HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`
`BELRAPZO safely and effectively. See full prescribing information for
`BELRAPZO.
`
`BELRAPZO™ (bendamustine hydrochloride injection), for intravenous
`use.
`
`Initial U.S. Approval: 2008
`
`
`
`
`-------------------------INDICATIONS AND USAGE-----------------------------
`
`
`BELRAPZO 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 progressed during
`
`
`or within six months of treatment with rituximab or a rituximab-containing
`
`
`regimen. (1.2)
`
`
`
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`For CLL:
`
`
`
` 100 mg/m2 infused intravenously over 30 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 60 minutes on Days 1 and 2 of a
`
`
`
`
`
`
` 21-day cycle, up to 8 cycles. (2.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`------------------------DOSAGE FORMS AND STRENGTHS-------------------
`Injection: 100 mg/4mL (25 mg/mL) in a multiple-dose vial. (3)
`
`
`---------------------------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 hydrochloride have included
`
`anaphylaxis and anaphylactoid reactions. (4, 5.3)
`
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
`
`
`
`
`
` Myelosuppression: Delay or reduce dose, and. restart treatment based on
`ANC and platelet count recovery. (2.1)
`Infections: Monitor for fever and other signs of infection or reactivation of
`
`
`infections and treat promptly. (5.2)
`
`
` Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have
`
`occurred. Monitor clinically and discontinue durg for severe reactions.
`
`
`
`Pre-medicate in subsequent cycles for milder reactions. (5.3)
`
`
`
`
`
`
` Tumor Lysis Syndrome: May lead to acute renal failure and death;
`
`anticipate and use supportive measures in patients at high risk. (5.4)
`
` Skin Reactions: Discontinue for severe skin reactions. Cases of SJS,
`
`DRESS and TEN, some fatal, have been reported. (5.5)
`
` Hepatotoxicity: Monitor liver chemistry tests prior to and during
`
`
`
`
`treatment. (5.6)
`
` Other Malignancies: Pre-malignant and malignant diseases have been
`
`reported. (5.7)
`
`
` Extravasation Injury: Take precautions to avoid extravasation, including
`
`monitoring intravenous infusion site during and after administration. (5.8)
`
`
` Embryo-fetal toxicity: Can cause fetal harm. Advise females of
`
`reproductive potential of the potential risk to a fetus and to use an
`effective method of contraception. (5.9, 8.1)
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
` Adverse reactions (frequency >5%) during infusion and within 24 hours
`
`
`
`post-infusion are nausea and fatigue. (6.1)
`
`
` Most common adverse reactions (≥15%) for CLL are anemia,
`
`
`thrombocytopenia, neutropenia, lymphopenia, leukopenia,
`
`
`
`
`hyperbilirubinemia, pyrexia, nausea, vomiting. (6.2, 6.3)
`
`
`
` Most common adverse reactions (≥15%) for NHL are lymphopenia,
`
`
`
`
`leukopenia, anemia neutropenia, thrombocytopenia, nausea, fatigue,
`
`
`
`
`
`vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache,
`
`
`
`
`weight decreased, dyspnea, rash, and stomatitis.(6.2, 6.3).
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Eagle
`
`Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or
`
`
`
`http://www.fda.gov/medwatch
`
`
`
`
`
`
`
`
`
`------------------------------DRUG INTERACTIONS-------------------------------
`Consider alternative therapies that are no CYP1A2 inducers or inhibitors
`
`
`
`during treament with BELRAPZO (7.1)
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
` Lactation: Advise not to breastfeed. (8.2)
`
`
`Infertility: May impair fertility. (8.3)
`
`
` Renal Impairment: Do not use in patients with creatinine clearance < 30
`mL/min. (8.6)
`
`
` Hepatic Impairment: Do not use in patients with total bilirubin 1.5-3 x
