Bendamustine 25mg/100mg Injection

What Bendamustine is and What it is used for

Bendamustine is a medicine which is used for the treatment of certain types of cancer (cytotoxic medicine).

Bendamustine is used alone (monotherapy) or in combination with other medicines for the treatment of the following forms of cancer:

• chronic lymphocytic leukaemia in cases where fludarabine combination chemotherapy is not appropriate for you,
• non-Hodgkin’s lymphomas, which had not, or only shortly, responded to prior rituximab treatment,
• Multiple myeloma in cases where high-dose chemotherapy with autologous stem cell transplantation, thalidomide or bortezomib containing therapy is not appropriate for you.

Before you use Bendamustine

• if you are hypersensitive (allergic) to the active substance bendamustine hydrochloride or any of the other ingredients of Bendamustine;
• while breastfeeding;
• if you have severe liver dysfunction (damage to the functional cells of the liver);
• if you have yellowing of the skin or whites of the eyes caused by liver or blood problems (jaundice);
• if you have severely disturbed bone marrow function (bone marrow depression) and serious changes in your number of white blood cells and platelets in the blood (white blood cells and/or thrombocyte values drop to < 3,000/μl or < 75,000/μl, respectively.);
• if you have had major surgical operations less than 30 days before starting treatment;
• if you have an infection, especially one accompanied by a reduction in white blood cells (leucocytopenia);
• in combination with yellow fever vaccines.

• in case of reduced capability of the bone marrow to replace blood cells. You should have your number of white blood cells and platelets in the blood checked before starting treatment with Bendamustine , before each subsequent course of treatment and in the intervals between courses of treatment.
• in case of infections. You should contact your doctor if you have signs of infection, including fever or lung symptoms.
• in case of reactions on your skin during treatment with Bendamustine . The reactions may increase in severity.
• in cases of existing heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms).
• in case you notice any pain in your side, blood in your urine or reduced amount of urine. When your disease is very severe, your body may not be able to clear all the waste products from the dying cancer cells. This is called tumour lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of Bendamustine . Your doctor will be aware of this and may give you other medicines to help prevent it.
• in case of severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions after your first cycle of therapy.

Men receiving treatment with Bendamustine are advised not to conceive a child during treatment and for up to 6 months afterwards. Before starting treatment, you should seek advice on storing sperm because of the possibility of permanent infertility.

Unintentional injection into the tissue outside blood vessels (extravasal injection) should be stopped immediately. The needle should be removed after a short aspiration. Thereafter the affected area of tissue should be cooled. The arm should be elevated. Additional treatments like the use of corticosteroids are not of clear benefit (see section 4).

Please tell your doctor or pharmacist if you are taking or have recently taken other medicines, including medicines obtained without a prescription.

If Bendamustine is used in combination with medicines which inhibit the formation of blood in the bone marrow, the effect on the bone marrow may be intensified.

If Bendamustine is used in combination with medicines which alter your immune response, this effect may be intensified.

Cytostatic medicines may diminish the effectiveness of live-virus vaccination. Additionally cytostatic medicines increase the risk of an infection after vaccination with live vaccines (e.g. viral vaccination).

Pregnancy
Bendamustine can cause genetic damage and has caused malformations in animal studies. You should not use Bendamustine during pregnancy unless certainly indicated by your doctor. In case of treatment you should use medical consultation about the risk of potential adverse effects of your therapy for the unborn child and genetic consultation is recommended.

If you are a woman of childbearing potential you must use an effective method of contraception both before and during treatment with Bendamustine. If pregnancy occurs during your treatment with Bendamustine you must immediately inform your doctor and should use genetic consultation.

If you are a man, you should avoid fathering a child during treatment with Bendamustine and for up to 6 months after treatment has stopped. There is a risk that treatment with Bendamustine will lead to infertility and you may wish to seek advice on conservation of sperm before treatment starts.

Breastfeeding
Bendamustine must not be administered during breastfeeding. If treatment with Bendamustine is necessary during lactation you must discontinue breastfeeding.

Ask your doctor or pharmacist for advice before taking any medicine.

No studies on the effects on the ability to drive and to use machines have been performed. Do not drive or operate machines if you experience side effects, such as dizziness or lack of coordination.

How to use Bendamustine

Bendamustine is administered into a vein over 30-60 minutes in various dosages, either alone (monotherapy) or in combination with other medicines.

Treatment should not be started if your white blood cells (leukocytes) have fallen to counts below 3,000 cells/μl and/or your blood platelets have fallen to counts below 75,000 cells/μl.

Your doctor will determine these values at regular intervals.

Bendamustine 100 mg per square metre of your body surface area (based on your height and weight) on Days 1+2

Repeat the cycle after 4 weeks up to 6 times

Bendamustine 120 mg per square metre of your body surface area (based on your height and weight) on Days 1 + 2

Repeat the cycle after 3 weeks at least 6 times

Bendamustine 120 - 150 mg per square metre of your body surface area (based on your height and weight) on Days 1 + 2

Prednisone 60 mg per square metre of your body surface area (based on your height and weight) i.v. on Days 1 - 4

Repeat the cycle after 4 weeks at least 3 times

Treatment should be terminated if white blood cell (leukocyte) and/or platelet values drop to < 3,000/μl or < 75,000/μl, respectively. Treatment can be continued after white blood cell values have increased to > 4,000/μl and platelet values to > 100,000/μl.

Dependent on the degree of impairment of your liver function it may be necessary to adjust your dose (by 30% in case of moderate liver dysfunction). No dose adjustment is necessary in case of impairment of kidney function. Your attending doctor will decide whether a dosage adjustment is necessary.

How it is administered
Treatment with Bendamustine should be undertaken only by doctors experienced in tumour therapy. Your doctor will give you the exact dose of Bendamustine and use the necessary precautions.

Your attending doctor will administer the solution for infusion after preparation as prescribed. The solution is administered into a vein as a short-term infusion over 30 – 60 minutes.

Duration of use
Treatment with Bendamustine should be undertaken only by doctors experienced in tumour therapy. Your doctor will give you the exact dose of Bendamustine and use the necessary precautions.

Your attending doctor will administer the solution for infusion after preparation as prescribed. The solution is administered into a vein as a short-term infusion over 30 – 60 minutes.

If a dose of Bendamustine has been forgotten, your doctor will usually retain the normal dosage schedule.

The doctor treating you will decide whether to interrupt the treatment or to change over to a different preparation.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Bendamustine can cause side-effects, although not everybody gets them.

The following definitions of frequency are used when assessing side-effects:

Very common: affects more than 1 user in 10
Common: affects 1 to 10 users in 100
Uncommon: affects 1 to 10 users in 1,000
Rare: affects 1 to 10 users in 10,000
Very rare: affects less than 1 user in 10,000
Not known: frequency cannot be estimated from the available data

Tissue changes (necrosis) have been observed very rarely following unintentional injection into the tissue outside blood vessels (extravascular). A burning sensation where the infusion needle is inserted may be a sign for administration outside the blood vessels. The consequence of administration in this way can be pain and poorly healing skin defects.

The dose-limiting side-effect of Bendamustine is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function increases the risk of infection.

• Low counts of white blood cells (leukocytopenia)
• Decrease in the red pigment of the blood (haemoglobin)
• Low counts of platelets (thrombocytopenia)
• Infections
• Feeling sick (nausea)
• Vomiting
• Mucosal inflammation
• Increased blood level of creatinine
• Increased blood level of urea
• Fever
• Fatigue

• Bleeding (haemorrhage)
• Disturbed metabolism caused by dying cancer cells releasing their contents into the blood stream
• Reduction in red blood cells which can make the skin pale and cause weakness or breathlessness (anaemia)
• Low counts of neutrophils (neutropenia)
• Hypersensitivity reactions such as allergic inflammation of the skin (dermatitis), nettle rash (urticaria)
• A rise in liver enzymes AST/ALT
• A rise in the enzyme alkaline phosphatase
• A rise in bile pigment
• Low potassium blood levels
• Disturbed function (dysfunction) of the heart
• Disturbed heart rhythms (arrhythmia)
• Low or high blood pressure (hypotension or hypertension)
• Disturbed lung function
• Diarrhoea
• Constipation
• Sore mouth (Stomatitis)
• Loss of appetite
• Hair loss
• Skin changes
• Missed periods (amenorrhoea)
• Pain
• Insomnia
• Chills
• Dehydration

• Accumulation of fluid in the heart sac (escape of fluid into the pericardial space)

• Infection of the blood (sepsis)
• Severe allergic hypersensitivity reactions (anaphylactic reactions)
• Signs similar to anaphylactic reactions (anaphylactoid reactions)
• Drowsiness
• Loss of voice (aphonia)
• Acute circulatory collapse
• Reddening of the skin (erythema)
• Inflammation of the skin (dermatitis)
• Itching (pruritus)
• Skin rash (macular exanthema)
• Excessive sweating (hyperhidrosis)

