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Bendamustine Hydrochloride

Pronunciation: (BEN-da-MUS-teen HYE-droe-KLOR-ide)
Class: Alkylating agent

Trade Names

Treanda
- Injection, lyophilized powder for solution 25 mg
- Injection, lyophilized powder for solution 100 mg

Pharmacology

Inhibits cell proliferation. The exact mechanism is unknown.

Pharmacokinetics

Absorption

C _max occurs at the end of infusion.

Distribution

Plasma protein binding ranges from 94% to 96%. Steady-state Vd is approximately 25 L.

Metabolism

Metabolized by hydrolysis to compounds with low cytotoxic activity. Two active minor metabolites, M3 and M4, are formed via CYP1A2.

Elimination

Approximately 90% recovered in excreta, primarily in the feces. Intermediate half-life of the parent compound is 40 min; the terminal elimination half-life of M3 and M4 are approximately 3 h and 30 min, respectively. Cl is approximately 700 mL/min.

Special Populations

Renal Function Impairment

Pharmacokinetics are not different for patients with CrCl 40 to 80 mL/min. Pharmacokinetics in patients with CrCl less than 40 mL/min have not been studied; therefore, do not use in these patients.

Hepatic Function Impairment

Mild hepatic impairment has no effect on pharmacokinetics. Moderate to severe hepatic impairment has not been studied; therefore, do not use in these patients.

Elderly

No difference in pharmacokinetics between patients at least 65 yr of age and younger patients.

Gender

No difference in pharmacokinetics between men and women.

Race

Safety and efficacy not established based on race; however, exposure to the drug was 40% higher in Japanese patients than in non-Japanese patients.

Indications and Usage

Treatment of chronic lymphocytic leukemia; treatment of indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 mo of treatment with rituximab or a rituximab-containing regimen.

Contraindications

Known hypersensitivity to bendamustine or mannitol.

Dosage and Administration

Chronic Lymphocytic Leukemia
Adults

IV 100 mg/m ² infused over 30 min on days 1 and 2 of a 28-day cycle for up to 6 cycles.

Dose Modifications Delays

Delay therapy in the event of grade 4 hematologic toxicity or grade 2 or higher nonhematologic toxicity. Once nonhematologic toxicity has recovered to grade 1 or less and/or blood cell counts have improved (absolute neutrophil count [ANC] at least 1 × 10 ⁹ /L; platelets at least 75 × 10 ⁹ /L), therapy can be reinstated. Dose reduction may be needed.

Modification

For grade 3 or higher hematologic toxicity, reduce dose to 50 mg/m ² on days 1 and 2 of each cycle. If grade 3 or higher toxicity recurs, reduce dose to 25 mg/m ² on days 1 and 2 of each cycle. For grade 3 or higher nonhematologic toxicity, reduce dose to 50 mg/m ² on days 1 and 2 of each cycle.

Dose re-escalation

Re-escalation of dose in subsequent cycles may be considered at the discretion of the treating health care provider.

Non-Hodgkin Lymphoma
Adults

IV 120 mg/m ² infused over 60 min on days 1 and 2 of a 21-day cycle, up to 8 cycles.

Dose Modifications Delays

Delay therapy in the event of grade 4 hematologic toxicity or grade 2 or higher nonhematologic toxicity. Once nonhematologic toxicity has recovered to grade 1 or less and/or blood cell counts have improved (ANC at least 1 x 10 ⁹ /L; platelets at least 75 x 10 ⁹ /L), therapy can be reinstated. Dose reduction may be needed.

Modifications

For grade 4 hematologic toxicity, reduce the dose to 90 mg/m ² on days 1 and 2 of each cycle. If grade 4 toxicity recurs, reduce dose to 60 mg/m ² on days 1 and 2 of each cycle. For grade 3 or higher nonhematologic toxicity, reduce dose to 90 mg/m ² on days 1 or 2 of each cycle. If grade 3 or higher toxicity recurs, reduce dose to 60 mg/m ² on days 1 and 2 of each cycle.

General Advice

Reconstitute bendamustine only with sterile water for injection. For the 25 mg vial, add 5 mL of sterile water for injection. For the 100 mg vial, add 20 mL of sterile water for injection.
Transfer reconstituted solution to a 500 mL infusion bag of sodium chloride 0.9% or dextrose 2.5%/sodium chloride 0.45% injection within 30 min of reconstitution.
Compatibility with diluents other than sterile water for injection, sodium chloride 0.9% injection, or dextrose 2.5%/sodium chloride 0.45% injection has not been determined.
Consider measures to prevent severe infusion reactions, including antihistamines and corticosteroids, in subsequent cycles in patients who have previously experienced grade 1 or 2 infusion reactions. Consider discontinuations in patients with grade 3 or 4 infusion reactions.

Storage/Stability

Store at 77° to 86°F. Protect from light. Once diluted, the final admixture is stable for 24 h when stored under refrigeration at 36° to 47°F or for 3 h when stored at 59° to 86°F in room light. Administration should be completed within this time period.

Drug Interactions

Inducers of CYP1A2 (eg, omeprazole, smoking)

May decrease bendamustine plasma concentrations and increase levels of its active metabolites. Coadminister with caution.

Inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine)

May increase bendamustine plasma concentrations and decrease levels of its active metabolites. Coadminister with caution.

Adverse Reactions

Cardiovascular

Tachycardia (7%); hypotension (6%); cardiac failure.

CNS

Fatigue (57%); headache (21%); dizziness (14%); insomnia (13%); asthenia (11%); anxiety (8%); dysgeusia (7%); depression (6%).

Dermatologic

Rash (16%); pruritus (6%); dry skin, hyperhidrosis, night sweats (5%); skin necrosis; skin reactions, including Stevens-Johnson syndrome and TEN (postmarketing).

EENT

Pharyngolaryngeal pain (8%); nasopharyngitis (7%); nasal congestion (5%).

GI

Nausea (75%); vomiting (40%); diarrhea (37%); constipation (29%); stomatitis (15%); abdominal pain, decreased appetite (13%); dyspepsia (11%); gastroesophageal reflux disease (10%); dry mouth (9%); oral candidiasis (6%); abdominal distension, upper abdominal pain (5%).

Genitourinary

UTI (10%); acute renal failure.

Hypersensitivity

Hypersensitivity (5%); anaphylaxis (postmarketing).

Lab Tests

Decreased lymphocytes (99%); decreased leukocytes (94%); decreased hemoglobin (89%); decreased neutrophils, decreased platelets (86%); increased bilirubin (34%); elevated creatinine (2%).

Local

Infusion-site pain (6%); catheter-site pain (5%); infusion reactions; injection-site irritation, pain, pruritus, and swelling (postmarketing).

Metabolic-Nutritional

Anorexia (23%); decreased weight (18%); dehydration (14%); peripheral edema (13%); hypokalemia (9%); hyperuricemia (7%); hyperglycemia (3%); hypocalcemia, hyponatremia (2%).

Musculoskeletal

Back pain (14%); arthralgia (6%); bone pain, pain in extremities (5%).

Respiratory

Cough (22%); dyspnea (16%); upper respiratory tract infection (10%); sinusitis (9%); pneumonia (8%); wheezing (5%); pulmonary fibrosis.

Miscellaneous

Pyrexia (34%); chills (14%); herpes zoster (10%); chest pain, febrile neutropenia, infection, pain (6%); herpes simplex (3%); myelodysplastic syndrome; sepsis; tumor lysis syndrome.

Precautions

Monitor

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin, and neutrophils closely. Monitor hemoglobin and WBC differential counts every week initially and platelet counts each cycle. Monitor for infusion reactions and anaphylaxis. Monitor blood chemistry, particularly potassium and uric acid, for the development of tumor lysis syndrome. Closely monitor patients with skin reactions.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Use with caution in patients with mild or moderate renal impairment. Do not use in patients with CrCl less than 40 mL/min.

Hepatic Function

Use with caution in patients with mild hepatic impairment. Avoid use in patients with moderate to severe hepatic impairment.

Anaphylaxis

Anaphylaxis and anaphylactoid reactions have been reported, especially in the second and subsequent cycles of therapy.

Infections

Infections, including pneumonia and sepsis, have been reported. Patients experiencing myelosuppression after treatment are more susceptible to infections.

Infusion reactions

Reported frequently in clinical trials. Symptoms include chills, fever, pruritus, and rash.

Malignancies

Premalignant and malignant diseases, including acute myeloid leukemia and bronchial carcinoma, myelodysplastic syndrome, and myeloproliferative disorders, have been reported.

Myelosuppression

Likely to occur.

Skin reactions

Have been reported and may include bullous exanthema, toxic skin reactions, and rash. If reactions are severe or progressive, withhold or discontinue treatment.

Tumor lysis syndrome

Has been reported, and the onset tends to be within the first treatment cycle. Monitor blood chemistry, particularly potassium, and uric acid levels. Without intervention, acute renal failure and death may occur. Consider using allopurinol as prevention for patients at high risk of tumor lysis syndrome.

Overdosage

Symptoms

ECG changes, including QT prolongation, sinus tachycardia, ST- and T-wave deviations, and left anterior fascicular block.

Patient Information

Caution patients that tiredness may occur and to avoid driving or operating machinery if this occurs.
Advise patients that nausea and/or vomiting and diarrhea may occur.
Advise patients that a mild rash or itching may occur during treatment.
Inform patients of the possibility of mild or serious allergic reactions and to report if rash, facial swelling, or difficulty breathing occurs soon after infusion.
Inform patients of the need for frequent monitoring of complete blood cell counts.
Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection to their health care provider immediately.
Advise women of childbearing age to avoid becoming pregnant during therapy and for 3 mo after discontinuation. Advise men receiving bendamustine to use reliable contraception for the same time period.
Advise women to avoid breast-feeding during therapy.