Bendeka Injection, Solution Uses, Dosage & Side Effects

Uses and indications

BENDEKA 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. (1.1) • Indolent B-cell non-Hodgkin lymphoma (NHL) that has…

Contraindications

BENDEKA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. [see Warnings and Precautions (5.4)]

Side effects

The following clinically significant adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the prescribing information. Myelosuppression [see Warnings and Precautions (5.1)] Infections…

Precautions

• Myelosuppression: Delay or reduce dose, and restart treatment based on ANC and platelet count recovery. (2.1, 5.1) • Infections: Monitor for fever and other signs of infection or reactivation of infections and treat promptly. (5.2) • Progressive multifocal leukoencephalopathy…

• Myelosuppression: Delay or reduce dose, and restart treatment based on ANC and platelet count recovery. (2.1, 5.1)

• Infections: Monitor for fever and other signs of infection or reactivation of infections and treat promptly. (5.2)

• Progressive multifocal leukoencephalopathy (PML): Monitor for new or worsening neurological, cognitive or behavioral signs or symptoms suggestive of PML. (5.3)

• Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have occurred. Monitor clinically and discontinue drug for severe reactions. Pre-medicate in subsequent cycles for milder reactions. (5.4)

• Tumor Lysis Syndrome: May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk. (5.5)

• Skin Reactions: Discontinue for severe skin reactions. Cases of SJS, DRESS and TEN, some fatal, have been reported. (5.6).

• Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment. (5.7)

• Other Malignancies: Pre-malignant and malignant diseases have been reported. (5.8)

• Extravasation Injury: Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration. (5.9)

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. (5.10, 8.1, 8.3) 5.1 Myelosuppression

Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies [see Adverse Reactions (6.1)]. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

BENDEKA causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs occurred predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L.

[see Dosage and Administration (2.1)] 5.2 Infections

Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride [see Adverse Reactions (6.1, 6.2)]. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following BENDEKA treatment to contact a physician immediately if they have symptoms or signs of infection.

Patients treated with BENDEKA are at 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. 5.3 Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab [see Adverse Reactions (6.2)]. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold BENDEKA treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.4 Anaphylaxis and Infusion Reactions

Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials [see Adverse Reactions (6.1)]. Symptoms include fever, chills, pruritus and rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue BENDEKA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.5 Tumor Lysis Syndrome

Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in postmarketing reports [see Adverse Reactions (6.1)]. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.

[see Warnings and Precautions (5.6)

] 5.6 Skin Reactions

Fatal and serious skin reactions have been reported with bendamustine hydrochloride injection treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash [see Adverse Reactions (6.1 and 6.2)]. Events occurred when bendamustine hydrochloride injection was given as a single agent and in combination with other anticancer agents or allopurinol.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue BENDEKA. 5.7 Hepatotoxicity

Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection [see Adverse Reactions (6.1)]. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients [see Warnings and Precautions (5.2)]. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during BENDEKA therapy. 5.8 Other Malignancies

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma [see Adverse Reactions (6.2)].

Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with BENDEKA. 5.9 Extravasation Injury

Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain [see Adverse Reactions (6.2)]. Assure good venous access prior to starting drug infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BENDEKA. 5.10 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and the drug’s mechanism of action, BENDEKA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with BENDEKA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for 3 months after the last dose.

[see (Use in Specific Populations 8.1, 8.3) and Clinical Pharmacology (12.1)

]

Dosage

For CLL: • 100 mg/m2 infused intravenously over 10 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. (2.1) For NHL: • 120 mg/m2 infused intravenously over 10 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. (2.2) 2.1 Dosing Instructions for CLL Recommended…

For CLL: • 100 mg/m2 infused intravenously over 10 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. (2.1) For NHL: • 120 mg/m2 infused intravenously over 10 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. (2.2) 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dosage is 100 mg/m2 administered intravenously over 10 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dosage Modifications and Reinitiation of Therapy for CLL: Delay BENDEKA administration in the event of Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) greater than or equal to 1 x 109/L, platelets greater than or equal to 75 x 109/L], reinitiate BENDEKA (bendamustine hydrochloride) injection at the discretion of the treating physician. In addition, consider dose reduction. [see Warnings and Precautions (5.1)] Dosage modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dosage modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Consider dosage re-escalation in subsequent cycles at the discretion of the treating physician. 2.2 Dosing Instructions for NHL Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 10 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dosage Modifications and Reinitiation of Therapy for NHL: Delay BENDEKA administration in the event of a Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) greater than or equal to 1 x 109/L, platelets greater than or equal to 75 x 109/L], reinitiate BENDEKA at the discretion of the treating physician. In addition, consider dose reduction. [see Warnings and Precautions (5.1)] Dosage modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dosage modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. 2.3 Preparation for Intravenous Administration BENDEKA is a hazardous drug. Follow applicable special handling and disposal procedures.1 BENDEKA is in a multiple-dose vial. At room temperature, BENDEKA is a clear, and colorless to yellow ready-to-dilute solution. Store BENDEKA 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. Do not use the product if particulate matter is observed after achieving room temperature. Intravenous Infusion • Aseptically withdraw the volume needed for the required dose from the 25 mg/mL solution as per Table A below and immediately transfer the solution to a 50 mL infusion bag of one of the following diluents: • – 0.9% Sodium Chloride Injection, USP; or • – 2.5% Dextrose/0.45% Sodium Chloride Injection, USP; or • – 5% Dextrose Injection, USP. The resulting final concentration of bendamustine hydrochloride in the infusion bag should be within 0.49 mg/mL to 5.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear, and colorless to yellow solution. No other diluents have been shown to be compatible. The 5% Dextrose Injection, USP, offers a sodium-free method of administration for patients with certain medical conditions requiring restricted sodium intake. Table A: Volume (mL) of BENDEKA required for dilution into 50 mL of 0.9% saline, or 0.45% saline/2.5% dextrose or 5% dextrose for a given dose (mg/m2) and Body Surface Area (m2) Body Surface Area (m2) Volume of BENDEKA to withdraw (mL) 120 mg/m2 100 mg/m2 90 mg/m2 60 mg/m2 50 mg/m2 25 mg/m2 1 4.8 4 3.6 2.4 2 1 1.1 5.3 4.4 4 2.6 2.2 1.1 1.2 5.8 4.8 4.3 2.9 2.4 1.2 1.3 6.2 5.2 4.7 3.1 2.6 1.3 1.4 6.7 5.6 5 3.4 2.8 1.4 1.5 7.2 6 5.4 3.6 3 1.5 1.6 7.7 6.4 5.8 3.8 3.2 1.6 1.7 8.2 6.8 6.1 4.1 3.4 1.7 1.8 8.6 7.2 6.5 4.3 3.6 1.8 1.9 9.1 7.6 6.8 4.6 3.8 1.9 2 9.6 8 7.2 4.8 4 2 2.1 10.1 8.4 7.6 5 4.2 2.1 2.2 10.6 8.8 7.9 5.3 4.4 2.2 2.3 11 9.2 8.3 5.5 4.6 2.3 2.4 11.5 9.6 8.6 5.8 4.8 2.4 2.5 12 10 9 6 5 2.5 2.6 12.5 10.4 9.4 6.2 5.2 2.6 2.7 13 10.8 9.7 6.5 5.4 2.7 2.8 13.4 11.2 10.1 6.7 5.6 2.8 2.9 13.9 11.6 10.4 7 5.8 2.9 3 14.4 12 10.8 7.2 6 3 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. 2.4 Admixture Stability BENDEKA contains no antimicrobial preservative. Prepare the admixture 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 6 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light. Administration of diluted BENDEKA (bendamustine hydrochloride) injection must be completed within this period of time. In the event that 5% Dextrose Injection, USP is utilized, the final admixture is stable for 24 hours when stored refrigerated (2°C to 8°C or 36°F to 46°F) or for only 3 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light. Administration of diluted BENDEKA must be completed within this period of time. 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. 2.5 Stability of Partially Used Vials (Needle Punched Vials) BENDEKA is supplied in a multiple-dose vial. Although it does not contain any antimicrobial preservative, BENDEKA 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°C to 46°F). Each vial is not recommended for more than a total of six (6) dose withdrawals. After first use, store the partially used vial in the refrigerator in the original carton at 2°C to 8°C or 36°F to 46°F and then discard after 28 days.

Injection: 100 mg/4 mL (25 mg/mL) as a clear and colorless to yellow ready-to-dilute solution in a multiple-dose vial.

Drug interactions

Consider alternative therapies that are not CYP1A2 inducers or inhibitors during treatment with BENDEKA. (7.1) 7.1 Effect of Other Drugs on BENDEKA CYP1A2 Inhibitors The coadministration of BENDEKA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may…

References

Source: DailyMed, U.S. National Library of Medicine. Additional information compiled from online sources.