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.

BESPONSA (BLA-761040)

(INOTUZUMAB OZOGAMICIN)

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

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03/06/2024 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

Additions and revisions underlined:

BESPONSA can cause hepatotoxicity, including VOD. In adult patients in the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD occurred in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment. VOD occurred up to 56 days after the final dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days).

In the BESPONSA arm, among the 79 patients who proceeded to a subsequent HSCT, VOD occurred in 18/79 patients (23%), and among all 164 patients treated, VOD occurred in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT.

The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with BESPONSA.

In Study WI203581 (ITCC-059) VOD occurred in 8/53 (15%) of pediatric patients treated with single agent BESPONSA. Among the 26 pediatric patients who underwent HSCT, VOD occurred in 5 (19%) patients [see Adverse Reactions (6.1)].

Monitor closely for signs and symptoms of VOD including elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles [see Dosage and Administration (2.1)]. For patients who proceed to HSCT, monitor liver tests at least weekly during the first month post-HSCT, then less frequently thereafter, according to standard medical practice.

In adult patients in the INO-VATE ALL trial, increases in liver test abnormalities occurred. Grade 3 or 4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively.

In pediatric patients in Study WI203581 (ITCC-059), liver test abnormalities occurred, with Grade 3 or 4 increases in AST, ALT, and blood bilirubin in 11/53 (21%), 11/53 (21%), and 5/53 (9%) of patients, respectively [see Adverse Reactions (6.1)].

In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Based on elevations of liver tests withhold, reduce dose, or permanently discontinue BESPONSA [see Dosage and Administration (2.3)].

5.2 Increased Risk of Post-Transplant Non-Relapse Mortality

Additions and revisions underlined:

In adult patients in the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigator’s choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.

. . .

In pediatric patients in Study WI203581 (ITCC-059), 26/53 patients (49%) had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 7/26 (27%).

5.3 Myelosuppression

Additions and revisions underlined:

BESPONSA can cause myelosuppression, including thrombocytopenia and neutropenia [see Adverse Reactions (6.1)].

In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia occurred in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia occurred in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia occurred in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, occurred in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to > 50,000/mm3 was later than 45 days after the final dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients (2%) who received Investigator’s choice of chemotherapy.

Complications associated with myelosuppression (including infections and bleeding/hemorrhage) occurred in patients receiving BESPONSA [see Adverse Reactions (6.1)]. Infections, including serious infections, some of which were life-threatening or fatal, occurred in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, occurred in 8/164 patients (5%). Bacterial, viral, and fungal infections occurred.

Hemorrhage occurred in 54/164 patients (33%). Grade 3 or 4 hemorrhage occurred in 8/164 patients (5%), including a fatality in 1/164 patients (1%) (intra-abdominal hemorrhage). The most common type of hemorrhage was epistaxis which occurred in 24/164 patients (15%).

In pediatric patients in Study WI203581 (ITCC-059), Grade 3 or 4 thrombocytopenia occurred in

24/53 (45%) patients. Grade 3 or 4 neutropenia occurred in 21/53 (40%) patients. Infections occurred in 23/53 (43%) patients, and hemorrhage occurred in 22/53 (42%) patients. The most common types of hemorrhage were hematoma in 8/53 (15%), mouth hemorrhage in 6/53 (11%), and epistaxis in 6/53 (11%) patients [see Adverse Reactions (6.1)].

Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with BESPONSA. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with BESPONSA. Based on the severity of myelosuppression, reduce dose, temporarily withhold, or permanently discontinue BESPONSA [see Dosage and Administration (2.3)]

5.4 Infusion Related Reactions

Additions and revisions underlined:

BESPONSA can cause infusion related reactions. In adult patients in the INO-VATE ALL trial, infusion related reactions occurred in patients who received BESPONSA. Infusion related reactions (all Grade 2) occurred in 4/164 patients (2%) [see Adverse Reactions (6.1)]. Infusion related reactions generallyoccurred in Cycle 1 shortly after the end of the BESPONSA infusion and resolved spontaneously or with medical management.

In pediatric patients in Study WI203581 (ITCC-059), infusion related reactions occurred in 4/53 (8%) patients [see Adverse Reactions (6.1)].

. . .

5.5 QT Interval Prolongation

Additions and revisions underlined:

BESPONSA can cause QT interval prolongation. In adult patients in the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia’s formula (QTcF) of ? to 60 msec from baseline occurred in 4/162 patients (3%). Grade 2 QT prolongation was reported in 2/164 patients (1%) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2)].

In pediatric patients in Study WI203581 (ITCC-059), increases in QTcF of > 60 msec from baseline occurred in 7/49 (14%) patients. 3/52 (6%) of patients had QTcF values > 500 msec [see Adverse Reactions (6.1)].

. . .

5.6 Embryo-Fetal Toxicity

Additions and revisions underlined:

Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise

females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose. Advise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.2 Lactation

Additions and revisions underlined:

Risk Summary

There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BESPONSA and for 2 months after the last dose.

8.4 Pediatric Use

Additions and revisions underlined:

The safety and effectiveness of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established. The use of BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059)

[see Adverse Reactions (6.1), Clinical Studies (14.1)]. The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to

< 12 years old, and 20 patients 12 years to < 17 years old. Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults.

The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.