Bendamustine Hydrochloride

Name: Bendamustine Hydrochloride

Introduction

Antineoplastic agent; nitrogen mustard-derivative alkylating agent and purine analog.1 2 3 4 6 7 8 12 13

Uses for Bendamustine Hydrochloride

Chronic Lymphocytic Leukemia

Treatment of chronic lymphocytic leukemia (CLL)1 2 3 (designated an orphan drug by FDA for this use).10

Prolonged progression-free survival and increased overall response rate observed with bendamustine compared with chlorambucil in patients with previously untreated, Binet stage B or C (Rai stages I–IV) CLL.1 2 3 4 9 Incidence of adverse effects generally also higher with bendamustine than with chlorambucil.1 4

Efficacy of bendamustine relative to first-line therapies other than chlorambucil not established.1 2

Non-Hodgkin’s Lymphoma

Treatment of rituximab-refractory, indolent, B-cell non-Hodgkin’s lymphoma (NHL).1 10004 10005

Use in combination with rituximab† for treatment of previously untreated† advanced-stage indolent NHL or for treatment of previously untreated advanced-stage mantle cell lymphoma† is a reasonable choice (accepted, with possible conditions); however, consider histologic subtype of NHL when selecting a combination chemotherapy regimen.10001 10018 10019

Use in combination with rituximab† for treatment of relapsed or refractory† indolent NHL or for treatment of relapsed or refractory mantle cell lymphoma† is recommended (accepted).10002 10003 10020

Bendamustine Hydrochloride Dosage and Administration

General

  • To minimize risk of infusion-related reactions in patients who have previously experienced grade 1 or 2 infusion reactions, consider premedication with an antihistamine, antipyretic, and corticosteroid during subsequent treatment cycles.1 (See Infusion Reactions and Anaphylaxis under Cautions.)

  • In patients at high risk for tumor lysis syndrome, take appropriate measures (e.g., adequate hydration) during the first few weeks of therapy to prevent hyperuricemia.1 (See Tumor Lysis Syndrome under Cautions.)

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Handle cautiously; use protective equipment (e.g., gloves, safety glasses) to minimize risk of exposure.1 If skin or mucosal contact occurs, immediately and thoroughly wash skin with soap and water and flush mucosa with water.1

Avoid extravasation.1 Ensure good venous access prior to administration; monitor infusion site for erythema, swelling, pain, infection, and necrosis during and after administration.1 (See Local Effects under Cautions.)

Commercially available as injection concentrate and lyophilized powder.1 Lyophilized powder must be reconstituted and then diluted to prepare final infusion solution.1 Injection concentrate must be diluted prior to IV administration.1 Do not mix or combine the formulations.1

Precautions for Use of Injection Concentrate

N, N-Dimethylacetamide (DMA), a solvent in bendamustine hydrochloride injection concentrate, is incompatible with devices containing polycarbonate or acrylonitrile butadiene styrene (ABS).1 16 17 Use of the injection concentrate with incompatible devices may result in device failure (e.g., leaking, breaking, operational failure of closed-system transfer device [CSTD] components), contamination of the drug solution, and occupational exposure resulting in serious adverse effects or skin reactions.1 Bendamustine infusion solutions containing dissolved ABS or polycarbonate may result in small blood vessel blockage in patients.1

CSTDs, adapters, and syringes containing polycarbonate or ABS can dissolve when contact with DMA occurs.1 16 17 Do not use devices containing polycarbonate or ABS to withdraw and transfer the injection concentrate from the vial into the infusion bag.18 19 20 However, devices, including infusion sets, that contain polycarbonate or ABS may be used with the final diluted infusion solution.18 19 20

Devices that are compatible with the injection concentrate are commercially available;18 19 20 prior to preparing infusion solutions from the injection concentrate, verify with the manufacturers that the device to be used is compatible with the injection concentrate.19 20

If a CSTD or adapter that contains polycarbonate or ABS will be used to prepare the infusion solution, bendamustine hydrochloride powder for injection must be used.18 19 20

When using a syringe to withdraw and transfer the injection concentrate from the vial into the infusion bag, use only a polypropylene syringe with metal needle and polypropylene hub.18 19 20

Dilute the injection concentrate in a biosafety cabinet or containment isolator.1 16

Dilution of Injection Concentrate

Do not use CSTDs, adapters, or syringes containing polycarbonate or ABS to withdraw and transfer bendamustine hydrochloride injection concentrate from the vial into the infusion bag.18 19 20

Prior to preparing infusion solution, verify with the manufacturers that the device to be used is compatible with the injection concentrate.19 20

