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Prescribing Information

Dose modifications

Toxicity grade On Days 1 and 2,
reduce dose to*
Hematologic toxicity Initial ≥3 50 mg/m2
Recurrence ≥3 25 mg/m2
Non-hematologic toxicity ≥3 50 mg/m2

*Dose re-escalation may be considered.

General dosing considerations

  • Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 non-hematologic toxicity
  • Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109 /L, platelets ≥ 75 x 109 /L], BELRAPZO can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted.
  • Concomitant CYP1A2 inducers or inhibitors have the potential to affect the exposure of  Bendamustine
  • BELRAPZO® should not be used in patients with creatinine clearance (CrCL) less than 30 mL/min
  • BELRAPZO® should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin greater than 3 X ULN) hepatic impairment

Dose adjustment and treatment monitoring

Delay treatment for Grade 4 hematologic toxicity or clinically significant Grade 2 or greater non-hematologic toxicity. In the event that myelosuppression occurs, dose delays and/or dose reductions may be needed if recovery to the recommended values has not been met by the first day of the next scheduled cycle.

It is important to monitor patients closely in the event that an infusion reaction occurs. Fatal and serious skin reactions have been reported. In rare cases, severe anaphylactic and anaphylactoid reactions have occurred, specifically in the second and subsequent cycles of therapy.

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed 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.

Prepare when needed
BELRAPZO® is supplied as a ready-to-dilute solution

The final admixture is stable for

24 hours

when refrigerated
(2°C to 8°C or 36°F to 46°F)

or

3 hours

when stored at room temperature
(15°C to 30°C or 59°F to 86°F)

Multiple-dose vial

Partially used vials are


stable for up to 28 days

when stored in their original cartons under refrigeration
(2°C to 8°C or 36°F to 46°F)

Two diluent options

Volume of BELRAPZO® to withdraw
Body Surface Area (m2) Volume (mL) of BELRAPZO® required
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

indications

BELRAPZO® (bendamustine hydrochloride injection) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

BELRAPZO® (bendamustine hydrochloride injection) is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

important safety information

Contraindications: BELRAPZO® is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. Reactions to bendamustine HCl have included anaphylaxis and anaphylactoid reactions.

Myelosuppression: Bendamustine HCl caused severe myelosuppression (Grade 3-4) in 98% of patients in the 2 NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. 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 absolute neutrophil count (ANC) should be ≥1 x 109/L and the platelet count should be ≥75 x 109/L.

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 HCl. Patients with myelosuppression following treatment with bendamustine HCl are more susceptible to infections. Advise patients with myelosuppression following BELRAPZO® treatment to contact a physician immediately if they have symptoms or signs of infection. Patients treated with bendamustine HCl 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.

Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine HCl have occurred commonly in clinical trials. 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 experience Grade 3 or worse allergic-type reactions should not be 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 BELRAPZO® for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine HCl has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of bendamustine HCl 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 HCl therapy. However, there may be an increased risk of severe skin toxicity when bendamustine HCl and allopurinol are administered concomitantly.

Skin Reactions: Fatal and serious skin reactions have been reported with bendamustine HCl 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. Events occurred when bendamustine HCl 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 BELRAPZO®.

Hepatotoxicity: Fatal and serious cases of liver injury have been reported with bendamustine HCl. Combination therapy, progressive disease, or reactivation of hepatitis B were confounding factors in some patients. Most cases were reported within the first 3 months of starting therapy. Monitor liver chemistry tests prior to and during BELRAPZO® therapy.

Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine HCl, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma.

Extravasation Injury: Bendamustine HCl extravasations resulting in hospitalizations from erythema, marked swelling, and pain have been reported in postmarketing. Ensure good venous access prior to starting BELRAPZO® infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BELRAPZO®.

Embryo-fetal Toxicity: Bendamustine HCl can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise women to avoid becoming pregnant while using BELRAPZO®.

Most Common Adverse Reactions

TO REPORT ADVERSE REACTIONS, contact Eagle Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Please see full Prescribing Information, including Dosing and Administration for BELRAPZO®.