Bendamustine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as hydrochloride:

Belrapzo: 100 mg/4 mL (4 mL) [contains polyethylene glycol, propylene glycol]

Bendeka: 100 mg/4 mL (4 mL) [contains polyethylene glycol, propylene glycol]

Treanda: 45 mg/0.5 mL (0.5 mL [DSC]); 180 mg/2 mL (2 mL [DSC]) [contains propylene glycol]

Generic: 100 mg/4 mL (4 mL)

Solution Reconstituted, Intravenous, as hydrochloride [preservative free]:

Treanda: 25 mg (1 ea); 100 mg (1 ea)

Pharmacology

Mechanism of Action

Bendamustine is an alkylating agent (nitrogen mustard derivative) with a benzimidazole ring (purine analog) which demonstrates only partial cross-resistance (in vitro) with other alkylating agents. It leads to cell death via single and double strand DNA cross-linking. Bendamustine is active against quiescent and dividing cells. The primary cytotoxic activity is due to bendamustine (as compared to metabolites).

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: ~20 to 25 L

Metabolism

Hepatic (extensive), via CYP1A2 to active (minor) metabolites gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4); also via hydrolysis to low cytotoxic metabolites, monohydroxy bendamustine (HP1) and dihydroxy bendamustine (HP2)

Excretion

Feces (~25%); urine (~50%; ~3% as active parent drug)

Time to Peak

Typically at end of infusion

Half-Life Elimination

Bendamustine: ~40 minutes; M3: ~3 hours; M4: ~30 minutes

Protein Binding

94% to 96%

Use in Specific Populations

Special Populations: Race

Bendamustine exposure was 40% higher in Japanese patients compared to non-Japanese patients.

Use: Labeled Indications

Chronic lymphocytic leukemia: Treatment of chronic lymphocytic leukemia (CLL)

Non-Hodgkin lymphoma: Treatment of indolent B-cell non-Hodgkin lymphoma (NHL) which has progressed during or within 6 months of rituximab treatment or a rituximab-containing regimen

Use: Off Label

Hodgkin lymphoma (relapsed or refractory)b

Data from a phase II study supports the use of bendamustine in the treatment of relapsed or refractory Hodgkin lymphoma following failure of autologous stem cell transplant as a bridge to allogeneic stem cell transplant Moskowitz 2013.

Multiple myeloma (salvage therapy)c

Data from a limited number of patients studied suggest that bendamustine may be beneficial as a salvage treatment for recurrent multiple myeloma Knop 2005, Lentzsch 2012.

Non-Hodgkin lymphoma, indolent (eg, follicular, marginal zone), and mantle cell; first-line treatmenta

Data from 2 multi-center, randomized, phase III studies support the use of bendamustine (in combination with rituximab) as first-line treatment of indolent B-cell, follicular or mantle cell non-Hodgkin lymphoma Flinn 2014, Rummel 2013.

Non-Hodgkin lymphoma, mantle cell (relapsed or refractory)b

Data from a phase II study (which included patients with mantle cell lymphoma) supports the use of bendamustine (in combination with rituximab) in the treatment of mantle cell non-Hodgkin lymphoma Rummel 2005.

Waldenström macroglobulinemiab

Data from a phase II study (which included patients with Waldenström macroglobulinemia) supports the use of bendamustine (in combination with rituximab) in the treatment of Waldenström macroglobulinemia Rummel 2005. Data from a retrospective study also supports the use of bendamustine (in combination with rituximab) for the treatment of Waldenström macroglobulinemia Treon 2011.

Contraindications

Known hypersensitivity (eg, anaphylactic or anaphylactoid reactions) to bendamustine or any component of the formulation. Belrapzo and Bendeka are also contraindicated in patients with hypersensitivity to polyethylene glycol 400, propylene glycol, or monothioglycerol.

Dosage and Administration

Dosing: Adult

Note: Treanda liquid solution formulation (45 mg/0.5 mL and 180 mg/2 mL) has been discontinued in the US for more than 1 year.

