Bendamustine

Bendamustine 





Medication Safety Issues

Sound-alike/look-alike issues:

Bendamustine may be confused with carmustine

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Pronunciation

(ben da MUS teen)
U.S. Brand Names

Treanda®
Pharmacologic Category

Antineoplastic Agent, Alkylating Agent
Use: Labeled Indications

Treatment of chronic lymphocytic leukemia (CLL); treatment of progressed indolent B-cell non-Hodgkin’s lymphoma (NHL)
Use: Unlabeled/Investigational

Treatment of mantle cell lymphoma; salvage therapy for relapsed multiple myeloma
Dosing: Adults

CLL: I.V.: 100 mg/m2 on days 1 and 2 of a 28-day treatment cycle (for up to 6 cycles)

NHL: I.V.: 120 mg/m2 on days 1 and 2 of a 21-day treatment cycle for up to 8 cycles

Mantle cell lymphoma (unlabeled use): I.V.: 90 mg/m2 days 2 and 3 of a 28-day treatment cycle for up to 4 cycles (Rummel, 2005)

Multiple myeloma (unlabeled use): I.V.: 90-100 mg/m2 on days 1 and 2 of a 28-day treatment cycle for at least 2 cycles (Knop, 2005)
Dosing: Elderly

Refer to adult dosing.
Dosing: Renal Impairment

Mild-to-moderate renal impairment: Use with caution.

Clcr <40 mL/minute: Use is not recommended.
Dosing: Hepatic Impairment

Mild hepatic impairment: Use with caution.

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

Severe hepatic impairment (total bilirubin >3 times ULN): Use is not recommended.
Dosing: Adjustment for Toxicity

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: Combination Regimens

Lymphoma, non-Hodgkin's: Bendamustine-Rituximab

Lymphoma, non-Hodgkin's: (Mantle Cell): Bendamustine-Rituximab
Calculations
Body Surface Area: Adults
Creatinine Clearance: Adults
Administration: I.V.

Infuse over 30 minutes for the treatment of CLL and over 60 minutes for NHL. Prophylactic treatment with allopurinol may be needed in patients at risk for tumor lysis syndrome. Consider premedication with antihistamines, antipyretics, and/or corticosteroids for patients with a previous grade 1 or 2 infusion reaction to bendamustine.
Administration: I.V. Detail

pH: 2.5-3.5
Dietary Considerations

Patients should maintain adequate hydration.
Storage

Prior to reconstitution, store intact vials at 25°C (77°F); excursions 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 for infusion is stable for 24 hours refrigerated or 3 hours at room temperature and room light. Infusion must be completed within these time frames.
Reconstitution

Use appropriate precautions for handling and disposal. Reconstitute 100 mg vial with 20 mL of sterile water for injection to a concentration of 5 mg/mL; powder usually dissolves within 5 minutes. Prior to administration, dilute appropriate dose in 500 mL NS (or D2.51/2NS) to a final concentration of 0.2-0.6 mg/mL; mix thoroughly.
Compatibility

Stable in NS, D2.51/2NS
Contraindications

Hypersensitivity to bendamustine, mannitol, or any component of the formulation
Warnings/Precautions

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

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. Complications due to febrile neutropenia and severe thrombocytopenia have been reported. ANC should recover to ≥1000/mm3 and platelets to ≥75,000/mm3 prior to therapy/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. Toxic epidermal necrolysis has been reported when used in combination with rituximab. Discontinue bendamustine treatment for severe or progressive skin reaction.

• 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). In general, patients who experienced grade 3 or 4 allergic reactions were not rechallenged in CLL clinical trials. Consider premedication with antihistamines, antipyretics and/or corticosteroids for patients with a history of grade 1 or 2 infusion reaction. Discontinue for severe allergic reaction; consider discontinuation with grade 3 or 4 infusion reaction.

• Infection: Infections, including pneumonia and sepsis have been reported with use; may require hospitalization; septic shock and fatalities have occurred. Patients with myelosuppression are more susceptible to infection; monitor closely.

• Malignancy: Malignancies (including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial cancer) have been reported in patients who have received bendamustine.

• Tumor lysis syndrome: Tumor lysis syndrome may occur as a consequence of leukemia treatment, including treatment with bendamustine, usually occurring in the first treatment cycle. May lead to life threatening acute renal failure; adequate hydration and prophylactic allopurinol should be instituted prior to treatment in high risk patients; monitor closely.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with mild hepatic impairment. Use is not recommended in patients with moderate (AST or ALT 2.5-10 times ULN and total bilirubin 1.5-3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment.

