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.

ONCASPAR (BLA-103411)

(PEGASPARGASE)

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

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03/13/2024 (SUPPL-5207)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Hepatotoxicity, Including Hepatic Veno-Occlusive Disease

Subsection title revised

Additions and/or revisions underlined:

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with ONCASPAR in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy [see Adverse Reactions (6)]. Do not administer ONCASPAR to patients with severe hepatic impairment [see Contraindications (4)]. Evaluate bilirubin and transaminases prior to each dose of ONCASPAR and at least weekly, during cycles of treatment that include ONCASPAR, through 6 weeks after the last dose of ONCASPAR. 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 ONCASPAR, 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 ONCASPAR and provide supportive care [see Dosage and Administration (2.3)].

6 Adverse Reactions

Additions and/or revisions underlined:

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

Anaphylaxis and serious hypersensitivity reactions [see Warnings and Precautions (5.1)]
Thrombosis [see Warnings and Precautions (5.2)]
Pancreatitis [see Warnings and Precautions (5.3)]
Glucose intolerance [see Warnings and Precautions (5.4)]
Hemorrhage [see Warnings and Precautions (5.5)]
Hepatotoxicity, including VOD [see Warnings and Precautions (5.6)]

6.3 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of ONCASPAR. 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.

Blood and lymphatic system disorders: Coagulopathy.

Gastrointestinal disorders: Hepatic impairment, pancreatic cyst, pancreatitis.

Hepatic: Veno-occlusive disease.

Immune system disorders: Anaphylactic shock, hypersensitivity reaction.

Investigations: Blood cholesterol increased.

Metabolism and nutrition disorders: Hyperglycemia, hyperammonemia.

Musculoskeletal and connective tissue disorders: Osteonecrosis.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hepatotoxicity, including Veno-Occlusive Liver Disease (VOD)

Inform patients that liver problems, including severe, life-threatening, or fatal VOD and abnormalities in liver tests, may develop during ONCASPAR treatment. Advise patients to contact their healthcare provider immediately if they experience jaundice, rapid weight gain, abdominal swelling, or right upper abdominal pain or tenderness [see Warnings and Precautions (5.6)].

…

12/22/2022 (SUPPL-5205)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes to table 2; please refer to label

11/02/2021 (SUPPL-5201)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Anaphylaxis and Serious Hypersensitivity Reactions

Additions and/or revisions underlined:

Anaphylaxis and serious hypersensitivity reactions can occur in patients receiving ONCASPAR. The risk of serious hypersensitivity reactions is higher in patients with known hypersensitivity to (E.) coli derived L-asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritus, and rash [see Adverse Reactions (6.1)].

Premedicate patients 30-60 minutes prior to administration of ONCASPAR. [see Dosage and Administration (2.2)]. Observe patients for 1 hour after administration of ONCASPAR in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.4)]. Discontinue ONCASPAR in patients with serious hypersensitivity reactions.

5.2 Thrombosis

Additions and/or revisions underlined:

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving ONCASPAR [see Adverse Reactions (6.1)]. Discontinue ONCASPAR in patients with serious thrombotic events [see Dosage and Administration (2.3)].

5.3 Pancreatitis

Additions and/or revisions underlined:

Pancreatitis can occur in patients receiving ONCASPAR. Hemorrhagic or necrotizing pancreatitis with fatal outcomes have been reported [see Adverse Reactions (6.1)].

… Discontinue ONCASPAR in patients where pancreatitis is suspected. If pancreatitis is confirmed, do not resume ONCASPAR [see Dosage and Administration (2.3)].

5.4 Glucose Intolerance

Additions and/or revisions underlined:

Glucose intolerance can occur in patients receiving ONCASPAR [see Adverse Reactions (6.1]. In some cases, glucose intolerance is irreversible. Monitor serum glucose [see Dosage and Administration (2.3)].

5.5 Hemorrhage

Additions and/or revisions underlined:

Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving ONCASPAR [see Adverse Reactions (6.1)]. Evaluate patients with signs and symptoms of hemorrhage with coagulation parameters including PT, PTT, fibrinogen … Discontinue ONCASPAR for severe or life-threatening hemorrhage. [see Dosage and Administration (2.3)].

5.6 Hepatoxicity

Additions and/or revisions underlined:

… In the event of serious liver toxicity, discontinue treatment with ONCASPAR and provide supportive care [see Dosage and Administration (2.3)].

6 Adverse Reactions

6.3 Postmarketing Experience

Newly added information:

Musculoskeletal and connective tissue disorders: Osteonecrosis

7 Drug Interactions

Newly added subsection to newly created section:

7.1 Glucocorticoids

Pegaspargase may increase the risk of glucocorticoid-induced toxicities, including osteonecrosis, through a potential increase in exposure of dexamethasone [see Adverse Reactions (6.3)].