Note: Bendamustine is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Chronic lymphocytic leukemia (CLL): IV: 100 mg/m² on days 1 and 2 of a 28-day treatment cycle (as a single agent) for up to 6 cycles (Knauf 2009; Knauf 2012)

CLL, first-line treatment (off-label dosing): IV: 90 mg/m² on days 1 and 2 of a 28-day treatment cycle (in combination with rituximab) for up to 6 cycles (Fischer 2012)

CLL, relapsed/refractory (off-label dosing): IV: 70 mg/m² on days 1 and 2 of a 28-day treatment cycle (in combination with rituximab) for up to 6 cycles (Fischer 2011)

Non-Hodgkin lymphomas: IV:

Lymphoma, indolent B-cell, refractory: 120 mg/m² on days 1 and 2 of a 21-day treatment cycle (as a single agent) for up to 8 cycles (Kahl 2010)

Lymphoma, indolent (eg, follicular, marginal zone) and mantle cell; first-line treatment (off-label use): 90 mg/m² over 30 to 60 minutes on days 1 and 2 of a 28-day treatment cycle (in combination with rituximab) for up to 6 cycles (Rummel 2013) or 90 mg/m² over 30 minutes on days 1 and 2 of a 28-day treatment cycle (in combination with rituximab) for 6 to 8 cycles (Flinn 2014)

Lymphoma, follicular, relapsed or refractory (off-label dosing): 90 mg/m² over 60 minutes on days 1 and 2 of a 35-day treatment cycle (in combination with bortezomib and rituximab) for 5 cycles (Fowler 2011) or 90 mg/m² on days 1 and 2 of a 28-day treatment cycle for 6 cycles (in combination with obinutuzumab, then followed by obinutuzumab monotherapy in patients with stable disease, complete response, or partial response after 6 cycles of combination therapy) (Sehn 2016)

Lymphoma, mantle cell, relapsed or refractory (off-label use): 90 mg/m² over 30 minutes on days 2 and 3 of a 28-day treatment cycle (in combination with rituximab) for up to 4 cycles (Rummel 2005)

Hodgkin lymphoma, relapsed or refractory (off-label use): IV: 120 mg/m² over 30 minutes on days 1 and 2 of a 28-day treatment cycle for up to 6 cycles (Moskowitz 2013)

Multiple myeloma, salvage therapy (off-label use): IV: 90 to 100 mg/m² on days 1 and 2 of a 28-day treatment cycle for at least 2 cycles (Knop, 2005) or 75 mg/m² on days 1 and 2 of a 28-day treatment cycle (in combination with lenalidomide and dexamethasone) for up to 8 cycles (Lentzsch 2012)

Waldenström macroglobulinemia, refractory (off-label use): IV: 90 mg/m² on days 1 and 2 of a 28-day treatment cycle (in combination with rituximab) for 6 cycles (Treon 2011) or 90 mg/m² over 30 minutes on days 2 and 3 of a 28-day treatment cycle (in combination with rituximab) for 4 cycles (Rummel 2005)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Infusion reactions:

Grade 1 or 2: Consider premedication with antihistamines, antipyretics, and corticosteroids in subsequent cycles

Grade 3: Consider discontinuing treatment

Grade 4: Discontinue treatment

Skin reaction, severe or progressive: Withhold or discontinue treatment

Treatment delay:

Hematologic toxicity ≥ grade 4: Delay treatment until resolves (ANC ≥1000/mm³, platelets ≥75,000/mm³); may reinitiate with discretion (may require dose reduction).

Nonhematologic toxicity ≥ grade 2 (clinically significant): Delay treatment until resolves to ≤ grade 1; may reinitiate with discretion (may require dose reduction).

Dose modification in CLL:

Hematologic toxicity ≥ grade 3: Reduce dose to 50 mg/m² on days 1 and 2 of each treatment cycle. For recurrent hematologic toxicity (≥ grade 3), further reduce dose to 25 mg/m² on days 1 and 2 of the treatment cycle. May cautiously re-escalate dose in subsequent cycles.

Nonhematologic toxicity ≥ grade 3 (clinically significant): Reduce dose to 50 mg/m² on days 1 and 2 of the treatment cycle. May cautiously re-escalate dose in subsequent cycles with discretion.

Dose modification in NHL:

Hematologic toxicity grade 4: Reduce dose to 90 mg/m² on days 1 and 2 of each treatment cycle. For recurrent hematologic toxicity (grade 4), further reduce dose to 60 mg/m² on days 1 and 2 of each treatment cycle.

Nonhematologic toxicity ≥ grade 3: Reduce dose to 90 mg/m² on days 1 and 2 of the treatment cycle with discretion. For recurrent toxicity ≥ grade 3, further reduce dose to 60 mg/m² on days 1 and 2 of each treatment cycle.

