PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Nitrogen Mustard Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Mechlorethamine derivative with antimetabolite and alkylator properties
    Approved for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen
    Available as a standard IV infusion product (Treanda) and as a rapid IV infusion product (Beneka)

    COMMON BRAND NAMES

    BELRAPZO, BENDEKA, Treanda

    HOW SUPPLIED

    Bendamustine/BENDEKA Intravenous Inj Sol: 1mL, 25mg
    Treanda Intravenous Inj Pwd F/Sol: 25mg, 100mg

    DOSAGE & INDICATIONS

    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 over 30 minutes (Treanda) or IV over 10 minutes (Bendeka) 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 relapsed or refractory CLL, in combination with idelalisib and rituximab†.
    Intravenous dosage
    Adults

    70 mg/m2 IV on days 1 and 2 in combination with rituximab (375 mg/m2 IV on day 1 in cycle 1; 500 mg/m2 IV on day 1 in cycles 2 to 6) repeated every 28 days for 6 cycles and idelalisib 150 mg orally twice daily until disease progression was evaluated in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 416).[61861] Temporary interruption of therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[55945] [60454]

    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 over 30 minutes 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.[56410] Temporary interruption of bendamustine therapy and a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[55945] [60454] 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).[60768]

    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 over 60 minutes (Treanda) or IV over 10 minutes (Bendeka) 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 previously untreated indolent NHL (including follicular lymphoma), in combination with rituximab†.
    Intravenous dosage (Treanda)
    Adults

    90 mg/m2 IV over 30 to 60 minutes 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.

    For the treatment of previously treated indolent NHL (including follicular lymphoma), in combination with rituximab†.
    Intravenous dosage (Treanda)
    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. In a phase 2 trial of 67 patients with relapsed indolent B-cell NHL or mantle-cell lymphoma, patients received B-R. An additional dose of rituximab was administered 1 week prior to the first cycle of B-R and 4 weeks after the last cycle. Patients receiving B-R had an overall response rate of 92% with a median progression-free survival of 23 months. Grade 3 or 4 neutropenia (36%) and thrombocytopenia (9%) occurred. Several dose adjustment criteria were used in the study. For example, in the event of grade 3 nonhematologic or grade 4 hematologic toxicity, the bendamustine dose was reduced to 60 mg/m2 in the subsequent cycle. If a similar severity toxicity occurred at the reduced dose, bendamustine was discontinued. In another phase II trial, 57 of 63 patients (ORR 90%) with relapsed or refractory mantle-cell or low-grade lymphomas responded to B-R and median PFS was 24 months.

    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 (Treanda)
    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. 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 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 complete response rate was 45% and 18% in a cohort of patients with relapsed or refractory DLBCL who received polatuzumab vedotinin plus bendamustine and rituximab (BR) (n = 40) and BR alone (n = 40), respectively, in a multicenter, randomized trial (study GO29365). Patients (median age, 69 years; range, 30 to 86 years) in this trial were not eligible for an autologous hematopoietic stem-cell transplantation and had received a median of 2 prior therapies (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 (Treanda)
    Adults

    90 mg/m2 IV over 30 to 60 minutes 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 III trial that compared B-R to standard cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (R-CHOP) in 514 patients with indolent or mantle cell lymphomas.

    For the treatment of previously treated MCL, in combination with rituximab†.
    Intravenous dosage (Treanda)
    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. In a phase II trial of 67 patients with relapsed indolent B-cell NHL or mantle-cell lymphoma, patients received B-R. An additional dose of rituximab was administered 1 week prior to the first cycle of B-R and 4 weeks after the last cycle. Patients receiving B-R had an overall response rate of 92% with a median progression-free survival of 23 months. Grade 3 or 4 neutropenia (36%) and thrombocytopenia (9%) occurred. Several dose adjustment criteria were used in the study. For example, in the event of grade 3 nonhematologic or grade 4 hematologic toxicity, the bendamustine dose was reduced to 60 mg/m2 in the subsequent cycle. If a similar severity toxicity occurred at the reduced dose, bendamustine was discontinued. In another phase II trial, 57 of 63 patients (ORR 90%) with relapsed or refractory mantle-cell or low-grade lymphomas responded to B-R and median PFS was 24 months.

