Belrapzo Drug Information

Chronic Lymphocytic Leukemia (CLL) BELRAPZO is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

Non-Hodgkin Lymphoma (NHL) BELRAPZO 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.

Admixture Stability

BELRAPZO contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. If diluted with 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°C to 8°C or 36°F to 46°F) or for 3 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light.

Administration of diluted BELRAPZO must be completed within this period of time. BELRAPZO (bendamustine hydrochloride injection) is supplied in a multiple-dose vial. Retain the partially used vial in original package to protect from light and store refrigerated (2°C to 8°C or 36°F to 46°F) if additional dose withdrawal from the same vial is intended.

Stability of Partially Used Vials (Needle Punched Vials) BELRAPZO is supplied as a multiple-dose vial. Although it does not contain any antimicrobial preservative, BELRAPZO is bacteriostatic. The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2°C to 8°C or 36°F to 46°F).

Each vial is not recommended for more than a total of six dose withdrawals. After first use, store the partially used vial in original carton at 2°C to 8°C (36°F to 46°F), and then discard after 28 days.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in CLL The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled, randomized trial.

The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. Adverse reactions were reported according to NCI CTC v.2.0. Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in the randomized CLL clinical study and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%).

Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. These findings confirm the myelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study 30 In the randomized CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Patients treated with bendamustine hydrochloride 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. Clinical Trials Experience in NHL The data described below reflect exposure to bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Bendamustine Hydrochloride by System Organ Class and Preferred Term (N=176) 10 2 Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride.

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 post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions.

Adverse reactions occurring less frequently but possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic systems disorders: Pancytopenia Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling) Immune system disorders: Anaphylaxis Infections and infestations: Pneumocystis jirovecii pneumonia, progressive multifocal leukoencephalopathy (PML) Renal and urinary disorders: Nephrogenic diabetes insipidus (NDI) Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

Effect of Other Drugs on BELRAPZO CYP1A2 Inhibitors

The coadministration of BELRAPZO with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with BELRAPZO. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with BELRAPZO. CYP1A2 Inducers The coadministration of BELRAPZO with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of BELRAPZO.

Pregnancy Risk Summary In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth ( see Data ). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.

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

Data Animal data Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m 2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 (approximately the MRHD) on gestation days and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses.

A significant increase in external (effect on tail, head, and herniation of external organs ) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.

Females and Males of Reproductive Potential BELRAPZO can cause embryo-fetal harm when administered to a pregnant woman. Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with BELRAPZO. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with BELRAPZO and for 6 months after the last dose.

Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with BELRAPZO and for 3 months after the last dose. Infertility Based on findings from clinical studies, BELRAPZO may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs.

In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Advise patients of the potential risk to their reproductive capacities. Based on findings from animal studies, BELRAPZO may impair male fertility due to an increase in morphologically abnormal spermatozoa.

The long-term effects of BELRAPZO on male fertility, including the reversibility of adverse effects, have not been studied.

BELRAPZO is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. BELRAPZO is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions.

The intravenous LD50 of bendamustine hydrochloride is 240 mg/m 2 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 2.

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 hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.