anti- FABRAZYME IgE antibodies. There are no marketed tests for antibodies against FABRAZYME. If testing is warranted, contact Genzyme Corporation at 1-800-745-4447 [see Adverse Reactions (6.2)].
Patients who have had a positive skin test to FABRAZYME or who have tested positive for FABRAZYME-specific IgE antibodies have been rechallenged with FABRAZYME using a rechallenge protocol. Rechallenge of these patients should only occur under the direct supervision of qualified personnel with appropriate medical monitoring and support measures readily available [see Dosage and Administration (2.3) and Adverse Reactions (6.2)].

5.2 Risk of Loss of Life

Additions and/or revisions underlined:

In clinical trials of FABRAZYME, 59% of patients experienced infusion-associated reactions (IARs) during FABRAZYME administration, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. The incidence of infusion-associated reactions was higher in patients who were positive for anti- FABRAZYME antibodies than in patients who were negative for anti-FABRAZYME antibodies [see Adverse Reactions (6.2)].

Severe infusion-associated reactions experienced by more than one patient in clinical trials of FABRAZYME included chills, vomiting, hypotension, and paresthesia. Other infusion- associated reactions included pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, urticaria, bradycardia, and somnolence [see Adverse Reactions (6.1)].

Prior to FABRAZYME administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of infusion-associated reactions (IARs). However, IARs may still occur in patients after receiving pre-treatment. IARs tended to decline in frequency with continued use of FABRAZYME. However, IARs may still occur despite extended duration of FABRAZYME treatment. Appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, should be readily during FABRAZYME administration.

If a severe IAR occurs, discontinue FABRAZYME immediately and initiate appropriate medical treatment. Consider the risks and benefits of re-administering FABRAZYME following a severe IAR and monitor patients closely upon re-administration of FABRAZYME.
If a mild or moderate IAR occurs, consider temporarily holding the infusion, slowing the infusion rate, and/or reducing the FABRAZYME dosage.

Patients with advanced Fabry disease may have compromised cardiac function which may predispose them to a higher risk of severe complications from IARs. Closely monitor patients with compromised cardiac function if FABRAZYME is administered to these patients.

6 Adverse Reactions

Additions and/or revisions underlined:

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

Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]
Infusion-Associated Reactions [see Warnings and Precautions (5.2)]

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data). Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal development (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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.

Data

Human Data

Available data from a pregnancy sub-study within the Fabry Disease registry, post-marketing case reports, and case series with FABRAZYME use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In the Fabry Disease registry pregnancy sub-study, 33 pregnancies exposed to FABRAZYME prior to or during pregnancy had a known outcome; 5 were reported as exposed in the first trimester.

Animal Data

The effects of agalsidase beta on embryo-fetal development in rats were evaluated at doses of 3, 10, and 30 mg/kg/day (up to 68 times the human dose of 1 mg/kg every 2 weeks on a body surface area basis) during gestation days 7 to 17. Hepatocellular necrosis consistent with accumulation of test article was evident in maternal livers in the 10 and 30 mg/kg/day groups (23 and 68 times the human dose on a body surface area basis). There were no adverse effects of agalsidase beta on embryo-fetal development in rats.

8.2 Lactation

Additions and/or revisions underlined:

The available human data detected small amounts of agalsidase beta in human milk. Available data from the clinical study, global pharmacovigilance database, and published scientific literature are insufficient to determine the effects of FABRAZYME on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FABRAZYME and any potential adverse effects on the breastfed child from FABRAZYME or from the underlying maternal condition.

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 the patient and caregiver that reactions related to the infusion may occur during and after FABRAZYME treatment, including life-threatening hypersensitivity reactions, including anaphylaxis, and IARs. Inform the patient and caregiver of the signs and symptoms of hypersensitivity reactions and IARs and to seek medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.2)].

FABRAZYME Exposure During Pregnancy or Lactation

Advise a pregnant or lactating woman exposed to FABRAZYME to report FABRAZYME exposure to her healthcare provider and by calling 1-800-633-1610, option 1 [see Use in Specific Populations (8.1., 8.2)].

