Bendamustine Hydrochloride

Trade Names:Treanda- 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.

Elimination

Approximately 90% recovered in excreta, primarily in the feces. Intermediate half-life of the parent compound is 40 min.

Special Populations

Pharmacokinetics 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.

Mild hepatic function impairment has no effect on pharmacokinetics. Moderate to severe hepatic function impairment has not been studied.

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

No difference in pharmacokinetics between men and women.

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

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

Hypersensitivity to mannitol or any component of the product.

Dosage and Administration

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

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.

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.

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

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

IV 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.

IV 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 with sterile water for injection.
• Transfer reconstituted solution to the infusion bag 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 have not been determined.

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

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

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

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

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

CNS

Fatigue (57%); anorexia (23%); headache (21%); dizziness (14%); decreased appetite, insomnia (13%); asthenia (11%); anxiety (8%); dysgeusia (7%); depression (6%).

Dermatologic

Rash (16%); pruritus (6%); dry skin, hyperhidrosis, night sweats (5%).

EENT

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

GI

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

Genitourinary

UTI (10%).

Hematologic

Febrile neutropenia (6%).

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%); injection-site irritation, pain, pruritus, and swelling (postmarketing).

Metabolic-Nutritional

Decreased weight (18%); dehydration (14%); hypokalemia (9%); hyperuricemia (7%); 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%).

Miscellaneous

Pyrexia (34%); chills (14%); peripheral edema (13%); herpes zoster (10%); chest pain, infection, pain (6%); herpes simplex (3%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

No differences in the adverse reaction profile in patients 65 yr of age and older compared with younger patients.

Renal Function

Do not use in patients with CrCl less than 40 mL/min.

Hepatic Function

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

Were reported frequently in clinical trials.

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. 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 dangerous 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.
• Advise patients to report bleeding, fever, shortness of breath, significant fatigue, or other signs of infection.

Copyright © 2009 Wolters Kluwer Health.