Bendamustine

358.26

358.26

9266D9P3PQ

DTXSID2046888

C73261

L01AA09|L - Antineoplastic and immunomodulating agents

2933990090

58.4

4.23 (est)

1.31±0.1 g/cm3(Predicted)

585.2±50.0 °C(Predicted)

307.7±30.1 °C

1.599

1.3X10-11 mm Hg at 25 deg C (est)

Henry's Law constant = 3.9X10-13 atm-cu m/mole at 25 °C (est)

pKa = 6.85 (imine) (est)

MW: 394.7 ... supplied as a sterile non-pyrogenic white to off-white powder. /Bandamustine hydrochloride/|Hydroxyl radical reaction rate constant = 2.1X10-10 cu cm/molecule-sec at 25 °C (est)

P201, P202, P264, P270, P281, P301+P310, P308+P313, P321, P330, P405, P501

H301

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for Bendamustine (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl bendamustine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Bendamustine hydrochloride/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for Bendamustine (19 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

Risk for tumor-lysis syndrome. Discontinue use in the event of severe/progressive skin reactions. Hematologic malignancies of different forms reported. Discontinue use in the case of severe infusion reactions. May cause extravasation. Mild to moderate renal impairment. Mild hepatic impairment. Sepsis (infections) may occur. Avoid use if pregnant. Possibility of anaphylaxis or infusion reactions- severe in rare cases.

Mild and transient elevations in serum aminotransferase levels are found in up to 20% of patients treated with bendamustine, but elevations above 5 times the upper limit of normal occur in less than 3% of patients. The abnormalities are generally transient, unaccompanied by symptoms and rarely require dose modification. Clinically apparent liver injury from bendamustine has been limited to a small number of cases of mild hepatitis with features of hypersensitivity including eosinophilia, rash or other systemic symptoms. Autoantibody formation is uncommon. The course is generally self-limited, but may require corticosteroid therapy for control of symptoms and timely recovery.

LD50 Rat oral 200-300 mg/kg /Bendamustine hydrochloride/[The Merck Index, Fourteenth Edition (2006)|LD50 Rat iv 40 mg/kg /Bendamustine hydrochloride/[The Merck Index, Fourteenth Edition (2006)|LD50 Mouse oral 400-500 mg/kg /Bendamustine hydrochloride/[The Merck Index, Fourteenth Edition (2006)|LD50 Mouse iv 80 mg/kg /Bendamustine hydrochloride/[The Merck Index, Fourteenth Edition (2006)

In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs.

Bendamustine's production and use as a medication to treat chronic lymphocytic leukemia(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5,200(SRC), determined from a structure estimation method(2), indicates that bendamustine is expected to be immobile in soil(SRC). Bendamustine is a zwitterion with cationic tendencies at environmental pH values of 5 to 9(3). Volatilization of bendamustine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.9X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Bendamustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-11 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2009).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5,200(SRC), determined from a structure estimation method(2), indicates that bendamustine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.9X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 4.2(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Bendamustine is an alkylating agent that may hydrolyze under environmental conditions(3). Biodegradation data were not available(SRC, 2009).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bendamustine, which has an estimated vapor pressure of 1.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase Bendamustine may be removed from the air by wet or dry deposition(SRC). Bendamustine does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of bendamustine with photochemically-produced hydroxyl radicals has been estimated as 2.1X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.8 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Bendamustine is an alkylating agent that may hydrolyze under environmental conditions(2). Bendamustine does not contain chromophores that absorb at wavelengths >290 nm(2) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for bendamustine(SRC), using an estimated log Kow of 4.23(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of bendamustine can be estimated to be 5200(SRC). According to a classification scheme(2), this estimated Koc value suggests that bendamustine is expected to be immobile in soil. Bendamustine is a zwitterion with cationic tendencies at environmental pH values of 5 to 9(3).

