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.

ASPARLAS (BLA-761102)

(CALASPARGASE PEGOL-MKNL)

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

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11/29/2023 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

ASPARLAS is contraindicated in patients with:

History of serious hypersensitivity reactions, including anaphylaxis, to pegylated L-asparaginase therapy [see Warnings and Precautions (5.1)]
History of serious pancreatitis during previous L-asparaginase therapy [see Warnings and Precautions (5.2)]
History of serious thrombosis during previous L-asparaginase therapy [see Warnings and Precautions (5.3)]
History of serious hemorrhagic events during previous L-asparaginase therapy [see Warnings and Precautions (5.4)]

Severe hepatic impairment [see Warnings and Precautions (5.5)]

5 Warnings and Precautions

5.1 Hypersensitivity

Additions and/or revisions underlined:

Grade 3 and 4 hypersensitivity reactions, including anaphylaxis, have been reported in clinical trials with ASPARLAS with an incidence between 7 and 21% [see Contraindications (4), Adverse Reactions (6.1)]. Hypersensitivity reactions observed with other asparaginases 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 ASPARLAS [see Dosage and Administration (2.2)]. Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer ASPARLAS in a clinical setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.4)] and observe patients for 1 hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions.

5.2 Pancreatitis

Additions and/or revisions underlined:

Cases of pancreatitis have been reported in clinical trials with ASPARLAS with an incidence between 12 and 16% [see Adverse Reactions (6.1)]. Hemorrhagic or necrotizing pancreatitis have been reported with other asparaginases.

Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Assess serum amylase and/or lipase levels to identify early signs of pancreatic inflammation. Discontinue ASPARLAS if pancreatitis is suspected; if pancreatitis is confirmed, do not resume ASPARLAS [see Dosage and Administration (2.3)].

5.5 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 ASPARLAS in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy [see Adverse Reactions (6). Do not administer ASPARLAS to patients with severe hepatic impairment [see Contraindications (4)].

Evaluate bilirubin and transaminases prior to each dose of ASPARLAS and at least weekly, during cycles of treatment that include ASPARLAS, through 6 weeks after the last dose of ASPARLAS. 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 ASPARLAS, 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 ASPARLAS and provide supportive care [see Dosage and Administration (2.3)].

6 Adverse Reactions

Additions and/or revisions underlined:

…

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions

In Study DFCI 11-001, hypersensitivity reactions occurred in 80% of ASPARLAS-treated patients with new or an increased titer of anti-drug antibodies (ADA) and in 6% of those without ADA [see Clinical Pharmacology (12.6)]. Two patients with ADA experienced anaphylaxis [see Warnings and Precautions (5.1)].

6.2 Postmarketing Experience

Newly added subsection:
The following adverse reactions have been identified during post approval use of ASPARLAS. 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

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

…

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 ASPARLAS 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 (5.5)].

…

12/21/2021 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity

Additions and/or revisions underlined:

Grade 3 and 4 hypersensitivity reactions including anaphylaxis have been reported in clinical trials with ASPARLAS with an incidence between 7 to 21% [see Contraindications (4), Adverse Reactions (6.1)]. Hypersensitivity reactions observed with other asparaginases 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 ASPARLAS. [see Dosage and Administration (2.2)]. Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer ASPARLAS in a clinical setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.4)] and observe patients for 1 hour after administration. Discontinue ASPARLAS in patients with serious hypersensitivity reactions.

5.3 Thrombosis

Additions and/or revisions underlined:

Serious thrombotic events, including sagittal sinus thrombosis, have been reported in clinical trials with ASPARLAS with an incidence of 9 to 12%. Discontinue ASPARLAS in patients experiencing serious thrombotic events [see Dosage and Administration (2.4), Adverse Reactions (6.1)].

5.4 Hemorrhage

Additions and/or revisions underlined:

Hemorrhage associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia have been reported in patients receiving ASPARLAS [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.4)].

5.5 Hepatotoxicity

Additions and/or revisions underlined:

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 ASPARLAS through 6 weeks after the last dose of ASPARLAS. In the event of serious liver toxicity, discontinue treatment with ASPARLAS and provide supportive care [see Dosage and Administration (2.4), Contraindications (4), Adverse Reactions (6.1)].

06/24/2020 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

(Additions and/or revisions underlined)

As with all therapeutic proteins, there is a 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 to ASPARLAS in the studies described below with the incidence of antibodies in other studies or to other asparaginase products may be misleading.

Immunogenicity was assessed using enzyme linked immunosorbent assays (ELISA) in Study DFCI 11-001. Of 98 evaluable patients treated with ASPARLAS, 15 (15%) patients developed new or an increased titer of anti-drug antibodies (ADA) during treatment; 14 of these 15 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

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

Based on published literature studies with L-asparaginase in pregnant animals, ASPARLAS can cause fetal harm when administered to a pregnant woman. There are no available data on ASPARLAS use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to 1 times the maximum recommended human doses did not result in adverse developmental outcomes. Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring. Advise pregnant women of the potential risk to a fetus.

The estimated 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%-4% and 15%-20%, respectively.

Data

Animal Data

In an embryofetal development study, calaspargase pegol-mknl was administered intravenously at doses of 75, 150, and 300 U/kg (0.2, 0.6 and 1 times the maximum recommended human dose, respectively, based on AUC) to pregnant rats during the period of organogenesis. Maternal toxicity of decreased body weight and food consumption was seen at all dose levels resulting in reductions in gravid uterine and placental weights, and slight reductions in fetal body weights. No evidence of structural abnormalities or embryo-fetal mortality were observed in this study at any of the doses tested. Published literature studies in which pregnant rabbits were administered L-asparaginase suggested harm to the animal offspring.

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

There are no data on the presence of calaspargase pegol-mknl in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ASPARLAS and for 3 months after the last dose.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

ASPARLAS can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Pregnancy testing is recommended in females of reproductive potential prior to initiating ASPARLAS.

Contraception

Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with ASPARLAS and for at least 3 months after the last dose. Counsel patients to use non-

hormonal method(s) of contraception since ASPARLAS can render hormonal contraceptives ineffective.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Hypersensitivity

Inform patients on the possibility of serious allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms.

Pancreatitis

Instruct patients on the signs and symptoms of pancreatitis and to seek immediate medical attention if they experience severe abdominal pain.

Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination.

Thombosis

Instruct patients on the risk of thrombosis and to seek medical advice immediately if they experience severe headache, arm or leg swelling, shortness of breath, or chest pain.

Hemorrhage

Advise patients to report any unusual bleeding or bruising to their healthcare provider.

Hepatotoxicity

Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding.

Pregnancy

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.

Advise females of reproductive potential to use effective non-hormonal contraceptionduring treatment with ASPARLAS and for at least 3 months after the last dose.

Lactation

Advise women not to breastfeed during treatment with ASPARLAS and for at least 3 months after the last dose.

09/05/2019 (SUPPL-2)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

There are no available data on ASPARLAS use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of calaspargase pegol-mknl to pregnant rats during organogenesis at doses 0.2 to 1 times the maximum recommended human doses did not result in adverse developmental outcomes. Published literature studies in pregnant rabbits, however, suggest asparagine depletion may cause harm to the animal offspring. Advise patients of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) 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 2-4% and 15-20%, respectively.

Data

Animal Data