Dosing and uses of Bendeka (bendamustine)
Adult dosage forms and strengths
solution for injection (Bendeka)
- 90mg/mL (45mg/0.5mL vial; 180mg/2mL vial) (Treanda)
- 100mg/4mL (25mg/mL) (Bendeka)
lyophilized powder single vials (Treanda)
- 25mg
- 100mg
- Teva announced that Bendeka (bendamustine HCl) injection solution is now available to replace Treanda (bendamustine HCl) lyophilized powder for reconstitution
- Teva will continue to process orders for Treanda through March 30, 2016, after which any submitted or open orders will be canceled
Chronic Lymphocytic Leukemia
100 mg/m² IV infution on days 1 & 2 of 28-day cycle, repeated for up to 6 cycles
Dosage modifications
- Hematologic toxicity
- ≥Grade 3: Reduce dose to 50 mg/m² on Days 1 and 2
- If ≥grade 3 toxicity reoccurs, reduce dose to 25 mg/m² on Days 1 and 2
- Nonhematologic toxicity
- Clinically significant toxicity ≥grade 3: Reduce dose to 50 mg/m² on Days 1 and 2 of each cycle
- Dose re-escalation may be considered
Orphan designation
- Oral dosage formulation for CLL
- Sponsor
- Exinda Theapeutics LLC; 8430 Rovana Circle, Suite B; Sacramento, California 95828
Non-Hodgkin Lymphoma
Indicated for treatment of indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen
120 mg/m² IV infusion on days 1 and 2 of 21-day cycle repeated for up to 8 cycles
Dosage modifications
- Hematologic toxicity
- Grade 4: Reduce dose to 90 mg/m² on Days 1 and 2 of each cycle
- If grade 4 toxicity recurs, reduce dose to 60 mg/m² on Days 1 and 2 of each cycle
- Non-hematologic toxicity
- ≥Grade 3: Reduce dose to 90 mg/m² on Days 1 and 2 of each cycle
- If toxicity ≥grade 3 reoccurs, reduce dose to 60 mg/m² on Days 1 and 2 of each cycle
Renal Impairment
Mild-to-moderate: Use caution
CrCl <40 mL/min: Not recommended
Hepatic Impairment
Mild: Use caution
Moderate (AST or ALT 2.5-10 xULN and bilirubin 1.5-3 xULN): Use not recommended
Severe hepatic impairment (bilirubin >3 times ULN): Use not recommended
Mantle Cell Lymphoma (Off-label)
90 mg/m² IV days 2 and 3 of 28-day cycle in combination with rituximab for up to 4 cycles
Pediatric dosage forms and strengths
Safety and efficacy not established
Bendeka (bendamustine) adverse (side) effects
>10%
Lymphopenia (68-99%)
Leukopenia (61-94%; grade 3/4, 28-56%)
Anemia (88-89%; grades 3/4 11-13%)
Thrombocytopenia (77-86%; grade 3/4, 11-25%)
Neutropenia (75-86%; grade 3/4, 43-60%)
Nausea (20-75%)
Fatigue (9-57%)
Vomiting (16-40%)
Diarrhea (9-37%)
Bilirubin increased (<34%; grade 3/4, 3%)
Constipation (<29%)
Fever (24-34%)
Pyrexia (24%)
Anorexia (<23%)
Cough (4-22%)
Headache (<21%)
Weight loss (7-18%)
Dehydration (<16%)
Rash (8-16%)
Stomatitis (<15%)
Back pain (<14%)
Dizziness (<14%)
Chills (6-14%)
Peripheral edema (13%)
Abdominal pain (5-13%)
Insomnia (<13%)
Dyspepsia (<11%)
Weakness (8-11%)
1-10%
Upper respiratory infection (10%)
Gastroesophageal reflux disease (<10%)
Urinary tract infection (<10%)
Xerostomia (9%)
Hypokalemia (<9%)
Anxiety (8%)
Hyperuricemia (<7%)
Tachycardia (<7%)
Taste alteration (<7%)
Arthralgia (<6%)
Chest pain (<6%)
Depression (<6%)
Hypotension (<6%)
Injection site pain (<6%)
Pain (<6%)
Pruritus (5-6%)
Febrile neutropenia (3-6%)
Rash (5%)
Postmarketing Reports
Injection or infusion site reactions including phlebitis
Blood and lymphatic systems disorders: Pancytopenia
Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation
General disorders and administration site conditions: Injection site reactions (including irritation, swelling), infusion site reactions (including pruritus, irritation, swelling)
Immune system disorders: Anaphylaxis Infections and infestations: Pneumocystis jiroveci pneumonia
Respiratory, thoracic and mediastinal disorders: Pneumonitis
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (with concomitant allopurinol and other medications known to cause the syndrome), Toxic epidermal necrolysis (with concomitant allopurinol and other medications known to cause the condition)
Warnings
Contraindications
Hypersensitivity to bendamustine or mannitoL
Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation
Cautions
Interrupt if severe infusion reactions
Mild-mod renal impairment, mild hepatic impairment
Possibility of anaphylactic/infusion reactions: severe in rare cases