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Several formulations of bendamustine are available: A liquid solution formulation (45 mg/0.5 mL and 180 mg/2 mL [Treanda] and 100 mg/4 mL [Belrapzo, Bendeka]) and the powder for reconstitution (5 mg/mL after reconstitution [Treanda]). Concentrations, storage, and compatibility differ between formulations. Use caution when selecting bendamustine formulation for preparation and administration. Do not mix or combine the formulations.

Belrapzo: Prior to administration, allow vial(s) to reach room temperature. Refrigerated vials may partially freeze while under refrigeration; do not use if particles are observed after reaching room temperature. Dilute appropriate dose in 500 mL of NS or D2.5¹/₂NS to a final concentration of 0.2 to 0.7 mg/mL; thoroughly mix. The resulting solution should be clear and colorless to yellow. Dilute only in NS or D2.5¹/₂NS; do not use other solutions.

Bendeka: Prior to administration, allow vial(s) to reach room temperature. Refrigerated vials may partially freeze while under refrigeration; do not use if particles are observed after reaching room temperature. Dilute appropriate dose in 50 mL of NS, D2.5¹/₂NS, or D5W to a final concentration of 1.85 to 5.6 mg/mL; thoroughly mix. The resulting solution should be clear and colorless to yellow.

Treanda:

Powder for solution (for reconstitution): Reconstitute 25 mg vial with 5 mL and 100 mg vial with 20 mL of sterile water for injection to a concentration of 5 mg/mL; powder usually dissolves within 5 minutes (do not use if particulates are visible). Within 30 minutes of reconstitution, dilute appropriate dose for infusion in 500 mL NS (or D2.5¹/₂NS) to a final concentration of 0.2 to 0.6 mg/mL; mix thoroughly. Closed-system transfer devices (CSTDs) or adaptors containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) are safe to use with the lyophilized powder formulation.

Solution: Prior to administration, dilute appropriate dose (using polypropylene syringes with a metal needle and polypropylene hub) in 500 mL NS (or D2.5¹/₂NS) to a final concentration of 0.2 to 0.7 mg/mL; resulting solution should be colorless to yellow. Bendamustine contains N,N-dimethylacetamide, which may be incompatible with some CSTDs, adapters, and syringes containing polycarbonate or ABS. When used to prepare or transfer the concentrated bendamustine solution into the infusion bag, the plastic components of some CSTDs may dissolve, resulting in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). If using a syringe to withdraw and transfer bendamustine solution from the vial into the infusion bag, only use polypropylene syringes (translucent in appearance) with a metal needle and polypropylene hub. After dilution into the infusion bag, devices containing polycarbonate or ABS (including infusion sets) may be used. Refer to the specific CSTD device manufacturer for compatibility data.

Administration

IV: For chronic lymphocytic leukemia, infuse over 30 minutes (Belrapzo, Treanda) or 10 minutes (Bendeka). For non-Hodgkin lymphoma, infuse over 60 minutes (Belrapzo, Treanda) or 10 minutes (Bendeka). Administration times for off-label uses/doses vary by protocol.

Bendamustine solution (45 mg/0.5 mL and 180 mg/2 mL [Treanda]) contains N, N-dimethylacetamide, which may be incompatible with some closed-system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS). After dilution of bendamustine solution (Treanda) into the infusion bag, devices containing polycarbonate or ABS (including infusion sets) may be used. Refer to the specific CSTD device manufacturer for compatibility data.

Consider premedication with antihistamines, antipyretics, and corticosteroids for patients with a previous grade 1 or 2 infusion reaction to bendamustine. Bendamustine is associated with a moderate emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation; monitor IV site for redness, swelling, or pain.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry cold compresses for 20 minutes 4 times daily (Perez Fidalgo 2012). May be managed with sodium thiosulfate in the same manner as mechlorethamine extravasation (Schulmeister 2011).

Sodium thiosulfate 1/6 M solution (instructions for mechlorethamine): Inject subcutaneously into extravasation area using 2 mL for each mg of drug suspected to have extravasated (Perez Fidalgo 2012; Polovich 2009).

