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.

BENDEKA (NDA-208194)

(BENDAMUSTINE HYDROCHLORIDE)

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

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01/11/2024 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Renal and urinary disorders: Nephrogenic diabetes insipidus (NDI)

11/08/2019 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

10/08/2019 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on findings from animal reproduction studies and the drug’s mechanism of action, BENDEKA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with BENDEKA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for at least 3 months after the final dose.

7 Drug Interactions

7.1 Effect of other drugs on BENDEKA

Newly added information:

CYP1A2 Inhibitors

The coadministration of BENDEKA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with BENDEKA. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with BENDEKA.

CYP1A2 Inducers

The coadministration of BENDEKA with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of BENDEKA. Consider alternative therapies that are not CYP1A2 inducers during treatment with BENDEKA.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of bendamustine hydrochloride or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with BENDEKA, and for at least 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

PLLR conversion; additions and/or revisions underlined:

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

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiation BENDEKA.

Contraception

Females

BENDEKA can cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with BENDEKA and for 6 months after the final dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for at least 3 months after the final dose

Infertility

Males

Based on findings from clinical studies, BENDEKA may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances, spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Advise patients of the potential risk to their reproductive capacities.

Based on findings from animal studies, BENDEKA may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of BENDEKA on male fertility, including the reversibility of adverse effects, have not been studied.

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness in pediatric patients have not been established.

Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1-19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient. The safety profile in these patients was consistent with that seen in adults, and no new safety signals were identified.

The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area.

8.5 Geriatric Use

Additions and/or revisions underlined:

No overall differences in safety were observed between patients greater than or equal to 65 years of age and younger patients. Efficacy was lower in patients 65 and over with CLL receiving bendamustine hydrochloride based upon an overall response rate of 47% for patients 65 and over and 70% for younger patients. Progression free survival was also longer in younger patients with CLL receiving bendamustine (19 months vs. 12 months). No overall differences in efficacy in patients non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.

8.6 Renal Impairment

Additions and/or revisions underlined:

Do not use BENDEKA (bendamustine hydrochloride) injection should not be used in patients with creatinine clearance (CLcr) less than 30 mL/min.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

Do not use BENDEKA (bendamustine hydrochloride) injection should not be used in patients with moderate (AST or ALT 2.5-10 X × upper limit of normal (ULN) and total bilirubin 1.5-3 X× ULN), or severe (total bilirubin greater than 3 X× ULN) hepatic impairment.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise female patients of reproductive potential to use effective contraception during treatment with BENDEKA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for 3 months after the final dose.

Lactation

Advise females not to breastfeed during treatment with BENDEKA and for at least 1 week after the final dose.

Infertility

Advise males of reproductive potential that BENDEKA may impair fertility.

07/30/2018 (SUPPL-13)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Renal Impairment

CrCL levels revised to CrCL less than 30 mL/min.

02/09/2017 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Tumor Lysis Syndrome

(addition underlined)

Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in reports. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.

5.5 Skin Reactions

(additions underlined)

Fatal and serious skin reactions have been reported with bendamustine hydrochloride injection treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash. Events occurred when bendamustine hydrochloride injection was given as a single agent and in combination with other anticancer agents or allopurinol.Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue BENDEKA (bendamustine hydrochloride) injection.

5.6 Hepatotoxicity

(new subsection added)

Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients [see Warnings and Precautions (5.2)]. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy.

6 Adverse Reactions

6.2 Clinical Trials Experience in CLL

(addition underlined)

The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled randomized trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose…

6.4 Postmarketing Experience

(addition underlined)

The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. 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 systems disorders: Pancytopenia.

Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation.

General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).

Immune system disorders: Anaphylaxis.

Infections and infestations: Pneumocystis jiroveci pneumonia.

Respiratory, thoracic and mediastinal disorders: Pneumonitis.

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms).

(addition underlined)

· Myelosuppression

· Infections

· Anaphylaxis and Infusion Reactions

· Tumor Lysis Syndrome

· Skin Reactions

· Hepatotoxicity

· Other Malignancies

· Extravasation Injury

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

17 PATIENT COUNSELING INFORMATION

(addition underlined)

Hepatotoxicity

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising.

06/23/2016 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

Infections

Addition of paragraph...Patients treated with bendamustine hydrochloride are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration.

6 Adverse Reactions

Post-Marketing Experience (addition of the following sub-sections):

Blood and lymphatic systems disorders: Pancytopenia.
Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation.
General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).
Immune system disorders: Anaphylaxis.
Infections and infestations: Pneumocystis jiroveci pneumonia.
Respiratory, thoracic and mediastinal disorders: Pneumonitis.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (with concomitant allopurinol and other medications known to cause the syndrome), Toxic epidermal necrolysis (with concomitant allopurinol and other medications known to cause the condition).