Bendamustine is a mechlorethamine-derivative alkylating agent. It is indicated for the treatment of adults with chronic lymphocytic leukemia or adults with indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Severe myelosuppression, infection, and anaphylactic reactions have been reported with bendamustine therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate cautions for preparing, handling, and administering solutions of cytotoxic drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-Wash the affected area immediately with soap and water if bendamustine comes into contact with the skin; flush the affected area thoroughly with water bendamustine comes into contact with mucous membranes.
Emetic Risk
-Moderate
-Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
-Vesicant
-Administer drug through a central venous line.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Bendamustine hydrochloride is available as single-dose lyophilized powder vials (Treanda) and multiple-dose solution vials (Bendeka, Belrapzo, and Vivimusta); there are also generic products available.
-Dilution is required prior to administration.
-Recommended dilution solutions, admixture final concentrations and storage, and administration infusion times differ among products; refer to the manufacturer package insert for specific instructions, particularly for generic bendamustine products.
Reconstitution of Lyophilized Powder Vials:
-Add 5 mL Sterile Water for Injection to the 25-mg vial and 20 mL Sterile Water for Injection to the 100-mg vial for a final vial concentration of 5 mg/mL.
-Shake well; the lyophilized powder should completely dissolve in 5 minutes.
-Further dilute the reconstituted vial(s) within 30 minutes.
Dilution:
-If applicable, allow the refrigerated vials to warm to room temperature (15 to 30 degrees C; 59 to 86 degrees F); do not use if solid or particulate matter is present.
-Withdraw the calculated dose/volume from the reconstituted vial (5 mg/mL) or the solution (25 mg/mL) and transfer to an infusion bag containing the recommended volume of 0.9% Sodium Chloride Injection or 2.5% Dextrose/0.45% Sodium Chloride Injection. Bendeka is also compatible with 5% Dextrose injection.
--Treanda: 500 mL; final admixture concentration of 0.2 to 0.6 mg/mL.
-Belrapzo: 500 mL; final admixture concentration of 0.05 to 0.7 mg/mL.
-Vivimusta: 250 mL; final admixture concentration of 0.1 to 1.36 mg/mL.
-Bendeka: 50 mL; final admixture concentration of 0.49 to 5.6 mg/mL.
-Thoroughly mix the contents of the infusion bag.
-Storage of multiple-dose vial: Store in the refrigerator in the original carton (to protect from light) for up to 28 days; do not access the vials for more than 6 dose withdrawals.
-Storage of diluted admixture: Use within 24 hours if stored in the refrigerator (2 to 8 degrees C; 36 to 46 degrees F); refer to the manufacturer package insert for storage at room temperature.
Intravenous (IV) infusion:
Administer the diluted bendamustine admixture based on manufacturers recommendations.
-Treanda or Belrapzo:
--CLL: 100 mg/m2 dose, infuse IV over 30 minutes
-NHL: 120 mg/m2 dose, infuse IV over 60 minutes.
-Vivimusta: Infuse IV over 20 minutes.
-Bendeka: Infuse IV over 10 minutes.
Serious infection (e.g., sepsis) has occurred in adult and pediatric patients who received bendamustine therapy including postmarketing reports of pneumocystis jiroveci pneumonia. Infection has resulted in hospitalization, septic shock, and death in some cases. Patients who experience myelosuppression are at increased risk for developing an infection. Monitor patients for signs and symptoms of infection prior to and during therapy; assess if the patient has a history of bacterial or viral infection that may be reactivated (e.g., mycobacterium tuberculosis, hepatitis B virus, cytomegalovirus (CMV), and herpes zoster virus). Prior to starting bendamustine therapy, treat active infections and/or administer appropriate prophylactic treatment in patients who have a history of infection; promptly treat patients who develop an infection during therapy. Infection (6%; grade 3 and 4, 2%), nasopharyngitis (7%), and herpes simplex infection (3%) occurred in patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Additionally, herpes zoster infection (10%; grade 3 and 4, 3%), upper respiratory tract infection (10%), urinary tract infection (10%; grade 3 and 4, 2%), sinusitis (9%), pneumonia (8%; grade 3 and 4, 5%), oral candidiasis (6%; grade 3 and 4, 1%), and nasopharyngitis (6%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma.
Hematologic toxicity (e.g., leukopenia, neutropenia, lymphopenia, anemia, thrombocytopenia, and hemolysis) has been reported with bendamustine therapy in clinical trials. Complete blood counts were monitored weekly initially in bendamustine-treated patients in clinical trials. Hematologic nadirs were typically observed in the third week of therapy. Bendamustine therapy may need to be dose reduced or delayed for grade 3 or 4 myelotoxicity. Do not administer a new cycle of bendamustine therapy until the absolute neutrophil count is at least 1 x 109 cells/L and the platelet count is at least 75 x 109 cells/L. Decreased hemoglobin concentrations (89%; grade 3 and 4, 13%); decreased platelet (77%; grade 3 and 4, 11%), neutrophil (75%; grade 3 and 4, 43%), lymphocyte (68%; grade 3 and 4, 47%), and leukocyte (61%; grade 3 and 4, 28%) counts occurred in patients who received bendamustine (n = 150) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Hematologic toxicity rates were more pronounced in patients with non-Hodgkin's lymphoma (NHL) who received bendamustine in clinical trials. Grade 3 or 4 myelosuppression occurred in 98% of patients; 3 patients (2%) died from myelosuppression-related adverse events including neutropenic sepsis, diffuse alveolar hemorrhage, and pneumonia from an opportunistic infection with CMV. Decreased hemoglobin concentrations (88%; grade 3 and 4, 11%); decreased platelet (86%; grade 3 and 4, 25%), neutrophil (86%; grade 3 and 4, 60%), lymphocyte (99%; grade 3 and 4, 94%), and leukocyte (94%; grade 3 and 4, 56%) counts; and febrile neutropenia (grade 3 and 4, 6%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell NHL. Pancytopenia has been reported in postmarketing surveillance of patients who received bendamustine therapy.
