BENTERO

Bendamustine is a nitrogen mustard drug which has been used in the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL).

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.

Bendamustine is indicated for use in the treatment of indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

The indication for chronic lymphocytic leukemia (CLL) was removed from the US drug label in April 2024.

No mean changes in

QTc interval greater than 20 milliseconds were detected up to one hour post-infusion.

Following a single Intravenous dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion.

The dose proportionality of bendamustine has not been studied.

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.

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.

Hover over products below to view reaction partners Bendamustine γ-hydroxybendamustine (Bendamustine metabolite M3) N-desmethyl-bendamustine (Bendamustine metabolite M4) monohydroxy-bendamustine (bendamustine metabolite HP1) dihydroxy-bendamustine (bendamustine metabolite HP2).

Mean recovery of total radioactivity in cancer patients following Intravenous infusion of 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.

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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.

Bendamustine hydrochloride injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, absolute ethanol, sodium hydroxide and monothioglycerol.

Bendamustine hydrochloride injection is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, absolute ethanol, sodium hydroxide and monothioglycerol.

Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions.

• 120 mg/m 2 infused intravenously over 60 minutes on Days and 2 of a 21-day cycle, up to 8 cycles 2.1 Dosing Instructions for NHL Recommended Dosage: The recommended dosage is 120 mg/m 2 administered intravenously over 60 minutes on Days and 2 of a 21-day cycle, up to 8 cycles.

Delays, Dosage Modifications and Reinitiation of Therapy for NHL: Delay bendamustine hydrochloride injection administration in the event of a Grade 4 hematologic toxicity or clinically significant greater or equal to Grade 2 non-hematologic toxicity.

Once non-hematologic toxicity has recovered to ≤ Grade and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 10 9 /L, platelets ≥ 75 x 10 9 /L], reinitiate bendamustine hydrochloride injection at the discretion of the treating physician.

In addition, consider dose reduction.

Dosage modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m on Days and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m on Days and 2 of each cycle.

Dosage modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m on Days and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m on Days and 2 of each cycle. 2.2 Preparation for Intravenous Administration Bendamustine hydrochloride injection is a hazardous drug.

Follow applicable special handling and disposal procedures.

Bendamustine hydrochloride injection is in a multiple-dose vial.

Bendamustine hydrochloride injection is a clear and colorless to yellow solution.

Store bendamustine hydrochloride injection at recommended refrigerated storage conditions (2°C to 8°C or 36°F to 46°F).

When refrigerated the contents may freeze.

Allow the vial to reach room temperature (15°C to 30°C or 59°F to 86°F) prior to use.

Observe the contents of the vial for any visible solid or particulate matter and discoloration.

Do not use the product if solid or particulate matter is observed after reaching room temperature.

• 2.5% Dextrose/0.45% Sodium Chloride Injection, USP.

The resulting final concentration of bendamustine hydrochloride injection in the infusion bag should be within 0.05 mg/mL to 0.7 mg/mL.

After transferring, thoroughly mix the contents of the infusion bag.

The admixture should be a clear and colorless to slightly yellow solution.

Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above.

No other diluents have been shown to be compatible.

Volume (mL) of Bendamustine Hydrochloride Injection required for dilution into 500 mL of 0.9% Sodium Chloride Injection, USP, or 0.45% Sodium Chloride/2.5% Dextrose Injection, USP for a given dose (mg/m 2 ) and Body Surface Area (m 2 ) Body Surface Area (m 2 ) Volume of Bendamustine Hydrochloride Injection to withdraw (mL) 120 mg/m 2 90 mg/m 2 60 mg/m 2 1 4.8 3.6 2.4 1.1 5.3 4 2.6 1.2 5.8 4.3 2.9 1.3 6.2 4.7 3.1 1.4 6.7 5 3.4 1.5 7.2 5.4 3.6 1.6 7.7 5.8 3.8 1.7 8.2 6.1 4.1 1.8 8.6 6.5 4.3 1.9 9.1 6.8 4.6 2 9.6 7.2 4.8 2.1 10.1 7.6 5 2.2 10.6 7.9 5.3 2.3 11 8.3 5.5 2.4 11.5 8.6 5.8 2.5 12 9 6 2.6 12.5 9.4 6.2 2.7 13 9.7 6.5 2.8 13.4 10.1 6.7 2.9 13.9 10.4 7 3 14.4 10.8 7.2 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.3 Admixture Stability Bendamustine hydrochloride injection contains no antimicrobial preservative.

The admixture should be prepared as close as possible to the time of patient administration.

If diluted with 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2°C to 8°C or 36°F to 46°F) or for 3 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light.

Administration of diluted bendamustine hydrochloride injection must be completed within this period of time.

Bendamustine hydrochloride injection is supplied in a multiple-dose vial.

Retain the partially used vial in original package to protect from light and store refrigerated (2°C to 8°C or 36°F to 46°F) if additional dose withdrawal from the same vial is intended. 2.4 Stability of Partially Used Vials (Needle Punched Vials) Bendamustine hydrochloride injection is supplied as a multiple-dose vial.

Although it does not contain any antimicrobial preservative, bendamustine hydrochloride injection is bacteriostatic.

The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2°C to 8°C or 36°F to 46°F).

Each vial is not recommended for more than a total of six dose withdrawals.

After first use, store the partially used vial in original carton at 2°C to 8°C (36°F to 46°F), and then discard after 28 days.

Bendamustine hydrochloride injection is a hazardous drug.

Follow applicable special handling and disposal procedures 1.

Care should be exercised in the handling and preparation of solutions prepared from bendamustine hydrochloride injection.

The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.

If gloves come in contact with bendamustine hydrochloride injection prior to dilution, remove gloves and follow disposal procedures 1.

If a solution of bendamustine hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water.

If bendamustine hydrochloride injection contacts the mucous membranes, flush thoroughly with water.

Bendamustine hydrochloride injection is supplied in individual cartons of clear multiple-dose vials containing 100 mg of bendamustine hydrochloride as a clear, and colorless to yellow solution.

NDC 60505-6228-0: 100 mg/4 mL (25 mg/mL).

Store bendamustine hydrochloride injection in refrigerator, 2ºC to 8ºC (36ºF to 46ºF).

Retain in original carton until contents are used to protect from light.

In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth.

There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m 2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights.

This dose did not appear to be maternally toxic and lower doses were not evaluated.

Repeat intraperitoneal administration of bendamustine hydrochloride in mice on gestation days to 11 resulted in an increase in resorptions from 75 mg/m 2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m 2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration.

Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses.

A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.

Safety and effectiveness in pediatric patients have not been established.

Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged to 19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML).

Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days and 2 of each 21-day cycle.

There was no treatment response (CR+ CRp) in any patient.

The safety profile in these patients was consistent with that seen in adults, and no new safety signals were identified.

The pharmacokinetics of bendamustine in 43 patients, aged to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area.

No overall differences in safety were observed between patients ≥65 years of age and younger patients.

No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.