• Renal impairment: Use with caution in patients with mild-to-moderate renal impairment. Use is not recommended in patient with Clcr <40 mL/minute.

Special populations:

• Pediatrics: Safety and efficacy have not been established in children.
Pregnancy Risk Factor

D
Pregnancy Considerations

Teratogenic and nonteratogenic events were observed in animal studies following intraperitoneal dosing. There are no adequate and well-controlled studies in pregnant women. May cause fetal harm if administered during pregnancy. Effective contraception is recommended during and for 3 months after treatment for women and men of reproductive potential.
Lactation

Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations

Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (≤13%)

Central nervous system: Fatigue (9% to 57%), fever (24% to 34%), headache (≤21%), chills (6% to 14%), dizziness (≤14%), insomnia (≤13%)

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

Endocrine & metabolic: Dehydration (≤14%)

Gastrointestinal: Nausea (20% to 75%), vomiting (16% to 40%), diarrhea (9% to 37%), constipation (≤29%), anorexia (≤23%), weight loss (7% to 18%), stomatitis (≤15%), abdominal pain (5% to 13%), appetite loss (≤13%), dyspepsia (≤11%)

Hematologic: Myelosuppression (nadir: in week 3), lymphopenia (68% to 99%; grades 3/4: 47% to 94%), leukopenia (61% to 94%; grades 3/4: 28% to 56%), anemia (88% to 89%; grades 3/4: 11% to 13%), thrombocytopenia (77% to 86%; grades 3/4: 11% to 25%), neutropenia (75% to 86%; grades 3/4: 43% to 60%)

Hepatic: Bilirubin increased (≤34%; grades 3/4: 3%)

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

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

1% to 10%:

Cardiovascular: Tachycardia (≤7%), hypotension (≤6%), chest pain (≤6%), hypertension aggravated (≤3%)

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

Dermatologic: Pruritus (5% to 6%), dry skin (≤5%)

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

Gastrointestinal: Gastroesophageal reflux disease (≤10%), xerostomia (9%), taste alteration (≤7%), oral candidiasis (≤6%), abdominal distention (≤5%)

Genitourinary: Urinary tract infection (≤10%)

Hematologic: Febrile neutropenia (3% to 6%)

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

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

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

Renal: Creatinine increased (grades 3/4: ≤2%)

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

Miscellaneous: Herpes infection (3% to 10%), infection (≤6%; grades 3/4: 2%), hypersensitivity (≤5%; grades 3/4: 1%), diaphoresis (≤5%), night sweats (≤5%)

<1%, postmarketing, and/or case reports: Acute renal failure, alopecia, anaphylaxis, bullous exanthema, cardiac failure, dermatitis, erythema, hemolysis, infusion reaction, injection/infusion site reaction (irritation, pruritus, swelling), malaise, mucosal inflammation, myelodysplastic syndrome, pulmonary fibrosis, sepsis, septic shock, skin necrosis, somnolence, toxic epidermal necrolysis, toxic skin reactions, tumor lysis syndrome
Oncology: Emetic Potential

Low (10% to 30%)
Metabolism/Transport Effects

Substrate of CYP1A2; P-glycoprotein (ABCB1); BCRP (ABCG2)
Drug Interactions

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

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

CBC with differential (in clinical trials, WBC with differential and hemoglobin were monitored weekly; platelets were monitored with each cycle); serum creatinine (pretreatment); ALT, AST, and total bilirubin (pretreatment); monitor potassium and uric acid levels in patients at risk for tumor lysis syndrome
Nursing: Physical Assessment/Monitoring

Use with caution in presence of hepatic or renal impairment. Assess all other pharmacological or herbal products patient may be taking for potential interactions or toxicity. See specific instructions for reconstitution and administration. Assess results of laboratory tests at baseline and periodically during therapy (myelosuppression may require therapy delay or dose reduction). Monitor therapeutic response and adverse effects regularly during therapy (infusion reactions, including toxic skin reactions, can occur with first or subsequent cycles and may require premedication or discontinuation). Teach patient or caregiver possible side effects/appropriate interventions, and adverse symptoms to report.
Monitoring: Lab Tests

CBC with differential (in clinical trials, WBC with differential and hemoglobin were monitored weekly; platelets were monitored with each cycle); serum creatinine (pretreatment); ALT, AST, and total bilirubin (pretreatment); monitor potassium and uric acid levels in patients at risk for tumor lysis syndrome
Patient Education