Infusion-related reactions (fever, chills, pruritus, rash) have been commonly reported during therapy with bendamustine in clinical trials. Rarely, anaphylactoid reactions have occurred, usually in the second and subsequent courses of therapy. Fever (24%; grade 3 and 4, 4%), chills (6%), hypersensitivity (5%; grade 3 and 4, 1%), and pruritus (5%) occurred in patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Fever (34%; grade 3 and 4, 2%), chills (14%), and pruritus (6%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma. Monitor patients for severe reactions after their first course of therapy. For patients who develop grade 1 or 2 reactions, consider premedication with antihistamines, corticosteroids, and antipyretics prior to subsequent treatments. Consider discontinuation of therapy for patients who develop grade 3 or 4 reactions; patients who experienced grade 3 or 4 reactions in clinical trials typically were not rechallenged.
Gastrointestinal adverse reactions including diarrhea (9% to 37%), nausea (8.2% to 75%), and vomiting (16% to 40%) have been reported with bendamustine use in clinical trials. Nausea (20%; grade 3 and 4, less than 1%), vomiting (16%; grade 3 and 4, less than 1%), and diarrhea (9%; grade 3 and 4, 1%) occurred in patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia (CLL) in a randomized active-control trial. Additionally, nausea (75%; grade 3 and 4, 4%), vomiting (40%; grade 3 and 4, 3%), diarrhea (37%; grade 3 and 4, 3%), constipation (29%; grade 3 and 4, less than 1%), anorexia (23%; grade 3 and 4, 2%), stomatitis (15%; grade 3 and 4, less than 1%), abdominal pain (13%; grade 3 and 4, 1%), decreased appetite (13%; grade 3 and 4, less than 1%), dyspepsia (11%), gastroesophageal reflux (10%), xerostomia (9%; grade 3 and 4, less than 1%), upper abdominal pain (5%), and abdominal distention (5%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma. In an 8-week clinical study in 81 patients with solid tumors and hematologic malignancies (excluding CLL) who received a rapid infusion formulation of bendamustine (Bendeka), nausea was reported in 8.2% of patients during or 1-hour post the infusion and in 10.9% of patients within 24 hours of the infusion.
Tumor lysis syndrome (TLS) and acute renal failure have been reported with bendamustine use in clinical trials or in postmarketing reports. Adequate measures should be taken to prevent hyperuricemia and TLS. These may include hydration to maintain adequate volume status, monitoring of blood chemistry (i.e., potassium and uric acid), and the use of allopurinol during the start of bendamustine therapy in patients at high-risk for TLS. The concomitant use of allopurinol and bendamustine may result in an increased risk of severe skin toxicities. Monitor kidney function tests in patients with abnormal kidney function. Use is not recommended in patients with a creatinine clearance of less than 30 mL/min. Onset of TLS typically occurs within the first treatment cycle and lack of intervention may lead to acute renal failure or death. Hyperuricemia (7%; grade 3 and 4, 2%) occurred in patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Grade 3 or 4 elevated creatinine levels were reported in 2% of patients with indolent B-cell non-Hodgkin lymphoma treated with bendamustine in a pooled analysis of 2 single-arm studies (n = 176).
Fatal and serious skin rash (e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), and bullous rash/exanthema) has been reported in clinical trials and postmarketing safety reports. Closely monitor patients who develop skin reactions; hold or discontinue bendamustine for severe or progressive rash. Rash occurred in 8% (grade 3 and 4, 3%) of patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial and in 16% (grade 3 and 4, less than 1%) of patients with indolent B-cell non-Hodgkin lymphoma (NHL) treated with bendamustine in a pooled analysis of 2 single-arm studies (n = 176). Other toxicities experienced by patients with NHL included xerosis (5%), night sweats (5%), and hyperhidrosis (5%). Monitor patients who develop a skin reaction closely; if skin reactions are severe or progressive, bendamustine should be withheld or discontinued.
Fatal and serious hepatic impairment has been reported with bendamustine use; most cases occurred within the first 3 months of starting therapy. Monitor liver function tests prior to and during bendamustine therapy. Hyperbilirubinemia with or without elevated hepatic enzymes (e.g., increased AST or ALT levels) occurred in 34% (grade 3 or 4, 3%) of patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Grade 3 or 4 elevated AST and ALT levels occurred in 1% and 3% of patients, respectively. Monitor liver function tests in patients with abnormal hepatic function. Do not administer bendamustine to patients with AST or ALT level of 2.5 to 10 times the ULN and total bilirubin level 1.5 to 3 times the ULN OR total bilirubin level more than 3 times the ULN.
Cardiovascular adverse events have been reported with bendamustine therapy in clinical trials or postmarketing surveillance. Worsening hypertension occurred in 4 patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial; 3 of these 4 patients experienced a hypertensive crisis that resolved following treatment with oral medications. Peripheral edema (13%; grade 3 and 4, less than 1%), sinus tachycardia (7%), chest pain (unspecified) (6%; grade 3 and 4, less than 1%), and hypotension (6%; grade 3 and 4, 1%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma. Atrial fibrillation, congestive heart failure (CHF), myocardial infarction (MI), and palpitations have been reported in postmarketing surveillance of patients who received bendamustine therapy; some cases of CHF and MI resulted in death.
New primary malignancy, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer (including basal cell carcinoma and squamous cell carcinoma), has been reported in patients who have received bendamustine. Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with bendamustine.
Spermatogenesis inhibition, azoospermia, and total germinal aplasia have been reported in patients receiving alkylating agents, especially when given in combination with other antineoplastic drugs. Spermatogenesis has returned in some patients in remission several years after intensive chemotherapy was discontinued. Advise patients of the potential risk of infertility prior to beginning treatment with bendamustine.
