These highlights do not include all the information needed to use TREANDA safely and effectively. See full prescribing information for TREANDA. TREANDA (bendamustine hydrochloride) injection, powder, lyophilized, for solution for intravenous use

TREANDA is indicatedfor the treatment of patients with chronic lymphocytic leukemia. Efficacyrelative to first line therapies other than chlorambucil has not beenestablished.

TREANDA for Injection isindicated for the treatment of patients with indolent B-cell non-Hodgkin’slymphoma that has progressed during or within six months of treatmentwith rituximab or a rituximab-containing regimen.

Recommended Dosage:      

The recommendeddose is 100 mg/m administered intravenously over 30 minuteson Days 1 and 2 of a 28-day cycle, up to 6 cycles.

Dose Delays, Dose Modifications and Reinitiationof Therapy for CLL :

TREANDA administration shouldbe delayed in the event of Grade 4 hematologic toxicity or clinicallysignificant ≥ Grade 2 non-hematologic toxicity.  Once non-hematologictoxicity has recovered to ≤ Grade 1 and/or the blood counts have improved[Absolute Neutrophil Count (ANC) ≥ 1 x 10/L, platelets≥ 75 x 10/L], TREANDA can be reinitiated at the discretionof the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)]

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

Dose modifications for non-hematologictoxicity: for clinically significant Grade 3 or greater toxicity,reduce the dose to 50 mg/m on Days 1 and 2 of each cycle.

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

Recommended Dosage: 

The recommended dose is 120 mg/m administered intravenously over 60 minutes on Days 1 and2 of a 21-day cycle, up to 8 cycles. 

Dose Delays, Dose Modifications and Reinitiationof Therapy for NHL:

TREANDA administration shouldbe delayed in the event of a Grade 4 hematologic toxicity or clinicallysignificant ≥ Grade 2 non-hematologic toxicity.  Once non-hematologictoxicity has recovered to ≤ Grade 1 and/or the blood counts have improved[Absolute Neutrophil Count (ANC) ≥ 1 x 10/L, platelets≥ 75 x 10/L], TREANDA can be reinitiated at the discretionof the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)]

Dose modifications for hematologic toxicity: for Grade4 toxicity, reduce the dose to 90 mg/m on Days 1 and 2of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m 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/m on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs,reduce the dose to 60 mg/m on Days 1 and 2 of each cycle.

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 shouldbe inspected visually for particulate matter and discoloration priorto administration whenever solution and container permit. Any unusedsolution should be discarded according to institutional proceduresfor antineoplastics.

TREANDA containsno antimicrobial preservative.  The admixture should be prepared asclose 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 ChlorideInjection, USP, the final admixture is stable for 24 hours when storedrefrigerated (2-8°C or 36-47°F) or for 3 hours when stored at roomtemperature (15-30°C or 59-86°F) and room light. Administration ofTREANDA must be completed within this period.

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

TREANDA is contraindicated inpatients with a known hypersensitivity (e.g., anaphylactic and anaphylactoidreactions) to bendamustine or mannitol. [See Warnings and Precautions (5.3)]

Patients treatedwith TREANDA are likely to experience myelosuppression. In the twoNHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table4). Three patients (2%) died from myelosuppression-related adversereactions; one each from neutropenic sepsis, diffuse alveolar hemorrhagewith Grade 3 thrombocytopenia, and pneumonia from an opportunisticinfection (CMV).

Inthe event of treatment-related myelosuppression, monitor leukocytes,platelets, hemoglobin (Hgb), and neutrophils closely. In the clinicaltrials, blood counts were monitored every week initially.  Hematologicnadirs were observed predominantly in the third week of therapy. Hematologicnadirs may require dose delays if recovery to the recommended valueshave not occurred by the first day of the next scheduled cycle.  Priorto the initiation of the next cycle of therapy, the ANC should be≥ 1 x 10/L and the platelet count should be ≥ 75 x 10/L. [See Dosage and Administration (2.1) and (2.2)]

Infection, including pneumoniaand sepsis, has been reported in patients in clinical trials and inpost-marketing reports. Infection has been associated with hospitalization,septic shock and death. Patients with myelosuppression following treatmentwith TREANDA are more susceptible to infections. Patients with myelosuppressionfollowing TREANDA treatment should be advised to contact a physicianif they have symptoms or signs of infection.

Infusion reactions to TREANDAhave occurred commonly in clinical trials. Symptoms include fever,chills, pruritus and rash. In rare instances severe anaphylactic andanaphylactoid reactions have occurred, particularly in the secondand subsequent cycles of therapy.  Monitor clinically and discontinuedrug for severe reactions. Patients should be asked about symptomssuggestive of infusion reactions after their first cycle of therapy.Patients who experienced Grade 3 or worse allergic-type reactionswere not typically rechallenged.  Measures to prevent severe reactions,including antihistamines, antipyretics and corticosteroids shouldbe considered in subsequent cycles in patients who have previouslyexperienced Grade 1 or 2 infusion reactions. Discontinuation shouldbe considered in patients with Grade 3 or 4 infusion reactions.

Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels.  Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

A number of skinreactions have been reported in clinical trials and post-marketingsafety reports. These events have included rash, toxic skin reactionsand bullous exanthema. Some events occurred when TREANDA was givenin combination with other anticancer agents, so the precise relationshipto TREANDA is uncertain.  

In a study of TREANDA (90 mg/m) in combination with rituximab,one case of toxic epidermal necrolysis (TEN) occurred. TEN has beenreported for rituximab (see rituximab package insert).  Cases of Stevens-Johnsonsyndrome (SJS) and TEN, some fatal, have been reported when TREANDAwas administered concomitantly with allopurinol and other medicationsknown to cause these syndromes. The relationship to TREANDA cannotbe determined.

Whereskin reactions occur, they may be progressive and increase in severitywith further treatment. Therefore, patients with skin reactions shouldbe monitored closely. If skin reactions are severe or progressive,TREANDA should be withheld or discontinued.

There are reports of pre-malignantand malignant diseases that have developed in patients who have beentreated with TREANDA, including myelodysplastic syndrome, myeloproliferativedisorders, acute myeloid leukemia and bronchial carcinoma.  The associationwith TREANDA therapy has not been determined.

There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.

TREANDA can cause fetalharm when administered to a pregnant woman.  Single intraperitonealdoses of bendamustine in mice and rats administered during organogenesiscaused an increase in resorptions, skeletal and visceral malformations,and decreased fetal body weights. [See Use in Specific Populations (8.1)]

The data described below reflectexposure to TREANDA in 349 patients who participated in an actively-controlledtrial (N=153) for the treatment of CLL and two single-arm studies(N=176) for the treatment of indolent B-cell NHL.  Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.

The following serious adverse reactions have been associatedwith TREANDA in clinical trials and are discussed in greater detailin other sections of the label.

The data described belowreflect exposure to TREANDA in 153 patients.  TREANDA was studiedin an active-controlled trial.  The population was 45-77 years ofage, 63% male, 100% white, and had treatment naïve CLL. All patientsstarted the study at a dose of 100 mg/m intravenously over 30 minutes on Days 1 and 2 every 28 days. 

Adverse reactions were reported accordingto NCI CTC v.2.0.  In the randomized CLL clinical study, non-hematologicadverse reactions (any grade) in the TREANDA group that occurred witha frequency greater than 15% were pyrexia (24%), nausea (20%), andvomiting (16%).  

Other adverse reactions seen frequently in one or more studies includedasthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough;constipation; headache; mucosal inflammation and stomatitis. 

Worsening hypertension was reportedin 4 patients treated with TREANDA in the randomized CLL clinicalstudy and none treated with chlorambucil.  Three of these 4 adversereactions were described as a hypertensive crisis and were managedwith oral medications and resolved.

The most frequent adverse reactions leading to studywithdrawal for patients receiving TREANDA were hypersensitivity (2%)and pyrexia (1%).

Table1 contains the treatment emergent adverse reactions, regardless ofattribution, that were reported in ≥ 5% of patients in either treatmentgroup in the randomized CLL clinical study.

The Grade 3 and 4 hematologylaboratory test values by treatment group in the randomized CLL clinicalstudy are described in Table 2. These findings confirm the myelosuppressiveeffects seen in patients treated with TREANDA. Red blood cell transfusionswere administered to 20% of patients receiving TREANDA compared with6% of patients receiving chlorambucil.

In the randomized CLLclinical study, 34% of patients had bilirubin elevations, some withoutassociated significant elevations in AST and ALT.  Grade 3 or 4 increasedbilirubin occurred in 3% of patients.  Increases in AST and ALT ofGrade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatininelevels. If abnormalities are detected, monitoring of these parametersshould be continued to ensure that significant deterioration doesnot occur.

The data described belowreflect exposure to TREANDA in 176 patients with indolent B-cell NHLtreated in two single-arm studies.  The population was 31-84 yearsof age, 60% male, and 40% female.  The race distribution was 89% White,7% Black, 3% Hispanic, 1% other, and <1% Asian. These patientsreceived TREANDA at a dose of 120 mg/m intravenously onDays 1 and 2 for up to 8 21-day cycles.

The adverse reactions occurring in at least5% of the NHL patients, regardless of severity, are shown in Table3. 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, hypokalemiaand 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, seriousadverse reactions, regardless of causality, were reported in 37% ofpatients receiving TREANDA.  The most common serious adverse reactionsoccurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trialsand/or post-marketing experience were acute renal failure, cardiacfailure, hypersensitivity, skin reactions, pulmonary fibrosis, andmyelodysplastic syndrome.

Serious drug-related adverse reactions reported in clinical trialsincluded myelosuppression, infection, pneumonia, tumor lysis syndromeand infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly relatedto TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypicalpneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

The following adverse reactions have been identified during post-approval use of TREANDA.  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.

Skin reactions including SJS and TEN have occurred when TREANDA wasadministered concomitantly with allopurinol and other medicationsknown to cause these syndromes.  [See Warnings and Precautions (5.5)].

No formal clinical assessmentsof pharmacokinetic drug-drug interactions between TREANDA and otherdrugs have been conducted. 

Bendamustine's active metabolites, gamma-hydroxy bendamustine (M3)and N-desmethyl-bendamustine (M4), are formed via cytochrome P450CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) havepotential to increase plasma concentrations of bendamustine and decreaseplasma concentrations of active metabolites.  Inducers of CYP1A2 (e.g.,omeprazole, smoking) have potential to decrease plasma concentrationsof bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitanttreatment with CYP1A2 inhibitors or inducers is needed. 

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

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

Pregnancy CategoryD [See Warnings and Precautions (5.8)]

TREANDA can cause fetal harm when administeredto a pregnant woman.  Single intraperitoneal doses of bendamustinefrom 210 mg/m (70 mg/kg) in mice administered during organogenesiscaused 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 bematernally toxic and lower doses were not eva luated.  Repeat intraperitonealdosing in mice on gestation days 7-11 resulted in an increase in resorptionsfrom 75 mg/m (25 mg/kg) and an increase in abnormalitiesfrom 112.5 mg/m (37.5 mg/kg) similar to those seen aftera single intraperitoneal administration.  Single intraperitoneal dosesof bendamustine from 120 mg/m (20 mg/kg) in rats administeredon gestation days 4, 7, 9, 11, or 13 caused embryo and fetal lethalityas indicated by increased resorptions and a decrease in live fetuses. Asignificant increase in external [effect on tail, head, and herniationof external organs (exomphalos)] and internal (hydronephrosis andhydrocephalus) malformations were seen in dosed rats.  There are noadequate and well-controlled studies in pregnant women.  If this drugis used during pregnancy, or if the patient becomes pregnant whiletaking this drug, the patient should be apprised of the potentialhazard to the fetus.

It is not known whetherthis drug is excreted in human milk. Because many drugs are excretedin human milk and because of the potential for serious adverse reactionsin nursing infants and tumorigenicity shown for bendamustine in animalstudies, a decision should be made whether to discontinue nursingor to discontinue the drug, taking into account the importance ofthe drug to the mother.

The safety and effectivenessof TREANDA in pediatric patients have not been established.

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

Chronic Lymphocytic Leukemia

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

Non-Hodgkin’s Lymphoma

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

No formal studies assessingthe impact of renal impairment on the pharmacokinetics of bendamustinehave been conducted.  TREANDA should be used with caution in patientswith mild or moderate renal impairment.  TREANDA should not be usedin patients with CrCL < 40 mL/min.  [See Clinical Pharmacology (12.3)]

No formal studies assessingthe impact of hepatic impairment on the pharmacokinetics of bendamustinehave been conducted.  TREANDA should be used with caution in patientswith mild hepatic impairment.  TREANDA should not be used in patientswith moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 XULN) or severe (total bilirubin > 3 X ULN) hepatic impairment.  [See ClinicalPharmacology (12.3)]

No clinically significantdifferences between genders were seen in the overall incidences ofadverse 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 TREANDA group was 60% and 57%,respectively.  The ORR for men (n=90) and women (n=58) in the chlorambucilgroup was 24% and 28%, respectively.  In this study, the median progression-freesurvival for men was 19 months in the TREANDA treatment group and6 months in the chlorambucil treatment group. For women, the medianprogression-free survival was 13 months in the TREANDA treatment groupand 8 months in the chlorambucil treatment group.  

Non-Hodgkin’s Lymphoma

The pharmacokineticsof bendamustine were similar in male and female patients with indolentNHL. No clinically-relevant differences between genders were seenin efficacy (ORR and DR).

The intravenous LD of bendamustine HCl is 240 mg/m in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratorydistress. 

Across all clinicalexperience, the reported maximum single dose received was 280 mg/m. Three of four patients treated at this dose showed ECG changesconsidered dose-limiting at 7 and 21 days post-dosing. These changesincluded QT prolongation (one patient), sinus tachycardia (one patient),ST and T wave deviations (two patients) and left anterior fascicularblock (one patient). Cardiac enzymes and ejection fractions remainednormal in all patients.

No specific antidote for TREANDA overdose is known. Management ofoverdosage should include general supportive measures, including monitoringof hematologic parameters and ECGs.

TREANDA 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 CHClNO ∙ HCl, and the molecular weight is 394.7. Bendamustine hydrochloridecontains a mechlorethamine group and a benzimidazole heterocyclicring with a butyric acid substituent, and has the following structuralformula:

Manufacturer

Cephalon, Inc.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011