`
`ULN and AST or ALT 2.5-10 x ULN, or total bilirubin > 3 x ULN. (8.7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`Revised: 10/2019
`
`
` 
`8.4 Pediatric Use
` 
`8.5 Geriatric Use
` 
`8.6 Renal Impairment
` 
`8.7 Hepatic Impairment
` 
`10 OVERDOSAGE
`
` 
`11 DESCRIPTION
` 
`12 CLINICAL PHARMACOLOGY
` 
`12.1 Mechanism of Action
`
` 
`12.2 Pharmacodynamics
` 
`12.3 Pharmacokinetics
` 
`13 NONCLINICAL TOXICOLOGY
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
`14 CLINICAL STUDIES
` 
`14.1 Chronic Lymphocytic Leukemia (CLL)
` 
`14.2 Non-Hodgkin Lymphoma (NHL)
`
` 
`15 REFERENCES
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 
`16.1 Safe Handling and Disposal
` 
`16.2 How Supplied
` 
`16.3 Storage
` 
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS
` 
`1 INDICATIONS AND USAGE
` 
`1.1 Chronic Lymphocytic Leukemia (CLL)
` 
`1.2 Non-Hodgkin Lymphoma (NHL)
`
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
`2.1 Dosing Instructions for CLL
`
` 
`2.2 Dosing Instructions for NHL
`
` 
`2.3 Preparation for Intravenous Administration
`
` 
`2.4 Admixture Stability
` 
`2.5 Stability of Partially Used Vials (Needle Punched Vials)
` 
`3 DOSAGE FORMS AND STRENGTHS
`
`
` 
`4 CONTRAINDICATIONS
` 
`5 WARNINGS AND PRECAUTIONS
`
` 
`5.1 Myelosuppression
` 
`5.2 Infections
` 
`5.3 Anaphylaxis and Infusion Reactions
` 
`5.4 Tumor Lysis Syndrome
`
` 
`5.5 Skin Reactions
` 
`5.6 Hepatotoxicity
` 
`5.7 Other Malignancies
`
` 
`5.8 Extravasation Injury
` 
`5.9 Embryo-Fetal Toxicity
` 
`6 ADVERSE REACTIONS
` 
`6.1 Clinical Trials Experience
` 
`6.2 Clinical Trials Experience in CLL
` 
`6.3 Clinical Trials Experience in NHL
` 
`6.4 Postmarketing Experience
` 
`7 DRUG INTERACTIONS
` 
`7.1 Effect of Other Drugs on BELRAPZO
`
` 
`8 USE IN SPECIFIC POPULATIONS
` 
`8.1 Pregnancy
` 
`8.2 Lactation
` 
`8.3 Females and Males of Reproductive Potential
`
`
`Reference ID: 4513249
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Chronic Lymphocytic Leukemia (CLL)
`BELRAPZO is indicated for the treatment of patients with chronic lymphocytic leukemia.
`Efficacy relative to first line therapies other than chlorambucil has not been established.
`
`
`1.2 Non-Hodgkin Lymphoma (NHL)
`
`BELRAPZO is indicated for the treatment of patients with indolent B-cell non-Hodgkin
`lymphoma that has progressed during or within six months of treatment with rituximab or a
`
`rituximab-containing regimen.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Instructions for CLL
`Recommended Dosage:
`
`The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and
`
`2 of a 28-day cycle, up to 6 cycles.
`
`Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:
`Delay BELRAPZO administration in the event of Grade 4 hematologic toxicity or clinically
`significant Grade 2 or greater 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) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], reinitiate BELRAPZO at the
`
` discretion of the treating physician. In addition, consider dose reduction. [see Warnings and
`
` Precautions (5.1)]
`Dose 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.
`Dose 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 dose 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 60 minutes on Days 1 and
`
`2 of a 21-day cycle, up to 8 cycles.
`
`
`Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL:
`Delay BELRAPZO 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 1 and/or the blood counts have improved [Absolute Neutrophil Count
`(ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], reinitiate BELRAPZO at the discretion of the treating
`physician. In addition, consider dose reduction. [see Warnings and Precautions (5.1)]
`
`
`Reference ID: 4513249
`
`2
`
`

`

` Dose 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.
`
`Dose 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
` BELRAPZO is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
`
`BELRAPZO is in a multiple-dose vial. BELRAPZO is a clear and colorless to yellow solution.
`Store BELRAPZO at recommended refrigerated storage conditions (2° to 8°C or 36° to 46°F).
`When refrigerated the contents may partially freeze. Allow the vial to reach room temperature
`(15° to 30°C or 59° to 86°F) prior to use. Observe the contents of the vial for any visible solid or
`particulate matter. Do not use the product if solid or particulate matter is observed after reaching
`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 to a 500 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.
`-
`
`The resulting final concentration of bendamustine HCl in the infusion bag should be within
`0.2 – 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.
`
`Table A: Volume (mL) of BELRAPZO required for dilution into 500 mL of 0.9% Saline, or
`
`
` 0.45% Saline/2.5% Dextrose for a given dose (mg/m2) and Body Surface Area (m2)
`
`Body Surface Area (m2)
`
`
`
`Volume of BELRAPZO to withdraw (mL)
`
`1
`1.1
`
`1.2
`
`1.3
`1.4
`1.5
`
`1.6
`
`1.7
`
`120 mg/m2
`4.8
`5.3
`
`5.8
`
`6.2
`6.7
`7.2
`
`7.7
`
`8.2
`
`100
`
`
` mg/m2
`4
`4.4
`
`4.8
`
`5.2
`5.6
`6
`
`6.4
`
`6.8
`
`
`
` 90
`
` mg/m2
`3.6
`4
`
`4.3
`
`4.7
`5
`5.4
`
`5.8
`
`6.1
`
`
`
` 60
`
` mg/m2
`2.4
`2.6
`
`2.9
`
`3.1
`3.4
`3.6
`
`3.8
`
`4.1
`
`
`
` 50
`
` mg/m2
`2
`2.2
`
`2.4
`
`2.6
`2.8
`3
`
`3.2
`
`3.4
`
`
`
` 25
`
`
` mg/m2
`1
`1.1
`
`1.2
`
`1.3
`1.4
`1.5
`
`1.6
`
`1.7
`
`Reference ID: 4513249
`
`3
`
`

`

`Body Surface Area (m2)
`
`
`
`Volume of BELRAPZO to withdraw (mL)
`
`
` 1.8
`
`1.9
`2
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`2.7
`2.8
`2.9
`3
`
`120 mg/m2
`
` 8.6
`
`9.1
`9.6
`
`10.1
`
`10.6
`
`11
`
`11.5
`
`12
`12.5
`
`13
`13.4
`13.9
`14.4
`
`100
`
`
` mg/m2
` 7.2
`
`
`7.6
`8
`8.4
`8.8
`9.2
`9.6
`10
`10.4
`10.8
`11.2
`11.6
`12
`
`
`
` 90
`
` mg/m2
`
` 6.5
`
`6.8
`7.2
`7.6
`7.9
`8.3
`8.6
`9
`9.4
`9.7
`10.1
`10.4
`10.8
`
`
`
` 60
`
` mg/m2
`
` 4.3
`
`4.6
`4.8
`
`5
`5.3
`5.5
`5.8
`6
`6.2
`6.5
`6.7
`
`7
`7.2
`
`
`
` 50
`
` mg/m2
`
` 3.6
`
`3.8
`4
`4.2
`4.4
`4.6
`4.8
`5
`5.2
`5.4
`5.6
`5.8
`
`6
`
`
`
` 25
`
`
` mg/m2
`
` 1.8
`
`1.9
`2
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`2.7
`2.8
`2.9
`
`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
`
`BELRAPZO 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° to
`8°C or 36° to 46°F) or for 3 hours when stored at room temperature (15° to 30°C or 59° to 86°F)
`and room light. Administration of diluted BELRAPZO must be completed within this period of
`time.
`BELRAPZO (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° to 8°C
`or 36° to 46°F) if additional dose withdrawal from the same vial is intended.
`
`
`
`2.5 Stability of Partially Used Vials (Needle Punched Vials)
`BELRAPZO is supplied as a multiple-dose vial. Although it does not contain any antimicrobial
`preservative, BELRAPZO is bacteriostatic. The partially used vials are stable for up to 28 days
`when stored in its original carton under refrigeration (2° to 8°C or 36° 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 original carton at 2° to 8°C (36° to 46°F), and then
`discard after 28 days.
`
`Reference ID: 4513249
`
`4
`
`

`

` 3 DOSAGE FORMS AND STRENGTHS
`
`Injection: 100 mg/4 mL (25 mg/mL) as a clear and colorless to yellow ready-to dilute solution in
`
` a multiple-dose vial.
`
` 4 CONTRAINDICATIONS
`
`BELRAPZO 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 (5.3)]
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Myelosuppression
`
`Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in
`the two NHL studies (see Table 4). 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).
`BELRAPZO 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 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. [see Dosage and Administration (2.1) and (2.2)]
`
`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. Patients with myelosuppression following treatment with bendamustine
`hydrochloride 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 BELRAPZO 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 Anaphylaxis and Infusion Reactions
`Infusion reactions to bendamustine hydrochloride 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
`
`Reference ID: 4513249
`
`5
`
`

`

`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.
`
`
`5.4 Tumor Lysis Syndrome
`Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in
`clinical trials and in post-marketing reports. 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 (5.5)]
`
`5.5 Skin Reactions
`Fatal and serious skin reactions have been reported with bendamustine hydrochloride 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 hydrochloride 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.
`
`5.6 Hepatotoxicity
`Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride
`injection. 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 BELRAPZO therapy.
`
`5.7 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 and bronchial carcinoma. The association
`with bendamustine hydrochloride therapy has not been determined.
`
`5.8 Extravasation Injury
`
`Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in
`hospitalizations from erythema, marked swelling, and pain. Assure 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.
`
`
`Reference ID: 4513249
`
`6
`
`

`

`5.9 Embryo-Fetal Toxicity
`Based on findings from animal reproduction studies and the drug’s mechanism of action,
`
`
`BELRAPZO 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 BELRAPZO and for at least 6 months after the final dose. Advise males
`with female partners of reproductive potential to use effective contraception during treatment
`with BELRAPZO and for at least 3 months after the final dose. [see Use in Specific Populations
`
`
`(8.1, 8.3) and Clinical Pharmacology (12.1)]
`
`
`6 ADVERSE REACTIONS
`The following clinically significant serious adverse reactions are discussed in greater detail in
`other sections of the prescribing information.
`
` Myelosuppression [see Warnings and Precautions (5.1)]
`
`
`Infections [see Warnings and Precautions (5.2)]
`
`
`
` Anaphylaxis and Infusion Reactions[see Warnings and Precautions (5.3)]
`
`
` Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
`
`
` Skin Reactions [see Warnings and Precautions (5.5)]
`
`
` Hepatotoxicity [see Warnings and Precautions (5.6)]
`
`
` Other Malignancies [see Warnings and Precautions (5.7)]
`
`
`
`
` Extravasation Injury [see Warnings and Precautions (5.8)]
`
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice.
`
`
`6.2 Clinical Trials Experience in CLL
`The data described below reflect exposure to bendamustine hydrochloride in 153 patients.
`Bendamustine hydrochloride was studied in an active-controlled, randomized trial. The
`population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All
`patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2
`every 28 days.
`Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical
`study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group
`that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and
`vomiting (16%).
`
`Reference ID: 4513249
`
`7
`
`

`

`Other adverse reactions seen frequently in one or more studies included asthenia, fatigue,
`malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal
`inflammation and stomatitis.
`
`Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in
`the randomized CLL clinical study and in none treated with chlorambucil. Three of these 4
`adverse reactions were described as a hypertensive crisis and were managed with oral
`medications and resolved.
`The most frequent adverse reactions leading to study withdrawal for patients receiving
`bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%).
`Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were
`reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.
`Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical
`Study in at Least 5% of Patients
`
`
`
`Number (%) of patients
`
`
`Bendamustine Hydrochloride
`(N=153)
`
`Grade 3/4
`
`
`All Grades
`
`
`Body System
`Adverse Reaction
`
`Total number of patients
`
`
`with at least 1 adverse
`reaction
`
`Gastrointestinal disorders
`
` Nausea
`
` Vomiting
`
` Diarrhea
`General disorders and
`administration site
`conditions
`
`
` Pyrexia
`
` Fatigue
` Asthenia
` Chills
`Immune system disorders
`
`
` Hypersensitivity
`Infections and infestations
`
`
`
` Nasopharyngitis
` Infection
`
` Herpes simplex
`Investigations
`
` Weight decreased
`
`Metabolism and nutrition
`disorders
`
` Hyperuricemia
`
`Respiratory, thoracic and
`mediastinal disorders
`
` Cough
`
`Skin and subcutaneous
`tissue disorders
`
`
` Rash
`
`Reference ID: 4513249
`
`Chlorambucil
`(N=143)
`
`All Grades
`
`
`
`Grade 3/4
`
`
`121 (79)
`
`
`
`31 (20)
`
` 24 (16)
`14 (9)
`
`
`36 (24)
`14 (9)
`13 (8)
`9 (6)
`
`7 (5)
`
`
` 10 (7)
`
`9 (6)
`5 (3)
`
`
`(7)
`
`
` 11
`
`11 (7)
`
`
`
` 6 (4)
`
`
`12 (8)
`
`52 (34)
`
`
`
`1 (<1)
`1 (<1)
`2 (1)
`
`
` 6 (4)
`
`2 (1)
`0
`0
`
`
`
` 2 (1)
`
`0
`3 (2)
`0
`
`
`
` 0
`
`
`3 (2)
`
`
`1 (<1)
`
`
`4 (3)
`
`8
`
`96 (67)
`
`
`
`21 (15)
`9 (6)
`
`5 (3)
`
`
`8 (6)
`
` 8 (6)
`
`6 (4)
`1 (<1)
`
`3 (2)
`
`12 (8)
`
`1 (<1)
`7 (5)
`
` 5
`
`
` (3)
`
`
`
` 2 (1)
`
`
`7 (5)
`
`
`
`7 (5)
`
`25 (17)
`
`
`1 (<1)
`0
`0
`
`
` 2 (1)
`
`0
`0
`0
`
`0
`
`0
`
`1 (<1)
`0
`
`
`
` 0
`
`
`0
`
`
`
` 1 (<1)
`
`
`3 (2)
`
`
`
`

`

`Number (%) of patients
`
`
`Bendamustine Hydrochloride
`(N=153)
`
`8 (5)
`
`0
`
`0
`
`Chlorambucil
`(N=143)
`
`
`2 (1)
`
`
`
`
` Pruritus
`
`Laboratory
`
`Abnormality
`
`
`
`Hemoglobin
`
`Decreased
`Platelets
`
`Decreased
`
`Leukocytes
`
`Decreased
`
`Lymphocytes
`
`Decreased
`Neutrophils
`
`Decreased
`
`
`The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL
`clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen
`in patients treated with bendamustine hydrochloride. Red blood cell transfusions were
`administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of
`patients receiving chlorambucil.
`Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received
`Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study
`Chlorambucil
`Bendamustine Hydrochloride N=150
`
`
`N=141
`
`
`All Grades
`Grade 3/4
`
`
`n (%)
`n (%)
`
`
`
`
`134 (89)
`20 (13)
`
`All Grades
`
`n (%)
`
`
`115 (82)
`
`
`Grade 3/4
`
`n (%)
`
`12 (9)
`
`
`116 (77)
`
`
`92 (61)
`
`
`102 (68)
`
`
`113 (75)
`
`
`
`16 (11)
`
`
`42 (28)
`
`
`
`70 (47)
`
`
`
`65 (43)
`
`
`
`110 (78)
`
`
`26 (18)
`
`
`
`27 (19)
`
`
`
`86 (61)
`
`
`14 (10)
`
`
`4 (3)
`
`
`
`6 (4)
`
`
`
`30 (21)
`
`
`In the randomized CLL trial, 34% of patients had bilirubin elevations, some without associated
`significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of
`patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients,
`respectively. Patients treated with bendamustine hydrochloride may also have changes in their
`creatinine levels. If abnormalities are detected, monitoring of these parameters should be
`continued to ensure that further deterioration does not occur.
`
`6.3 Clinical Trials Experience in NHL
`The data described below reflect exposure to bendamustine hydrochloride in 176 patients with
`
`indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age,
`60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1%
`other, and <1% Asian. These patients received bendamustine hydrochloride at a dose of 120
`mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.
`The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are
`shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea
`(75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common
`non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia
`(6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.
`
`Reference ID: 4513249
`
`9
`
`

`

`Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients
`Treated with Bendamustine Hydrochloride by System Organ Class and Preferred Term
`(N=176)
` Body System
`
`
`Adverse Reaction
`Total number of patients with at
`
`least 1 adverse reaction
`
`Cardiac Disorders
`
` Tachycardia
`Gastrointestinal disorders
`
` Nausea
`
`
` Vomiting
` Diarrhea
`
` Constipation
`
`
` Stomatitis
` Abdominal pain
` Dyspepsia
` Gastroesophageal reflux disease
`
` Dry mouth
`
` Abdominal pain upper
` Abdominal distension
`
`
`General disorders and administration site conditions
` Fatigue
` Pyrexia
`
` Chills
`
`
` Edema peripheral
` Asthenia
`
` Chest pain
`
`
` Infusion site pain
`
`
` Pain
`
`
` Catheter site pain
`Infections and infestations
`
` Herpes zoster
`
`
` Upper respiratory tract infection
`
`
` Urinary tract infection
` Sinusitis
`Pneumonia
`
`
` Febrile neutropenia
` Oral candidiasis
` Nasopharyngitis
`Investigations
`
` Weight decreased
`Metabolism and nutrition disorders
`
` Anorexia
`
` Dehydration
`
`
` Decreased appetite
` Hypokalemia
`
`Musculoskeletal and connective tissue disorders
`
`
` Back pain
` Arthralgia
`
`
`
`
`
`Reference ID: 4513249
`
`10
`
` Number (%) of patients*
`
`
`
`All Grades
`Grade 3/4
`176 (100)
`94 (53)
`
`
`
`
`13 (7)
`
`
`132 (75)
`
`71 (40)
`
`65 (37)
`
`51 (29)
`
`27 (15)
`
`22 (13)
`
`20 (11)
`
`18 (10)
`
`15 (9)
`
`8 (5)
`
`8 (5)
`
`
`101 (57)
`
`59 (34)
`
`24 (14)
`
`23 (13)
`
`19 (11)
`
`11 (6)
`
`11 (6)
`
`10 (6)
`
`8 (5)
`
`
`18 (10)
`
`18 (10)
`
`17 (10)
`
`15 (9)
`
`14 (8)
`
`11 (6)
`
`11 (6)
`
`11 (6)
`
`
`31 (18)
`
`
`40 (23)
`
`24 (14)
`
`22 (13)
`
`15 (9)
`
`
`25 (14)
`
`11 (6)
`
`0
`
`
`7 (4)
`
`5 (3)
`
`6 (3)
`
`1 (<1)
`
`1 (<1)
`
`2 (1)
`
`0
`
`0
`
`1 (<1)
`0
`0
`
`
`19 (11)
`
`3 (2)
`
`0
`
`1 (<1)
`
`4 (2)
`
`1 (<1)
`0
`0
`0
`
`
`5 (3)
`
`0
`
`4 (2)
`0
`
`9 (5)
`
`11 (6)
`
`2 (1)
`0
`
`
`3 (2)
`
`
`3 (2)
`
`8 (5)
`
`1 (<1)
`
`9 (5)
`
`
`5 (3)
`0
`
`

`

` Number (%) of patients*
`
`
`
`All Grades
`Grade 3/4
`8 (5)
`2 (1)
`
`
`
`8 (5)
`0
`
` Body System
`
`
`Adverse Reaction
` Pain in extremity
`
`
`
`
`
` Bone pain
`
`Nervous system disorders
`
` Headache
` Dizziness
` Dysgeusia
`Psychiatric disorder
`
` Insomnia
` Anxiety
` Depression
`
`
`Respiratory, thoracic and mediastinal disorders
`
`
` Cough
` Dyspnea
`
` Pharyngolaryngeal pain
`
` Wheezing
` Nasal congestion
`
`Skin and subcutaneous tissue disorders
`
`
`
` Rash
`
`
` Pruritus
`
`
` Dry skin
`
`
` Night sweats
`
`
` Hyperhidrosis
`Vascular disorders
`
`
` Hypotension
`
`
`
`*Patients may have reported more than 1 adverse reaction.
`
`
`NOTE: Patients counted only once in each preferred term category and once in each system organ class category
`
`
`
`
`
`
`
`Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in
`
` both single arm studies combined are described in Table 4. Clinically important chemistry
`laboratory values that were new or worsened from baseline and occurred in >1% of patients at
`
` Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia
`(3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).
`
`Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received
`Bendamustine Hydrochloride in the NHL Studies
`
`
`36 (21)
`
`25 (14)
`
`13 (7)
`
`
`23 (13)
`
`14 (8)
`
`10 (6)
`
`
`38 (22)
`
`28 (16)
`
`14 (8)
`
`8 (5)
`
`8 (5)
`
`
`28 (16)
`
`11 (6)
`
`9 (5)
`
`9 (5)
`
`8 (5)
`
`
`10 (6)
`
`
`0
`
`0
`0
`
`
`0
`
`1 (<1)
`0
`
`
`1 (<1)
`
`3 (2)
`
`1 (<1)
`0
`0
`
`
`1 (<1)
`0
`0
`0
`
`0
`
`
`2 (1)
`
`
`
` Hematology Variable
`
`Lymphocytes Decreased
`
`Leukocytes Decreased
`Hemoglobin Decreased
`
`Neutrophils Decreased
`Platelets Decreased
`
`
`
` Percent of Patients
`
`All Grades
`
`99
`
`94
`88
`
`86
`86
`
`Grade 3/4
`
`94
`
`56
`11
`
`60
`25
`
`
`In both studies, serious adverse reactions, regardless of causality, were reported in 37% of
`patients receiving bendamustine hydrochloride. The most common serious adverse reactions
`occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious
`
`Reference ID: 4513249
`
`11
`
`

`

`adverse reactions reported in clinical trials and/or post-marketing experience were acute renal
`failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic
`syndrome.
`Serious drug-related adverse reactions reported in clinical trials included myelosuppression,
`
`infection, pneumonia, tumor lysis syndrome and infusion reactions. [see Warnings and
`Precautions (5)] Adverse reactions occurring less frequently but possibly related to
`bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical
`pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.
`
`6.4 Postmarketing Experience
`The following adverse reactions have been identified duri