Treanda Information
Treanda (Bendamustine)
Treanda (Bendamustine) Dosage and Administration
Recommended Dosage:
The recommended dose is 100 mg/m administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
Treanda (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 10/L, platelets ≥ 75 x 10/L], Treanda (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/m on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m 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/m 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/m 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:
Treanda (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 10/L, platelets ≥ 75 x 10/L], Treanda (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/m on Days 1 and 2 of 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 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.
Treanda (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 Treanda (Bendamustine) must be completed within this period.
Treanda (Bendamustine) Dosage Forms And Strengths
Treanda (Bendamustine) for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.
Treanda (Bendamustine) Contraindications
Treanda (Bendamustine) is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine or mannitol.
Treanda (Bendamustine) Warnings And Precautions
Patients treated with Treanda (Bendamustine) are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (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 closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have 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 10/L and the platelet count should be ≥ 75 x 10/L.
A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when Treanda (Bendamustine) was given in combination with other anticancer agents, so the precise relationship to Treanda (Bendamustine) is uncertain.
In a study of Treanda (Bendamustine) (90 mg/m) 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 Treanda (Bendamustine) was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to Treanda (Bendamustine) cannot be determined.
Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, Treanda (Bendamustine) should be withheld or discontinued.
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 (Bendamustine) .
Treanda (Bendamustine) Adverse Reactions
The data described below reflect exposure to Treanda (Bendamustine) in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following serious adverse reactions have been associated with Treanda (Bendamustine) in clinical trials and are discussed in greater detail in other sections of the label.
Treanda (Bendamustine) Drug Interactions
No formal clinical assessments of pharmacokinetic drug-drug interactions between Treanda (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. data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport.
Based on 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.
Treanda (Bendamustine) Use In Specific Populations
Pregnancy Category D
Treanda (Bendamustine) can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine from 210 mg/m (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/m (25 mg/kg) and an increase in abnormalities from 112.5 mg/m (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m (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.
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 Treanda (Bendamustine) . The overall response rate for patients younger than 65 years of age was 70% (n=82) for Treanda (Bendamustine) and 30% (n = 69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for Treanda (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 Treanda (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 Treanda (Bendamustine) group and 8 months in the chlorambucil group.
Non-Hodgkin’s Lymphoma
Efficacy (Overall Response Rate and Duration of Response) was similar in patients
No clinically significant differences between genders were seen in the overall incidences of adverse reactions in either CLL or NHL studies.
In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the Treanda (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 Treanda (Bendamustine) treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the Treanda (Bendamustine) treatment group and 8 months in the chlorambucil treatment group.
Non-Hodgkin’s 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).
Treanda (Bendamustine) Overdosage
The intravenous LD of bendamustine HCl is 240 mg/m 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/m. 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 Treanda (Bendamustine) overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.
Treanda (Bendamustine) Description
Treanda (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 CHClNO 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:
Treanda (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.
Treanda (Bendamustine) Clinical Studies
The safety and efficacy of Treanda (Bendamustine) were evaluated in an open-label, randomized, controlled multicenter trial comparing Treanda (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 Treanda (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 65.7x10/L vs. 65.1x10/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 Treanda (Bendamustine) at 100 mg/m, 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 CLL.
The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for Treanda (Bendamustine) compared to chlorambucil (see Table 5). Survival data are not mature.
Kaplan-Meier estimates of progression-free survival comparing Treanda (Bendamustine) with chlorambucil are shown in Figure 1.
The efficacy of Treanda (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 Treanda (Bendamustine) intravenously at a dose of 120 mg/m, 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.
Treanda (Bendamustine) 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 Treanda (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 Treanda (Bendamustine) contacts the skin, wash the skin immediately and thoroughly with soap and water. If Treanda (Bendamustine) contacts the mucous membranes, flush thoroughly with water.
Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Treanda (Bendamustine) (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows:
NDC 63459-390-08 Treanda (Bendamustine) (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial
NDC 63459-391-20 Treanda (Bendamustine) (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial
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