Patient Registry

Inform the patient and/or caregiver that a registry has been established for Fabry patients in order to better understand the variability and progression of Fabry disease in the population as a whole, and in women along with monitoring and evaluating long-term treatment effects of FABRAZYME. Additionally, the registry also monitors the effect of FABRAZYME on pregnant women and their offspring. Encourage the patient and/or caregiver to contact the registry program by visiting www. registrynxt.com or by calling 1-800-745-4447, extension 15500.

03/11/2021 (SUPPL-5309)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Anaphylaxis and Hypersensitivity Reactions

Additions underlined

In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe hypersensitivity reactions during Fabrazyme infusion.

In clinical trials with Fabrazyme, 10 of 238 patients developed IgE antibodies or skin test reactivity specific to Fabrazyme. Two of six patients in the rechallenge study discontinued treatment with Fabrazyme prematurely due to recurrent infusion-associated reactions. Four serious infusion-associated reactions occurred in three patients during Fabrazyme infusions, including bronchospasm, urticaria, hypotension, and development of Fabrazyme-specific antibodies. Other infusion-associated reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus.

Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-Fabrazyme antibodies and in adult patients with high antibody titer compared to that in antibody negative adult patients [see Adverse Reactions (6.2)].

…

The risks and benefits of readministering Fabrazyme following an anaphylactic or severe hypersensitivity reaction should be considered. If a decision is made to readminister the product, ensure that appropriate medical emergency support is available [see Dosage and Administration (2.1) and Adverse Reactions (6.2)].

Physicians should consider testing for IgE antibodies in patients who experienced suspected hypersensitivity reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies. There are no marketed tests for antibodies against Fabrazyme. If testing is warranted, contact Genzyme Corporation at 1-800-745-4447.

Patients who have had a positive skin test to Fabrazyme or who have tested positive for Fabrazyme-specific IgE antibody have been rechallenged with Fabrazyme using a rechallenge protocol. Rechallenge of these patients should only occur under the direct supervision of qualified personnel, with appropriate medical support measures readily available [see Dosage and Administration (2.1) and Adverse Reactions (6.2)].

5.2 Infusion-Associated Reactions

Additions underlined

…

In clinical trials of Fabrazyme, 59% of patients experienced infusion-associated reactions during Fabrazyme administration, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion. The incidence of infusion- associated reactions was higher in patients who were positive for anti-Fabrazyme antibodies than in patients who were negative for anti-Fabrazyme antibodies [see Adverse Reactions (6.2)].

…

Because of the potential for severe infusion-associated reactions, ensure appropriate medical support measures are readily available when Fabrazyme is administered. Monitor closely patients who have experienced infusion-associated reactions when readministering Fabrazyme.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Most Common Adverse Reactions

Table 2 enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies (14)]. The most common adverse reactions reported with Fabrazyme were infusion-associated reactions, (Fabrazyme 59% vs placebo 27%) some of which were severe (Fabrazyme 5.0% vs placebo 1.7%). Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion.

Common adverse reactions which occurred in greater than or equal to 20% of patients treated with Fabrazyme and >2.5% compared to placebo are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness and rash. Table 2 lists the common adverse reactions (greater than or equal to 5%):

Table 2: Summary of Common Adverse Reactions* in Clinical Trials (Study 1 and 2) of Patients with Fabry Disease

Please refer to label to view Table 2

…

Adverse Reactions in Pediatric Patients

In Study 3, the safety profile of Fabrazyme in pediatric Fabry disease patients, ages 8 to 16 years, was similar to that seen in adults. The most common adverse reactions (>20%) were headache, abdominal pain, pharyngitis, fever, nausea, vomiting, rhinitis, diarrhea, arthralgia, and dizziness [see Use in Specific Populations (8.4) and Clinical Studies (14)].

