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bendamustine
Bendamustine is a mechlorethamine derivative containing a purine-like benzimidazole ring and is an alkylating agent. It shows limited cross resistance to other alkylating agents.
The efficacy of bendamustine in patients with relapsed indolent B-cell NHL is based on overall response rate and duration of response data from a single-arm pivotal trial (SDX-105-03).
The efficacy in treatment-naive patients with symptomatic CLL is based on progression-free survival and overall response rate of bendamustine compared to chlorambucil.
Dose proportionality of bendamustine has not been studied in humans but plasma concentrations were often greater than dose proportional in animal studies.
| PPB | 94 - 96% |
| Cross blood brain barrier? | Not significant |
| Distribution Sites | kidneys and liver (mice and rat models) |
Extensively metabolized via hydrolytic and conjugative pathways. Oxidative metabolism also occurs via CYP1A2 to form active minor metabolites.
| Main enzymes involved | CYP1A2 |
| Active metabolites | M3 and M4 (minor) |
| Inactive metabolites | monohydroxy and dihydroxy-bendamustine metabolites (major) |
| Urine | 46% (minor pathway for unmodified bendamustine) |
| Feces | 25% |
| Clearance | 700 mL/minute |
| Half-life | 40 minutes |
- Non-Hodgkin Lymphoma (NHL)
- Chronic lymphocytic leukemia (CLL)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
Extravasation Potential: Irritant
(from NHL trials in general)
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (5%) | E | |||
| Arterial thromboembolism (rare) | E | ||||
| Cardiotoxicity (rare) | E D | ||||
| Hypertension (5%) (may be severe) | I E | ||||
| QT interval prolonged (rare) | E | ||||
| Sudden death (2%) | E D | ||||
| Dermatological | Rash, pruritus (15%) (may be severe) | E D | |||
| Gastrointestinal | Abdominal pain (14%) | E | |||
| Anorexia, weight loss (24%) | E D | ||||
| Constipation (31%) | E | ||||
| Diarrhea (42%) | E | ||||
| Dyspepsia (14%) | E | ||||
| Mucositis (21%) | E | ||||
| Nausea, vomiting (77%) | I E | ||||
| General | Fatigue (64%) | I E | |||
| Fever, chills (36%) | E | ||||
| Fluid retention (14%) | E D | ||||
| Pain (9%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (4%) (Grade 3 or 4; may be severe) | E | |||
| Hepatobiliary | ↑ LFTs (3%) (Grade 3 or 4; may be severe) | E | |||
| Hypersensitivity | Infusion related reaction (5%) | I | |||
| Infection | Immunosuppression/ atypical infection (12%) | E D | |||
| Injection site | Pain (7%) | I E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (11%) | E D | |||
| Tumour lysis syndrome (2%) | E | ||||
| Musculoskeletal | Pain (13%) | E | |||
| Neoplastic | Secondary malignancy (1%) (includes MDS, lymphoma and squamous cell carcinoma) | D L | |||
| Nervous System | Dizziness (15%) | I E | |||
| Dysgeusia (11%) | E | ||||
| Headache (21%) | E | ||||
| Insomnia (15%) | E | ||||
| Mood changes (8%) | E D | ||||
| Renal | Renal failure (1%) | D | |||
| Respiratory | Acute respiratory distress syndrome (ARDS) (rare) | E | |||
| Cough, dyspnea (17%) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for bendamustine include nausea, vomiting , fatigue, myelosuppression, diarrhea, fever, chills, constipation, anorexia, weight loss, headache and mucositis.
Secondary malignancies (mainly hematologic) have been reported with bendamustine use.
Cardiac disorders (may be severe and fatal) have been reported in patients receiving bendamustine. Correct for hypokalemia and other electrolyte abnormalities prior to and during treatment with bendamustine, especially in patients with pre-existing cardiac disorders.
Hypertension, including hypertensive crisis, have been reported. Blood pressure should be well-controlled prior to starting treatment with bendamustine.
Tumour lysis syndrome, particularly with bulky disease, may occur within the first treatment cycle. Preventative measures, including adequate volume status and correction of electrolytes (particularly potassium and uric acid), is recommended. If using allopurinol concurrently with bendamustine, an increased risk of severe skin toxicity (including Stevens-Johnson syndrome and toxic epidermal necrolysis) was noted.
Myelosuppression occurred commonly and was fatal in 2% of patients in the NHL study. Infections, including atypical infections such as CMV and HZV are common. Reactivation of hepatitis B in patients who are chronic carriers has occurred and may be fatal. Patients should be monitored for atypical infections and receive appropriate prophylaxis and/or treatment as required.
Infusion reactions are common. Symptoms were generally mild but severe anaphylactic and anaphylactoid reactions were described, particularly in the second and subsequent cycles of treatment. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Preventative measures to prevent Grade 1 or 2 reactions on subsequent cycles include antihistamines, antipyretics and corticosteroids should be considered.
Bendamustine extravasation has resulted in hospitalizations. Injection sites should be monitored for redness, swelling, pain, infection and necrosis during and after administration.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.
Hypertension should be controlled prior to starting treatment.
Do not retreat until ANC ≥ 1 x 109/L and platelets ≥ 75 x 109/L and non-hematologic toxicity has recovered to ≤ grade 1.
Pre-medication (only for patients with Grade 1 or 2 reactions with prior infusion):
- Analgesic/antipyretic (e.g. acetaminophen), corticosteroid and an antihistamine (e.g. diphenhydramine) should be considered in subsequent cycles.
Dosing instructions
|
Setting
|
Dosing
|
Dose level -1 | Dose level -2 |
|
Non-Hodgkin’s Lymphoma*
|
120 mg/m2 on Days 1 and 2 of a 21-day cycle; up to 8 cycles
|
90 mg/m2 | 60 mg/m2 |
|
Chronic Lymphocytic Leukemia**
|
100 mg/m2 on Days 1 and 2 of a 28-day cycle; up to 6 cycles
|
50 mg/m2 | 25 mg/m2 |
*Do not re-escalate after dose modification for toxicity
**Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician
|
Toxicity
|
Modification
|
|
Grade 4 Hematologic toxicities
|
Delay until ANC ≥ 1 x 109/L, platelets ≥ 75 x 109/L then reduce by 1 dose level
|
|
≥ Grade 3 Hypersensitivity reaction
|
Discontinue
|
|
≥ Grade 2 clinically significant Non-hematologic toxicities;
≥ Grade 3 Non-hematologic toxicities
|
Delay until recovered to ≤ grade 1, then reduce by one dose level
|
| Bilirubin | AST or ALT or ALP | Dose | |
| < 1.5 x ULN | OR | ≤ 2.5 x ULN | Caution |
| > 1.5 x ULN | OR | > 2.5 x ULN | Do not use |
|
Creatinine Clearance (mL/min)
|
Dose
|
|
>80
|
100%
|
|
40 - 80
|
Caution
|
|
< 40
|
Do not use
|
No dose adjustment required. No clinically significant differences in efficacy and safety were observed in those aged 65 and older and younger patients.
- NHL - infuse over 60 minutes
- CLL - infuse over 30 minutes
- Bendamustine infusions should be administered in a setting where full resuscitation facilities are immediately available, and under the close supervision of someone experienced and capable of dealing with severe infusion-related reactions.
- DO NOT administer as an IV push or bolus.
- Dilute to a final concentration of 0.2 - 0.6 mg/mL in 500 mL infusion bag of 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride.
- Reconstituted solution must be transferred to infusion bag within 30 minutes of reconstitution.
- Administer bendamustine through a dedicated line.
- Compatible with PVC or polyethylene bags.
- Do not admix with other drugs.
- Patients who have a hypersensitivity to this drug or any of its components (including mannitol)
- Patients with CrCl < 40 mls/min or moderate/severe hepatic impairment
- Patients with serious infections
- Avoid live or live-attenuated vaccines, since they may result in serious or fatal infections in patients immunocompromised by bendamustine
- Avoid in patients with relapsed indolent NHL who did not tolerate prior therapies (including other alkylating agents)
- Use with caution in patients with hypertension and patients with mild renal and hepatic impairment
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Mutagenicity:
Documented in animals
-
Genotoxicity:
Documented in animals
-
Embryotoxicity:
Documented in animals
-
Teratogenicity:
Documented in animals
-
Pregnancy:
Bendamustine is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners 2 weeks before, during treatment, and for at least 4 weeks after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended. -
Fertility effects:
Yes
Observed in clinical trials (in patients who can get others pregnant).
Impaired spermatogenesis has been reported; in some instances, it may return several years after intensive chemotherapy has been discontinued.
No clinical assessments of pharmacokinetic drug-drug interactions between bendamustine and other drugs have been conducted. The following are potential interactions with unknown clinical consequence(s). In vitro data suggest bendamustine may be a substrate for P-gp, but is unlikely to affect drug metabolism via CYP1A2, 2C9/10, 2D6, 2E1 or 3A4/5 or induce metabolism of substrates.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) | ↑ bendamustine concentration and/or toxicity | ↓ metabolism of bendamustine; ↓ formation of active metabolites | Caution |
| CYP1A2 inducers (e.g. omeprazole, smoking) | ↓ bendamustine concentration and/or efficacy; ↑ active metabolites concentration and /or toxicity | ↑ metabolism of bendamustine; ↑ formation of active metabolites | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each cycle |
| Liver function tests | Baseline and regular |
| Renal function tests | Baseline and regular |
| Electrolytes, including sodium, potassium, magnesium and uric acid | Baseline and regular |
Blood pressure |
Baseline and before each dose |
Clinical toxicity assessment for infection (including CMV and herpes zoster), tumour lysis syndrome, renal, cardiac, hepatic and skin toxicity, infusion reactions and secondary malignancies |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| HIV status | Baseline |
| ECG | As clinically indicated; periodic in the setting of cardiac disorders and electrolyte imbalances |
Blood glucose |
Baseline and periodic |
CMV testing in febrile patients |
As clinically indicated |
New Drug Funding Program (NDFP Website )
- Bendamustine - First Line - Chronic Lymphocytic Leukemia
- Bendamustine - Relapsed_Refractory - Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma
- Bendamustine - First Line - Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma
- Polatuzumab Vedotin with Bendamustine and Rituximab (Biosimilar) - Relapsed or Refractory Diffuse Large B-cell Lymphoma
Garnock-Jones, K. Bendamustine: a review of its use in the management of indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma. Drugs 2010; 70(13):1703-1718.
Prescribing Information: Treanda® (bendamustine). Cephalon Inc, July 2010.
Product Monograph: Treanda® (bendamustine). Lundbeck Canada Inc, February 2017.
Product Monograph: Treanda® (bendamustine). Teva Canada Limited. January 25, 2023.
Van der Jagt R, Laneuville P, MacDonald D, et al. A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma. Curr Oncol 2012; 19(3):160-167.
November 2024 Updated Dosing, Pregnancy and Lactation, and Monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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