Fatigue has been reported in 5.5% to 57% of patients who received bendamustine in clinical trials. Fatigue occurred in 9% of patients (grade 3 and 4, 1%) who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia (CLL) in a randomized active-control trial and in 57% (grade 3 and 4, 11%) of patients with indolent B-cell non-Hodgkin lymphoma (NHL) treated with bendamustine in a pooled analysis of 2 single-arm studies (n = 176). Additionally, asthenia was reported in 8% of CLL patients and in 11% (grade 3 and 4, 2%) of NHL patients. In an 8-week clinical study in 81 patients with solid tumors and hematologic malignancies (excluding CLL) who received a rapid infusion formulation of bendamustine (Bendeka), fatigue was reported in 5.5% of patients during or 1-hour post the infusion and in 8.2% of patients within 24 hours of the infusion.
There have been postmarketing reports of injection site reaction (e.g., erythema, phlebitis, skin irritation, pain, swelling) with IV bendamustine administration. Skin necrosis and extravasation resulting in hospitalization have also occurred with bendamustine use. Infusion site pain (6%) and catheter site pain (5%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma. Caution should be exercised to avoid extravasation of bendamustine including monitoring of the infusion site for redness, swelling, pain, infection, and tissue necrosis both during and after bendamustine infusion.
Back pain (14%; grade 3 and 4, 3%), arthralgia (6%), pain (6%), extremity pain (5%; grade 3 and 4, 1%), and bone pain (5%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma.
Central nervous system adverse reactions have been reported with bendamustine use in clinical trials. Headache and somnolence (drowsiness) were reported frequently in patients with chronic lymphocytic leukemia who received bendamustine in clinical studies. Additionally, headache (21%), dizziness (14%), and dysgeusia (7%) occurred with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma.
Insomnia (13%), anxiety (8%; grade 3 and 4, less than 1%), and depression (6%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma.
Serious pulmonary toxicity such as pulmonary fibrosis and pneumonitis has been reported with bendamustine therapy in clinical trials or postmarketing surveillance. Cough occurred in 4% (grade 3 or 4, less than 1%) of patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Additionally, cough (22%; grade 3 and 4, less than 1%), dyspnea (16%; grade 3 and 4, 2%), pharyngolaryngeal pain (8%; grade 3 and 4, less than 1%), wheezing (5%), and nasal congestion (5%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma.
Metabolic adverse effects and electrolyte abnormalities have been reported with bendamustine use in clinical trials. Weight loss occurred in 7% of patients who received bendamustine (n = 153) for the first-line treatment of chronic lymphocytic leukemia in a randomized active-control trial. Additionally, weight loss (18%; grade 3 and 4, 2%), dehydration (14%; grade 3 and 4, 5%), hypokalemia (9%; grade 3 and 4, 5%), hyperglycemia (3%), hyponatremia (2%), and hypocalcemia (2%) were reported with bendamustine use in pooled results from 2 single-arm studies in 176 patients with indolent B-cell non-Hodgkin lymphoma.
Progressive multifocal leukoencephalopathy (PML), including fatal cases, has been reported in postmarketing experience in patients treated with bendamustine, primarily in combination with rituximab or obinutuzumab. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. Hold bendamustine therapy if PML is suspected and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Nephrogenic diabetes insipidus was reported in postmarketing surveillance of bendamustine.
Serious hypersensitivity reactions or anaphylaxis have been reported with bendamustine therapy. Use is contraindicated in patients with a history of polyethylene glycol 400 or monothioglycerol hypersensitivity (Belrapzo, Bendeka, Vivimusta) and propylene glycol (Belrapzo, Bendeka) or dehydrated alcohol (Vivimusta) hypersensitivity.
Use in patients with severe renal impairment (creatinine clearance of less than 30 mL/min) is not recommended.
Fatal and serious hepatic disease/impairment has been reported with bendamustine use; most cases occurred within the first 3 months of starting therapy. Monitor liver function tests prior to and during bendamustine therapy. Bendamustine is not recommended in patients with AST or ALT level of 2.5 to 10 times the ULN and total bilirubin level of 1.5 to 3 times the ULN OR total bilirubin more than 3 times the ULN. Patients with progressive disease, receiving combination therapy, or hepatitis B virus reactivation may be at increased risk of developing hepatic dysfunction.
Severe infusion-related reactions, including anaphylactoid reactions, have been reported with bendamustine therapy; most severe cases occurred in the second or subsequent cycles of therapy. Monitor patients for evidence of infusion-related reactions; symptoms may include fever, chills, pruritus, and rash. Prophylactic premedications such as antihistamines, antipyretics, and corticosteroids may be administered prior to bendamustine infusion in patients who have experienced a grade 1 or 2 infusion reaction. Discontinue therapy in patients who experience a grade 4 infusion-related reaction; consider discontinuation of therapy in patients who have a grade 3 infusion-related reaction following a risk/benefit evaluation. In clinical trials, patients who experienced a grade 3 or higher infusion-related reaction with bendamustine were not typically rechallenged.
Tumor lysis syndrome (TLS) has been reported with bendamustine therapy in clinical trials and post-marketing reports; some cases may result in acute renal failure and death. Institute preventative measures (e.g., hydration, anti-uric acid agent), especially during the first cycle of bendamustine therapy. Monitor renal function (e.g., BUN, serum creatinine), serum electrolytes (e.g., potassium, phosphorus, magnesium), and uric acid levels. Patients who receive allopurinol with bendamustine may have an increased risk of developing severe skin toxicity.
Extravasation resulting in hospitalization has been reported in with bendamustine therapy. Assure good venous access before administering bendamustine to avoid extravasation. Monitor for infusion site redness, swelling, pain, infection, and necrosis both during and after bendamustine administration.