6.2 Immunogenicity

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

8 Use in Specific Populations

8.4 Pediatric Use

Additions underlined

The safety and effectiveness of Fabrazyme have been established in pediatric patients based on adequate and well-controlled studies in adults, a single-arm, open-label study in 16 pediatric patients with Fabry disease aged 8 to 16 years, and additional data in 24 patients with Fabry disease aged 2 to 7 years [see Clinical Pharmacology (12.2) and Clinical Studies (14)].

The overall safety profile of Fabrazyme was similar between the pediatric and the adult population [see Adverse Reactions (6.1) and Clinical Studies (14)].

12/18/2018 (SUPPL-5303)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

Anaphylaxis and Allergic Reactions
Infusion-associated Reactions
Compromised Cardiac Function
Immunogenicity and Rechallenge

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The data described below reflect exposure of 80 patients, ages 16 to 61 years, to 1 mg/kg Fabrazyme every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 1 to 35 months (mean 15.5 months). All 58 patients enrolled in one of the two studies continued into an open-label extension study of Fabrazyme treatment for up to 54 additional months. Patients were treated with antipyretics and antihistamines prior to the infusions.

Most Common Adverse reactions

Table 2 enumerates adverse reactions that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2).The most common adverse reactions reported with Fabrazyme were infusion-associated reactions, (Fabrazyme 59% vs placebo 27%) some of which were severe.

Common adverse reactions which occurred in ? 20% of patients treated with Fabrazyme and > 2.5% compared to placebo are: upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness and rash.

Serious and/or frequently occurring (greater than or equal to 5% incidence) related adverse reactions based on a pooled analysis of 150 patients treated with Fabrazyme…

6.2 Immunogenicity

(Additions and/or revisions are 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. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay 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 agalsidase products may be misleading.

The following data reflect the percentage of patients whose test results were considered positive for antibodies to Fabrazyme using an ELISA and radioimmunoprecipitation (RIP) assay for antibodies.

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

Cardiovascular: cardiorespiratory arrest, cardiac failure, myocardial infarction, palpitations,
Infections: sepsis and pneumonia
Infusion-associated reactions: anaphylaxis
General: hyperhidrosis, asthenia, infusion site reaction
Lymphatic: lymphadenopathy
Musculoskeletal: arthralgia
Nasopharyngeal: rhinorrhea
Neurologic: cerebrovascular accident, hypoesthesia, oral hypoesthesia
Ophthalmologic: increased lacrimation
Pulmonary: respiratory failure, hypoxia
Renal: renal failure
Dermatologic: erythema
Vascular: leukocytoclastic vasculitis

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Pregnant women and women of reproductive potential should be encouraged to enroll in the Fabry patient registry. The registry will monitor the effect of Fabrazyme on pregnant women and their offspring. For more information, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.

Risk Summary

Available data from postmarketing case reports and case series with Fabrazyme use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal development.

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, 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.

Data Animal data

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There are no data on the presence of agalsidase beta in either human or animal milk, the effects of the drug on the breastfed infant, or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fabrazyme and any potential adverse effects on the breastfed child from Fabrazyme or from the underlying maternal condition.

Lactating women with Fabry disease treated with Fabrazyme should be encouraged to enroll in the Fabry registry.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of Fabrazyme have been established in pediatric patients 8 years of age and older. Use of Fabrazyme in this age group is supported by evidence from a multinational, multicenter, uncontrolled, open-label study in 16 pediatric patients with Fabry disease (14 males, 2 females) ages 8 to 16 years.

The safety and effectiveness of Fabrazyme have not been established in pediatric patients less than 8 years of age.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Inform patients that a Registry has been established in order to better understand the variability and progression of Fabry disease in the population as a whole and in women, and to monitor and evaluate long-term treatment effects of Fabrazyme. The Registry will also monitor the effect of Fabrazyme on pregnant women and their offspring.

Encourage patients to participate. Advise patients that their participation is voluntary and may involve long-term follow-up. For more information, visit www. registrynxt.com or call 1-800- 745-4447, extension 15500.