BELRAPZO

DESCRIPTION

BELRAPZO (bendamustine hydrochloride) is an alkylating agent. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]­1-methyl-, monohydrochloride. Its empirical molecular formula is C₁₆H₂₁Cl₂N₃O₂•HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula:

 

 

BELRAPZO (bendamustine hydrochloride) injection for intravenous use is supplied as a sterile, clear, and colorless to yellow ready-to-dilutesolution in a multiple-dose clear glass vial. . Each milliliter contains 25 mg of bendamustine hydrochloride, 0.1 mL of propylene glycol, USP, 5 mg of monothioglycerol, NF and q.s. to 1 mL polyethylene glycol 400, NF.

The following clinically significant serious adverse reactions are discussed in greater detail in other sections of the prescribing information.

• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Progressive Multifocal Leukoencephalopathy [ see WARNINGS AND PRECAUTIONS]
• Anaphylaxis and Infusion Reactions [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Skin Reactions [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Other Malignancies [see WARNINGS AND PRECAUTIONS]
• Extravasation Injury [see WARNINGS AND PRECAUTIONS]

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 ratesin the clinical trials of another drug and may not reflect the rates observed in practice.

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, randomizedtrial. 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 intravenouslyover 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 thebendamustine 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 randomizedCLL

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% ofPatients

Body System Adverse Reaction	Number (%) of patients
	Bendamustine Hydrochloride (N=153)		Chlorambucil (N=143)
	All Grades	Grade 3/4	All Grades	Grade 3/4
Total number of patients with at least 1 adverse reaction	121 (79)	52 (34)	96 (67)	25 (17)
Gastrointestinal disorders
Nausea	31 (20)	1 (<1)	21 (15)	1 (<1)
Vomiting	24 (16)	1 (<1)	9 (6)	0
Diarrhea	14 (9)	2 (1)	5 (3)	0
General disorders and administration site conditions
Pyrexia	36 (24)	6 (4)	8 (6)	2 (1)
Fatigue	14 (9)	2 (1)	8 (6)	0
Asthenia	13 (8)	0	6 (4)	0
Chills	9 (6)	0	1 (<1)	0
Immune system disorders
Hypersensitivity	7 (5)	2 (1)	3 (2)	0
Infections and infestations
Nasopharyngitis	10 (7)	0	12 (8)	0
Infection	9 (6)	3 (2)	1 (<1)	1 (<1)
Herpes simplex	5 (3)	0	7 (5)	0
Investigations
Weight decreased	11 (7)	0	5 (3)	0
Metabolism and nutrition disorders
Hyperuricemia	11 (7)	3 (2)	2 (1)	0
Respiratory, thoracic and mediastinal disorders
Cough	6 (4)	1 (<1)	7 (5)	1 (<1)
Skin and subcutaneous tissue disorders
Rash	12 (8)	4 (3)	7 (5)	3 (2)
Pruritus	8 (5)	0	2 (1)	0

 

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 themyelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receivingbendamustine hydrochloride compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received BendamustineHydrochloride or Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality	Bendamustine Hydrochloride N=150		Chlorambucil N=141
	All Grades n (%)	Grade 3/4 n (%)	All Grades n (%)	Grade 3/4 n (%)
Hemoglobin Decreased	134 (89)	20 (13)	115 (82)	12 (9)
Platelets Decreased	116 (77)	16 (11)	110 (78)	14 (10)
Leukocytes Decreased	92 (61)	42 (28)	26 (18)	4 (3)
Lymphocytes Decreased	102 (68)	70 (47)	27 (19)	6 (4)
Neutrophils Decreased	113 (75)	65 (43)	86 (61)	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 bilirubinoccurred 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 bendamustinehydrochloride may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that furtherdeterioration 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 populationwas 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 receivedbendamustine 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 withBendamustine Hydrochloride by System Organ Class and Preferred Term (N=176)

Body System	Number (%) of patients *
Adverse Reaction	All Grades	Grade 3/4
Total number of patients with at least 1 adverse reaction	176 (100)	94 (53)
Cardiac Disorders
Tachycardia	13 (7)	0
Gastrointestinal disorders
Nausea	132 (75)	7 (4)
Vomiting	71 (40)	5 (3)
Diarrhea	65 (37)	6 (3)
Constipation	51 (29)	1 (<1)
Stomatitis	27 (15)	1 (<1)
Abdominal pain	22 (13)	2 (1)
Dyspepsia	20 (11)	0
Gastroesophageal reflux disease	18 (10)	0
Dry mouth	15 (9)	1 (<1)
Abdominal pain upper	8 (5)	0
Abdominal distension	8 (5)	0
General disorders and administration site conditions
Fatigue	101 (57)	19 (11)
Pyrexia	59 (34)	3 (2)
Chills	24 (14)	0
Edema peripheral	23 (13)	1 (<1)
Asthenia	19 (11)	4 (2)
Chest pain	11 (6)	1 (<1)
Infusion site pain	11 (6)	0
Pain	10 (6)	0
Catheter site pain	8 (5)	0
Infections and infestations
Herpes zoster	18 (10)	5 (3)
Upper respiratory tract infection	18 (10)	0
Urinary tract infection	17 (10)	4 (2)
Sinusitis	15 (9)	0
Pneumonia	14 (8)	9 (5)
Febrile neutropenia	11 (6)	11 (6)
Oral candidiasis	11 (6)	2 (1)
Nasopharyngitis	11 (6)	0
Investigations
Weight decreased	31 (18)	3 (2)
Metabolism and nutrition disorders
Anorexia	40 (23)	3 (2)
Dehydration	24 (14)	8 (5)
Decreased appetite	22 (13)	1 (<1)
Hypokalemia	15 (9)	9 (5)
Musculoskeletal and connective tissue disorders
Back pain	25 (14)	5 (3)
Arthralgia	11 (6)	0
Pain in extremity	8 (5)	2 (1)
Bone pain	8 (5)	0
Nervous system disorders
Headache	36 (21)	0
Dizziness	25 (14)	0
Dysgeusia	13 (7)	0
Psychiatric disorder
Insomnia	23 (13)	0
Anxiety	14 (8)	1 (<1)
Depression	10 (6)	0
Respiratory, thoracic and mediastinal disorders
Cough	38 (22)	1 (<1)
Dyspnea	28 (16)	3 (2)
Pharyngolaryngeal pain	14 (8)	1 (<1)
Wheezing	8 (5)	0
Nasal congestion	8 (5)	0
Skin and subcutaneous tissue disorders
Rash	28 (16)	1 (<1)
Pruritus	11 (6)	0
Dry skin	9 (5)	0
Night sweats	9 (5)	0
Hyperhidrosis	8 (5)	0
Vascular disorders
Hypotension	10 (6)	2 (1)
*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. Clinicallyimportant 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 singlearm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).]

Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received BendamustineHydrochloride in the NHL Studies

Hematology Variable	Percent of Patients
	All Grades	Grade 3/4
Lymphocytes Decreased	99	94
Leukocytes Decreased	94	56
Hemoglobin Decreased	88	11
Neutrophils Decreased	86	60
Platelets Decreased	86	25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride. The most common seriousadverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious 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.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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. Because these reactions are reported voluntarily from apopulation 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 (includingphlebitis, pruritus, irritation, pain, swelling)

Immune system disorders: Anaphylaxis

Infections and infestations: Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy (PML)

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnsonsyndrome (SJS), toxic epidermal necrolysis (TEN).

DRUG INTERACTIONS

Effect Of Other Drugs On BELRAPZO

CYP1A2 Inhibitors

The coadministration of BELRAPZO with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adversereactions with BELRAPZO [see CLINICAL PHARMACOLOGY]. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with BELRAPZO.

