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Bendamustine

Pronunciation

Pronunciation

(ben da MUS teen)

Index Terms

  • Bendamustine HCl
  • Bendamustine Hydrochloride
  • Cytostasan
  • SDX-105

Dosage Forms

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

Solution, Intravenous, as hydrochloride:

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]

Solution Reconstituted, Intravenous, as hydrochloride:

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

Brand Names: U.S.

  • Bendeka
  • Treanda

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)

Pharmacology

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).

Distribution

Vss: ~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

At end of infusion

Half-Life Elimination

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

Protein Binding

94% to 96%

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: Unlabeled

Treatment of relapsed or refractory Hodgkin lymphoma; treatment of mantle cell lymphoma; salvage therapy for relapsed multiple myeloma; first-line therapy for follicular lymphoma; treatment of Waldenström macroglobulinemia

Contraindications

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

Dosing: Adult

Note: Bendamustine is associated with a moderate emetic potential (Basch 2011; Roila 2010); 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 B-cell, follicular, or mantle cell, first-line (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 use): 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: Renal Impairment

CrCl <40 mL/minute: Use is not recommended (according to the manufacturer's labeling).

Study data suggest minor changes in systemic exposure may occur with mild-to-moderate renal impairment. Based on a pharmacokinetic study (patients receiving 120 mg/m2 for 2 days every 21 days), only slight differences in bendamustine AUC and Cmax were demonstrated 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 study of bendamustine in CLL and NHL patients with renal impairment (CrCl <40 mL/minute) compared to those without (CrCl ≥60 mL/minute) found no significant difference in lab toxicities in CLL patients with renal impairment compared to those without renal impairment, although an increase in grades 3/4 thrombocytopenia was noted in NHL patients and grades 3/4 BUN increases were higher when combining data for CLL and NHL (Nordstrom 2012).

Note: UK manufacturer's labeling (Levact [prescribing information], October 2010) recommends no dosage adjustment is necessary for patients with CrCl >10 mL/minute.

Dosing: Hepatic Impairment

Mild impairment: Use with caution. However, a pharmacokinetic study showed only slight differences in bendamustine AUC and Cmax in patients with mild hepatic impairment (defined in the study as total bilirubin 1 to 1.5 times ULN or AST greater than ULN), compared to patients with normal hepatic function (Owen 2010).

Moderate impairment (AST or ALT 2.5 to 10 times ULN and total bilirubin 1.5 to 3 times ULN): Use is not recommended.

Severe impairment (total bilirubin >3 times ULN): Use is not recommended.

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)

Nonhematologic toxicity ≥grade 2 (clinically significant): Delay treatment until resolves to ≤grade 1

Dose modification 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 with discretion. May cautiously re-escalate dose in subsequent cycles.

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

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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 [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.

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 is incompatible with 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 these devices 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.

Administration

For chronic lymphocytic leukemia, infuse over 30 minutes (Treanda) or 10 minutes (Bendeka). For non-Hodgkin lymphoma, infuse over 60 minutes (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 is incompatible with 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.

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 (Basch 2011; Dupuis 2011; Roila 2010); 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 Fildago 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).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Bendeka: Stable in NS, D2.51/2NS, D5W.

Treanda: Stable in NS, D2.51/2NS.

Storage

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 6 hours when stored at 15°C to 30°C (59°F to 86°F) and room light. Solutions 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. Bendeka is a multiple-dose vial; 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.

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

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

CYP1A2 Inducers (Strong): May decrease the serum concentration of Bendamustine. Concentrations of active metabolites may be increased. Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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. Consider therapy modification

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

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (13%)

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

Dermatologic: Skin rash (8% to 16%; grades 3/4: ≤3%)

Endocrine & metabolic: Weight loss (NHL 18%; CLL 7%), dehydration (14%)

Gastrointestinal: Nausea (NHL 75%; CLL 20%), vomiting (NHL 40%; CLL 16%), diarrhea (NHL 37%; CLL 9%), constipation (29%), anorexia (23%), stomatitis (15%), abdominal pain (13%), decreased appetite (13%), dyspepsia (11%)

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

Hepatic: Increased serum bilirubin (34%)

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

Respiratory: Cough (NHL 22%; CLL 4%), dyspnea (16%)

Miscellaneous: Fever (NHL 34%; CLL 24%)

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 ALT (grades 3/4: 3%), increased serum AST (grades 3/4: 1%)

Hypersensitivity: Hypersensitivity (5%; grades 3/4: 1%)

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

Local: Infusion site reaction (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

Gastrointestinal: Mucositis

<1% (Limited to important or life-threatening): Acute renal failure, anaphylactoid reaction, anaphylaxis, atrial fibrillation, bronchogenic carcinoma, bullous rash, cardiac failure, dermatological reaction (toxic), hemolysis, hepatitis, infusion related reaction, myelodysplastic syndrome, myeloid leukemia (acute), myeloproliferative disease, myocardial infarction, neutropenic sepsis, pancytopenia, pneumonia due to Pneumocystis jiroveci, 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, skin necrosis, Stevens-Johnson syndrome (with concomitant allopurinol and other medications known to cause the syndrome), toxic epidermal necrolysis (with concomitant allopurinol and other medications known to cause the syndrome), 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 ≥1000/mm3 and platelets to ≥75,000/mm3 prior to cycle initiation.

• Dermatologic toxicity: Rash, toxic skin reactions and bullous exanthema have been reported with monotherapy and in combination with other antineoplastics; may be progressive or worsen with continued treatment; monitor closely. The risk for severe skin toxicity is increased with concurrent use of allopurinol and other medications known to cause skin toxicity; Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. TEN has also been reported when used in combination with rituximab. 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.

• Gastrointestinal toxicities: Bendamustine is associated with a moderate emetic potential (Basch 2011; Dupuis 2011; Roila 2010); antiemetics are recommended to prevent nausea and vomiting.

• 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 experienced grade 3 or higher 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.

• 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; 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: Use with caution in patients with mild hepatic impairment. A pharmacokinetic study showed only slight differences in bendamustine AUC and Cmax in patients with mild hepatic impairment (defined in the study as total bilirubin 1 to 1.5 times ULN or AST greater than 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 times ULN and total bilirubin 1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment.

• Renal impairment: Use with caution in patients with mild to moderate renal impairment. According to the manufacturer, use is not recommended in patients with CrCl <40 mL/minute. A pharmacokinetic study illustrated only slight differences in bendamustine AUC and Cmax 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 no significant difference in lab toxicities between CLL patients with renal impairment (CrCl <40 mL/minute) compared to those without renal impairment, although an increase in grades 3/4 thrombocytopenia and grades 3/4 BUN increases were detected in patients with renal impairment (Nordstrom 2012); monitor blood counts and renal function. Note: UK labeling (Levact prescribing information, October 2010) recommends no dosage adjustment for patients with CrCl >10 mL/minute.

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 is incompatible with 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 these devices 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.

• 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 [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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Monitoring Parameters

CBC with differential and platelets (monitored weekly [initially] in clinical trials); serum creatinine; ALT, AST, and total bilirubin; 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.

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. For women and men of reproductive potential, effective contraception should be used during and for 3 months after treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, heartburn, back pain, constipation, dizziness, fatigue, headache, insomnia, or weight loss. Have patient report immediately to prescriber signs of infection; signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting); angina; shortness of breath; wound that does not heal; bruising; bleeding; severe loss of strength and energy; excessive weight gain; swelling of arms or legs; severe injection site pain; redness, burning, or irritation; signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish); or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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