• Primary atypical inflammation of the lungs (pneumonia)
• Break-down of red blood cells
• Rapid decrease in blood pressure sometimes with skin reactions or rash (anaphylactic shock)
• Disturbed sense of taste
• Altered sensations (paraesthesia)
• Malaise and pain in the limbs (peripheral neuropathy)
• Disease of the nervous system (anticholinergic syndrome)
• Neurological disorders
• Lack of coordination (ataxia)
• Inflammation of the brain (encephalitis)
• Increased heart rate (tachycardia)
• Heart attack, chest pain (myocardial infarct)
• Heart failure
• Inflammation of the veins (phlebitis)
• Formation of tissue in the lungs (fibrosis of the lungs)
• Bleeding inflammation of the gullet (haemorrhagic oesophagitis)
• Bleeding of stomach or gut
• Infertility
• Multiple organ failure

There have been reports of secondary tumours (myelodysplastic syndrome, AML, bronchial carcinoma) following treatment with Bendamustine . No clear relationship with Bendamustine could be determined.

A small number of cases of severe skin reactions (Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis) have been reported. The relationship with Bendamustine is unclear.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

How To Store Bendamustine

Keep out of the reach and sight of children.

Do not use Bendamustine after the expiry date which is stated on the label and the carton. The expiry date refers to the last day of that month.

Keep the container in the outer carton to protect the content from light.
Note on shelf-life after opening or preparing the solution

Solutions for infusions prepared according to the directions listed at the end of this leaflet are stable in polyethylene bags at room temperature / 60% relative humidity for 3.5 hours, and in a refrigerator they are stable for 2 days. Bendamustine contains no preservatives. The solutions should not therefore be used after these lengths of time.

It is the responsibility of the user to maintain aseptic conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Taj Oncology generics

Indications and Usage

Bendamustine is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

Bendamustine is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION

Recommended Dosage:
The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:
Bendamustine administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.  Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], Bendamustine 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.

Recommended Dosage:
The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. 

Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL:
Bendamustine administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.  Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], Bendamustine 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.

Aseptically reconstitute each Bendamustine vial as follows:

• 25 mg Bendamustine vial: Add 5 mL of only Sterile Water for Injection, USP.
• 100 mg Bendamustine vial: Add 20 mL of only Sterile Water for Injection, USP.

Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used.

Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered.  The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag.  The admixture should be a clear and colorless to slightly yellow solution.

Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above.  No other diluents have been shown to be compatible.

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.

Bendamustine contains no antimicrobial preservative.  The admixture should be prepared as close as possible to the time of patient administration.

Once diluted with either 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 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of Bendamustine must be completed within this period.

DOSAGE FORMS AND STRENGTHS

Bendamustine for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

CONTRAINDICATIONS

Bendamustine is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

5 WARNINGS AND PRECAUTIONS

Bendamustine 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).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L.

Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with Bendamustine are more susceptible to infections. Advise patients with myelosuppression following Bendamustine treatment to contact a physician if they have symptoms or signs of infection.

Infusion reactions to Bendamustine have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue Bendamustine for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

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

Skin reactions have been reported with Bendamustine treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when Bendamustine was given in combination with other anticancer agents.

In a study of Bendamustine (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when Bendamustine was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to Bendamustine cannot be determined.

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.

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with Bendamustine, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma.  The association with Bendamustine therapy has not been determined.

Bendamustine extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting Bendamustine infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of Bendamustine.

Bendamustine 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.

ADVERSE REACTIONS

The following serious adverse reactions have been associated with Bendamustine in clinical trials and are discussed in greater detail in other sections of the label.

• Myelosuppression
• Infections
• Anaphylaxis and Infusion Reactions and Anaphylaxis
• Tumor Lysis Syndrome
• Skin Reactions
• Other Malignancies
• Extravasation injury

The data described below reflect exposure to Bendamustine in 329 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm trials (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 data described below reflect exposure to Bendamustine in 153 patients with CLL studied in an active-controlled, randomized trial.  The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. 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.  Non-hematologic adverse reactions (any grade) in the Bendamustine 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 in the CLL trial 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 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.

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. Red blood cell transfusions were administered to 20% of patients receiving Bendamustine compared with 6% of patients receiving chlorambucil.