CYP1A2 Inducers

The coadministration of BELRAPZO with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of BELRAPZO [see CLINICAL PHARMACOLOGY]. Consider alternative therapies that are not CYP1A2 inducers during treatment with BELRAPZO.

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 ADVERSE REACTIONS]. Three patients (2%)died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumoniafrom an opportunistic infection (CMV).

BELRAPZO causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinicaltrials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may requiredose 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 theinitiation 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]

Infections

Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports forbendamustine hydrochloride [see ADVERSE REACTIONS]. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptibleto 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, andherpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infectionreactivation prior to administration.

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination withrituximab or obinutuzumab [see ADVERSE REACTIONS]. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive orbehavioral signs or symptoms. If PML is suspected, withhold BELRAPZO treatment and perform appropriate diagnostic evaluations. Consider discontinuation orreduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

Anaphylaxis And Infusion Reactions

Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials [see ADVERSE REACTIONS]. Symptoms include fever, chills, pruritus andrash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinicallyand discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroidsin subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue BELRAPZO for patients with Grade 4 infusion reactions. Considerdiscontinuation 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 post-marketing reports [see ADVERSE REACTIONS]. 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 andallopurinol are administered concomitantly. [see Skin Reactions]

Skin Reactions

Fatal and serious skin reactions have been reported with bendamustine hydrochloride treatment in clinical trials and postmarketing safety reports, including toxic skinreactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), bullousexanthema, and rash [see ADVERSE REACTIONS]. Events occurred when bendamustine hydrochloride was given as a single agent and in combination withother 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 aresevere or progressive, withhold or discontinue BELRAPZO.

Hepatotoxicity

Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation ofhepatitis B were confounding factors in some patients. [see Infections] Most cases were reported within the first three 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 hydrochloride, includingmyelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia , bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinomaand squamous cell carcinoma [see ADVERSE REACTIONS].

Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with BELRAPZO.

Extravasation Injury

Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain [see ADVERSE REACTIONS]. Assure good venous access prior to starting BELRAPZO infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, andnecrosis during and after administration of BELRAPZO.

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 duringorganogenesis 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 withBELRAPZO and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment withBELRAPZO and for 3 months after the last dose. [see Use In Specific Populations and CLINICAL PHARMACOLOGY]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m² /day (the lowest dose tested, approximately 0.3 times the maximumrecommended human dose [MRHD]) and 75 mg/m² /day (approximately 0.6 times the MRHD) for 4 days, peritoneal sarcomas in female AB/jena mice were produced.Oral administration at 187.5 mg/m² /day (the only dose tested, approximately 1.6 times the MRHD) for 4 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 absenceand presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro , and in rat bone marrow cells in vivo (increase in micronucleatedpolychromatic erythrocytes) from 37.5 mg/m² , (the lowest dose tested, approximately 0.3 times the MRHD).

Bendamustine induced morphologic abnormalities in spermatozoa in mice. Following tail vein injection of bendamustine at 120 mg/m² or a saline control on days 1 and2 for a total of three weeks, the number of spermatozoa with morphologic abnormalities was 16% higher in the bendamustine-treated group as compared to the salinecontrol group.

Use In Specific Populations

Pregnancy

Risk Summary

In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximumrecommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are noavailable data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal orfetal outcomes. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect,loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal data

Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m² (approximately 1.8 times the MRHD) during organogenesis and causedan increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride in mice ongestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m² (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m² (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration.

Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m² (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 andcaused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, andherniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.

Lactation

Risk Summary

There are no data on the presence of bendamustine hydrochloride or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects onmilk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatmentwith BELRAPZO, and for 1 week after the last dose.

Females And Males Of Reproductive Potential

BELRAPZO can cause embryo-fetal harm when administered to a pregnant woman [see Pregnancy].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with BELRAPZO [see Pregnancy].

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with BELRAPZO and for 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with BELRAPZO and for 3months after the last dose [see Nonclinical Toxicology].

Infertility

Based on findings from clinical studies, BELRAPZO may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reportedin male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, butthis may occur only several years after intensive chemotherapy has been discontinued. Advise patients of the potential risk to their reproductive capacities.

Based on findings from animal studies, BELRAPZO may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects ofBELRAPZO on male fertility, including the reversibility of adverse effects, have not been studied [see Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1 to 19 years with relapsed or refractory acuteleukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride wasadministered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient. The safetyprofile in these patients was consistent with that seen in adults, and no new safety signals were identified.

The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given thesame dose based on body surface area.

Geriatric Use

No overall differences in safety were observed between patients ≥65 years of age and younger patients. Efficacy was lower in patients 65 and over with CLL receivingbendamustine hydrochloride based upon an overall response rate of 47% for patients 65 and over and 70% for younger patients. Progression free survival was alsolonger in younger patients with CLL receiving bendamustine (19 months vs. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphomawere observed between geriatric patients and younger patients.

Renal Impairment

Do not use BELRAPZO in patients with creatinine clearance (CLcr) < 30 mL/min [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Do not use BELRAPZO in patients with AST or ALT 2.5-10 × upper limit of normal (ULN) and total bilirubin 1.5-3 × ULN, or total bilirubin > 3 × ULN [see CLINICAL PHARMACOLOGY]

OVERDOSE

The intravenous LD50 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 considereddose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (twopatients) 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 monitoringof hematologic parameters and ECGs.

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]

CLINICAL PHARMACOLOGY

Mechanism Of Action

Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkylgroups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can leadto cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.

Pharmacodynamics

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 ofrituximab 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.

Pharmacokinetics

Absorption

Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not beenstudied.

Distribution

The protein binding of bendamustine ranged from 94 to 96% and was concentration independent from 1 to 50 μg/mL. The blood to plasma concentration ratios inhuman blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 μg/mL.

The mean steady-state volume of distribution (V ) of bendamustine was approximately 20 to 25 L.

Elimination

After a single intravenous dose of 120 mg/m² of bendamustine over 1 hour, the intermediate half-life (t_1/2 ) of the parent compound is approximately 40 minutes. Themean terminal elimination t_1/2 of two active metabolites, γ-hydroxybendamustine (M3) and N-desmethylbendamustine (M4) are approximately 3 hours and 30 minutes,respectively. Bendamustine clearance in humans is approximately 700 mL/min.

Metabolism

Bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. Bendamustine is primarily metabolized via hydrolysis to monohydroxy(HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity in vitro. Two active minor metabolites, M3 and M4, are primarily formed viaCYP1A2 in vitro. M3 and M4 concentrations of these metabolites in plasma are 1/10^th and 1/100^th that of the parent compound, respectively.

Excretion

Following IV infusion of radiolabeled bendamustine hydrochloride in cancer patients, approximately 76% of the dose was recovered. Approximately 50% of the dosewas recovered in the urine (3.3% unchanged) and approximately 25% of the dose was recovered in the feces. Less than 1% of the dose was recovered in the urine as M3and M4, and less than 5% of the dose was recovered in the urine as HP2.

Specific Populations

No clinically meaningful effects on the pharmacokinetics of bendamustine were observed based on age (31 to 84 years), sex, mild to moderate renal impairment (CLcr≥ 30 mL/min), or hepatic impairment with total bilirubin 1.5 < ULN and AST or ALT < 2.5 x ULN. The effects of severe renal impairment (CLcr < 30 mL/min), orhepatic impairment with total bilirubin 1.5-3 x ULN and AST or ALT 2.5-10 x ULN or total bilirubin > 3 x ULN on the pharmacokinetics of bendamustine is unknown.

Race/Ethnicity

Exposures in Japanese subjects (n=6) were 40% higher than that in non-Japanese subjects receiving the same dose. The clinical importance of this difference on thesafety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established.

Drug Interaction Studies

In Vitro Studies

Effect of Bendamustine on CYP Substrates

Bendamustine did 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.

