Drug: Beleodaq

Beleodaq is a histone deacetylase inhibitor with a sulfonamide-hydroxamide structure. The chemical name of belinostat is (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide. The structural formula is as follows: The molecular formula is C15H14N2O4S and the molecular weight is 318.35 g/mol. Belinostat is a white to off-white powder. It is slightly soluble in distilled water (0.14 mg/mL) and polyethylene glycol 400 (about 1.5 mg/mL), and is freely soluble in ethanol ( > 200 mg/mL). The pKa values are 7.87 and 8.71 by potentiometry and 7.86 and 8.59 by UV. Beleodaq (belinostat) for injection is supplied as a sterile lyophilized yellow powder containing 500 mg belinostat as the active ingredient. Each vial also contains 1000 mg L-Arginine, USP as an inactive ingredient. The drug product is supplied in a single-use 30 mL clear glass vial with a coated stopper and aluminum crimp seal with “flip-off” cap. Beleodaq is intended for intravenous administration after reconstitution with 9 mL Sterile Water for injection, and the reconstituted solution is further diluted with 250 mL of sterile 0.9% Sodium Chloride injection prior to infusion [see DOSAGE AND ADMINISTRATION]. Last reviewed on RxList: 8/1/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

The following serious adverse reactions are described in more detail in other sections of the prescribing information.
  • Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
  • Infection [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Toxicity [see WARNINGS AND PRECAUTIONS]
The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with Beleodaq were nausea, fatigue, pyrexia, anemia, and vomiting [see Clinical Studies]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Beleodaq may not reflect the rates observed in practice. Adverse Reactions in Patients with Peripheral T-Cell Lymphoma The safety of Beleodaq was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Beleodaq at a dosage of 1,000 mg/m² administered over 30 minutes by IV infusion once daily on Days 1-5 of a 21-day cycle [see Clinical Studies]. The median duration of treatment was 2 cycles (range 1 – 33 cycles). Table 2 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL. Table 2: Adverse Reactions Occurring in ≥ 10% of Patients by Preferred Term and Severity in Patients with Relapsed or Refractory PTCL (NCI-CTC Grade 1-4)
MedDRA Preferred Term Percentage of Patients (%)
(N=129) All Grades Grade 3 or 4 All Adverse Reactions 97 61 Nausea 42 1 Fatigue 37 5 Pyrexia 35 2 Anemia 32 11 Vomiting 29 1 Constipation 23 1 Diarrhea 23 2 Dyspnea 22 6 Rash 20 1 Peripheral Edema 20 0 Cough 19 0 Thrombocytopenia 16 7 Pruritus 16 3 Chills 16 1 Increased Blood Lactate Dehydrogenase 16 2 Decreased Appetite 15 2 Headache 15 0 Infusion Site Pain 14 0 Hypokalemia 12 4 Prolonged QT 11 4 Abdominal pain 11 1 Hypotension 10 3 Phlebitis 10 1 Dizziness 10 0 Note: Adverse reactions are listed by order of incidence in the “All Grades” category first, then by incidence in “ the Grade 3 or 4” category; MedDRA = Medical Dictionary for Regulatory Activities; Severity measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 Serious Adverse Reactions Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq . The most common serious adverse reactions ( > 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial. One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with Beleodaq. ECG analysis did not identify QTc prolongation. Discontinuations due to Adverse Reactions Twenty-five patients (19.4%) discontinued treatment with Beleodaq due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure. Dosage Modifications due to Adverse Reactions In the trial, dosage adjustments due to adverse reactions occurred in 12% of Beleodaq-treated patients. Read the Beleodaq (belinostat for injection for intravenous use) Side Effects Center for a complete guide to possible side effectsLearn More »

Source: http://www.rxlist.com

Dosing Information The recommended dosage of Beleodaq is 1,000 mg/m² administered over 30 minutes by intravenous infusion once daily on Days 1-5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. Dosage Modification For Hematologic And Non-Hematologic Toxicities Table 1 displays the recommended Beleodaq dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy.
  • Absolute neutrophil count (ANC) should be greater than or equal to 1.0 x 109/L and the platelet count should be greater than or equal to 50 x 109/L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Beleodaq according to the guidelines described in Table 1 below. Discontinue Beleodaq in patients who have recurrent ANC nadirs less than 0.5 x 109/L and/or recurrent platelet count nadirs less than 25 x 109/L after two dosage reductions.
  • Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment.
Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle. Table 1: Dosage Modifications for Hematologic and Non-Hematologic Toxicities
  Dosage Modification Dosage Modifications due to Hematologic Toxicities   Platelet count ≥ 25 x 109/L and nadir ANC ≥ 0.5 x 109/L No Change   Nadir ANC < 0.5 x 109/L (any platelet count) Decrease dosage by 25% (750 mg/m2)   Platelet count < 25 x 109/L (any nadir ANC) Dosage Modifications due to Non-Hematologic Toxicities   Any CTCAE Grade 3 or 4 adverse reactiona Decrease dosage by 25% (750 mg/m2)   Recurrence of CTCAE Grade 3 or 4 adverse reaction after two dosage reductions Discontinue Beleodaq aFor nausea, vomiting, and diarrhea, only dose modify if the duration is greater than 7 days with supportive management Patients With Reduced UGT1A1 Activity Reduce the starting dose of Beleodaq to 750 mg/m² in patients known to be homozygous for the UGT1A1*28 allele [see CLINICAL PHARMACOLOGY]. Preparation And Administration Precautions As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Beleodaq. Reconstitution And Infusion Instructions
  1. Aseptically reconstitute each vial of Beleodaq by adding 9 mL of Sterile Water for injection, USP, into the Beleodaq vial with a suitable syringe to achieve a concentration of 50 mg of belinostat per mL. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted product may be stored for up to 12 hours at ambient temperature (15-25°C; 59-77°F).
  2. Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient's BSA [m²]) and transfer to an infusion bag containing 250 mL of 0.9 % Sodium Chloride injection. The infusion bag with drug solution may be stored at ambient room temperature (15-25°C; 59-77°F) for up to 36 hours including infusion time.
  3. Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed.
  4. Connect the infusion bag containing drug solution to an infusion set with a 0.22 μm in-line filter for administration.
  5. Infuse intravenously over 30 minutes. If infusion site pain or other symptoms potentially attributable to the infusion occur, the infusion time may be extended to 45 minutes.