    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 per day IV over 30 to 60 minutes on days 1 and 2 repeated every 3 weeks for up to 6 cycles has been studied in a multicenter, nonrandomized phase II trial (n = 60).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    100 mg/m2 on days 1 and 2 every 28 days for CLL; 120 mg/m2 on days 1 and 2 every 21 days for NHL.

    Geriatric

    100 mg/m2 on days 1 and 2 every 28 days for CLL; 120 mg/m2 on days 1 and 2 every 21 days for NHL.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    A bendamustine dose adjustment is not necessary in patients with mild hepatic impairment. Use is not recommended in patients with moderate (AST/ALT level 2.5- to 10-times the upper limit of normal (ULN) and total bilirubin level of 1.5- to 3-times the ULN) or severe (total bilirubin level greater than 3-times the ULN) hepatic impairment.

    Renal Impairment

    A dose adjustment is not necessary in patients with a creatinine clearance (CrCl) of 30 mL/min or greater. Use is not recommended in patients with CrCl of less than 30 mL/min.

    ADMINISTRATION

     
    Observe and exercise usual precautions for handling, preparing, and administering cytotoxic drugs. If bendamustine contacts the skin, wash the skin immediately with soap and water. If bendamustine contacts the mucous membranes, flush thoroughly with water.

    Injectable Administration

    Visually inspect parenteral products for particular matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Bendamustine hydrochloride is available as a single-use lyophilized powder vial (Treanda), a single-use 90 mg/mL solution vial (Treanda), and a multiple-use 25 mg/mL solution vial (Bendeka); do NOT mix or combine the products or formulations.
    Dilution is required prior to administration.[55945] [60454]
     
    Lyophilized powder single-dose vials (Treanda and generics)
    Only use the Treanda single-use lyophilized powder vial formulation if closed-system transfer devices (CSTDs), adapters, and syringes that contain polycarbonate or acrylonitrile-butadiene-styrene (ABS) are used prior to dilution in the infusion bag.
    Reconstitution
    Reconstitute each vial with Sterile Water for Injection, USP (100 mg vial with 20 mL, 25 mg vial with 5 mL) to a final concentration of 5 mg/mL; shake well.
    Lyophilized powder should completely dissolve in 5 minutes; do not use the reconstituted product if particulate matter is observed.
    Further dilute reconstituted vials within 30 minutes.
    Dilution
    Dilute the appropriate amount of bendamustine in 500 mL of 0.9% Sodium Chloride Injection, USP or 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP to a final concentration between 0.2 and 0.6 mg/mL; the diluted solution should be a clear colorless to yellow solution.
    Storage: The diluted admixture is stable for 24 hours under refrigeration (2 to 8 degrees C or 36 to 47 degrees F) or for 3 hours at room temperature (15 to 30 degrees C or 59 to 86 degrees F) and room light.
    Intermittent IV infusion
    Administer the diluted bendamustine solution IV over 30 or 60 minutes; infusion time is dependent on the dose/indication.[55945]
     
    Liquid single-dose 90 mg/mL vials (Treanda and generics)
    The Treanda 90 mg/mL solution vial contains N,N-dimethylacetamide (DMA). DMA is incompatible with and will dissolve devices containing polycarbonate or ABS leading to device failure and possible product contamination. This could result in potentially serious adverse health consequences, including skin reactions in health care professionals that prepare and administer the product and the risk of small blood vessel blockage in patients.[59117] [55945]
    The FDA has provided information on specific devices including IV administration sets that were tested and found to be compatible with Treanda 90 mg/mL solution. Prior to use of the specific devices listed by the FDA, contact the device manufacturer to ensure there have been no changes made to the material composition of the devices that would be incompatible with using the 90 mg/mL solution.[59117]
    Dilution
    In a biosafety cabinet, withdraw and transfer the bendamustine solution using only a polypropylene syringe (which is translucent in appearance) with a metal needle and polypropylene hub.
    Do not use devices that contain polycarbonate or ABS when preparing and transferring contents from the 90 mg/mL solution vial to the infusion bag; devices that contain polycarbonate or ABS, including infusion sets, may be used after bendamustine is diluted in the infusion bag.
    Dilute the appropriate amount of bendamustine in 500 mL of 0.9% Sodium Chloride Injection, USP or 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP to a final concentration between 0.2 and 0.7 mg/mL; the diluted solution should be a clear colorless to yellow solution.
    Storage: The diluted admixture is stable for 24 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) or for 2 hours at room temperature (15 to 30 degrees C or 59 to 86 degrees F) and room light.
    Intermittent IV infusion
    Administer the diluted bendamustine solution IV over 30 or 60 minutes; infusion time is dependent on the dose/indication.[55945]
     
