Belinostat: Difference between revisions

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{{DrugProjectFormSinglePage
{{DrugProjectFormSinglePage
|authorTag=
|authorTag={{AV}}
 
|genericName=Belinostat
 
|aOrAn=an
<!--Overview-->
|adverseReactions=<!--Black Box Warning-->
 
|blackBoxWarningTitle=Title
|genericName=
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
 
 
 
|aOrAn=
 
a
 
|drugClass=
 
 
 
|indication=
 
 
 
|hasBlackBoxWarning=
 
Yes
 
|adverseReactions=
 
 
 
<!--Black Box Warning-->
 
|blackBoxWarningTitle=
Title
 
|blackBoxWarningBody=
<i><span style="color:#FF0000;">ConditionName: </span></i>


* Content
* Content
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<!--FDA-Labeled Indications and Dosage (Adult)-->
<!--FDA-Labeled Indications and Dosage (Adult)-->
|fdaLIADAdult======Condition1=====
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 (14)]. 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
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.


|fdaLIADAdult=
2.2 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.


=====Condition1=====
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 Beleodaq according to the guidelines described in Table 1 below. Discontinue Beleodaq 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.
TABLE02
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 (12.5)].


* Dosing Information
2.4 Preparation and Administration Precautions
As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Beleodaq.


2.5 Reconstitution and Infusion Instructions
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).
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.
:* Dosage
:* Dosage


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<!--Guideline-Supported Use (Adult)-->
<!--Guideline-Supported Use (Adult)-->
 
|offLabelAdultGuideSupport======Condition1=====
|offLabelAdultGuideSupport=
 
=====Condition1=====


* Developed by:  
* Developed by:  
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<!--Non–Guideline-Supported Use (Adult)-->
<!--Non–Guideline-Supported Use (Adult)-->
 
|offLabelAdultNoGuideSupport======Condition1=====
|offLabelAdultNoGuideSupport=
 
=====Condition1=====


* Dosing Information
* Dosing Information
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<!--FDA-Labeled Indications and Dosage (Pediatric)-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
 
|fdaLIADPed======Condition1=====
|fdaLIADPed=
 
=====Condition1=====


* Dosing Information
* Dosing Information
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<!--Guideline-Supported Use (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
 
|offLabelPedGuideSupport======Condition1=====
|offLabelPedGuideSupport=
 
=====Condition1=====


* Developed by:  
* Developed by:  
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<!--Non–Guideline-Supported Use (Pediatric)-->
<!--Non–Guideline-Supported Use (Pediatric)-->
 
|offLabelPedNoGuideSupport======Condition1=====
|offLabelPedNoGuideSupport=
 
=====Condition1=====


* Dosing Information
* Dosing Information
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<!--Contraindications-->
<!--Contraindications-->
|contraindications=* None.
<!--Warnings-->
|warnings=* 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 (2.2) and Adverse Reactions(6.1)].


|contraindications=
5.2 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 (6.1)].


* Condition1
5.3 Hepatotoxicity
Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. 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 (2.2)].


<!--Warnings-->
5.4 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 (14)]. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see Adverse Reactions (6.1)].


|warnings=
5.5 Gastrointestinal Toxicity
Nausea, vomiting and diarrhea occur with Beleodaq [see Adverse Reactions (6.1)] and may require the use of antiemetic and antidiarrheal medications.


* Description
5.6 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 (13.1)]. 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


====Precautions====
====Precautions====
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<!--Clinical Trials Experience-->
<!--Clinical Trials Experience-->
|clinicalTrials=The following serious adverse reactions are described in more detail in other sections of the prescribing information.
Hematologic Toxicity  [see Warnings and Precautions ( 5.1)]
Infection [see Warnings and Precautions (5.2)]
Hepatotoxicity [see Warnings and Precautions (5.3)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
Gastrointestinal Toxicity [see Warnings and Precautions (5.5)]
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 (14)].
6.1 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 (14)]. 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.
TABLE04
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.


|clinicalTrials=
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.
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.


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<!--Postmarketing Experience-->
<!--Postmarketing Experience-->
 
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
|postmarketing=
 
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.


=====Body as a Whole=====
=====Body as a Whole=====
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<!--Drug Interactions-->
<!--Drug Interactions-->
|drugInteractions=*UGT1A1 Inhibitors
Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1 [see Clinical Pharmacology (12.3)].


|drugInteractions=
7.2 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
<!--Use in Specific Populations-->
|useInPregnancyFDA=*Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.6)].


