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Guide
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.
TREANDA (NDA-022249)
(BENDAMUSTINE HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/25/2022 (SUPPL-26)
5 Warnings and Precautions
5.10 Embryo-Fetal ToxicityAdditions and/or revisions underlined:
… 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 TREANDA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]
6 Adverse Reactions
6.2 Postmarketing ExperienceNewly added information:
Renal and urinary disorders: Nephrogenic diabetes insipidis (NDI)
8 Use in Specific Populations
8.3 Females and Males of Reproductive PotentialAdditions and/or revisions underlined:
Contraception
Females
TREANDA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Advise female patients of reproductive potential to use effective contraception during treatment with TREANDA and for 6 months after the last dose.
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
Embryo-Fetal Toxicity
… Advise female patients of reproductive potential to use effective contraception during treatment with TREANDA and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for 3 months after the last dose [see Use in Specific Populations (8.3), and Nonclinical Toxicology (13.1)].
Lactation
Advise females not to breastfeed during treatment with TREANDA and for 1 week after the last dose [see Use in Specific Populations (8.2)].
06/10/2021 (SUPPL-25)
5 Warnings and Precautions
5.3 Progressive Multifocal Leukoencephalopathy (PML)(Newly added subsection)
Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab [see Adverse Reactions (6.2)]. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold TREANDA treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
(Additions and/or revisions underlined)
There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma [see Adverse Reactions (6.2)].
Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with TREANDA.
6 Adverse Reactions
(Addition of the following to the bulleted line listing)
Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)]
(Additions and/or revisions underlined)
The following adverse reactions have been identified during post-approval use of TREANDA. 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, progressive multifocal leukoencephalopathy (PML)
Respiratory, thoracic and mediastinal disorders: Pneumonitis
Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non- melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
Allergic (Hypersensitivity) Reactions
Inform patients of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion [see Warnings and Precautions (5.4)].
Myelosuppression
Inform patients of the likelihood that TREANDA will cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1)].
Progressive Multifocal Leukoencephalopathy (PML)
Inform patients to immediately contact their healthcare provider if they experience confusion, memory loss, trouble thinking, difficulty talking or walking, vision loss or other neurological or cognitive symptoms [see Warnings and Precautions (5.3)].
Hepatotoxicity
Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.7)].
Fatigue
Advise patients that TREANDA may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect [see Adverse Reactions (6.1)].
Nausea and Vomiting
Advise patients that TREANDA may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].
Diarrhea
Advise patients that TREANDA may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].
Rash
Advise patients that a rash or itching may occur during treatment with TREANDA. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions (5.6)].
Non-Melanoma Skin Cancer (NMSC)
Advise patients to undergo regular skin cancer screenings, and to report any suspicious skin changes to their healthcare provider [see Warnings and Precautions (5.8)].
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 [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3), and Nonclinical Toxicology (13.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with TREANDA and for at least 6 months after the final dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for at least 3 months after the final dose [see Use in Specific Populations (8.3), and Nonclinical Toxicology (13.1)].
Lactation
Advise females not to breastfeed during treatment with TREANDA and for at least 1 week after the final dose [see Use in Specific Populations (8.2)].
Infertility
Advise males of reproductive potential that TREANDA may impair fertility [see Use in Specific Populations (8.3)].
11/21/2019 (SUPPL-24)
5 Warnings and Precautions
5.1 Myelosuppression
(Additions and/or revisions underlined)
TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).
Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently…
5.7 Other Malignancies
(Additions and/or revisions underlined)
There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with bendamustine hydrochloride therapy has not been determined.
5.9 Embryo-Fetal Toxicity
(Additions and/or revisions underlined)
Based on findings from animal reproduction studies and the drug’s mechanism of action, TREANDA 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 TREANDA 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 TREANDA and for at least 3 months after the final dose.
7 Drug Interactions
7.1 Effect of Other Drugs on TREANDA
(Additions and/or revisions underlined)
CYP1A2 Inhibitors
The coadministration of TREANDA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with TREANDA. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with TREANDA.
CYP1A2 Inducers
The coadministration of TREANDA with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of TREANDA. Consider alternative therapies that are not CYP1A2 inducers during treatment with TREANDA.
8 Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions underlined)
Risk Summary
In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth. There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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
Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities), and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride to mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration.
Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions underlined)
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 TREANDA, and for at least 1 week after the last dose.
8.3 Females and Males of Reproductive Potential
(Newly Added Subsection)
TREANDA can cause fetal harm when administered to a pregnant woman.
Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with TREANDA. Contraception
TREANDA can cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with TREANDA and for at least 6 months after the final dose.
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for at least 3 months after the final dose.
Based on findings from clinical studies, TREANDA 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. Patients should be warned of the potential risk to their reproductive capacities.
Based on findings from animal studies, TREANDA may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of TREANDA 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). TREANDA 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 in the Phase 2 portion of the trial at a dose of 120 mg/m2. However, 2 patients with ALL achieved CR at a dose of 90 mg/m2 in the Phase 1 portion of the study. 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 TREANDA 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 TREANDA (19 months vs. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.
8.6 Renal Impairment
(Additions and/or revisions underlined)
Do not use TREANDA in patients with creatinine clearance (CLcr) < 30 mL/min.
8.7 Hepatic Impairment
(Additions and/or revisions underlined)
Do not use TREANDA in patients with AST or ALT 2.5-10 × upper limit of normal (ULN) and total bilirubin 1.5-3 × ULN, or total bilirubin > 3 × ULN.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions underlined)
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 TREANDA 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 TREANDA and for at least 3 months after the final dose.
Lactation
Advise females not to breastfeed during treatment with TREANDA and for at least 1 week after the final dose.
Infertility
Advise males of reproductive potential that TREANDA may impair fertility.
12/15/2017 (SUPPL-23)
8 Use in Specific Populations
8.6 Renal Impairment(addition/revision underlined)
No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should not be used in patients with CrCL < 30 mL/min.
10/18/2016 (SUPPL-22)
5 Warnings and Precautions
5.5 Skin Reactions (addition underlined)Fatal and serious skin reactions have been reported with TREANDA 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 TREANDA was given as a single agent and in combination with other anticancer agents or allopurinol.
Fatal and serious cases of liver injury have been reported with TREANDA. 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
(addition underlined)
Hepatotoxicity
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms).
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 health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising.