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.

ALDURAZYME (BLA-125058)

(LARONIDASE)

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

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12/14/2023 (SUPPL-246)

Approved Drug Label (PDF)

Boxed Warning

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

5 Warnings and Precautions

5.1 Hypersensitivity Reactions Including Anaphylaxis

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

5.3 Acute Cardiorespiratory Failure

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

6 Adverse Reactions

(Additions and/or revisions underlined)

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

Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]
Acute Respiratory Complications Associated with Administration [see Warnings and Precautions (5.2)]
Acute Cardiorespiratory Failure [see Warnings and Precautions (5.3)]
Infusion-Associated Reactions [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Clinical Trials in Patients 6 Years and Older

A 26-week, double-blind, placebo-controlled clinical study (Study 1) of ALDURAZYME was conducted in 45 patients with MPS I, ages 6 to 43 years old, gender evenly distributed (N=23 females and 22 males). Of these 45 patients, 1 was clinically assessed as having Hurler form, 37 Hurler- Scheie, and 7 Scheie. Patients were randomized to receive either 0.58 mg/kg intravenously of ALDURAZYME per week for 26 weeks or placebo. All patients were treated with antipyretics and antihistamines prior to the infusions. Infusion reactions were reported in 32% (7 of 22) of ALDURAZYME-treated patients.

The most common adverse reactions reported in patients who received ALDURAZYME were flushing, pyrexia, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME; the other reactions were less frequent. Less common infusion reactions included angioedema (including face edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough. Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.

Table 2 enumerates adverse reactions and selected laboratory abnormalities that occurred during the 26-week placebo-controlled study (Study 1) that were reported in at least 2 patients more in the ALDURAZYME group than in the placebo group.

…

All 45 patients who completed the placebo-controlled study (Study 1) continued treatment in an open- label, uncontrolled extension study (Study 2). All patients received ALDURAZYME 0.58 mg/kg of body weight once weekly for up to 182 weeks. The most serious adverse reactions reported with ALDURAZYME infusions in Study 2 were anaphylactic and hypersensitivity reactions [see Warnings and Precautions (5)]. One patient had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME-specific IgG and IgE binding antibodies and complement activation. The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with ALDURAZYME. The most common adverse reactions reported in patients who received ALDURAZYME were rash (13%), flushing (11%), pyrexia (11%), headache (9%), abdominal pain or discomfort (9%), and injection site reaction (9%). Less commonly reported infusion reactions included nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4%), arthralgia (4%), and urticaria (4%).Additional common adverse reactions included back pain and musculoskeletal pain. Additional common adverse reactions included back pain and musculoskeletal pain.

…

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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

In postmarketing experience with ALDURAZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock [see Warnings and Precautions (5.1)] and laryngeal edema.

Adverse reactions resulting in death reported in the postmarketing setting with ALDURAZYME treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, and pneumonia. These events have been reported in MPS I patients with underlying disease [see Warnings and Precautions (5.3)].

Additional adverse reactions included fatigue, peripheral edema, erythema and cyanosis.

There have been a small number of reports of extravasation in patients treated with ALDURAZYME. There have been no reports of tissue necrosis associated with extravasation.

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Including Anaphylaxis

In the MPS I Registry and other postmarketing setting, laronidase-specific IgE and/or IgG antibodies appeared to be associated with anaphylaxis and suspected hypersensitivity reactions in ALDURAZYME-treated patients [see Clinical Pharmacology (12.6)].

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Pregnancy Exposure Registry

An MPS I Registry has been established. Pregnant women with MPS I and healthcare providers are encouraged to contact the pregnancy sub-registry by visiting www.registrynxt.com or calling 1-800- 745-4447 ext. 15500.

Risk Summary

Available data from the MPS I Registry pregnancy sub-registry, published case reports, and the global pharmacovigilance database with ALDURAZYME use in more than 30 pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The continuation of treatment for MPS I during pregnancy should be individualized to the pregnant woman. Untreated MPS I may result in adverse pregnancy and infant outcomes (see Clinical

Considerations). No evidence of fetal harm has been observed in rats when laronidase was administered during organogenesis at doses up to 6.2 times the recommended human dose (see Data).

…

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

Available information from one mother:infant pair are insufficient to evaluate the presence or absence of laronidase in human milk. No adverse effects have been reported in breastfed infants in postmarketing cases of ALDURAZYME use in lactating women. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALDURAZYME and any potential adverse effects on the breastfed child from ALDURAZYME or from the underlying maternal condition.