* Drug
Risk Summary
:* Description


<!--Use in Specific Populations-->
Beleodaq may cause teratogenicity and/or embryo-fetal lethality because it is a genotoxic drug and targets actively dividing cells [see Nonclinical Toxicology (13.1)]. 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.


|useInPregnancyFDA=
Animal Data
* '''Pregnancy Category'''


|useInPregnancyAUS=
No reproductive and developmental animal toxicology studies have been conducted with belinostat.
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''


There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=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.
|useInPed=Pediatric patients were not included in clinical trials. The safety and effectiveness of Beleodaq in pediatric patients have not been established.
|useInGeri=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 (14)]. 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).
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=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.
|useInHepaticImpair= 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.


|useInLaborDelivery=
There is insufficient data to recommend a dose of Beleodaq in patients with moderate and severe hepatic impairment  
There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
 
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
 
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
 
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
 
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
 
|useInRace=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
 
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
 
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
 
|useInReproPotential=
There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
 
|useInImmunocomp=
There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.


<!--Administration and Monitoring-->
<!--Administration and Monitoring-->
 
|administration=* Oral
|administration=
 
* Oral


* Intravenous
* Intravenous
 
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
|monitoring=
 
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.


* Description
* Description


<!--IV Compatibility-->
<!--IV Compatibility-->
 
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
|IVCompat=
 
There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.


<!--Overdosage-->
<!--Overdosage-->
 
|overdose=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
|overdose=
 
===Acute Overdose===
 
====Signs and Symptoms====
 
* Description
 
====Management====
 
* Description
 
===Chronic Overdose===
 
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
 
<!--Pharmacology-->
<!--Pharmacology-->


<!--Drug box 2-->
<!--Drug box 2-->
|drugBox=<!--Mechanism of Action-->
|mechAction=*Mechanism of Action
Beleodaq 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).


|drugBox=
<!--Structure-->
|structure=*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:


: [[File:{{PAGENAME}}01.png|thumb|none|600px|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.


<!--Mechanism of Action-->
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
<!--Pharmacodynamics-->
|PD=Cardiac Electrophysiology


|mechAction=
Multiple clinical trials have been conducted with Beleodaq, 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 Beleodaq on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Beleodaq 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.
|PK=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


<!--Structure-->
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.


|structure=
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.


: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
Excretion


<!--Pharmacodynamics-->
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).


|PD=
Drug-Drug Interactions


There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
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.


<!--Pharmacokinetics-->
In cancer patients, co-administration of Beleodaq (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.


|PK=
Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp.


There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
12.5 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 Beleodaq to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities.
<!--Nonclinical Toxicology-->
<!--Nonclinical Toxicology-->
|nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with belinostat.


|nonClinToxic=
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.


There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
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
<!--Clinical Studies-->
|clinicalStudies=Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)


<!--Clinical Studies-->
In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Beleodaq 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.


|clinicalStudies=
Table 3 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy.


There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
TABLE 04


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 Beleodaq.
<!--How Supplied-->
<!--How Supplied-->
|howSupplied=* How Supplied


|howSupplied=
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.


<!--Patient Counseling Information-->
16.2 Storage and Handling


|fdaPatientInfo=
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].


There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
Beleodaq is a cytotoxic drug. Follow special handling and disposal procedures


<!--Precautions with Alcohol-->
<!--Patient Counseling Information-->
|fdaPatientInfo=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.


|alcohol=
Advise the patient or the caregiver to read the FDA-approved patient labeling (Patient Information).


* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Advise patients or their caregivers:


<!--Brand Names-->
To report symptoms of nausea, vomiting and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered [see Warnings and Precautions (5.5)].
To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia [see Warnings and Precautions ( 5.1 )].
To immediately report symptoms of infection (e.g., pyrexia) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Of the potential risk to the fetus and for women to avoid pregnancy while receiving Beleodaq [see Warnings and Precautions (5.6)].
To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury


|brandNames=
<!--Precautions with Alcohol-->
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.


* ®<ref>{{Cite web | title =  | url =  }}</ref>
<!--Brand Names-->
|brandNames=* ®<ref>{{Cite web | title =  | url =  }}</ref>


<!--Look-Alike Drug Names-->
<!--Look-Alike Drug Names-->
 
|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>
|lookAlike=
 
* A® — B®<ref name="www.ismp.org">{{Cite web  | last =  | first =  | title = http://www.ismp.org | url = http://www.ismp.org | publisher =  | date =  }}</ref>


<!--Drug Shortage Status-->
<!--Drug Shortage Status-->
|drugShortage=
|drugShortage=
}}
}}
{{PillImage
|fileName=No image.jpg
}}
{{LabelImage
|fileName={{PAGENAME}}05.png
}}
{{LabelImage
|fileName={{PAGENAME}}06.png
}}
<!--Pill Image-->


<!--Pill Image-->


{{PillImage
|fileName=No image.jpg|This image is provided by the National Library of Medicine.
|drugName=
|NDC=
|drugAuthor=
|ingredients=
|pillImprint=
|dosageValue=
|dosageUnit=
|pillColor=
|pillShape=
|pillSize=
|pillScore=
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<!--Label Display Image-->
<!--Label Display Image-->


{{LabelImage
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
}}


{{LabelImage
 
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
 
}}


<!--Category-->
<!--Category-->


[[Category:Drug]]
[[Category:Drug]]

Revision as of 15:05, 9 February 2015

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 {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1

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 (14)]. 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
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.

2.2 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 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 Beleodaq according to the guidelines described in Table 1 below. Discontinue Beleodaq 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. TABLE02 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 (12.5)].

2.4 Preparation and Administration Precautions As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Beleodaq.

2.5 Reconstitution and Infusion Instructions 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). 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.

  • Dosage
Condition2
  • Dosing Information
  • Dosage
Condition3
  • Dosing Information
  • Dosage
Condition4
  • Dosing Information
  • Dosage

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

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

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

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)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Belinostat in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

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

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

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

Contraindications

  • None.

Warnings

  • 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 (2.2) and Adverse Reactions(6.1)].

5.2 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 (6.1)].

5.3 Hepatotoxicity Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. 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 (2.2)].

5.4 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 (14)]. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see Adverse Reactions (6.1)].

5.5 Gastrointestinal Toxicity Nausea, vomiting and diarrhea occur with Beleodaq [see Adverse Reactions (6.1)] and may require the use of antiemetic and antidiarrheal medications.

5.6 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 (13.1)]. 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

Precautions

  • Description

Adverse Reactions

Clinical Trials Experience

The following serious adverse reactions are described in more detail in other sections of the prescribing information.

Hematologic Toxicity [see Warnings and Precautions ( 5.1)] Infection [see Warnings and Precautions (5.2)] Hepatotoxicity [see Warnings and Precautions (5.3)] Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] Gastrointestinal Toxicity [see Warnings and Precautions (5.5)] 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 (14)].

6.1 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 (14)]. 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. TABLE04 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. There is limited information regarding Clinical Trial Experience of Belinostat in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Postmarketing Experience

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

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Drug Interactions

  • UGT1A1 Inhibitors

Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1 [see Clinical Pharmacology (12.3)].

7.2 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

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.6)].

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 (13.1)]. 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.
Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

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 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.

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 [see Clinical Studies (14)]. 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).

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

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.

Hepatic Impairment

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

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

  • Oral
  • Intravenous

Monitoring

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

  • Description

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 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

Pharmacology

There is limited information regarding Belinostat Pharmacology in the drug label.

Mechanism of Action

  • Mechanism of Action

Beleodaq 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

  • 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:
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.

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

Pharmacodynamics

Cardiac Electrophysiology

Multiple clinical trials have been conducted with Beleodaq, 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 Beleodaq on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Beleodaq 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 Beleodaq (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.

12.5 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 Beleodaq 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 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

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 Beleodaq 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.

TABLE 04

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 Beleodaq.

How Supplied

  • How Supplied

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.

16.2 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

Storage

There is limited information regarding Belinostat Storage in the drug label.

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 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 (5.5)]. To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia [see Warnings and Precautions ( 5.1 )]. To immediately report symptoms of infection (e.g., pyrexia) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Of the potential risk to the fetus and for women to avoid pregnancy while receiving Beleodaq [see Warnings and Precautions (5.6)]. To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury

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

Look-Alike Drug Names

Drug Shortage Status

Price

References

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

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