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

… Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONCASPAR and for 1 month after the last dose.

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

PATIENT COUNSELING INFORMATION

Lactation

Additions and/or revisions underlined:

Advise women not to breastfeed during treatment with ONCASPAR and for 1 month after the last dose [see Use in Specific Populations (8.2)].

06/17/2020 (SUPPL-5198)

Approved Drug Label (PDF)

5 Warnings and Precautions

Hemorrhage

(Newly added information)

Discontinue ONCASPAR for severe or life-threatening hemorrhage.

Immunogenicity

(Additions and/or revisions underlined)

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 asparaginase products may be misleading . . . ). In study CCG 1962, there is insufficient information to determine whether the development of antibodies is associated with an increased risk of clinical allergic reactions or altered pharmacokinetics (i.e., loss of asparaginase activity).

In Study DFCI 11-001, of the 100 evaluable patients treated with ONCASPAR, 19 (19%) patients developed anti-drug antibodies (ADA) during treatment;18 of these 19 patients were positive for anti-PEG antibodies. The presence of ADA correlated with the occurrence of hypersensitivity reactions. There is insufficient information to determine whether the development of antibodies is associated with altered pharmacokinetics (i.e., loss of asparaginase activity).

8 Use in Specific Populations

Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

ONCASPAR can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy testing is recommended for females of reproductive potential prior to initiating ONCASPAR.

Contraception

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ONCASPAR and for at least 3 months after the last dose. Counsel patients to use non- hormonal method(s) of contraception, since ONCASPAR can render hormonal contraceptives ineffective.

Pregnancy

(Additions and/or revisions underlined)

Risk summary

Based on published literature studies with L-asparaginase in pregnant animals, ONCASPAR can cause fetal harm when administered to a pregnant woman. There are no available data on ONCASPAR use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Published literature studies in pregnant animals suggest asparagine depletion may cause harm to the animal offspring (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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

Patient Counseling Information

(Additions and/or revisions underlined)

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ONCASPAR and for at least 3 months after the last dose [see Use in Specific Populations (8.3)].

01/03/2019 (SUPPL-5196)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

ONCASPAR is contraindicated in patients with a:

History of serious hypersensitivity reactions, including anaphylaxis, to ONCASPAR or to any of the excipients.
History of serious thrombosis with prior L-asparaginase therapy. History of pancreatitis, including pancreatitis related to prior L-asparaginase therapy.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Anaphylaxis and Serious Hypersensitivity Reactions

Anaphylaxis and serious hypersensitivity reactions can occur in patients receiving ONCASPAR. The risk of serious hypersensitivity reactions is higher in patients with known hypersensitivity to E. coli derived L-asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritus, and rash.

Observe patients for 1 hour … Discontinue ONCASPAR in patients with serious hypersensitivity reactions.

5.3 Pancreatitis

Pancreatitis can occur in patients receiving ONCASPAR. Hemorrhagic or necrotizing pancreatitis with fatal outcomes have been reported.

Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Assess serum amylase and/or lipase levels to confirm early signs of pancreatic inflammation. Discontinue ONCASPAR in patients where pancreatitis is suspected. If pancreatitis is confirmed, do not resume ONCASPAR.

5.5 Hemorrhage

… can occur in patients receiving ONCASPAR. Evaluate patients with signs and symptoms of hemorrhage with coagulation parameters including PT, PTT, fibrinogen. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy.

5.6 Hepatotoxicity

Hepatotoxicity and abnormal liver function, including elevations of transaminase, bilirubin (direct and indirect), reduced serum albumin, and plasma fibrinogen can occur. Evaluate bilirubin and transaminases at least weekly during cycles of treatment that include ONCASPAR through at least 6 weeks after the last dose of ONCASPAR. In the event of serious liver toxicity, discontinue treatment with ONCASPAR and provide supportive care.

6 Adverse Reactions

Extensively changed; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

PLLR conversion; extensive changes. Please refer to label for complete information.

8.4 Pediatric Use

Addition of the following:

The safety and effectiveness of ONCASPAR in the treatment of ALL have been established in pediatric patients. Use of ONCASPAR in these age groups is supported by evidence of efficacy as first-line treatment from one adequate and well-controlled trial, and evidence of efficacy for treatment of patients with hypersensitivity to asparaginase from four adequate and well-controlled trials, and safety data from 7 total trials. The pediatric patients treated with ONCASPAR 2,500 International Units/m2 on these trials included 26 infants (1 month to <2 years old), 165 children (2 years to <12 years old), and 39 adolescents (12 to 17 years old).

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

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label for complete information.

10/07/2016 (SUPPL-5188)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Glucose Intolerance (Addition underlined)

Glucose intolerance can occur in patients receiving Oncaspar ®. In some cases, glucose intolerance is irreversible. Monitor serum glucose.