When using a syringe to withdraw and transfer the injection concentrate from the vial into the infusion bag, use only a polypropylene syringe with metal needle and polypropylene hub.18 19 20

Dilute in a biosafety cabinet or containment isolator.1 16

Injection concentrate contains no preservatives; infusion solution preferably should be prepared immediately before use.1 Discard any unused portions.1

Withdraw appropriate dose of bendamustine hydrochloride injection concentrate from the vial (containing 90 mg/mL) into a polypropylene syringe with metal needle and polypropylene hub1 16 and further dilute immediately in 500 mL of either 0.9% sodium chloride injection or 2.5% dextrose and 0.45% sodium chloride injection to a final concentration of 0.2–0.7 mg/mL.1

Administration must be completed within 24 hours of dilution when diluted solution is stored under refrigeration or within 2 hours when stored at room temperature under normal room light conditions.1 (See Storage under Stability.)

Reconstitution and Dilution (Lyophilized Powder for Injection)

Reconstitute vial containing 25 or 100 mg of bendamustine hydrochloride powder with 5 or 20 mL of sterile water for injection, respectively, to provide a solution containing 5 mg/mL.1

Shake well to ensure complete dissolution;1 14 lyophilized powder should dissolve within 5 minutes.1 Must be diluted further before IV administration.1

Reconstituted solution contains no preservatives; solution preferably should be prepared immediately before use.1 Discard any unused portions.1

Within 30 minutes of reconstitution, withdraw appropriate volume of reconstituted solution from the vial and further dilute immediately in 500 mL of either 0.9% sodium chloride injection or 2.5% dextrose and 0.45% sodium chloride injection to a final concentration of 0.2–0.6 mg/mL.1 Mix thoroughly.1

Administration must be completed within 24 hours of dilution when diluted solution is stored under refrigeration or within 3 hours when stored at room temperature under normal room light conditions.1 (See Storage under Stability.)

Rate of Administration

In patients with CLL, administer by IV infusion over 30 minutes.1

In patients with rituximab-refractory, indolent, B-cell NHL, administer by IV infusion over 60 minutes.1

In patients with untreated† or relapsed/refractory† indolent NHL or untreated or relapsed/refractory mantle cell lymphoma†, bendamustine has been infused IV over 30–60 minutes.10001 10002 10003 10018

Dosage

Available as bendamustine hydrochloride; dosage expressed in terms of the salt.1

Adults

Chronic Lymphocytic Leukemia IV

100 mg/m2 on days 1 and 2 of each 28-day cycle, for up to 6 cycles.1 5

Dosage Modification for Toxicity in CLL IV

If toxicity occurs, delay initiation of next treatment cycle until blood counts have recovered to recommended values (ANC ≥1000/mm3 and platelet count ≥75,000/mm3) and nonhematologic toxicity has improved to grade 1 or better.1

If grade 4 hematologic toxicity occurs, interrupt therapy.1 When blood counts improve (ANC ≥1000/mm3 and platelet count ≥75,000/mm3), resume therapy at clinician’s discretion.1 For grade 3 or 4 hematologic toxicity, reduce dosage to 50 mg/m2 on days 1 and 2 of each treatment cycle.1 If grade 3 or 4 toxicity recurs, further reduce dosage to 25 mg/m2 on days 1 and 2 of each cycle.1 Re-escalation of dosage in subsequent cycles may be considered.1

If clinically important grade 2 or greater nonhematologic toxicity occurs, interrupt therapy; when toxicity improves to grade 1 or better, resume therapy at clinician’s discretion.1 If nonhematologic toxicity was grade 3 or 4, reduce subsequent dosage to 50 mg/m2 on days 1 and 2 of each treatment cycle.1 Re-escalation of dosage in subsequent cycles may be considered.1

Non-Hodgkin’s Lymphoma Rituximab-refractory, Indolent, B-cell NHL IV

120 mg/m2 on days 1 and 2 of each 21-day cycle, for up to 8 cycles.1 10004

Dosage Modification for Toxicity in Rituximab-refractory, Indolent, B-cell NHL IV

If toxicity occurs, delay initiation of next treatment cycle until blood counts have recovered to recommended values (ANC ≥1000/mm3 and platelet count ≥75,000/mm3) and nonhematologic toxicity has improved to grade 1 or better.1

If grade 4 hematologic toxicity occurs, interrupt therapy.1 When blood counts improve (ANC ≥1000/mm3 and platelet count ≥75,000/mm3), resume therapy at clinician’s discretion; reduce dosage to 90 mg/m2 on days 1 and 2 of each treatment cycle.1 If grade 4 toxicity recurs, further reduce dosage to 60 mg/m2 on days 1 and 2 of each cycle.1