Serious infection (i.e., pneumonia, sepsis, septic shock, and hepatitis) has been reported with bendamustine therapy; some cases have resulted in death. Patients who experience myelosuppression are at increased risk for developing an infection. Monitor patients for signs and symptoms of infection prior to and during therapy; assess if the patient has a history of bacterial infection (e.g., mycobacterial infection, tuberculosis) or viral infection (e.g., hepatitis B virus or herpes infection such as herpes zoster) that may be reactivated. Prior to starting bendamustine therapy, treat active infections and/or administer appropriate prophylactic treatment in patients who have a history of infection; promptly treat patients who develop an infection during therapy.
Severe bone marrow suppression/myelosuppression (e.g., anemia, neutropenia, thrombocytopenia) has been reported with bendamustine therapy; death has resulted from myelosuppression-related complications including neutropenic sepsis, opportunistic infections, and bleeding. Monitor complete blood counts (CBC) with differential frequently; CBCs were obtained weekly initially in the clinical trials. Temporary interruption of therapy or a dosage reduction may be necessary in patients who develop myelosuppression. Do not start the next cycle of therapy until the absolute neutrophil count is 1 x 109 cells/L or greater and the platelet count is 75 x 109 cells/L or greater. Hematologic nadirs typically occur at 3 weeks after the dose.
Fatal and serious rash (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), and bullous rash/exanthema) has been reported with single-agent bendamustine and when bendamustine was administered as part of combination chemotherapy or concomitantly with allopurinol. Further bendamustine treatment may result in a progressive and increasingly severe skin reaction. Closely monitor patients who develop skin reactions; hold or discontinue bendamustine for severe or progressive rash.
Bendamustine may increase the risk for a new primary malignancy. There have been reports of pre-malignant and malignant disease that have developed in patients treated with bendamustine including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer (including basal cell carcinoma and squamous cell carcinoma). Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with bendamustine.
Progressive multifocal leukoencephalopathy (PML), including fatal cases, has occurred in patients treated with bendamustine, primarily in combination with rituximab or obinutuzumab. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. Hold bendamustine therapy if PML is suspected and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Bendamustine may cause fetal harm if used during pregnancy based on data from animal studies; there is no data in humans. Patients of reproductive potential should avoid pregnancy during and after bendamustine therapy. Advise these patients of the potential risk to the fetus. Skeletal and visceral malformations (e.g., exencephaly and cleft palates, accessory rib, and spinal deformities), hydronephrosis, hydrocephalus, and decreased fetal body weights were reported when intraperitoneal bendamustine was given to pregnant mice and rats at doses that were 0.6 to 1.8 times the maximum recommended human dose.
Counsel patients about the reproductive risk and contraception requirements during bendamustine treatment. Pregnancy testing is recommended for patients of reproductive potential prior to starting bendamustine. Advise these patients to use effective contraception during treatment and for at least 6 months after the final dose. Due to male-mediated teratogenicity, advise patients with partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose. Patients who become pregnant while receiving bendamustine should be apprised of the potential hazard to the fetus. Based on data from animal studies, there is a risk of infertility with bendamustine therapy. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in patients who received other alkylating agents, particularly in combination with other chemotherapy drugs. Spermatogenesis may return to some patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued.
Breast-feeding is not recommended during bendamustine treatment and for 1 week after the last dose due to the potential for serious adverse reactions. There are no data on the presence of bendamustine or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production.
For the treatment of chronic lymphocytic leukemia (CLL):
NOTE: The FDA has designated bendamustine as an orphan drug for the treatment of CLL.
-for the treatment of CLL, as a single agent:
Intravenous dosage:
Adults: 100 mg/m2 IV on days 1 and 2 repeated every 28 days for up to 6 cycles. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up time of 35 months (range, 1 to 68 months), treatment with bendamustine (median of 6 cycles) resulted in significantly improved overall response rate (68% vs. 31%; p less than 0.0001) and median progression-free survival time (21.6 months vs. 8.3 months; p less than 0.0001) compared with chlorambucil in previously untreated patients with advanced chronic lymphocytic leukemia in a multicenter, randomized, phase 3 study (n = 319). At a median follow-up time of 54 months, the median overall survival times were not significantly different between treatment arms (median time not reached vs. 78.8 months; hazard ratio = 1.3; 95% CI, 0.89 to 1.91; adjusted p value = 0.1801).
-for the treatment of CLL or small lymphocytic lymphoma (SLL)* in combination with ibrutinib and rituximab:
NOTE: Ibrutinib is FDA approved in combination with bendamustine and rituximab for the treatment of CLL/SLL.
Intravenous dosage:
Adults: 70 mg/m2 IV on days 2 and 3 of cycle 1 and on days 1 and 2 for cycles 2 to 6 in combination with ibrutinib 420 mg orally once daily until disease progression and rituximab 375 mg/m2 IV on day 1 of cycle 1 and then 500 mg/m2 IV on day 1 for cycles 2 to 6. Treatment with bendamustine and rituximab is repeated every 28 days for up to 6 cycles. Consider administering ibrutinib before rituximab on days these agents are given on the same day. Temporary interruption of bendamustine therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a median follow-up time of 17 months, the median progression-free survival (PFS) time was significantly improved with ibrutinib plus bendamustine and rituximab compared with placebo plus bendamustine and rituximab (median time not reached vs. 13.3 months; hazard ratio (HR) = 0.203; 95% CI, 0.15 to 0.276; p less than 0.0001) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; n = 64; 11%) who had received at least 1 prior treatment including at least 2 cycles of a chemotherapy-containing regimen in a prespecified interim analysis of a multinational, randomized, double-blind, phase 3 trial (the HELIOS trial; n = 578). The 18-month PFS rates were 79% and 24% in the ibrutinib- and placebo-containing arms, respectively. There was no statistically significant difference in overall survival between treatment arms at the time of analysis; however, 31% of patients in the placebo arm crossed over to the ibrutinib arm after disease progression. Patients with a 17p deletion or who had a prior hematopoietic stem-cell transplant were excluded in this study. In the ibrutinib-containing arm, the median duration of therapy was 14.7 months and patients had a mean of 2 prior therapies (range, 1 to 11 therapies).
