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.

RYLAZE (BLA-761179)

(ASPARAGINASE ERWINIA CHRYSANTHEMI (RECOMBINANT)-RYWN)

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

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04/15/2024 (SUPPL-7)

Approved Drug Label (PDF)

4 Contraindications

Additions and revisions underlined:

RYLAZE is contraindicated in patients with:

History of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis [see Warnings and Precautions (5.1)];
History of serious pancreatitis during previous asparaginase therapy [see Warnings and Precautions (5.2)];
History of serious thrombosis during previous asparaginase therapy [see Warnings and Precautions (5.3)];
History of serious hemorrhagic events during previous asparaginase therapy [see Warnings and Precautions (5.4)].
Severe hepatic impairment [see Warnings and Precautions (5.5)].

5 Warnings and Precautions

5.5 Hepatotoxicity, including Hepatic Veno-Occlusive Disease

Newly added information:

Elevated bilirubin and/or transaminases occurred in 75% of patients treated with RYLAZE in clinical trials, and 26% had Grade > or = 3 elevations. Elevated bilirubin occurred in 28% of patients treated with RYLAZE in clinical trials, and 2% had Grade > or = 3 elevations. Elevated transaminases occurred in 73% of patients treated with RYLAZE in clinical trials, and 25% had Grade > or = 3 elevations [see Adverse Reactions (6.1)].

Hepatotoxicity, including severe, life-threatening, and potential fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with asparaginase class products in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy [see Adverse Reactions (6)]. Do not administer RYLAZE to patients with severe hepatic impairment [see Contraindications (4)]. Inform patients of the signs and symptoms of hepatotoxicity.

Evaluate bilirubin and transaminases prior to each cycle of RYLAZE and at least weekly during cycles of treatment that include RYLAZE, through four weeks after the last dose of RYLAZE. Monitor frequently for signs and symptoms of hepatic VOD, which may include rapid weight gain, fluid retention with ascites, hepatomegaly (which may be painful), and rapid increase of bilirubin. For patients who develop abnormal liver tests after RYLAZE, more frequent monitoring for liver test abnormalities and clinical signs and symptoms of VOD is recommended. In the event of serious liver toxicity, including VOD, discontinue treatment with RYLAZE and provide supportive care [see Dosage and Administration (2.3)].

6 Adverse Reactions

Additions and revisions underlined:

The following clinically significant adverse reactions are described in greater detail in other sections of the labeling:

Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
Pancreatic Toxicity [see Warnings and Precautions (5.2)]
Thrombosis [see Warnings and Precautions (5.3)]
Hemorrhage [see Warnings and Precautions (5.4)]
Hepatotoxicity, including VOD [see Warnings and Precautions (5.5)]

6.2 Postmarketing Experience

Newly added subsection:

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

Hepatic: Veno-occlusive disease (VOD)

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

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

. . .

Hepatotoxicity, including Veno-Occlusive Liver Disease

Inform patients that liver problems, including severe, life-threatening, or fatal VOD and abnormalities in liver tests, may develop during RYLAZE treatment. Advise patients to report any jaundice, severe nausea or vomiting, or easy bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.5)].

. . .

11/18/2022 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions

Additions and revisions underlined:

Hypersensitivity reactions after the use of RYLAZE occurred in 29% of patients in clinical trials, and it was severe in 6% of patients [see Adverse Reactions (6.1)]. Anaphylaxis was observed in 2% of patients after intramuscular administration. Discontinuation of RYLAZE due to hypersensitivity reactions occurred in 5% of patients. Hypersensitivity reactions were higher in patients who received intravenous asparaginase erwinia chrysanthemi (recombinant)-rywn. The intravenous route of administration is not approved.

In patients administered RYLAZE intramuscularly in clinical trials, the median number of doses of RYLAZE that patients received prior to the onset of the first hypersensitivity reaction was 12 doses (range: 1-64 doses). The most commonly observed reaction was rash (19%), and 1 patient (1%) experienced a severe rash.

Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus.

Premedicate patients prior to administration of RYLAZE as recommended [see Dosage and Administration (2.2)].

5.2 Pancreatitis

Additions and revisions underlined:

Pancreatitis, including elevated amylase or lipase, was reported in 20% of patients in clinical trials of RYLAZE and was severe in 8% [see Adverse Reactions (6.1)]. Symptomatic pancreatitis occurred in 7% of patients, and it was severe in 6% of patients. Elevated amylase or lipase without symptomatic pancreatitis was observed in 13% of patients treated with RYLAZE. Hemorrhagic or necrotizing pancreatitis have been reported with L-asparaginase class products.

5.3 Thrombosis

Additions and revisions underlined:

Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported in 1% of patients following treatment with RYLAZE.

5.4 Hemorrhage

Additions and revisions underlined:

Bleeding was reported in 25% of patients treated with RYLAZE, and it was severe in 2%. Most commonly observed reactions were bruising (12%) and nose bleed (9%). [see Adverse Reactions (6.1)].

5.5 Hepatotoxicity

Additions and revisions underlined:

Elevated bilirubin and/or transaminases occurred in 75% of patients treated with RYLAZE in clinical trials, and 26% had Grade > or equal to 3 elevations. Elevated bilirubin occurred in 28% of patients treated with RYLAZE in clinical trials, and 2% had Grade > or equal to 3 elevations. Elevated transaminases occurred in 73% of patients treated with RYLAZE in clinical trials, and 25% had Grade > or equal to 3 elevations [see Adverse Reactions (6.1)].

6 Adverse Reactions

Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients 1 month to < 17 years who have developed hypersensitivity to a long-acting E. coli- derived asparaginase. Use of RYLAZE in these age groups is supported by evidence from an adequate and well-controlled study in adults and pediatric patients. The trial included 139 pediatric patients, including 2 infants (1 month to < 2 years), 99 children (2 years to < 12 years old), and 38 adolescents (12 years to < 17 years old).

For patients with colitis, additional treatment, such as enteric-acting and/or systemic steroids, may be required [see Dosage and Administration (2.3)].