If clinically important grade 2 or greater nonhematologic toxicity occurs, interrupt therapy; when toxicity improves to grade 1 or better, resume therapy at clinician’s discretion.1 If nonhematologic toxicity was grade 3 or 4, reduce subsequent dosage to 90 mg/m2 on days 1 and 2 of each treatment cycle.1 If grade 3 or 4 toxicity recurs, further reduce dosage to 60 mg/m2 on days 1 and 2 of each cycle.1

Previously Untreated† Advanced-stage Indolent NHL or Previously Untreated Advanced-stage Mantle Cell Lymphoma† IV

90 mg/m2 has been administered on days 1 and 2 of a 28-day cycle for up to 8 cycles, in combination with rituximab† (375 mg/m2 IV on day 1).10001 10018

Relapsed or Refractory† Indolent NHL or Relapsed or Refractory Mantle Cell Lymphoma† IV

90 mg/m 2 has been administered on days 2 and 3 of a 28-day cycle for a total of 4–6 cycles, in combination with rituximab† (375 mg/m2 IV on day 1).10002 10003 An additional dose of rituximab has been administered one week prior to the first bendamustine-rituximab treatment cycle and repeated at 28 days following the last bendamustine-rituximab treatment cycle.10002 10003

Special Populations

Hepatic Impairment

Use not recommended in patients with moderate or severe hepatic impairment.1 No specific dosage recommendations for patients with mild hepatic impairment; use with caution.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Use not recommended in patients with severe renal impairment.1 No specific dosage recommendations for patients with mild or moderate renal impairment; use with caution.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Bendamustine Hydrochloride

Contraindications

  • Known history of hypersensitivity (e.g., anaphylactic or anaphylactoid reaction) to bendamustine.1

Warnings/Precautions

Sensitivity Reactions

Infusion Reactions and Anaphylaxis

Infusion reactions (e.g., fever, chills, pruritus, rash) occur commonly.1 Severe anaphylactic and anaphylactoid reactions reported rarely, mainly in the second and subsequent cycles of therapy.1

Monitor patients clinically; discontinue therapy if a severe reaction occurs.1 After the first cycle of therapy, ask the patient about symptoms suggestive of infusion reactions.1

If grade 1 or 2 infusion reactions occur, consider a premedication regimen (e.g., antihistamine, antipyretic, and corticosteroid) during subsequent treatment cycles.1

If grade 4 infusion reactions occur, discontinue therapy.1 If clinically appropriate, consider discontinuing therapy if grade 3 infusion reactions occur.1

If grade 3 or worse allergic-type reactions occur, permanently discontinue therapy.1

Hematologic Effects

Risk of severe (grade 3 or 4) and potentially fatal myelosuppression, manifested primarily as lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.1 Neutropenic sepsis, diffuse alveolar hemorrhage, and cytomegalovirus pneumonia reported.1

Monitor leukocytes, platelets, hemoglobin, and neutrophils frequently;1 in clinical trials, blood counts were monitored weekly initially.1

Hematologic nadirs occur during the third week of the treatment cycle; dose delays and/or dosage reductions may be required if recovery to recommended values (i.e., ANC ≥1000/mm3 and platelet count ≥75,000/mm3) has not occurred prior to initiation of the next cycle of therapy.1 (See Dosage under Dosage and Administration.)

Infectious Complications

Infections (e.g., pneumonia, sepsis) resulting in hospitalization, septic shock, and death have occurred.1 Increased risk of infection in patients with myelosuppression.1 (See Hematologic Effects under Cautions.)

Tumor Lysis Syndrome

Tumor lysis syndrome reported, generally during the first cycle of therapy; without appropriate intervention, acute renal failure and death may occur.1

Closely monitor blood chemistries (particularly potassium and uric acid concentrations) and take appropriate measures (e.g., adequate hydration) in patients at high risk for tumor lysis syndrome.1

Manufacturer no longer recommends concomitant allopurinol therapy; such use may increase the risk of severe skin reactions.1 15 (See Dermatologic Reactions under Cautions.)

