MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Bendamustine may be confused with carmustine, lomustine
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.
U.S. BRAND NAMES — Treanda®
PHARMACOLOGIC CATEGORY
Antineoplastic Agent
Antineoplastic Agent, Alkylating Agent
Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)
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
Infusion reactions:
Grade 1 or 2: Consider premedication with antihistamines, antipyretics, and corticosteroids in subsequent cycles
Grade 3 or 4: Consider discontinuing 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.
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]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Treanda®: 100 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — 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.
COMPATIBILITY — Stable in NS, D2.51/2NS
USE — 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
ADVERSE REACTIONS SIGNIFICANT
>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% (Limited to important or life-threatening): Acute myeloid leukemia, acute renal failure, alopecia, anaphylaxis, bronchial carcinoma, bullous exanthema, cardiac failure, dermatitis, erythema, hemolysis, infusion reaction, injection/infusion site reaction (irritation, pruritus, swelling), malaise, mucosal inflammation, myelodysplastic syndrome, myeloproliferative disorders, pulmonary fibrosis, sepsis, septic shock, skin necrosis, somnolence, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxic skin reactions, tumor lysis syndrome
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; 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 and toxic epidermal necrolysis (TEN) have been reported. TEN has also 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) and premalignant diseases 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.
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
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — 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.
DIETARY CONSIDERATIONS — Patients should maintain adequate hydration.
MONITORING PARAMETERS — CBC with differential (monitored weekly [initially] in clinical trials); serum creatinine (pretreatment); ALT, AST, and total bilirubin (pretreatment); monitor potassium and uric acid levels in patients at risk for tumor lysis syndrome; monitor for infusion reactions anaphylaxis, infection and dermatologic toxicity
INTERNATIONAL BRAND NAMES — Ribomustin (DE)
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%)