Bendamustine Hydrochloride

Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult patients with:

• •Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. (
  1.1 Chronic Lymphocytic Leukemia (CLL)

  Bendamustine q Hydrochloride Injection is indicated for the treatment of adult patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.
  )
• •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 Non-Hodgkin Lymphoma (NHL)

  Bendamustine Hydrochloride Injection is indicated for the treatment of adult 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.
  )

• •100 mg/m² infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. (
  2.1 Dosing Instructions for CLL

  Recommended Dosage

  :

  The recommended dose is 100 mg/m²administered 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 Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection at the discretion of the treating physician. In addition, consider dose reduction.

  [see Warnings and Precautions ]

  Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m²on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m²on 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/m²on Days 1 and 2 of each cycle.

  Consider dose re-escalation in subsequent cycles at the discretion of the treating physician.
  )

• •120 mg/m² infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. (
  2.2 Dosing Instructions for NHL

  Recommended Dosage

  :

  The recommended dose is 120 mg/m²administered 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 Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection at the discretion of the treating physician. In addition, consider dose reduction.

  [see Warnings and Precautions ]

  Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m²on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m²on 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/m²on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m²on Days 1 and 2 of each cycle.
  )

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

• •Lactation: Advise not to breastfeed (
  8.2 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 on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Bendamustine Hydrochloride Injection, and for 1 week after the last dose.
  )
• •Infertility: May impair fertility (
  8.3 Females and Males of Reproductive Potential

  Bendamustine Hydrochloride Injection can cause embryo-fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with Bendamustine Hydrochloride Injection.

  Contraception

  Females

  Advise female patients of reproductive potential to use effective contraception during treatment with Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection and for 3 months after the last dose

  [see Nonclinical Toxicology ]

  .

  Infertility

  Based on findings from clinical studies, Bendamustine Hydrochloride Injection may impair male fertility. 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. Advise patients of the potential risk to their reproductive capacities.

  Based on findings from animal studies, Bendamustine Hydrochloride Injection may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of Bendamustine Hydrochloride Injection on male fertility, including the reversibility of adverse effects, have not been studied

  [see Nonclinical Toxicology ]

  .
  )
• •Renal Impairment: Do not use in patients with creatinine clearance < 30 mL/min (
  8.6 Renal Impairment

  Do not use Bendamustine Hydrochloride Injection in patients with creatinine clearance (CLcr) < 30 mL/min

  [see Clinical Pharmacology ]

  .
  )
• •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 Hepatic Impairment

  Do not use Bendamustine Hydrochloride Injection 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 ]
  )

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

  Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies

  [see Adverse Reactions (6.1)]

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

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

  Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride

  [see Adverse Reactions (6.1)]

  . Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following Bendamustine Hydrochloride Injection treatment to contact a physician immediately if they have symptoms or signs of infection.

  Patients treated with Bendamustine Hydrochloride Injection 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.
  )
• •Progressive Multifocal Leukoencephalopathy (PML): Monitor for new or worsening neurological, cognitive or behavioral signs or symptoms suggestive of PML. (
  5.3 Progressive Multifocal Leukoencephalopathy (PML)

  Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab

  [see Adverse Reactions

  (6.2)

  ]

  . Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold Bendamustine Hydrochloride Injection treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
  )
• •Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have occurred. Monitor clinically and discontinue drug for severe reactions. Pre-medicate in subsequent cycles for milder reactions. (
  5.4 Anaphylaxis and Infusion Reactions

  Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials

  [see Adverse Reactions (6.1)]

  . Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who 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 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: May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk. (
  5.5 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 (6.1)]

  . The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.

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

  [see Adverse Reactions (6.1and 6.2)].

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

  Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during Bendamustine Hydrochloride Injection therapy.
  )
• •Other Malignancies: Pre-malignant and malignant diseases have been reported. (
  5.8 Other Malignancies

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

  [see Adverse Reactions (6.2)]

  .

  Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with Bendamustine Hydrochloride Injection.
  )
• •Extravasation Injury: Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration. (
  5.9 Extravasation Injury

  Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain

  [see Adverse Reactions

  (6.2)

  ]

  . Assure good venous access prior to starting Bendamustine Hydrochloride Injection infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of Bendamustine Hydrochloride Injection.
  )
• •Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. (
  5.10 Embryo-Fetal Toxicity

  Based on findings from animal reproduction studies and the drug’s mechanism of action, Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bendamustine Hydrochloride Injection and for 3 months after the last dose

  [see Use in Specific Populations and Clinical Pharmacology ].
  ,
  8.1 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 maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see

  Data

  ). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal 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 recognized pregnancies 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 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 administration of bendamustine hydrochloride in mice on gestation 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 and 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.
  )