Storage

Belrapzo, Bendeka:

Solution: Store intact vials between 2°C to 8°C (36°F to 46°F); protect from light. Refrigerated vials may partially freeze at the recommended storage temperature; allow to come to room temperature prior to use. Solutions for infusion should be prepared as close as possible to administration. Solutions diluted with NS or D2.5¹/₂NS are stable for up to 24 hours when stored at 2°C to 8°C (36°F to 46°F) or for up to 3 hours (Belrapzo) or 6 hours (Bendeka) when stored at 15°C to 30°C (59°F to 86°F) and room light. Solutions (Bendeka) diluted with D5W are stable for up to 24 hours when stored at 2°C to 8°C (36°F to 46°F) or for up to 3 hours when stored at 15°C to 30°C (59°F to 86°F) and room light. Infusion must be completed within these time frames. Belrapzo and Bendeka are multiple-dose vials; after the first use, partially used vials are stable for up to 28 days when stored in the original carton at 2°C to 8°C (36°F to 46°F). Do not withdraw more than 6 doses from each vial.

Treanda:

Powder for solution: Prior to reconstitution, store intact vials up to 25°C (77°F); excursions are permitted up to 30°C (86°F). Protect from light. The solution in the vial (reconstituted with SWFI) is stable for 30 minutes (transfer to 500 mL infusion bag within that 30 minutes). The solution diluted in 500 mL of NS or D2.5¹/₂NS for infusion is stable for 24 hours refrigerated (2°C to 8°C [36°F to 46°F]) or 3 hours at room temperature (15°C to 30°C [59°F to 86°F]) and room light. Infusion must be completed within these time frames.

Solution: Store intact vials between 2°C to 8°C (36°F to 46°F); protect from light. Solutions diluted for infusion in NS or D2.5¹/₂NS are stable for up to 24 hours when stored at 2°C to 8°C (36°F to 46°F) or for up to 2 hours when stored at 15°C to 30°C (59°F to 86°F) and room light. Infusion must be completed within these time frames.

Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

Drug Interactions

Allopurinol: May enhance the adverse/toxic effect of Bendamustine. Specifically, the risk of severe skin reactions may be enhanced. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of Bendamustine. Concentrations of active metabolites may be increased. Management: Consider alternatives to moderate CYP1A2 inducers during therapy with bendamustine due to the potential for decreased bendamustine plasma concentrations and reduced efficacy. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Bendamustine. Management: Consider alternatives to moderate CYP1A2 inhibitors during therapy with bendamustine due to the potential for increased bendamustine plasma concentrations and increased bendamustine toxicity. Consider therapy modification

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Management: Consider alternatives to strong CYP1A2 inhibitors during therapy with bendamustine due to the potential for increased bendamustine plasma concentrations and increased bendamustine toxicity. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (13%)

Central nervous system: Fatigue (9% to 57%), headache (21%), dizziness (14%), chills (6% to 14%), insomnia (13%)

Dermatologic: Skin rash (8% to 16%)

Endocrine & metabolic: Weight loss (7% to 18%), dehydration (14%)

Gastrointestinal: Nausea (20% to 75%), vomiting (16% to 40%), diarrhea (9% to 37%), constipation (29%), anorexia (23%), stomatitis (15%; grades 3/4: <1%), abdominal pain (13%), decreased appetite (13%), dyspepsia (11%)

Hematologic & oncologic: Lymphocytopenia (68% to 99%; grades 3/4: 47% to 94%), bone marrow depression (grades 3/4: 98%; nadir in week 3), leukopenia (61% to 94%; grades 3/4: 28% to 56%), decreased hemoglobin (88% to 89%; grades 3/4: 11% to 13%), decreased neutrophils (75% to 86%; grades 3/4: 43% to 60%), thrombocytopenia (77% to 86%; grades 3/4: 11% to 25%)

Hepatic: Increased serum bilirubin (34%)

Neuromuscular & skeletal: Back pain (14%), asthenia (8% to 11%)

Respiratory: Cough (4% to 22%), dyspnea (16%)

Miscellaneous: Fever (24% to 34%)

1% to 10%:

Cardiovascular: Tachycardia (7%), chest pain (6%), hypotension (6%), exacerbation of hypertension (3%)

Central nervous system: Anxiety (8%), depression (6%), pain (6%)

Dermatologic: Pruritus (5% to 6%), hyperhidrosis (5%), night sweats (5%), xeroderma (5%)

Endocrine & metabolic: Hypokalemia (9%), hyperuricemia (7%), hyperglycemia (grades 3/4: 3%), hypocalcemia (grades 3/4: 2%), hyponatremia (grades 3/4: 2%)

