Belinostat

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Belinostat
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]

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Overview

Belinostat is an antineoplastic agent that is FDA approved for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).. Common adverse reactions include nausea, fatigue, pyrexia, anemia, and vomiting, pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Peripheral T-cell lymphoma
  • Belinostat 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 . 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.

Dosing Information

  • The recommended dosage of Belinostat 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 Belinostat 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 10 9/L and the platelet count should be greater than or equal to 50 x 10 9/L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Belinostat according to the guidelines described in Table 1 below. Discontinue Belinostat in patients who have recurrent ANC nadirs less than 0.5 x 10 9/L and/or recurrent platelet count nadirs less than 25 x 10 9/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.
This image is provided by the National Library of Medicine.
Patients with Reduced UGT1A1 Activity
  • Reduce the starting dose of Belinostat to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele.
Preparation and Administration Precautions
  • As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Belinostat .
Reconstitution and Infusion Instructions
  • Aseptically reconstitute each vial of Belinostat by adding 9 mL of Sterile Water for injection, USP, into the Belinostat 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).
  • Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient’s BSA [m 2]) 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.
  • Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed.
  • Connect the infusion bag containing drug solution to an infusion set with a 0.22 µm in-line filter for administration.
  • 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belinostat in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belinostat in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Belinostat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belinostat in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belinostat in pediatric patients.

Contraindications

  • None.

Warnings

Hematologic Toxicity
Infections
Hepatotoxicity
  • Belinostat can cause fatal hepatotoxicity and liver function test abnormalities . Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Belinostat based on the severity of the hepatic toxicity
Tumor Lysis Syndrome
  • Tumor lysis syndrome has occurred in Belinostat -treated patients in the clinical trial of patients with relapsed or refractory PTCL . Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions .
Gastrointestinal Toxicity
Embryo-fetal Toxicity
  • Belinostat can cause fetal harm when administered to a pregnant woman. Belinostat may cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells . Women of childbearing potential should be advised to avoid pregnancy while receiving Belinostat . 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

Adverse Reactions

Clinical Trials Experience

  • The following serious adverse reactions are described in more detail in other sections of the prescribing information.
Clinical Trials Experience
  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Belinostat may not reflect the rates observed in practice.
Adverse Reactions in Patients with Peripheral T-Cell Lymphoma
  • The safety of Belinostat was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Belinostat 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 . 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.

This image is provided by the National Library of Medicine.

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
Discontinuations due to Adverse Reactions
  • Twenty-five patients (19.4%) discontinued treatment with Belinostat 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 Belinostat -treated patients.

There is limited information regarding Clinical Trial Experience of Belinostat in the drug label.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Belinostat in the drug label.

Drug Interactions

UGT1A1 Inhibitors
  • Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Belinostat with strong inhibitors of UGT1A1 .
Warfarin
  • Co-administration of Belinostat and warfarin resulted in no clinically relevant increase in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

Risk Summary
  • Belinostat may cause teratogenicity and/or embryo-fetal lethality because it is a genotoxic drug and targets actively dividing cells . Women should avoid pregnancy while receiving Belinostat . 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.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belinostat in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Belinostat during labor and delivery.

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 Belinostat , 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 Belinostat in pediatric patients have not been established.

Geriatic 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 . The median age of the trial population was 63 years. Patients ≥ 65 years of age had a higher response rate to Belinostat 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).

Gender

There is no FDA guidance on the use of Belinostat with respect to specific gender populations.

Race

There is no FDA guidance on the use of Belinostat with respect to specific racial populations.

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 Belinostat in patients with CLcr ≤ 39 mL/min.

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 Belinostat in patients with moderate and severe hepatic impairment

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Belinostat in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Belinostat in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Intravenous

Monitoring

IV Compatibility

There is limited information regarding IV Compatibility of Belinostat in the drug label.

Overdosage

  • No specific information is available on the treatment of overdosage of Belinostat . There is no antidote for Belinostat and it is not known if Belinostat 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

Pharmacology

This image is provided by the National Library of Medicine.

Mechanism of Action

  • Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM).

Structure

  • Belinostat 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:
This image is provided by the National Library of Medicine.

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.
  • Belinostat (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. Belinostat 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

Pharmacodynamics

Cardiac Electrophysiology
  • Multiple clinical trials have been conducted with Belinostat , in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Belinostat on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Belinostat on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes.

Pharmacokinetics

  • The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m2. The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent).
Distribution
  • The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL.
Metabolism
  • Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known.
Excretion
  • Belinostat is eliminated predominantly through metabolism with less than 2% of the dose recovered unchanged in urine. All major human metabolites (methyl belinostat, belinostat amide, belinostat acid, belinostat glucuronide, and 3-ASBA) are generally excreted in urine within the first 24 hours after dose administration. Metabolites 3-ASBA and belinostat glucuronide represented the highest fractions of the belinostat dose excreted in urine (4.61% and 30.5%, respectively).
Drug-Drug Interactions
  • In vitro studies showed belinostat and its metabolites (including belinostat glucuronide, belinostat amide, methyl belinostat) inhibited metabolic activities of CYP2C8 and CYP2C9. Other metabolites (3-ASBA and belinostat acid) inhibited CYP2C8.
  • In cancer patients, co-administration of Belinostat (1,000 mg/m2) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or Cmax of either R- or S-warfarin.
  • Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp.
Pharmacogenomics
  • UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 20% of the black population, 10% of the white population, and 2% of the Asian population are homozygous for the UGT1A1*28 allele. Additional reduced function alleles may be more prevalent in specific populations.
  • Because belinostat is primarily (80 -90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A1*28 allele). Reduce the starting dose of Belinostat to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Carcinogenicity studies have not been performed with belinostat.
  • Belinostat 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

Clinical Studies

Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)
  • In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Belinostat 1,000 mg/m2 administered over 30 minutes via IV infusion once daily on Days 1-5 of a 21-day cycle. There were 120 patients who had histologically confirmed PTCL by central review evaluable for efficacy. Patients were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity.
  • The primary efficacy endpoint was response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC) (Cheson 2007). The key secondary efficacy endpoint was duration of response. Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. Response and progression of disease were evaluated by the IRC using the IWC.
  • Table 3 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy.
This image is provided by the National Library of Medicine.
  • The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 – 29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3 - 50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Belinostat .

How Supplied

How Supplied
  • Belinostat (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 Belinostat 30 mL single-use vial containing 500 mg belinostat.

Storage

  • Store Belinostat (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. .
  • Belinostat is a cytotoxic drug. Follow special handling and disposal procedures

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

  • Physicians should discuss the FDA approved Patient Information Leaflet with patients prior to treatment with Belinostat . 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:

Precautions with Alcohol

  • Alcohol-Belinostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Belinostat ®

Look-Alike Drug Names

  • A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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