In the 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 may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

The data described below reflect exposure to Bendamustine 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 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.

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%).

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving Bendamustine.  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 treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 

The following adverse reactions have been identified during post-approval use of Bendamustine.  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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when Bendamustine was administered concomitantly with allopurinol and other medications known to cause these syndromes.

DRUG INTERACTIONS

No formal clinical assessments of pharmacokinetic drug-drug interactions between Bendamustine and other drugs have been conducted. 

Bendamustine's active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites.  Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites.  Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed. 

The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport.  

Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.

USE IN SPECIFIC POPULATIONS

Pregnancy Category D [See Warnings and Precautions]

Risk Summary
Bendamustine 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 Bendamustine 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 Bendamustine 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.

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.

The effectiveness of Bendamustine in pediatric patients has not been established. Bendamustine was evaluated in a single Phase 1/2 trial in pediatric patients with leukemia. The safety profile for Bendamustine 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 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 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 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/m2. The exposures (AUC0-24 and Cmax) 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.

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. The overall response rate for patients younger than 65 years of age was 70% (n=82) for Bendamustine and 30% (n = 69) for chlorambucil.  The overall response rate for patients 65 years or older was 47% (n=71) for Bendamustine 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 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 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.

No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted.  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.

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted.  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.

No clinically significant differences between genders were seen in the overall incidences of adverse reactions in either 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 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 treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the Bendamustine 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 (ORR and DR).

OVERDOSAGE

The intravenous LD50 of bendamustine HCl 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 post-dosing. 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 overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

DESCRIPTION

Bendamustine contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. 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: 

Bendamustine (bendamustine hydrochloride) for Injection is intended for intravenous infusion only after reconstitution with Sterile Water for Injection, USP, and after further dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. It is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-use vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 - 3.5.

CLINICAL PHARMACOLOGY

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

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

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 monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10th and 1/100th 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% the dose was recovered in the urine and approximately a 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.

Bendamustine clearance in humans is approximately 700 mL/minute. 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.

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 5.0 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 adult 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 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 in Japanese subjects has not been established.

NONCLINICAL TOXICOLOGY

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.

CLINICAL STUDIES

The safety and efficacy of Bendamustine were evaluated in an open-label, randomized, controlled multicenter trial comparing Bendamustine to chlorambucil.  The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (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 with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter’s syndrome, or transformation to prolymphocytic leukemia were excluded from the study.

The patient populations in the Bendamustine 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%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), “B” symptoms (51% vs. 53%), lymphocyte count (mean 65.7x109/L vs. 65.1x109/L), and serum lactate dehydrogenase 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 at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or 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 and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL1. 

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

Table 5: Efficacy Data for CLL

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

The efficacy of Bendamustine was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.  Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received Bendamustine intravenously at a dose of 120 mg/m2, on Days 1 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 patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. 

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

REFERENCES

1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

HOW SUPPLIED/STORAGE AND HANDLING

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from Bendamustine. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of Bendamustine contacts the skin, wash the skin immediately and thoroughly with soap and water. If Bendamustine contacts the mucous membranes, flush thoroughly with water.

Bendamustine is an antineoplastic product. Follow special handling and disposal procedures1.

Bendamustine Hydrochloride for Injection is supplied in individual cartons as follows:  

Bendamustine Hydrochloride for Injection, 25 mg in 8 mL amber single-use vial
Bendamustine Hydrochloride for Injection, 100 mg in 20 mL amber single-use vial

Bendamustine may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature).  Retain in original package until time of use to protect from light.

PATIENT COUNSELING INFORMATION

Allergic (Hypersensitivity) Reactions

Inform patients of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion.

Myelosuppression
Inform patients of the likelihood that Bendamustine will cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection.

Fatigue
Advise patients that Bendamustine may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.

Nausea and Vomiting
Advise patients that Bendamustine may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided.

Diarrhea
Advise patients that Bendamustine may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided.

Rash
Advise patients that a mild rash or itching may occur during treatment with Bendamustine. Advise patients to immediately report severe or worsening rash or itching.

Pregnancy and Nursing
Bendamustine can cause fetal harm. Women should be advised to avoid becoming pregnant throughout treatment and for 3 months after Bendamustine therapy has stopped. Men receiving Bendamustine should use reliable contraception for the same time period. Advise patients to report pregnancy immediately. Advise patients to avoid nursing while receiving Bendamustine.