Source: http://www.rxlist.com

UGT1A1 Inhibitors Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1 [see CLINICAL PHARMACOLOGY]. Warfarin Co-administration of Beleodaq and warfarin resulted in no clinically relevant increase in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment [see CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 8/1/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Beleodaq is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies]. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Source: http://www.rxlist.com

None Last reviewed on RxList: 8/1/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

No specific information is available on the treatment of overdosage of Beleodaq. There is no antidote for Beleodaq and it is not known if Beleodaq is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The elimination half-life of belinostat is 1.1 hours [see CLINICAL PHARMACOLOGY].

Source: http://www.rxlist.com

Dosage Forms And Strengths For injection: 500 mg, lyophilized powder in single-use vial for reconstitution Beleodaq (belinostat) for injection is supplied in single vial cartons; each 30 mL clear vial contains sterile, lyophilized powder equivalent to 500 mg belinostat. NDC 68152-108-09: Individual carton of Beleodaq 30 mL single-use vial containing 500 mg belinostat. Storage And Handling Store Beleodaq (belinostat) for injection at room temperature 20°C to 25°C (68°C to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Retain in original package until use. [see USP Controlled Room Temperature]. Beleodaq is a cytotoxic drug. Follow special handling and disposal procedures [see REFERENCES1]. REFERENCES 1 OSHA Hazardous Drugs. OSHA. [Accessed on 14 May 2014, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]. Manufactured for: Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Issued: July 2014 Last reviewed on RxList: 8/1/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Hematologic Toxicity Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Infections Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections [see ADVERSE REACTIONS]. Hepatotoxicity Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see ADVERSE REACTIONS]. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity [see DOSAGE AND ADMINISTRATION]. Tumor Lysis Syndrome Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL [see Clinical Studies]. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see ADVERSE REACTIONS]. Gastrointestinal Toxicity Nausea, vomiting and diarrhea occur with Beleodaq [see ADVERSE REACTIONS] and may require the use of antiemetic and antidiarrheal medications. Embryo-fetal Toxicity Beleodaq can cause fetal harm when administered to a pregnant woman. Beleodaq may cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells [see Nonclinical Toxicology]. Women of childbearing potential should be advised to avoid pregnancy while receiving Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus [see Use in Specific Populations]. Patient Counseling Informaton Physicians should discuss the FDA approved PATIENT INFORMATION Leaflet with patients prior to treatment with Beleodaq. Instruct patients to read the Patient Information Leaflet carefully. Advise the patient or the caregiver to read the FDA-approved patient labeling (PATIENT INFORMATION). Advise patients or their caregivers:
  • To report symptoms of nausea, vomiting and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered [see WARNINGS AND PRECAUTIONS].
  • To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia [see WARNINGS AND PRECAUTIONS].
  • To immediately report symptoms of infection (e.g., pyrexia) [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
  • Of the potential risk to the fetus and for women to avoid pregnancy while receiving Beleodaq [see WARNINGS AND PRECAUTIONS].
  • To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity studies have not been performed with belinostat. Belinostat was genotoxic in a bacterial reverse mutation test (Ames assay), an in vitro mouse lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay. Beleodaq may impair male fertility. Fertility studies using belinostat were not conducted. However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose dog toxicology study included reduced organ weights of the testes/epididymides that correlated with a delay in testicular maturation. Use In Specific Populations Pregnancy Pregnancy Category D [see WARNINGS AND PRECAUTIONS]. Risk Summary Beleodaq may cause teratogenicity and/or embryo-fetal lethality because it is a genotoxic drug and targets actively dividing cells [see Nonclinical Toxicology]. Women should avoid pregnancy while receiving Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus. Animal Data No reproductive and developmental animal toxicology studies have been conducted with belinostat. Nursing Mothers It is not known whether belinostat 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 from Beleodaq, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric patients were not included in clinical trials. The safety and effectiveness of Beleodaq in pediatric patients have not been established. Geriatric Use In the single-arm trial, 48% of patients (n = 62) were ≥ 65 years of age and 10% of patients (n=13) were ≥ 75 years of age [see Clinical Studies]. The median age of the trial population was 63 years. Patients ≥ 65 years of age had a higher response rate to Beleodaq treatment than patients < 65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients ≥ 75 years of age and those < 75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age ( < 65 years compared with ≥ 65 years or < 75 years of age compared with ≥ 75 years of age). Use In Patients With Hepatic Impairment Belinostat is metabolized in the liver and hepatic impairment is expected to increase exposure to belinostat. Patients with moderate and severe hepatic impairment (total bilirubin > 1.5 x upper limit of normal (ULN)) were excluded from clinical trials. There is insufficient data to recommend a dose of Beleodaq in patients with moderate and severe hepatic impairment [see CLINICAL PHARMACOLOGY]. Use In Patients With Renal Impairment Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites. Belinostat exposure is not altered in patients with Creatinine Clearance (CLcr) > 39 mL/min. There is insufficient data to recommend a dose of Beleodaq in patients with CLcr ≤ 39 mL/min. [see CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 8/1/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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