    Liquid multi-use 25 mg/mL vials (Bendeka)
    Dilution
    Allow the vial to reach room temperature. Dilute the appropriate amount of bendamustine in 50 mL of 0.9% Sodium Chloride Injection, 2.5% Dextrose and 0.45% Sodium Chloride Injection, or 5% Dextrose Injection to a final concentration between 1.85 and 5.6 mg/mL; the diluted solution should be a clear colorless to yellow solution.
    Storage: When diluted in 0.9% Sodium Chloride Injection or 2.5% Dextrose and 0.45% Sodium Chloride Injection, the admixture is stable for 24 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) or for 6 hours at room temperature (15 to 30 degrees C or 59 to 86 degrees F) and room light. When diluted in 5% Dextrose Injection, the admixture is stable for 24 hours under refrigeration for 3 hours at room temperature and room light.
    Storage of partially used/needle punctured vials: Store partially used vials in the refrigerator in the original carton at 2 to 8 degrees C (36 to 46 degrees F); discard 28 days from first use or after a total of 6 dose withdrawals. The vial contents may partially freeze when stored in the refrigerator.
    Intermittent IV infusion
    Administer IV over 10 minutes.[60454]
     
    Liquid multi-use 25 mg/mL vials (generic)
    Dilution
    Allow the vial to reach room temperature. Dilute the appropriate amount of bendamustine in 500 mL of 0.9% Sodium Chloride Injection or 2.5% Dextrose and 0.45% Sodium Chloride Injection to a final concentration between 0.2 and 0.7 mg/mL; the diluted solution should be a clear colorless to yellow solution.
    Storage: The admixture is stable for 24 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) or for 3 hours at room temperature (15 to 30 degrees C or 59 to 86 degrees F) and room light.
    Storage of partially used/needle punctured vials: Store partially used vials in the refrigerator in the original carton at 2 to 8 degrees C (36 to 46 degrees F); discard 28 days from first use or after a total of 6 dose withdrawals. The vial contents may partially freeze when stored in the refrigerator.
    Intermittent IV infusion
    Administer IV over 30 to 60 minutes.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use
    BELRAPZO:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use
    BENDEKA:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store between 36 to 46 degrees F
    - Store in original package until time of use
    Treanda:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use
    - Use diluted product within 24 hours when stored refrigerated (36 to 46 degrees F) or within 2 hours when stored at room temperature (59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Risk of serious hypersensitivity reactions or anaphylaxis

    Use is contraindicated in patients with a known hypersensitivity reaction to bendamustine or any components of the Treanda (e.g., propylene glycol, mannitol) or Bendeka (e.g., polyethylene glycol 400, propylene glycol, monothioglycerol) products due to a recurrent risk of serious hypersensitivity reactions or anaphylaxis.

    Renal impairment

    Use bendamustine with caution in patients with mild or moderate renal impairment. Use in patients with a creatinine clearance less than 30 mL/min is not recommended.

    Hepatic disease, hepatotoxicity

    Fatal and serious hepatotoxicity 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. Use bendamustine with caution in patients with mild hepatic disease/impairment; use in patients with moderate (AST/ALT level 2.5- to 10-times the upper limit of normal (ULN) and total bilirubin level of 1.5- to 3-times the ULN) or severe (total bilirubin greater than 3-times the ULN) hepatic impairment is not recommended. Patients with progressive disease, receiving combination therapy, or hepatitis B virus reactivation may be at increased risk of developing hepatic disease/dysfunction.