Lactating women with MPS I and healthcare providers are encouraged to contact the MPS I Registry by visiting www.registrynxt.com or calling 1-800-745-4447 ext. 15500.

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of ALDURAZYME have been established for the treatment of pediatric patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and the treatment of pediatric patients with the Scheie form of MPS I who have moderate to severe symptoms. The safety and effectiveness ALDURAZYME for the treatment of mildly affected pediatric patients with the Scheie form have not been established.

Use of ALDURAZYME for these indications is supported by evidence from an adequate and well- controlled clinical study (Study1) with an open label extension (Study 2) in adult and pediatric patients with MPS I, and from an open label, uncontrolled clinical study in pediatric patients with MPS I, 6 months to 5 years of age (Study 3). The safety and effectiveness of ALDURAZYME in pediatric patients 6 months of age to 5 years of age was found to be similar to pediatric patients 6 to 18 years of age and adults for these indications [see Adverse Reactions (6.1), Clinical Studies (14)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Advise the patient or caregiver that reactions related to the infusion may occur during and up to 3 hours after ALDURAZYME 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 Precaution (5.1, 5.4)].

Cardiac and Respiratory Adverse Reactions

Advise the patient and/or caregiver to report immediately to a healthcare provider if signs or symptoms of cardiac or respiratory decompensation occur during or following an infusion [see Warnings and Precautions (5.2, 5.3)]. 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.

Registry

Inform the patient and/or caregiver that a registry for MPS I patients has been established in order to better understand the MPS I disease and to track clinical outcomes of patients with MPS I over time. Additionally, the MPS I Registry also monitors the effect of ALDURAZYME on pregnant women, lactating women, and their infants. Encourage the patient and/or caregiver to contact the registry program by visiting www.registrynxt.com or by calling 1-800-745-4447 ext. 15500.

12/04/2019 (SUPPL-244)

Approved Drug Label (PDF)

6 Adverse Reactions

(additions underlined)

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

Anaphylaxis and Hypersensitivity Reactions
Acute Respiratory Complications Associated with Administration
Risk of Acute Cardiorespiratory Failure
Infusion Reactions

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Pregnancy Exposure Registry

An MPS I Registry has been established and pregnant women with MPS I should be encouraged to enroll in the pregnancy sub-registry. For more information, visit www.registrynxt.com or call 1-800-745-4447 ext. 15500.

Risk Summary

Available data from published case reports and postmarketing experience with ALDURAZYME use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No evidence of fetal harm has been observed in rats when laronidase was administered during organogenesis at doses up to 6.2 times the recommended human dose (see Data).

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

When laronidase was administered to pregnant female rats during organogenesis (gestation days [GD] 7-17) at doses of 0, 0.036, 0.36 or 3.6 mg/kg/day intravenously (equivalent to 7.3, 73.1, 730.8 units/kg/day) decreased maternal body weight gains and food consumption were observed with no corresponding effects on reproductive and litter parameters including number and distribution of corpora lutea, implantations and early and late resorptions at doses up to 3.6 mg/kg/day (6.2 times the recommended human dose of 0.58 mg/kg on a mg/kg basis). Laronidase has not been evaluated for effects on embryo-fetal development in any other species.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no available data on the presence of laronidase in human milk or the effects on milk production. No adverse effects have been reported in breastfed infants in a few postmarketing cases of laronidase use in lactating women. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALDURAZYME and any potential adverse effects on the breastfed child from ALDURAZYME or from the underlying maternal condition.

Lactating women with MPS I are encouraged to enroll in the MPS I Registry. For more information, visit www.registrynxt.com or call 1-800-745-4447 ext. 15500.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

Anaphylaxis, Hypersensitivity and Infusion Reactions

Inform the patient or caregiver that hypersensitivity reactions, including life-threatening anaphylaxis, and infusion reactions may occur with ALDURAZYME 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 ALDURAZYME. Hypersensitivity reactions may also occur up to 3 hours following an infusion of ALDURAZYME .

Cardiac and 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.

Registry

Patients should be informed that a registry for MPS I patients has been established in order to better understand the MPS I disease, and to track clinical outcomes of patients with MPS I over time. The MPS I Registry also monitors the effect of Aldurazyme on pregnant women, lactating women, and their infants. Patients should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. Information regarding the registry program may be found at www.registrynxt.com or by calling 1-800-745-4447 ext. 15500.