Effect of Transporters on Bendamustine Hydrochloride

Bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).

Clinical Studies

Chronic Lymphocytic Leukemia (CLL)

The safety and efficacy of bendamustine hydrochloride were evaluated in an open-label, randomized, controlled multicenter trial comparing bendamustinehydrochloride to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or Cmax (Rai Stages I – IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients withautoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter’s syndrome, or transformation to prolymphocytic leukemia were excluded from the study.

The patient populations in the bendamustine hydrochloride and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age(median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlargedliver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), “B” symptoms (51% vs. 53%), lymphocyte count (mean 65.7×10⁹/L vs. 65.1×10⁹/L), and serum lactatedehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5,CD23 and either CD19 or CD20 or both).

Patients were randomly assigned to receive either bendamustine hydrochloride at 100 mg/m² , administered intravenously over a period of 30 minutes on Days 1 and 2or chlorambucil at 0.8 mg/kg (Broca’s normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate andprogression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL.

The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for bendamustine hydrochloridecompared to chlorambucil ( see Table 5). Survival data are not mature.

Table 5: Efficacy Data for CLL

	Bendamustine Hydrochloride (N=153)	Chlorambucil (N=148)	p-value
Response Rate n (%)
Overall response rate	90 (59)	38 (26)	<0.0001
(95% CI)	(51, 66.6)	(18.6, 32.7)
Complete response (CR) *	13 (8)	1 (<1)
Nodular partial response (nPR) **	4 (3)	0
Partial response (PR) †	73 (48)	37 (25)
Progression-Free Survival ††
Median, months (95% CI)	18 (11.7, 23.5)	6 (5.6, 8.6)
Hazard ratio (95% CI)	0.27 (0.17, 0.43)		<0.0001
CI = confidence interval * CR was defined as peripheral lymphocyte count ≤ 4 x 109 /L, neutrophils ≥ 1.5 x 109 /L, platelets >100 x 109 /L,hemoglobin > 110g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes ≤ 1.5 cm, < 30%lymphocytes without nodularity in at least a normocellular bone marrow and absence of “B” symptoms. The clinicaland laboratory criteria were required to be maintained for a period of at least 56 days. ** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules. † PR was defined as ≥50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either≥50% reduction in lymphadenopathy, or ≥50% reduction in the size of spleen or liver, as well as one of the followinghematologic improvements: neutrophils ≥ 1.5 x 109 /L or 50% improvement over baseline, platelets >100 x 109 /L or50% improvement over baseline, hemoglobin >110g/L or 50% improvement over baseline without transfusions, for aperiod of at least 56 days. †† PFS was defined as time from randomization to progression or death from any cause.

Kaplan-Meier estimates of progression-free survival comparing bendamustine hydrochloride with chlorambucil are shown in Figure 1.

Non-Hodgkin Lymphoma (NHL)

The efficacy of bendamustine hydrochloride was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within sixmonths of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) orlast dose (maintenance regimen or combination therapy) of rituximab. All patients received bendamustine hydrochloride intravenously at a dose of 120 mg/m² , on Days1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.

The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%),diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patientshad received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen orcombination therapy) of rituximab.

Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete responseunconfirmed + partial response) and duration of response (DR) as summarized in Table 6.

Table 6: Efficacy Data for NHL *

	Bendamustine Hydrochloride (N=100)
Response Rate (%)
Overall response rate (CR+CRu+PR)	74
(95% CI)	(64.3, 82.3)
Complete response (CR)	13
Complete response unconfirmed (CRu)	4
Partial response (PR)	57
Duration of Response (DR)
Median, months (95% CI)	9.2 months (7.1, 10.8)
CI = confidence interval *IRC assessment was based on modified International Working Group response criteria(IWG-RC). Modifications to IWG-RC specified that a persistently positive bone marrow inpatients who met all other criteria for CR would be scored as PR. Bone marrow samplelengths were not required to be ≥20 mm