Gastrointestinal: Gastroesophageal reflux disease (10%), xerostomia (9%), dysgeusia (7%), oral candidiasis (6%), abdominal distention (5%), upper abdominal pain (5%)

Genitourinary: Urinary tract infection (10%)

Hematologic & oncologic: Febrile neutropenia (grades 3/4: 6%)

Hepatic: Increased serum alanine aminotransferase (grades 3/4: 3%), increased serum aspartate transaminase (grades 3/4: 1%)

Hypersensitivity: Hypersensitivity reaction (5%)

Infection: Herpes zoster infection (10%), infection (6%), herpes simplex infection (3%)

Local: Infusion site pain (6%), catheter pain (5%)

Neuromuscular & skeletal: Arthralgia (6%), limb pain (5%), ostealgia (5%)

Renal: Increased serum creatinine (grades 3/4: 2%)

Respiratory: Upper respiratory tract infection (10%), sinusitis (9%), pharyngolaryngeal pain (8%), pneumonia (8%), nasopharyngitis (6% to 7%), nasal congestion (5%), wheezing (5%)

Frequency not defined:

Central nervous system: Drowsiness, malaise

Dermatologic: Dermatitis, skin necrosis

Gastrointestinal: Mucositis

Hematologic & oncologic: Hemolysis

<1%, postmarketing, and/or case reports: Acute renal failure, anaphylactoid shock, anaphylaxis, atrial fibrillation, bronchogenic carcinoma, bullous rash, cardiac failure, dermatological reaction (toxic), DRESS syndrome, erythema, extravasation injury, hepatitis, hepatotoxicity, injection site reaction, myelodysplastic syndrome, myeloid leukemia (acute), myocardial infarction, neutropenic sepsis, palpitations, pancytopenia, pneumonia due to Pneumocystis jirovecii, pneumonitis, pulmonary alveolar hemorrhage (with grade 3 thrombocytopenia), pulmonary fibrosis, reactivation of disease (including, but not limited to hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, herpes zoster), sepsis, septic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, tumor lysis syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Myelosuppression (neutropenia, thrombocytopenia, and anemia) is a common toxicity; may require therapy delay and/or dose reduction; monitor blood counts frequently (nadirs typically occurred in the third week of treatment). Complications due to febrile neutropenia and severe thrombocytopenia have been reported (some fatal). ANC should recover to ≥1,000/mm³ and platelets to ≥75,000/mm³ prior to cycle initiation.
• Dermatologic toxicity: Serious and fatal dermatologic toxicities, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, bullous exanthema, and rash have been reported. Skin reactions have been reported with monotherapy and in combination with other antineoplastic agents or allopurinol and may be progressive or worsen with continued treatment. The risk for severe skin toxicity is increased with concurrent use of allopurinol and other medications known to cause skin toxicity. Monitor closely for dermatologic toxicity. Withhold or discontinue treatment for severe or progressive skin reaction.
• Extravasation: Bendamustine is an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Erythema, marked swelling, and pain have been reported with extravasation.
• GI toxicities: Bendamustine is associated with a moderate emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.
• Hepatotoxicity: Serious and fatal cases of liver injury have been reported, usually within the first 3 months of treatment initiation. Confounding factors in some patients included combination therapy, progressive disease, and/or hepatitis B reactivation. Monitor liver function tests.
• Hypersensitivity/infusion reaction: Infusion reactions, which may include chills, fever, pruritus, and rash, are common. Rarely, anaphylactic and anaphylactoid reactions have occurred, particularly with the second or subsequent cycle(s). Patients who experience ≥ grade 3 allergic reactions should not be rechallenged. Consider premedication with antihistamines, antipyretics and corticosteroids for patients with a history of grade 1 or 2 infusion reaction. Discontinue for severe allergic reaction or grade 4 infusion reaction; consider discontinuation with grade 3 infusion reaction.
• Hypokalemia: Has been reported with use; monitor potassium closely in patients with cardiac disease.
• Infection: Pneumonia, hepatitis, sepsis, and septic shock have been reported. Fatalities due to infection have occurred. Patients with myelosuppression are more susceptible to infection; monitor closely. Reactivation of hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster infection may occur in patients receiving bendamustine. Monitor; may require infection prophylaxis and/or treatment prior to bendamustine administration.
• Secondary malignancy: Malignancies (including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial cancer) and premalignant diseases have been reported in patients who have received bendamustine, although the association with bendamustine has not been determined.
• Tumor lysis syndrome: Tumor lysis syndrome (usually occurring in the first treatment cycle) may occur as a consequence of antineoplastic treatment, including treatment with bendamustine. May lead to life-threatening acute renal failure (without intervention); vigorous hydration and prophylactic measures (eg, antihyperuricemic therapy) should be instituted prior to treatment in high-risk patients; monitor closely. Note: Allopurinol may increase the risk for bendamustine skin toxicity.