Myelosuppression may occur; delay or reduce dose; restart treatment based on ANC and platelet count recovery; complications of myelosuppression may lead to death
Monitor for fever and other signs of infection and treat promptly
Severe infusion and anaphylactic reactions reported; monitor clinically and discontinue therapy; premedicate in subsequent cycles for milder reactions
Tumor lysis syndrome reported; acute renal failure and death may occur; anticipate and use supportive measures
Discontinue for severe skin reactions; cases of SJS and TEN, some fatal, reported when bendamustine was administered concomitantly with allopurinol and other medications known to cause these syndromes
Premalignant and malignant diseases reported
Erythema and maked swelling can occur with extravasation; assure good venous access and monitor infusion site during and after administration
Fetal harm can occur when administered to a pregnant woman; women should be advised to avoid becoming pregnant when receiving bendamustine
Increased risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster; patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration
Pregnancy and lactation
Pregnancy category: d
Lactation: It is not known whether this drug is excreted in milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Bendeka (bendamustine)
Mechanism of action
Alkylating agent that cross-links single or double DNA strands resulting in DNA breakdown; cell cycle-nonspecific
Pharmacokinetics
Protein Bound: 94-96%
Vd: 25 L
Half-Life: 40 min
Metabolism: CYP1A2 (low amount)
Time to peak (serum): At end of infusion
Excretion: Feces (90%); urine (1-10%)
Administration
IV Preparation
Available in 2 formulations, a solution and a lyophilized powder
Do not mix or combine the 2 formulations
Each formulation vial is intended for single dose only
Solution for injection (45 mg/0.5 mL or 180 mg/2 mL solution)
- Do NOT use the solution with devices containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) including closed system transfer devices (CSTDs), adapters, and syringes
- Contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS
- Only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer solution for injection
- Polypropylene syringes are translucent in appearance
- Solution for injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator using a polypropylene syringe with a metal needle and a polypropylene hub
- Aseptically transfer calculated dose amount to 500 mL 0.9% NaCl or 2.5% dextrose/0.45% NaCl infusion bag
- The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2-0.7 mg/mL
- Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration; the admixture should be a clear colorless to yellow solution
Lyophilized powder vials (25 mg/vial or 100 mg/vial)
- Aseptically reconstitute each lyophilized powder vial as follows:
- 25 mg vial: Add 5 mL of only sterile water for injection
- 100 mg vial: Add 20 mL of only sterile water for injection
- Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL
- The lyophilized powder should completely dissolve in 5 minutes
- The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution
- If particulate matter is observed, the reconstituted product should not be used
- Futher dilution
- Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to 500 mL 0.9% NaCl or 2.5% dextrose/0.45% NaCl infusion bag
- The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2-0.6 mg/mL
- After transferring, thoroughly mix the contents of the infusion bag
- Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration
- The admixture should be a clear and colorless to slightly yellow solution
IV Administration
CLL: Infuse over 30 min
NHL: Infuse over 60 min
Storage
Does not contain preservatives
Unopened vials
- Refrigerate between 2-8°C (36-46°F)
- Retain in original package until time of use to protect from light
Final admixture
- Refrigerated: Stable for 24 hr when stored under refrigerated conditions at 2-8°C (36-46°F)
- Room temperature: Stable at room temperature (15-30°C or 59-86°F) and room light for 2 hr (diluted solution for injection) or 3 hr (reconstituted and diluted lyophilized powder)
- Administration must be completed within this period