For the treatment of non-Hodgkin's lymphoma (NHL):
-for the treatment of indolent B-cell NHL that progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen:
Intravenous dosage:
Adults: 120 mg/m2 IV on days 1 and 2 repeated every 21 days for up to 8 cycles. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Treatment with bendamustine (median of 6 cycles; range, 1 to 8 cycles) led to an overall response rate of 75% and a 9.2 month duration of response in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma (follicular, 62%, small lymphocytic, 21%; marginal zone, 16%) in a multicenter, single-arm study (n = 100). The median number of prior chemotherapy regimens was 2 (range, 0 to 6 regimens) and 36% of patients were refractory to the last chemotherapy regimen.
-for the treatment of follicular lymphoma in patients who relapsed after or are refractory to a rituximab-containing regimen, in combination with obinutuzumab followed by obinutuzumab monotherapy*:
NOTE: Obinutuzumab is FDA approved in combination with bendamustine for this indication.
Intravenous dosage:
Adults: 90 mg/m2 IV on days 1 and 2 repeated every 28 days for 6 cycles in combination with obinutuzumab. Administer obinutuzumab 1,000 mg IV on days 1, 8, and 15 on cycle 1; begin the next cycle of therapy on day 29. For cycles 2 to 6, give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days. Continue single-agent obinutuzumab 1,000 mg IV every 2 months for 2 years in patients who achieve a complete response, partial response, or stable disease after 6 cycles of obinutuzumab plus bendamustine. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. A multinational, randomized, phase 3 trial (the GADOLIN trial; n = 396) was stopped early after results from a prespecified interim analysis demonstrated that the primary endpoint of median progression-free survival time (assessed by an independent review committee) was significantly improved with obinutuzumab plus bendamustine compared with bendamustine alone (median time not reached vs. 14.9 months; hazard ratio (HR) = 0.55; 95% CI, 0.4 to 0.74; p = 0.0001) in patients with CD20-positive, indolent non-Hodgkin lymphoma that was refractory to rituximab-containing therapy. The median follow-up time was 21.9 months in the obinutuzumab plus bendamustine arm and 20.3 months in the bendamustine alone arm. There was no difference in overall survival between treatment arms at the time of analysis. Patients in this study had received a median of 2 prior therapies (interquartile range, 1 to 2 therapies); 81% of patients (n = 321) had follicular lymphoma.
-for the treatment of previously untreated indolent NHL (including follicular lymphoma), in combination with rituximab*:
Intravenous dosage:
Adults: 90 mg/m2 IV on days 1 and 2 in combination with rituximab repeated every 28 days (B-R regimen) for up to 6 cycles has been evaluated in a phase 3 trial that compared B-R to standard cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (R-CHOP) in 514 patients with indolent or mantle cell lymphomas. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
-for the treatment of previously treated indolent NHL (including follicular lymphoma), in combination with rituximab*:
Intravenous dosage:
Adults: 90 mg/m2 IV on days 2 and 3 in combination with rituximab (375 mg/m2 IV on day 1) every 28 days for 4 to 6 cycles was evaluated in phase 2 studies. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
-for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) following at least 2 prior therapies, in combination with polatuzumab vedotin and rituximab*:
NOTE: Polatuzumab vedotin is FDA approved in combination with bendamustine and rituximab for this indication.
Intravenous dosage:
Adults: 90 mg/m2 IV daily on days 1 and 2 in combination with polatuzumab vedotin 1.8 mg/kg IV on day 1 and rituximab 375 mg/m2 IV on day 1 repeated every 21 days for 6 cycles. Consider prophylactic granulocyte colony-stimulating factor use. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The primary endpoint of complete response (CR) rate at the end of treatment, assessed by an independent review committee (IRC), was significantly improved in a randomly assigned cohort of transplant ineligible patients with relapsed or refractory DLBCL who received polatuzumab vedotin plus bendamustine and rituximab (BR) compared with BR alone (40% v 17.5%; p = 0.026) in a randomized phase 2 trial (n = 80; GO29365 trial). At a median follow-up time of 22.3 months, the median progression-free survival (PFS; 9.5 months vs. 3.7 months; hazard ratio (HR) = 0.36; 95% CI, 0.21 to 0.63) and overall survival (OS; 12.4 months vs. 4.7 months; HR = 0.42; 95% CI, 0.24 to 0.75) times were also significantly improved in the polatuzumab vedotin-containing arm. In 106 additional patients who received polatuzumab vedotin plus BR in a single-arm extension cohort (median follow-up, 15.2 months), the IRC-assessed CR rate was 38.7%, the median PFS time was 6.6 months, and the median OS time was 12.5 months. In a pooled analysis of 152 patients (median age, 69 years; range, 24 to 94 years) who received polatuzumab vedotin plus BR, the median number of prior therapies was 2 (range, 1 to 7 therapies).