Do not take any new prescription or over-the-counter medications, or herbal products during therapy without consulting prescriber. This medication can only be administered by I.V. Report immediately any pain, burning, swelling at infusion site; sudden onset chest pain, respiratory difficulty, difficulty swallowing. It is important that you maintain adequate nutrition between treatments (small, frequent meals may help) and adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You will be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea, vomiting, or weight loss (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); diarrhea (boiled milk, buttermilk, or yogurt may help). Report immediately chills, fever, skin rash, persistent unusual fatigue; unusual bruising/bleeding; signs of infection, or other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during therapy. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.
Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution:

Treanda®: 100 mg [contains mannitol 170 mg]
Generic Available

No
Manufacturer

Cephalon, Inc
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).
Pharmacodynamics/Kinetics

Distribution: Vss: ~25 L

Protein binding: 94% to 96%

Metabolism: Hepatic, via CYP1A2 to active (minor) metabolites gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4)

Half-life elimination: Bendamustine: ~40 minutes; M3: ~3 hours; M4: ~30 minutes

Time to peak, serum: At end of infusion

Excretion: Feces (~90%); urine (1% to 10%)
Related Information
Common Toxicity Criteria
Management of Nausea and Vomiting
Safe Handling of Hazardous Drugs
Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis, xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions
Mental Health: Effects on Mental Status

May cause fatigue
Mental Health: Effects on Psychiatric Treatment

Bone marrow suppression is common; use caution with clozapine, carbamazepine, and valproic acid. GI side effects are common; concomitant use with lithium, valproic acid, carbamazepine, and SSRIs may produce additive effects. Carbamazepine and phenobarbital may decease the levels/effects of bendamustine. Fluvoxamine may increase the levels/effects of bendamustine.
Index Terms

Bendamustine Hydrochloride; Cytostasan; SDX-105
References


Aivado M, Schulte K, Henze L, et al, “Bendamustine in the Treatment of Chronic Lymphocytic Leukemia: Results and Future Perspectives,” Semin Oncol, 2002, 29(4 Suppl 13):19-22. [PubMed 12170428]


Friedberg JW, Cohen P, Chen L, et al, “Bendamustine in Patients With Rituximab-Refractory Indolent and Transformed Non-Hodgkin's Lymphoma: Results From a Phase II Multicenter, Single-Agent Study,” J Clin Oncol, 2008, 26(2):204-10.[PubMed 18182663]


Kahl B, Bartlett NL, Leonard JP, et al, “Bendamustine Is Safe and Effective in Patients with Rituximab-Refractory, Indolent B-Cell Non-Hodgkin Lymphoma,” Blood, 2007, 110(11) [ASH Abstract 1351].


Knauf WU, Lissichkov T, Aldaoud A, et al, “Bendamustine Versus Chlorambucil in Treatment - Naïve Patients With B-Cell Chronic Lymphocytic Leukemia (B-CLL): Results of an International Phase III Study,” Blood, 2007, 110(11) [ASH Abstract 2043].


Knop S, Straka C, Haen M, et al, “The Efficacy and Toxicity of Bendamustine in Recurrent Multiple Myeloma After High-Dose Chemotherapy,” Haematologica, 2005, 90(9):1287-8. [PubMed 16154860]


National Comprehensive Cancer Network (NCCN), “Clinical Practice Guidelines in Oncology™: Multiple Myeloma,” Version 2, 2009. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf.


National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Non-Hodgkin’s Lymphomas,” Version 3, 2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf


Ponisch W and Niederwieser D, “Bendamustine in the Treatment of Multiple Myeloma: Results and Future Perspectives,” Semin Oncol, 2002, 29(4 Suppl 13):23-6.[PubMed 12170429]


Rummel MJ, Al-Batran SE, Kim SZ, et al, “Bendamustine Plus Rituximab is Effective and has a Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma,” J Clin Oncol, 2005, 23(15):3383-9.[PubMed 15908650]


Teichert J, Baumann F, Chao Q, et al, “Characterization of Two Phase I Metabolites of Bendamustine in Human Liver Microsomes and in Cancer Patients Treated With Bendamustine Hydrochloride,” Cancer Chemother Pharmacol, 2007, 59(6):759-70.[PubMed 16957931]


Teichert J, Sohr R, Baumann F, et al, “Synthesis and Characterization of Some New Phase II Metabolites of the Alkylator Bendamustine and Their Identification in Human Bile, Urine, and Plasma From Patients With Cholangiocarcinoma,” Drug Metab Dispos, 2005, 33(7):984-92. [PubMed 15845750]

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Sources : Drug Information Handbook, 17th Edition