Disease-related concerns:

• Hepatic impairment: A pharmacokinetic study showed only slight differences in bendamustine AUC and C_max in patients with mild hepatic impairment (defined in the study as total bilirubin 1 to 1.5 × ULN or AST > ULN), as compared to patients with normal hepatic function (Owen 2010). Use is not recommended in patients with moderate (AST or ALT 2.5 to 10 × ULN and total bilirubin 1.5 to 3 × ULN) or severe (total bilirubin >3 × ULN) hepatic impairment.
• Renal impairment: According to the manufacturer, use is not recommended in patients with CrCl <30 mL/minute. A pharmacokinetic study illustrated only slight differences in bendamustine AUC and C_max in patients with mild (CrCl >50 to ≤80 mL/minute) and moderate (CrCl >30 to ≤50 mL/minute) renal dysfunction, compared to patients with normal renal function (Owen 2010). A retrospective safety study found higher rates of grades 3 and 4 BUN increases and thrombocytopenia, and grades 1 and 2 fatigue, nausea, and alopecia in patients with renal impairment (CrCl <40 mL/minute) compared to those without renal impairment (Nordstrom 2014); monitor blood counts and renal function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Closed system transfer device incompatibility: Bendamustine solution (Treanda: 45 mg/0.5 mL and 180 mg/2 mL) contains N,N-dimethylacetamide, which may be incompatible with some closed-system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS). When used to prepare or transfer the concentrated bendamustine solution into the infusion bag, the plastic components of some CSTDs may dissolve, resulting in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). Do not use the liquid solution formulation if CSTDs, adapters, and syringes containing polycarbonate or ABS are used prior to dilution in the infusion bag. According to the Treanda manufacturer, after dilution into the infusion bag, devices containing polycarbonate or ABS (including infusion sets) may be used. Refer to the specific CSTD device manufacturer for compatibility data.
• Formulations: Several formulations of bendamustine are available: a liquid solution (45 mg/0.5 mL and 180 mg/2 mL [Treanda] and 100 mg/4 mL [Belrapzo, Bendeka]) and a powder for reconstitution (5 mg/mL after reconstitution [Treanda]). Concentrations, storage, and compatibility differ between formulations. Use caution when selecting bendamustine formulation for preparation and administration. Do not mix or combine the formulations.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.

Monitoring Parameters

CBC with differential and platelets (monitored weekly [initially] in clinical trials); serum creatinine; liver function tests (ALT, AST, and total bilirubin; prior to and during treatment); monitor potassium and uric acid levels in patients at risk for tumor lysis syndrome; monitor for infusion reactions anaphylaxis, infection (including reactivations), and dermatologic toxicity; monitor IV site during and after infusion. Evaluate pregnancy status prior to use in females of reproductive potential.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to bendamustine may cause fetal harm. The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy; the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided in the first trimester and there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Peccatori 2013).

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for ≥6 months after the last dose. Males with female partners of reproductive potential should use effective contraception during therapy and for ≥3 months after the last dose of bendamustine.

Adverse effects to male fertility have been observed in clinical studies. Effects include impaired spermatogenesis, azoospermia, and total germinal aplasia. Risks are increased with combination therapy. Spermatogenesis may return in some patients following remission and may occur several years after therapy has been discontinued.

A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499).

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.
• It is used to treat a type of lymphoma.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Abdominal pain
• Heartburn
• Back pain
• Bone pain
• Joint pain
• Constipation
• Diarrhea
• Dizziness
• Fatigue
• Headache
• Lack of appetite
• Mouth sores
• Mouth irritation
• Stuffy nose
• Sore throat
• Change in taste
• Anxiety
• Night sweats
• Sweating a lot
• Trouble sleeping
• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.
• Depression
• Bruising
• Bleeding
• Severe loss of strength and energy
• Severe injection site pain, redness, edema, burning, or irritation
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.