For the treatment of mantle cell lymphoma (MCL)*:
-for the treatment of previously untreated MCL, in combination with rituximab*:
Intravenous dosage:
Adults: 90 mg/m2 IV on days 1 and 2 in combination with rituximab (375 mg/m2 IV on day 1) repeated every 28 days (B-R regimen) for up to 6 cycles has been evaluated in a phase 3 trial that compared B-R to standard cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (R-CHOP) in 514 patients with indolent or mantle cell lymphomas. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
-for the treatment of previously treated MCL, in combination with rituximab*:
Intravenous dosage:
Adults: 90 mg/m2 IV on days 2 and 3 in combination with rituximab (375 mg/m2 IV on day 1) every 28 days for 4 to 6 cycles has been evaluated in phase 2 trials. An additional dose of rituximab was administered 1 week prior to the first cycle of B-R and 4 weeks after the last cycle. Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
For the treatment of relapsed or refractory acute lymphocytic leukemia (ALL)*:
Intravenous dosage:
Children, Adolescents, and Adults less than 21 years: The use of single-agent bendamustine for the treatment of relapsed or refractory pediatric acute lymphocytic leukemia has not been established.
For the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL)*:
Intravenous dosage:
Adults: 120 mg/m2 IV on days 1 and 2 repeated every 3 weeks for up to 6 cycles has been studied in a multicenter, nonrandomized phase 2 trial (n = 60). Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Chronic Lymphocytic Leukemia
Non-Hematologic Toxicity
Grade 2 toxicity: Hold therapy until the toxicity has recovered to grade 1 or less. If therapy is resumed, consider a dose reduction.
Grade 3 or 4 toxicity: Hold therapy until the toxicity has recovered to grade 1 or less. If therapy is resumed, reduce the dose to 50 mg/m2 on days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered.
Hematologic Toxicity
Grade 3 toxicity: Reduce the dose to 50 mg/m2 on days 1 and 2 of each cycle. For recurrent toxicity, further reduce the dose to 25 mg/m2 on days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered.
Grade 4 toxicity: Hold therapy until absolute neutrophil count (ANC) is 1 X 109 cells/L or more and the platelet count is 75 X 109 cells/L or more. If therapy is resumed, reduce the dose to 50 mg/m2 on days 1 and 2 of each cycle. For recurrent toxicity, further reduce the dose to 25 mg/m2 on days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered.
Non-Hodgkin Lymphoma
Non-Hematologic Toxicity
Grade 2 toxicity: Hold therapy until the toxicity has recovered to grade 1 or less. If therapy is resumed, consider a dose reduction.
Grade 3 or greater toxicity: Hold therapy until the toxicity has recovered to grade 1 or less. If therapy is resumed, reduce the dose to 90 mg/m2 on days 1 and 2 of each cycle. For recurrent toxicity, further reduce the dose to 60 mg/m2 on days 1 and 2 of each cycle.
Hematologic Toxicity
Grade 4 toxicity: Hold therapy until the ANC is 1 X 109 cells/L or more and the platelet count is 75 X 109 cells/L or more. If therapy is resumed, reduce the dose to 90 mg/m2 on days 1 and 2 of each cycle. For recurrent toxicity, further reduce the dose to 60 mg/m2 on days 1 and 2 of each cycle.
Maximum Dosage Limits:
-Adults
120 mg/m2 IV.
-Geriatric
120 mg/m2 IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Use not recommended in patients with a total bilirubin level of 1.5 to 3 times the ULN and ALT/AST level of 2.5 to 10 times the ULN OR total bilirubin level more than 3 times the ULN.
Patients with Renal Impairment Dosing
Use not recommended in patients with a creatinine clearance of less than 30 mL/min.
*non-FDA-approved indication
Acyclovir: (Major) Consider the use of an alternative therapy if acyclovir treatment is needed in patients receiving bendamustine. Concomitant use of acyclovir may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and acyclovir is a CYP1A2 inhibitor.
Allopurinol: (Major) Consider the use of an alternative therapy if allopurinol treatment is needed in patients receiving bendamustine. Concomitant use of allopurinol may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and allopurinol is a weak CYP1A2 inhibitor.
Amiodarone: (Major) Consider the use of an alternative therapy if amiodarone treatment is needed in patients receiving bendamustine. Concomitant use of amiodarone may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
Amobarbital: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Aspirin, ASA; Butalbital; Caffeine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Barbiturates: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Acetaminophen: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Acetaminophen; Caffeine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Cannabidiol: (Major) Consider the use of an alternative therapy if cannabidiol treatment is needed in patients receiving bendamustine. Cannabidiol may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor.
Capmatinib: (Major) Consider the use of an alternative therapy if capmatinib treatment is needed in patients receiving bendamustine. Concomitant use of capmatinib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and capmatinib is a CYP1A2 inhibitor.
Carbamazepine: (Major) Consider the use of an alternative therapy if carbamazepine treatment is needed in patients receiving bendamustine. Carbamazepine may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and carbamazepine is a CYP1A2 inducer.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Major) Consider the use of an alternative therapy if cimetidine treatment is needed in patients receiving bendamustine. Cimetidine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and cimetidine is a CYP1A2 inhibitor.
Ciprofloxacin: (Major) Consider the use of an alternative therapy if ciprofloxacin treatment is needed in patients receiving bendamustine. Ciprofloxacin may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and ciprofloxacin is a CYP1A2 inhibitor.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Deferasirox: (Major) Consider the use of an alternative therapy if deferasirox treatment is needed in patients receiving bendamustine. Deferasirox may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and deferasirox is a CYP1A2 inhibitor.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Disulfiram: (Major) Consider the use of an alternative therapy if disulfiram treatment is needed in patients receiving bendamustine. Disulfiram may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and disulfiram is a CYP1A2 inhibitor.
Enasidenib: (Major) Consider the use of an alternative therapy if enasidenib treatment is needed in patients receiving bendamustine. Concomitant use of enasidenib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Fexinidazole: (Major) Consider the use of an alternative therapy if fexinidazole treatment is needed in patients receiving bendamustine. Concomitant use of fexinidazole may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and fexinidazole is a CYP1A2 inhibitor.
Fluvoxamine: (Major) Consider the use of an alternative therapy if fluvoxamine treatment is needed in patients receiving bendamustine. Fluvoxamine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and fluvoxamine is a CYP1A2 inhibitor.
