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Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Adverse Reactions). 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. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has 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 & Administration.)
Infections: Infection, including pneumonia, sepsis, septic shock and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports (see Adverse Reactions). Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.
Progressive Multifocal Leukoencephalopathy (PML): Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab (see Adverse Reactions). 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.
Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials (see Adverse Reactions). 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. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.
Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports (see Adverse Reactions). 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 vigorous hydration 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 (see Precautions).
Skin Reactions: 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 (see Adverse Reactions). Events occurred when TREANDA 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 TREANDA.
Hepatotoxicity: Fatal and serious cases of liver injury have been reported with TREANDA (see Adverse Reactions). Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients (see Precautions). Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy.
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, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma (see Adverse Reactions).
Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with TREANDA.
Extravasation Injury: TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain (see Adverse Reactions). Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.
Embryo-Fetal Toxicity: 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 (see Use in Pregnancy & Lactation and Pharmacology: Pharmacodynamics: Mechanism of Action under Actions).
Renal Impairment: Do not use TREANDA in patients with CLcr < 30 mL/min (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: Do not use TREANDA in patients with AST or ALT 2.5-10 x upper limit of normal (ULN) and total bilirubin 1.5-3 x ULN, or total bilirubin > 3 x ULN (see Pharmacology: Pharmacokinetics under Actions).
Use in Children: 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.
Use in the Elderly: No overall differences in safety were observed between patients ≥ 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.
