Included as part of the PRECAUTIONS section.

Myelosuppression

Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (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).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 10⁹/L and the platelet count should be ≥ 75 x 10⁹/L. [See DOSAGE AND ADMINISTRATION]

Infections

Infection, including pneumonia and sepsis, has been reported in adult and pediatric patients in clinical trials and in postmarketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection.

Infusion Reactions and Anaphylaxts

Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions.

Tumor Lysis Syndrome

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

Skin Reactions

A number of skin reactions have been reported in clinical trials and postmarketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain.

In a study of TREANDA (90 mg/m²) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued.

Other Malignancies

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 TREANDA therapy has not been determined.

Extravasation

There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.

Use In Pregnancy

TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. [See Use In Specific Populations]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m²/day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m²/day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced. Oral administration at 187.5 mg/m²/day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas.

Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m², the lowest dose tested.

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.

Use In Specific Populations

Pregnancy

Pregnancy Category D [See WARNINGS AND PRECAUTIONS]

TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine from 210 mg/m² (70 mg/kg) in mice administered during organogenesis 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 dosing in mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m² (25 mg/kg) and an increase in abnormalities from 112.5 mg/m² (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m² (20 mg/kg) in rats administered on gestation days 4,7,9,11, or 13 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. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for bendamustine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of TREANDA in pediatric patients has not been established. TREANDA was evaluated in a single Phase 1/2 trial in pediatric patients with leukemia. The safety profile for TREANDA in pediatric patients was consistent with that seen in adults, and no new safety signals were identified.

The trial included pediatric patients from 1-19 years of age 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. Doses of 90 and 120 mg/m² were evaluated. The Phase 1 portion of the study determined that the recommended Phase 2 dose of TREANDA in pediatric patients was 120 mg/m².

A total of 32 patients entered the Phase 2 portion of the study at the recommended dose and were evaluated for response. There was no treatment response (CR+ CRp) in any patient at this dose. However, there were 2 patients with ALL who achieved a CR at a dose of 90 mg/m² in the Phase 1 portion of the study.

In the above-mentioned pediatric trial, the pharmacokinetics of TREANDA at 90 and 120 mg/m² doses were evaluated in 5 and 38 patients, respectively, aged 1 to 19 years (median age of 10 years).

The geometric mean body surface adjusted clearance of bendamustine was 14.2 L/h/m². The exposures (AUC_0-24 and Cmax) to bendamustine in pediatric patients following a 120 mg/m² intravenous infusion over 60 minutes were similar to those in adult patients following the same 120 mg/m² dose.

Geriatric Use

In CLL and NHL studies, there were no clinically significant differences in the adverse reaction profile between geriatric ( ≥ 65 years of age) and younger patients.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, 153 patients received TREANDA. The overall response rate for patients younger than 65 years of age was 70% (n=82) for TREANDA and 30% (n=69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for TREANDA and 22% (n=79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the TREANDA group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the TREANDA group and 8 months in the chlorambucil group.

Non-Hodgkin Lymphoma

Efficacy (Overall Response Rate and Duration of Response) was similar in patients < 65 years of age and patients ≥ 65 years. Irrespective of age, all of the 176 patients experienced at least one adverse reaction.

Renal Impairment

No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40 mL/min. [See CLINICAL PHARMACOLOGY]

Hepatic Impairment

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment. [See CLINICAL PHARMACOLOGY]

Effect of Gender

No clinically significant differences between genders were seen in the overall incidences of adverse reactions in either CLL or NHL studies.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the TREANDA group was 60% and 57%, respectively. The ORR for men (n=90) and women (n=58) in the chlorambucil group was 24% and 28%, respectively. In this study, the median progression-free survival for men was 19 months in the TREANDA treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the TREANDA treatment group and 8 months in the chlorambucil treatment group.

Non-Hodgkin Lymphoma

The pharmacokinetics of bendamustine were similar in male and female patients with indolent NHL. No clinically-relevant differences between genders were seen in efficacy (ORR and DR).

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.