The Henry's Law constant for bendamustine is estimated as 3.9X10-13 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that bendamustine is expected to be essentially nonvolatile from water surfaces(2). Bendamustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-11 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to bendamustine were not located(SRC, 2009), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Occupational exposure to bendamustine may occur through dermal contact with this compound at workplaces where bendamustine is produced or used. General population exposure may be limited to those administered bendamustine via its use as a medication. (SRC)

Bendamustine is indicated for use in the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.|FDA Label|Drug: Bendamustinehydrochloride

Bendamustine is a parenterally administered alkylating agent used alone and in combination with other antineoplastic agents in the treatment of chronic lymphocytic leukemia and refractory forms of non-Hodgkin lymphoma. Bendamustine therapy is associated with minor transient serum enzyme elevations during treatment and to rare instances of clinically apparent liver injury, with jaundice generally arising as a part of a generalized hypersensitivity syndrome. Bendamustine also has potent immunosuppressive activity and can cause reactivation of chronic hepatitis B that can be severe and even fatal.

Antineoplastic Agents, Alkylating Agents

Antineoplastic /Bendamustine hydrochloride/[The Merck Index, Fourteenth Edition (2006)|Bendamustine hydrochloride is used for the treatment of chronic lymphocytic leukemia (CLL) and is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition. /Included in US product label/|Bendamustine administered as monotherapy is active in rituximab-refractory indolent non-Hodgkin's lymphoma, predominantly in patients with nontransformed or with sensitive disease characteristics. Therefore, bendamustine may be considered a reasonable choice for rituximab-refractory, indolent non-Hodgkin's lymphoma; bendamustine may also may be considered an alternative in patients who are not candidates for radioimmunotherapy due to either patient selection (i.e., a clinical contraindication) or accessibility issues. /Included in US product label/|Treanda for Injection is an alkylating drug indicated for treatment of patients with: Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. Indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. /Included in US product label/|For more Therapeutic Uses (Complete) data for Bendamustine (8 total), please visit the HSDB record page.

Infections, including pneumonia and sepsis, have been reported in patients receiving bendamustine and have been associated with hospitalization, septic shock, and death. Patients with myelosuppression have increased susceptibility to infection and should be advised to contact their clinician if signs or symptoms of infection occur.|In the phase 3 study in patients with chronic lymphocytic leukemia, grade 3 or 4 neutropenia occurred in 24% and febrile neutropenia occurred in 3% of patients receiving bendamustine; red blood cell or platelet transfusions were administered to 20 or less than 1%, respectively, of patients receiving the drug. Leukocytes, platelets, hemoglobin, and neutrophils should be monitored closely in patients with bendamustine-related myelosuppression. In the phase 3 study of bendamustine in chronic lymphocytic leukemia, hemoglobin concentrations and leukocyte and differential counts were monitored weekly and platelet counts were monitored each cycle. Data from this study indicate that blood counts may be expected to reach a nadir during the third week of the treatment cycle; dose delays may be required if recovery to recommended values has not occurred by day 28. Prior to initiation of the next cycle of therapy, the absolute neutrophil count (ANC) should be at least 1000/cu mm and the platelet count at least 75,000/ cu mm.|Tumor lysis syndrome has been reported in patients receiving bendamustine in clinical trials and during postmarketing surveillance. The onset generally occurs during the first cycle of bendamustine therapy; without appropriate intervention, acute renal failure and death may occur. Appropriate measures (e.g., adequate hydration; close monitoring of blood chemistries, particularly potassium and uric acid concentrations; use of allopurinol during the first 1-2 weeks of bendamustine therapy) should be used in patients at high risk for tumor lysis syndrome.|Infusion reactions, including fever, chills, pruritus, and rash, occur commonly in patients receiving bendamustine. Severe anaphylactic and anaphylactoid reactions have occurred rarely, mainly in the second and subsequent cycles of therapy. Patients should be monitored clinically, and bendamustine should be discontinued if a severe reaction occurs. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. A premedication regimen (e.g., antihistamine, antipyretic, and corticosteroid) should be considered during subsequent treatment cycles in patients who experience grade 1 or 2 infusion reactions. Discontinuance of bendamustine therapy should be considered in patients who experience grade 3 or 4 infusion reactions. Patients who experienced grade 3 or worse allergic-type reactions typically were not rechallenged with the drug in the phase 3 study of bendamustine in chronic lymphocytic leukemia.|For more Drug Warnings (Complete) data for Bendamustine (15 total), please visit the HSDB record page.