Food: (Major) Advise patients to avoid cannabis use during bendamustine treatment due to decreased exposure of bendamustine which may alter its efficacy. Cannabis use induces CYP1A2 and bendamustine is a CYP1A2 substrate. The induction potential of cannabis is greatest with chronic inhalation. Other routes of administration or sporadic use may have less of an effect.
Fosphenytoin: (Major) Consider the use of an alternative therapy if fosphenytoin treatment is needed in patients receiving bendamustine. Fosphenytoin may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and fosphenytoin is a CYP1A2 inducer.
Givosiran: (Major) Consider the use of an alternative therapy if givosiran treatment is needed in patients receiving bendamustine. Givosiran may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate. Givosiran may moderately inhibit hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Consider the use of an alternative therapy if rifampin treatment is needed in patients receiving bendamustine. Rifampin may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
Isoniazid, INH; Rifampin: (Major) Consider the use of an alternative therapy if rifampin treatment is needed in patients receiving bendamustine. Rifampin may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
Leflunomide: (Major) Consider the use of an alternative therapy if leflunomide treatment is needed in patients receiving bendamustine. Leflunomide may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and leflunomide is a CYP1A2 inducer.
Leniolisib: (Major) Consider the use of an alternative therapy if leniolisib treatment is needed in patients receiving bendamustine. Concomitant use of leniolisib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and leniolisib is a CYP1A2 inhibitor.
Lopinavir; Ritonavir: (Major) Consider the use of an alternative therapy if ritonavir treatment is needed in patients receiving bendamustine. Ritonavir may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Meropenem: (Major) Consider the use of an alternative therapy if meropenem treatment is needed in patients receiving bendamustine. Concomitant use of meropenem may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and meropenem is a CYP1A2 inducer.
Meropenem; Vaborbactam: (Major) Consider the use of an alternative therapy if meropenem treatment is needed in patients receiving bendamustine. Concomitant use of meropenem may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and meropenem is a CYP1A2 inducer.
Methohexital: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Methoxsalen: (Major) Consider the use of an alternative therapy if methoxsalen treatment is needed in patients receiving bendamustine. Methoxsalen may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and methoxsalen is a CYP1A2 inhibitor.
Mexiletine: (Major) Consider the use of an alternative therapy if mexiletine treatment is needed in patients receiving bendamustine. Mexiletine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and mexiletine is a CYP1A2 inhibitor.
Nirmatrelvir; Ritonavir: (Major) Consider the use of an alternative therapy if ritonavir treatment is needed in patients receiving bendamustine. Ritonavir may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Obeticholic Acid: (Major) Consider the use of an alternative therapy if obeticholic acid treatment is needed in patients receiving bendamustine. Concomitant use of obeticholic acid may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and obeticholic acid is a CYP1A2 inhibitor.
Osilodrostat: (Major) Consider the use of an alternative therapy if osilodrostat treatment is needed in patients receiving bendamustine. Osilodrostat may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and osilodrostat is a CYP1A2 inhibitor.
Pacritinib: (Major) Consider the use of an alternative therapy if pacritinib treatment is needed in patients receiving bendamustine. Concomitant use of pacritinib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and pacritinib is a CYP1A2 inhibitor.
Peginterferon Alfa-2b: (Major) Consider the use of an alternative therapy if peginterferon alfa-2b treatment is needed in patients receiving bendamustine. Peginterferon alfa-2b may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and peginterferon alfa-2b is a CYP1A2 inhibitor.
Pentobarbital: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Phenobarbital: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Phenytoin: (Major) Consider the use of an alternative therapy if phenytoin treatment is needed in patients receiving bendamustine. Phenytoin may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
Primidone: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Rifampin: (Major) Consider the use of an alternative therapy if rifampin treatment is needed in patients receiving bendamustine. Rifampin may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
Ritlecitinib: (Major) Consider the use of an alternative therapy if ritlecitinib treatment is needed in patients receiving bendamustine. Concomitant use of ritlecitinib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and ritlecitinib is a CYP1A2 inhibitor.
Ritonavir: (Major) Consider the use of an alternative therapy if ritonavir treatment is needed in patients receiving bendamustine. Ritonavir may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Rucaparib: (Major) Consider the use of an alternative therapy if rucaparib treatment is needed in patients receiving bendamustine. Rucaparib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and rucaparib is a CYP1A2 inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Consider the use of an alternative therapy if barbiturate treatment is needed in patients receiving bendamustine. Barbiturates may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
Sodium Phenylbutyrate; Taurursodiol: (Major) Consider the use of an alternative therapy if taurursodiol treatment is needed in patients receiving bendamustine. Concomitant use of taurursodiol may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and taurursodiol is a CYP1A2 inducer.
Stiripentol: (Major) Consider the use of an alternative therapy if stiripentol treatment is needed in patients receiving bendamustine. Stiripentol may alter bendamustine exposure. Bendamustine is a CYP1A2 substrate and stiripentol is an inhibitor and inducer of CYP1A2 in vitro.
Teriflunomide: (Major) Consider the use of an alternative therapy if teriflunomide treatment is needed in patients receiving bendamustine. Teriflunomide may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and teriflunomide is a CYP1A2 inducer.
Tobacco: (Major) Advise patients to avoid tobacco products while receiving bendamustine. Smoking tobacco may cause a decrease in bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and tobacco is a CYP1A2 inducer.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Vemurafenib: (Major) Avoid the use of vemurafenib with bendamustine. Vemurafenib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and vemurafenib is a CYP1A2 inhibitor.
Viloxazine: (Major) Consider the use of an alternative therapy if viloxazine treatment is needed in patients receiving bendamustine. Concomitant use of viloxazine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
Zafirlukast: (Major) Consider the use of an alternative therapy if zafirlukast treatment is needed in patients receiving bendamustine. Zafirlukast may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and zafirlukast is a CYP1A2 inhibitor.
Zileuton: (Major) Consider the use of an alternative therapy if zileuton treatment is needed in patients receiving bendamustine. Concomitant use of zileuton may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Bendamustine has a unique chemical structure that provides antimetabolite and alkylating properties. It consists of three primary structural elements, a 2-chloroethylamine group, a benzimidazole ring, and a butyric acid side chain. The 2-chloroethylamine group is responsible for the alkylating properties of bendamustine and is shared with other alkylators in the nitrogen mustard family. The benzimidazole ring is unique to bendamustine and gives the drug antimetabolite function. The butyric acid side-chain is shared with chlorambucil, however the addition of a hydrochloride residue confers water solubility.
The mechanism of action of bendamustine is not completely understood, but is thought to consist of several components. Similar to other alkylators, bendamustine is a DNA cross-linking agent which causes DNA single-strand and double-strand breaks. The DNA damage caused by bendamustine however, is more extensive and more durable than damage produced by cisplatin, cyclophosphamide, or carmustine. Bendamustine increases the activation of p53 and p53-dependent genes, a pathway resulting in strong activation of intrinsic apoptosis and previously known to be induced by nitrogen mustard alkylating agents. The activation of this pathway appears to be stronger and more rapidly induced by bendamustine than by either chlorambucil or phosphoramide mustard (metabolite of cyclophosphamide). Bendamustine is also known to inhibit several mitotic checkpoints, which results in mitotic catastrophe, a necrotic form of cell death morphologically distinct from apoptosis that occurs during metaphase. Bendamustine prevents physiologic arrest and repair of DNA damage created by alkylation, causing cells to enter mitosis with DNA damage. Mitotic catastrophe may occur in the presence or absence of the functional pro-apoptotic gene p53, including pre-treated cells refractory to conventional apoptosis mechanisms. The combination of p53 activation and mitotic catastrophe may account for the increase in bendamustine sensitivity in previously chemo-refractory cells. In addition, bendamustine does not appear to induce an alkyltransferase mechanism of DNA repair, a limitation previously shown with chlorambucil, melphalan, and phosphoramide mustard. This suggests that bendamustine is less susceptible to drug resistance based on alkylguanyl transferase expression.
Bendamustine is administered intravenously. It is 94% to 96% bound to protein. Bendamustine has a blood to plasma concentration ratio ranging from 0.84 to 0.86 over a concentration range of 10 to 100 micrograms/mL. The mean steady-state volume of distribution is about 20 to 25 L, the intermediate half-life is about 40 minutes, and the clearance is about 700 mL/min following a single dose of bendamustine 120 mg/m2 IV given over 1 hour. Bendamustine is metabolized via hydrolytic, oxidative, and conjugative pathways. In vitro, metabolism mostly occurs via hydrolysis to monohydroxy (HP1) and dihydroxy (HP2) bendamustine metabolites that have low cytotoxic activity and to 2 active but minor metabolites, gamma-hydroxybendamustine (M3) and N-desmethylbendamustine (M4) that are primarily formed via CYP1A2. Plasma concentrations of M3 and M4 are 1/10th and 1/100th that of the parent drug, respectively. The mean terminal elimination half-lives of M3 and M4 are approximately 3 hours and 30 minutes, respectively. Following a radiolabeled bendamustine dose, 76% of the dose was recovered (50% in the urine, 25% in the feces) in cancer patients. In the urine, 3.3% of the dose was parent drug, less than 1% of the dose was M3 and M4 metabolites, and less than 5% of the dose was the HP2 metabolite.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, P-gp, BCRP
Bendamustine is a substrate of CYP1A2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug-drug interactions with CYP1A2 inhibitors.
-Route-Specific Pharmacokinetics
Intravenous Route
In a pharmacokinetic (PK) study in 78 adult patients, the mean Cmax and AUC0-24 hr values were 5,746 nanograms (ng)/mL and 7,121 ng x hour/mL, respectively, following a dose of bendamustine 120 mg/m2 IV over 1 hour. Bendamustine is concentration independent over the range of 1 to 50 micrograms/mL. Following a single dose of bendamustine (Bendeka) 120 mg/m2 IV over 10 minutes, the mean Cmax value was 35 (range, 6 to 49) microgram/mL. Minimal accumulation in the plasma is expected after bendamustine administration on days 1 and 2 of a 28-day cycle.
-Special Populations
Hepatic Impairment
Hepatic impairment that is defined as total bilirubin level of less than 1.5 times the ULN and AST/ALT level less than 2.5 times the ULN does not significantly impact the pharmacokinetic (PK) parameters of bendamustine. The effect of more severe hepatic impairment (defined as total bilirubin level of 1.5 to 3 times the ULN and ALT/AST level of 2.5 to 10 times the ULN OR total bilirubin level more than 3 times the ULN) on the PK parameters of bendamustine is unknown.
Renal Impairment
Mild to moderate renal impairment (creatinine clearance (CrCl), 30 mL/min or more) does not significantly impact the pharmacokinetic (PK) parameters of bendamustine. The effect of severe renal impairment (CrCl less than 30 mL/min) on the PK parameters of bendamustine is unknown.
Pediatrics
The pharmacokinetic parameters of bendamustine were similar in pediatric patients (n = 43; median, 10 years; range, 1 to 19 years) compared with adult patients given the same bendamustine dose based on body surface area.
Geriatric
Age (range, 31 to 84 years) does not significantly impact the pharmacokinetic parameters of bendamustine.
Gender Differences
Sex does not significantly impact the pharmacokinetic parameters of bendamustine.
Ethnic Differences
In a cross-study comparison, Japanese subjects (n = 6) had average exposures that were 40% higher than non-Japanese subjects receiving equivalent doses of bendamustine. The significance of this difference on the safety and efficacy of bendamustine in Japanese patients has not been established.