    Children, infants, neonates

    The effectiveness of bendamustine has not been established in adolescents, children, infants, and neonates. The safety profile in pediatric patients with relapsed or refractory acute leukemia who received bendamustine in small studies was similar to that observed in adult patients.

    Infusion-related reactions

    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)

    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

    Extravasation resulting in hospitalizations due to erythema, marked swelling, and pain have been reported in postmarketing reports with bendamustine. Use caution to avoid extravasation when administering bendamustine and monitor for infusion site redness, swelling, pain, infection, and necrosis both during and after bendamustine administration.

    Hepatitis, herpes infection, infection, mycobacterial infection, sepsis, tuberculosis, viral infection

    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.

    Anemia, bone marrow suppression, neutropenia, thrombocytopenia

    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.

    Serious rash

    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.

    Pregnancy

    Bendamustine may cause fetal harm if used during pregnancy based on data from animal studies; there is no data in humans. Females of reproductive potential should avoid pregnancy during and after bendamustine therapy. Advise pregnant women 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. 

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during bendamustine treatment. Pregnancy testing is recommended for females 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 males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose. Women 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 male 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

    Advise patients that breast-feeding is not recommended during bendamustine treatment and for at least 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.   The molecular weight of the parent compound and the presence of 2 active metabolites suggest that excretion into breast-milk will occur.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 47.0-94.0
    neutropenia / Delayed / 43.0-60.0
    leukopenia / Delayed / 28.0-56.0
    thrombocytopenia / Delayed / 11.0-25.0
    anemia / Delayed / 11.0-13.0
    fatigue / Early / 1.0-11.0
    hypokalemia / Delayed / 5.0-5.0
    dehydration / Delayed / 5.0-5.0
    fever / Early / 2.0-4.0
    nausea / Early / 0-4.0
    vomiting / Early / 0-3.0
    diarrhea / Early / 0-3.0
    rash / Early / 0-3.0
    hyperbilirubinemia / Delayed / 3.0-3.0
    elevated hepatic enzymes / Delayed / 1.0-3.0
    back pain / Delayed / 3.0-3.0
    anorexia / Delayed / 2.0-2.0
    hyperuricemia / Delayed / 2.0-2.0
    asthenia / Delayed / 0-2.0
    dyspnea / Early / 2.0-2.0
    weight loss / Delayed / 0-2.0
    anaphylactoid reactions / Rapid / 0-1.0
    abdominal pain / Early / 1.0-1.0
    stomatitis / Delayed / 0-1.0
    xerostomia / Early / 0-1.0
    constipation / Delayed / 0-1.0
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    hypertensive crisis / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    hypotension / Rapid / 1.0-1.0
    chest pain (unspecified) / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    pancytopenia / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known

    Moderate

    sinus tachycardia / Rapid / 7.0-7.0
    depression / Delayed / 6.0-6.0
    bone pain / Delayed / 5.0-5.0
    wheezing / Rapid / 5.0-5.0
    hyperglycemia / Delayed / 3.0-3.0
    hyponatremia / Delayed / 2.0-2.0
    hypocalcemia / Delayed / 2.0-2.0
    hypertension / Early / 0-1.0
    infusion-related reactions / Rapid / 10.0
    hepatitis / Delayed / Incidence not known
    hemolysis / Early / Incidence not known
    bullous rash / Early / Incidence not known
    palpitations / Early / Incidence not known
    infertility / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    erythema / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    headache / Early / 0-21.0
    chills / Rapid / 6.0-14.0
    dizziness / Early / 14.0-14.0
    insomnia / Early / 13.0-13.0
    dyspepsia / Early / 11.0-11.0
    gastroesophageal reflux / Delayed / 10.0-10.0
    pharyngitis / Delayed / 6.0-7.0
    dysgeusia / Early / 7.0-7.0
    pruritus / Rapid / 5.0-6.0
    arthralgia / Delayed / 6.0-6.0
    xerosis / Delayed / 5.0-5.0
    hyperhidrosis / Delayed / 5.0-5.0
    night sweats / Early / 5.0-5.0
    nasal congestion / Early / 5.0-5.0
    drowsiness / Early / 10.0
    spermatogenesis inhibition / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Amobarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Barbiturates: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Butabarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Carbamazepine: (Moderate) Use bendamustine and carbamazepine together with caution; concomitant use may result in decreased bendamustine plasma concentrations and reduced bendamustine effectiveness. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inducers, such as carbamazepine, may decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites.
    Cimetidine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as cimetidine may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Ciprofloxacin: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as ciprofloxacin may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with 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.
    Diclofenac: (Moderate) A theoretical increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia including myelosuppressive antineoplastic agents.
    Diclofenac; Misoprostol: (Moderate) A theoretical increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia including myelosuppressive antineoplastic agents.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ibuprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Diphenhydramine; Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving naproxen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Drospirenone; Ethinyl Estradiol: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Esomeprazole; Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving naproxen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Ethinyl Estradiol: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Desogestrel: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norethindrone: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norgestimate: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Ethinyl Estradiol; Norgestrel: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Etodolac: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving fenoprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ibuprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving fenoprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Fluvoxamine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as fluvoxamine may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ibuprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ibuprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ibuprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ibuprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving indomethacin concurrently with antineoplastic agents should be monitored closely for bleeding.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Use bendamustine and rifampin together with caution; concomitant use may result in decreased bendamustine plasma concentrations and reduced bendamustine effectiveness. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inducers, such as rifampin, may decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites.
    Isoniazid, INH; Rifampin: (Moderate) Use bendamustine and rifampin together with caution; concomitant use may result in decreased bendamustine plasma concentrations and reduced bendamustine effectiveness. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inducers, such as rifampin, may decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ketoprofen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving ketorolac concurrently with antineoplastic agents should be monitored closely for bleeding.
    Lansoprazole; Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving naproxen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving meclofenamate concurrently with antineoplastic agents should be monitored closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving mefenamic acid concurrently with antineoplastic agents should be monitored closely for bleeding.
    Meloxicam: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia due to decreases in platelet aggregation. Notable interactions may occur with myelosuppressive antineoplastic agents.
    Mephobarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Methohexital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Mexiletine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as mexiletine may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Nabumetone: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Patients receiving nabumetone concurrently with antineoplastic agents should be monitored closely for bleeding.
    Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving naproxen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Naproxen; Pseudoephedrine: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving naproxen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Naproxen; Sumatriptan: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving naproxen concurrently with antineoplastic agents should be monitored closely for bleeding.
    Norfloxacin: (Moderate) Use bendamustine and norfloxacin together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as norfloxacin, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Obeticholic Acid: (Major) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as bendamustine. Caution should be exercised, or alternative treatments considered with coadministration.
    Oxaprozin: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. However, oxaprozin may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Patients receiving oxaprozin concurrently with antineoplastic agents should be monitored closely for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Peginterferon Alfa-2b: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as peginterferon alfa-2b may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Phenobarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Piroxicam: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving piroxicam concurrently with antineoplastic agents should be monitored closely for bleeding.
    Primidone: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Rifampin: (Moderate) Use bendamustine and rifampin together with caution; concomitant use may result in decreased bendamustine plasma concentrations and reduced bendamustine effectiveness. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inducers, such as rifampin, may decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites.
    Rofecoxib: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. However, rofecoxib may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Patients receiving rofecoxib concurrently with antineoplastic agents should be monitored closely for bleeding.
    Rucaparib: (Moderate) Monitor for an increase in bendamustine-related adverse reactions if coadministration with rucaparib is necessary; consider alternative treatments if clinically appropriate. The active metabolites of bendamustine, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Rucaparib is a moderate CYP1A2 inhibitor. Formal clinical assessments of drug interactions between bendamustine and other drugs have not been conducted.
    Secobarbital: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Use bendamustine and ethinyl estradiol together with caution; concomitant use may result in increased bendamustine plasma concentrations and increased bendamustine toxicity. Use of alternative agents should be considered. Bendamustine is metabolized by CYP1A2 to form the active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); however, cytotoxic activity is primarily due to the parent bendamustine compound. CYP1A2 inhibitors, such as ethinyl estradiol, may increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites.
    Simeprevir: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as simeprevir (a mild inhibitior) may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Sulindac: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving nabumetone concurrently with antineoplastic agents should be monitored closely for bleeding.
    Tacrine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as tacrine may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Thiabendazole: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as thiabendazole may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Thiopental: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inducer such as the barbiturates may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound of Bendamustine is believed to be primarily responsible for the cytotoxicity against cancers. Caution should be exercised when coadministering bendamustine with a CYP1A2 inducer, or consider an alternative agent.
    Tobacco: (Moderate) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Smoking tobacco has been shown to induce CYP1A2, and may cause a decrease in bendamustine plasma concentrations and a potential decrease in cytotoxicity. The parent compound is believed to be primarily responsible for the cytotoxicity of this agent. Caution should be exercised, or smoking cessation considered, when coadministering bendamustine with a CYP1A2 inducer.
    Tolmetin: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. Patients receiving tolmetin concurrently with antineoplastic agents should be monitored closely for bleeding.
    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.
    Valdecoxib: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents. However, valdecoxib may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Patients receiving valdecoxib concurrently with antineoplastic agents should be monitored closely for bleeding.
    Vemurafenib: (Major) Concomitant use of vemurafenib and bendamustine may result in increased bendamustine concentrations. Vemurafenib is a CYP1A2 inhibitor and bendamustine is a CYP1A2 substrate. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Zileuton: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as zileuton may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    Bendamustine may cause fetal harm if used during pregnancy based on data from animal studies; there is no data in humans. Females of reproductive potential should avoid pregnancy during and after bendamustine therapy. Advise pregnant women 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 females 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 males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose. Women 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 male 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. 

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    Bendamustine is administered as an intravenous infusion. In vitro, it is 94% to 96% protein-bound, however it is not believed to displace or be displaced by highly protein-bound drugs in vivo. Bendamustine distributes freely in human red blood cells; it does not appear to distribute extensively into tissues. Metabolism occurs primarily by hydrolysis, oxidation, and conjugation to form 2 metabolites with low cytotoxic activity, monohydroxy-bendamustine (HP1) and dihydroxy-bendamustine (HP2). Additionally, gamma-hydroxybendamustine (M3) and N-desmethylbendamustine (M4) are 2 minor active metabolites primarily formed via CYP1A2. Plasma concentrations of these metabolites are low compared to the parent compound; therefore, the majority of the cytotoxic activity appears to be due to bendamustine. Following a single IV dose of bendamustine 120 mg/m2, the half-life values were 40 minutes for bendamustine, 3 hours for the M3 metabolite, and 30 minutes for the M4 metabolite. In a mass balance study that measured plasma radioactivity levels, there were unidentified bendamustine derived materials that were rapidly cleared and had a longer half-life than bendamustine and its active metabolites. The total bendamustine clearance is about 700 mL/min and the mean steady-state volume of distribution is about 20 to 25 L. Minimal if any plasma accumulation is expected after administration on days 1 and 2 of a 28-day cycle. In cancer patients, approximately 76% of the dose was recovered following a radiolabeled 14C-bendamustine dose; about 50% was recovered in the urine and about 25% was recovered in the feces. Of substances recovered in the urine, 3.3% of the dose was parent drug, less than 1% of the dose was M3 and M4, and less than 5% of the dose was HP2.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, P-gp, BCRP
    Bendamustine is a substrate of CYP1A2. According to the manufacturer, plasma bendamustine concentrations may be increased with concomitant CYP1A2 inhibitor use and decreased with concomitant CYP1A2 inducer use; therefore, use caution if these agents are used together or consider an alternative agent. In vitro data suggests that bendamustine may be a substrate for P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug–drug interactions with CYP1A2 inhibitors.

    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. The PK parameters of a rapid infusion formulation of bendamustine (Bendeka) were compared with a standard formulation of bendamustine (Treanda) in 60 adult patients with cancer. Following a single 120-mg/m2 IV dose, the Cmax value was higher and the AUC value was equivalent with Bendeka administered as a 10-minute infusion compared with Treanda administered as a 60-minute infusion. With Bendeka administration, the mean Cmax was 35 micrograms (mcg)/mL (range, 6 to 49 mcg/mL).