No mean changes in QTc interval greater than 20 milliseconds were detected up to one hour post-infusion.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)

Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.|Mean recovery of total radioactivity in cancer patients following IV infusion of [14C] bendamustine hydrochloride was approximately 76% of the dose. Approximately 50% of the dose was recovered in the urine and approximately 25% of the dose was recovered in the feces. Urinary excretion was confirmed as a relatively minor pathway of elimination of bendamustine, with approximately 3.3% of the dose recovered in the urine as parent. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.|The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20-25 L. Steady-state volume of distribution for total radioactivity was approximately 50 L, indicating that neither bendamustine nor total radioactivity are extensively distributed into the tissues.|700 mL/min|... Preclinical radiolabeled bendamustine studies showed that approximately 90% of drug administered was recovered in excreta primarily in the feces. Bendamustine clearance in humans is approximately 700 mL/minute. After a single dose of 120 mg/sq m bendamustine IV over 1-hour the intermediate half life of the parent compound is approximately 40 minutes. The mean apparent terminal elimination half life of M3 and M4 are approximately 3 hours and 30 minutes respectively. Little or no accumulation in plasma is expected for bendamustine administered on Days 1 and 2 of a 28-day cycle.|In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and was concentration independent from 1-50 ug/mL. Data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 ug/mL indicating that bendamustine distributes freely in human red blood cells. In humans, the mean steady state volume of distribution (Vss) was approximately 25 L.

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10th and 1/100th that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine. Results of a human mass balance study confirm that bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways.|... The detection of mercapturic acid pathway metabolites of bendamustine, namely, cysteine S-conjugates in human bile, which are supposed to subsequently undergo further metabolism /was recently reported/.. In this study, ... the identification and quantitation of consecutive bendamustine metabolites occurring in human bile using authentic reference standards and the synthesis and structural confirmation of these compounds /is described/. Mass spectrometry data along with high-performance liquid chromatography retention data (fluorescence detection) of the synthetic reference standards were consistent with those of the metabolites found in human bile after administration of bendamustine hydrochloride to cancer patients. Analysis of the purified synthetic reference compounds showed a purity of at least 95%. Structural confirmation was achieved by one- and two-dimensional proton as well as carbon-13 NMR spectroscopy and mass spectrometry. A total of 16 bendamustine-related compounds were detected in the bile of patients, 11 of them were recovered as conjugates. Eight conjugates have been structurally confirmed as novel mercapturic acids and sulfoxides. Biliary excretion of the sulfoxides was twice that of the mercapturate precursors. Glutathione S-conjugates of bendamustine have not been detected in bile samples, indicating rapid enzymatic cleavage in humans. Both the lack of glutathione (GSH) conjugates and occurrence of diastereomeric sulfoxides emphasize species-related differences in the GSH conjugation of bendamustine between humans and rats. The total amount recovered in the bile as the sum of all conjugates over the period of 24 hr after dosing averaged 5.2% of the administered dose.|In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. In vitro, studies indicate that two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10 and 1/100 that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine. In vitro studies using human liver microsomes indicate that bendamustine does not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzymes in primary cultures of human hepatocytes.

40 minutes|After a single dose of 120 mg/sq m bendamustine IV over 1-hour the intermediate half life of the parent compound is approximately 40 minutes.

Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action is unknown.|Multiple myeloma is a fatal hematological disease caused by malignant transformation of plasma cells. Bendamustine has been proven to be a potent alternative to melphalan in phase 3 studies, yet its molecular mode of action is still poorly understood. The four-myeloma cell lines NCI-H929, OPM-2, RPMI-8226, and U266 were cultured in vitro. Apoptosis was measured by flow cytometry after annexin V FITC and propidium iodide staining. Cell cycle distribution of cells was determined by DNA staining with propidium iodide. Intracellular levels of (phosphorylated) proteins were determined by western blot. /It was shown/ that bendamustine induces apoptosis with an IC50 of 35-65 mug/ml and with cleavage of caspase 3. Incubation with 10-30 mug/ml results in G2 cell cycle arrest in all four-cell lines. The primary DNA-damage signaling kinases ATM and Chk2, but not ATR and Chk1, are activated. The Chk2 substrate Cdc25A phosphatase is degraded and Cdc2 is inhibited by inhibitory phosphorylation of Tyr15 accompanied by increased cyclin B levels. Additionally, p53 activation occurs as phosphorylation of Ser15, the phosphorylation site for ATM. p53 promotes Cdc2 inhibition by upregulation of p21. Targeting of p38 MAPK by the selective inhibitor SB202190 significantly increases bendamustine induced apoptosis. Additionally, SB202190 completely abrogates G2 cell cycle arrest. Bendamustine induces ATM-Chk2-Cdc2-mediated G2 arrest and p53 mediated apoptosis. Inhibition of p38 MAPK augments apoptosis and abrogates G2 arrest and can be considered as a new therapeutic strategy in combination with bendamustine.|Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.|Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. Then give the following specific treatment: Place a heating pad over the area and apply heat intermittently for 24 hours; elevate the limb. Local injection of hyaluronidase may be beneficial. Do not use ice packs. /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Bendamustine is an alkylating agent with hybrid activity and proven efficacy in small-cell lung cancer associated with a favorable toxicity rate. This phase II study of carboplatin/bendamustine was conducted to evaluate the efficacy of this combination in patients with extensive disease small-cell lung cancer. Fifty-six untreated patients with extensive disease small-cell lung cancer were enrolled. Their median age was 63 years. Sixty-seven percent of patients were male and 18% had a World Health Organization performance status of 2. Bendamustine was administered as a 30- to 60-minute infusion at a dose of 80 mg/m2 on days 1 and 2, and carboplatin was given at an area under the curve of 5 on day 1 of a 21-day cycle. Fifty-five patients were assessable for response and toxicity. The overall response rate was 72.7% (95% confidence interval: 59%-84%), with one complete remission (1.8%). The median time to progression was 5.2 months (95% confidence interval: 4.2-5.6). At the time of evaluation, 71% of the patients had died. The median survival time reached 8.3 months (95% confidence interval: 6.6-9.9). The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (46%), thrombopenia (26%), anemia (15%), and infections (11%). Toxic death was recorded in two patients (3.6%). The carboplatin/bendamustine regimen is a well-tolerated cytostatic combination in extensive disease small-cell lung cancer with activity comparable with that of other platinum-based regimens.|/SIGNS AND SYMPTOMS/ Infections, including pneumonia and sepsis, have been reported in patients receiving bendamustine and have been associated with hospitalization, septic shock, and death. Patients with myelosuppression have increased susceptibility to infection and should be advised to contact their clinician if signs or symptoms of infection occur.|/SIGNS AND SYMPTOMS/ Tumor lysis syndrome has been reported in patients receiving bendamustine in clinical trials and during postmarketing surveillance. The onset generally occurs during the first cycle of bendamustine therapy; without appropriate intervention, acute renal failure and death may occur. Appropriate measures (e.g., adequate hydration; close monitoring of blood chemistries, particularly potassium and uric acid concentrations; use of allopurinol during the first 1-2 weeks of bendamustine therapy) should be used in patients at high risk for tumor lysis syndrome.|For more Human Toxicity Excerpts (Complete) data for Bendamustine (7 total), please visit the HSDB record page.

bendamustin

Parenteral: For injection, for IV infusion only: 100 mg Treanda (Cephalon). /Bendamustine hydrochloride/

Approved for B-cell non-Hodgkin lymphoma

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients