РОЗУСТИН

Chronic Lymphocytic Leukemia (CLL)

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

Non-Hodgkin Lymphoma (NHL)

РОЗУСТИН (bendamustine hydrochloride) injection 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.

Dosing Instructions For CLL

Recommended Dosage

The recommended dose 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, Dose Modifications And Reinitiation Of Therapy For CLL

РОЗУСТИН (bendamustine hydrochloride) injection administration should be delayed 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], РОЗУСТИН (bendamustine hydrochloride) injection can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted.

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.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

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, Dose Modifications And Reinitiation Of Therapy For NHL

РОЗУСТИН (bendamustine hydrochloride) injection administration should be delayed 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], РОЗУСТИН (bendamustine hydrochloride) injection can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted.

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.

Preparation For Intravenous Administration

РОЗУСТИН (bendamustine hydrochloride) injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

РОЗУСТИН is in a multiple-dose vial. At room temperature, РОЗУСТИН is a clear, and colorless to yellow ready-to-dilute solution. Store РОЗУСТИН at recommended refrigerated storage conditions (2-8°C or 36-46° F). When refrigerated, the contents may partially freeze. Allow the vial to reach room temperature (15-30°C or 59-86°F) prior to use. If particulate matter is observed after achieving room temperature, the product should not be used.

Intravenous Infusion

• Aseptically withdraw the volume needed for the required dose from the 25 mg/m²L 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 1.85 mg/mL – 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 РОЗУСТИН 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 )

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.

Admixture Stability

РОЗУСТИН (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 (2-8°C or 36-46°F) or for 6 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of diluted РОЗУСТИН (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 (2-8°C or 36-46°F) or for only 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of diluted РОЗУСТИН must be completed within this period of time.

Retain the partially used vial in original package to protect from light and store refrigerated (2-8°C or 36-46°F) if additional dose withdrawal from the same vial is intended.

Stability Of Partially Used Vials (Needle Punched Vials )

РОЗУСТИН is supplied in a multiple-dose vial. Although it does not contain any antimicrobial preservative, РОЗУСТИН is bacteriostatic. The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2-8°C or 36-46°F). Each vial is not recommended for more than a total of six (6) dose withdrawals.

After first use, the partially used vial should be stored in the refrigerator in the original carton at 2°- 8°C or 36-46°F and then discarded after 28 days.

РОЗУСТИН (bendamustine hydrochloride) injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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).

РОЗУСТИН (bendamustine hydrochloride) injection 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.

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 РОЗУСТИН (bendamustine hydrochloride) injection treatment to contact a physician immediately if they have symptoms or signs of infection.

Patients treated with bendamustine hydrochloride 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 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 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 РОЗУСТИН (bendamustine hydrochloride) injection 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 hydrochloride has occurred in patients in clinical trials and in postmarketing 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.

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. 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 РОЗУСТИН (bendamustine hydrochloride) injection.

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. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy.

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 РОЗУСТИН (bendamustine hydrochloride) injection therapy has not been determined.

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 drug infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of РОЗУСТИН (bendamustine hydrochloride) injection.

Embryo-Fetal Toxicity

Bendamustine hydrochloride 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m² /day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m² /day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced. Oral administration at 187.5 mg/m² /day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas.

Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m² , the lowest dose tested.

Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacities.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Bendamustine caused malformations in animals, when a single dose was administered to pregnant animals. Advise women to avoid becoming pregnant while receiving РОЗУСТИН (bendamustine hydrochloride) injection and for 3 months after therapy has stopped. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus. Advise men receiving РОЗУСТИН (bendamustine hydrochloride) injection to use reliable contraception for the same time period.

Animal Data

Single intraperitoneal doses of bendamustine from 210 mg/m² (70 mg/kg) in mice administered during organogenesis 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 dosing in mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m² (25 mg/kg) and an increase in abnormalities from 112.5 mg/m² (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m² (20 mg/kg) in rats administered on gestation days 4, 7, 9, 11, or 13 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. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for bendamustine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of bendamustine hydrochloride in pediatric patients has not been established. Bendamustine hydrochloride was evaluated in a single Phase 1/2 trial in pediatric patients with leukemia. The safety profile for bendamustine hydrochloride in pediatric patients was consistent with that seen in adults, and no new safety signals were identified.

The trial included pediatric patients from 1-19 years of age 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 1 and 2 of each 21-day cycle. Doses of 90 and 120 mg/m² were evaluated. The Phase 1 portion of the study determined that the recommended Phase 2 dose of bendamustine hydrochloride in pediatric patients was 120 mg/m².

A total of 32 patients entered the Phase 2 portion of the study at the recommended dose and were evaluated for response. There was no treatment response (CR+ CRp) in any patient at this dose. However, there were 2 patients with ALL who achieved a CR at a dose of 90 mg/m² in the Phase 1 portion of the study.

In the above-mentioned pediatric trial, the pharmacokinetics of bendamustine hydrochloride at 90 and 120 mg/m² doses were evaluated in 5 and 38 patients, respectively, aged 1 to 19 years (median age of 10 years).

The geometric mean body surface adjusted clearance of bendamustine was 14.2 L/h/m. The exposures (AUC and C ) to bendamustine in pediatric patients following a 120 mg/m² intravenous infusion over 60 minutes were similar to those in adult patients following the same 120 mg/m² dose.

Geriatric Use

In CLL and NHL studies, there were no clinically significant differences in the adverse reaction profile between geriatric (≥ 65 years of age) and younger patients.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, 153 patients received bendamustine hydrochloride. The overall response rate for patients younger than 65 years of age was 70% (n=82) for bendamustine hydrochloride and 30% (n=69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for bendamustine hydrochloride and 22% (n=79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the bendamustine hydrochloride group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the bendamustine hydrochloride group and 8 months in the chlorambucil group.

Non-Hodgkin Lymphoma

Efficacy (Overall Response Rate and Duration of Response) was similar in patients < 65 years of age and patients ≥ 65 years. Irrespective of age, all of the 176 patients experienced at least one adverse reaction.

Renal Impairment

No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. РОЗУСТИН (bendamustine hydrochloride) injection should be used with caution in patients with mild or moderate renal impairment. РОЗУСТИН (bendamustine hydrochloride) injection should not be used in patients with CrCL < 40 mL/min.

Hepatic Impairment

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. РОЗУСТИН (bendamustine hydrochloride) injection should be used with caution in patients with mild hepatic impairment. РОЗУСТИН (bendamustine hydrochloride) injection 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 > 3 X ULN) hepatic impairment.

Effect Of Gender

No clinically significant differences between genders were seen in the overall incidences of adverse reactions in CLL or NHL studies.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the bendamustine hydrochloride group was 60% and 57%, respectively. The ORR for men (n=90) and women (n=58) in the chlorambucil group was 24% and 28%, respectively. In this study, the median progression-free survival for men was 19 months in the bendamustine hydrochloride treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the bendamustine hydrochloride treatment group and 8 months in the chlorambucil treatment group.

Non-Hodgkin Lymphoma

The pharmacokinetics of bendamustine were similar in male and female patients with indolent NHL. No clinically-relevant differences between genders were seen in efficacy (Overall Response Rate and Duration of Response).

The following serious 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
• Infections
• Anaphylaxis and Infusion Reactions
• Tumor Lysis Syndrome
• Skin Reactions
• Hepatotoxicity
• Other Malignancies
• Extravasation Injury

Adverse Events In Clinical Trials

The data described below reflect exposure to bendamustine hydrochloride in 329 patients who participated in an actively controlled trial (N=153) for the treatment of CLL and two single arm studies (N=176) for the treatment of indolent B cell NHL. 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.

The safety of РОЗУСТИН (bendamustine hydrochloride) injection administered IV as a 50 mL admixture over a 10-minute infusion is supported by clinical trials using bendamustine hydrochloride administered IV as a 500 mL admixture over 30-60 minutes infusion time, as well as an open-label, crossover study in 81 ‘end-of-life’ cancer patients treated with РОЗУСТИН. In total, safety data from clinical studies are available from over 400 cancer patients exposed to bendamustine hydrochloride at doses in the range used in the treatment of CLL and NHL.

No clinically significant differences in the adverse event profile were noted among bendamustine hydrochloride administered as a 500 mL admixture over standard infusion time (30-60 minutes) and РОЗУСТИН administered as a 50 mL admixture in a ‘short-time’ infusion over 10 minutes.

The safety and tolerability of РОЗУСТИН was evaluated in an 8-week clinical study of РОЗУСТИН in 81 ‘end-of-life’ cancer patients, diagnosed with solid tumors and hematologic malignancies (excluding CLL). The population was 40-82 years of age, 58% females, 84% white, 12.3% Black, 1.2% Asian and 2.5% were classified as ‘other’. РОЗУСТИН was administered IV at a 120 mg/m² dose as a 50 mL admixture over 10 minutes. Patients in the study received РОЗУСТИН(50 mL IV, over 10 minutes) or bendamustine hydrochloride (500 mL IV, over 60 minutes) on Days 1 and 2 every 28 days for two consecutive 2-day cycles.

Adverse reactions (any grade) that occurred with a frequency greater than 5% during РОЗУСТИН infusion and within one hour post-infusion were nausea (8.2%) and fatigue (5.5%).

Adverse reactions (any grade) that occurred with a frequency greater than 5% within 24 hours of РОЗУСТИН were nausea (10.9%) and fatigue (8.2%).

Adverse reactions leading to study withdrawal in 4 patients receiving РОЗУСТИН were pyrexia (1.2%), nausea (1.2%), vomiting (1.2%), pneumonia (1.2%) and fatigue (1.2%).

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%).

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

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

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 significant deterioration does not occur.

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.

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)

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

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 adverse reactions reported in clinical trials and/or postmarketing 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. 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.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic systems disorders: Pancytopenia.

Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation.

General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling).

Immune system disorders: Anaphylaxis.

Infections and infestations: Pneumocystis jiroveci pneumonia.

Respiratory, thoracic and mediastinal disorders: Pneumonitis.

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms)..

The intravenous LD of bendamustine hydrochloride is 240 mg/m² in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.

Across all clinical experience, the reported maximum single dose received was 280 mg/m². Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days postdosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients.

No specific antidote for bendamustine hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

Based on the pharmacokinetics/pharmacodynamics analyses of data from adult NHL patients, nausea increased with increasing bendamustine Cmax.

Cardiac Electrophysiology

The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1 after administration of rituximab at 375 mg/m² intravenous infusion followed by a 30-minute intravenous infusion of bendamustine at 90 mg/m² /day. No mean changes greater than 20 milliseconds were detected up to one hour post infusion. The potential for delayed effects on the QT interval after one hour was not evaluated.

Absorption

In a pharmacokinetics study conducted in patients with cancer (N=60), a single IV dose of РОЗУСТИН (bendamustine hydrochloride) injection (120 mg/m² ; administered as a 10 minutes infusion), resulted in a higher maximum plasma concentration (Cmax ) and equivalent systemic exposure (AUC), compared to a single dose of Treanda^® (bendamustine hydrochloride) (120 mg/m² ) infused over 60 minutes. The mean Cmax achieved was 35 μg/mL (range 6 to 49 μg/mL), occurring typically at the end of infusion.

Distribution

In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and was concentration independent from 1-50 μg/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 μg/mL indicating that bendamustine distributes freely in human red blood cells.

In a mass balance study, plasma radioactivity levels were sustained for a greater period of time than plasma concentrations of bendamustine, γ hydroxybendamustine (M3), and N desmethylbendamustine (M4). This suggests that there are bendamustine derived materials (detected via the radiolabel), that are rapidly cleared and have a longer half-life than bendamustine and its active metabolites. 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.

Metabolism

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to monohyrdroxy (HP1) and dihydroxybendamustine (HP2) 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^th and 1/100^th 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. 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.

Elimination

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.

After a single dose of 120 mg/m² bendamustine IV over 1-hour the intermediate t½ of the parent compound is approximately 40 minutes. The mean apparent terminal elimination t½ 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. Bendamustine clearance in humans is approximately 700 mL/minute.

Renal Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m² , there was no meaningful effect of renal impairment (CrCL 40 - 80 mL/min, N=31) on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with CrCL < 40 mL/min.

These results are however limited, and therefore bendamustine should be used with caution in patients with mild or moderate renal impairment. Bendamustine should not be used in patients with CrCL < 40 mL/min.

Hepatic Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m² , there was no meaningful effect of mild (total bilirubin ≤ ULN, AST ≥ ULN to 2.5 x ULN, and/or ALP ≥ ULN to 5 x ULN, N=26) hepatic impairment on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with moderate or severe hepatic impairment.

These results are however limited, and therefore bendamustine should be used with caution in patients with mild hepatic impairment. Bendamustine 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 > 3 x ULN) hepatic impairment.

Effect Of Age

Bendamustine exposure (as measured by AUC and Cmax ) has been studied in patients ages 31 through 84 years. The pharmacokinetics of bendamustine (AUC and Cmax ) were not significantly different between patients less than or greater than/equal to 65 years of age.

Effect Of Gender

The pharmacokinetics of bendamustine were similar in male and female patients.

Effect Of Race

The effect of race on the safety, and/or efficacy of bendamustine hydrochloride has not been established. Based on a cross-study comparison, Japanese subjects (n = 6) had on average exposures that were 40% higher than non-Japanese subjects receiving the same dose. The significance of this difference on the safety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established.