Dermatologic Reactions

Possible dermatologic reactions (e.g., rash, toxic skin reactions, bullous exanthema);1 may be progressive and increase in severity with continued therapy.1 Monitor closely if dermatologic reactions occur; if reaction is severe or progressive, withhold or discontinue bendamustine.1

Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatalities, reported with concomitant use of bendamustine with allopurinol and other drugs, including rituximab, known to cause these reactions.1

Precise relationship between bendamustine and dermatologic reactions not established.1

Carcinogenicity

Development of premalignant (e.g., myelodysplastic syndrome, myeloproliferative disorders) and malignant diseases (e.g., acute myelogenous leukemia, bronchial carcinoma) reported; however, a causal relationship not fully established.1

Local Effects

Extravasation may cause pain, erythema, and marked swelling and may result in hospitalization.1 Monitor infusion site for erythema, swelling, pain, infection, and necrosis during and after administration of bendamustine.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; increased resorptions, skeletal and visceral malformations, and decreased fetal body weights demonstrated in animals.1

Avoid pregnancy during and for 3 months after discontinuance of therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1 Advise men with partners of childbearing potential to use a reliable method of contraception during and for 3 months after discontinuance of therapy.1 14

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether bendamustine is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Pharmacokinetic and adverse effect profiles in pediatric patients (1–19 years of age) with relapsed or refractory acute leukemia similar to those in adults.1

Efficacy not established in pediatric patients.1 Evaluated at a dosage of 90 or 120 mg/m2 IV daily on days 1 and 2 of each 21-day cycle in a phase 1–2 study in pediatric patients with relapsed or refractory acute leukemia.1 No responses observed in 32 patients during phase 2; however, complete responses observed in 2 patients with acute lymphocytic leukemia (ALL) during phase 1.1

Geriatric Use

Pharmacokinetic and adverse effect profiles similar to those in younger adults.1

Decreased progression-free survival and overall response rate observed in patients ≥65 years of age with CLL compared with younger adults.1 Overall response rate was 47% in patients ≥65 years of age versus 70% in younger adults.1 Median progression-free survival was 12 months in patients ≥65 years of age versus 19 months in younger adults.1

Overall response rate and duration of response in patients ≥65 years of age with NHL are similar to results in younger adults.1

Hepatic Impairment

Limited data indicate that pharmacokinetics are not substantially altered in patients with mild hepatic impairment; pharmacokinetics not evaluated in patients with moderate or severe hepatic impairment.1

Use with caution in patients with mild hepatic impairment; use not recommended in moderate hepatic impairment (serum AST/ALT 2.5–10 times the ULN and total serum bilirubin 1.5–3 times the ULN) or severe hepatic impairment (total bilirubin >3 times the ULN).1

Renal Impairment

Limited data indicate that pharmacokinetics are not substantially altered in patients with mild or moderate renal impairment; pharmacokinetics not evaluated in patients with severe renal impairment.1

Use with caution in patients with mild or moderate renal impairment; use not recommended in patients with severe renal impairment (Clcr <40 mL/minute).1

Gender

Pharmacokinetic and adverse effect profiles not affected substantially by gender.1

No clinically important differences in efficacy between men and women observed in patients with rituximab-refractory, indolent B-cell NHL.1

Overall response rates in men and women with CLL were 60 and 57%, respectively;1 median durations of progression-free survival in men and women with CLL were 19 and 13 months, respectively.1

Common Adverse Effects

Neutropenia,1 4 thrombocytopenia,1 4 5 6 7 anemia,1 4 5 6 leukopenia,1 4 6 7 pyrexia,1 nausea,1 6 vomiting,1 5 6 decreased lymphocyte counts,1 elevated bilirubin concentrations, fatigue,1 diarrhea,1 constipation,1 decreased weight,1 anorexia, 1 dyspnea,1 cough, 1 headache,1 rash,1 stomatitis.1

Interactions for Bendamustine Hydrochloride

No formal drug interaction studies performed to date.1

Metabolized mainly by hydrolysis and, to a lesser extent, by CYP1A2.1

Does not appear to inhibit CYP isoenzymes 1A2, 2C9, 2C10, 2D6, 2E1, 3A4, or 3A5 or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, or 3A5 in vitro.1

P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may affect bendamustine transport in vitro; role of active transport systems not fully evaluated.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2: Potential pharmacokinetic interaction (increased plasma concentrations of bendamustine).1 Use concomitantly with caution or consider alternative therapy.1

Inducers of CYP1A2: Potential pharmacokinetic interaction (decreased plasma concentrations of bendamustine).1 Use concomitantly with caution or consider alternative therapy.1

Protein-bound Drugs

Bendamustine unlikely to displace or be displaced by other highly protein-bound drugs.1

Specific Drugs

Drug

Interaction

Comments

Cigarette smoking

Possible decreased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Ciprofloxacin

Possible increased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Fluvoxamine

Possible increased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Omeprazole

Possible decreased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

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