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Belinostat

Class: Antineoplastic Agents
Chemical Name: N-Hydroxy-3-[3-[(phenylamino)sulfonyl]phenyl]-2-propenamide
Molecular Formula: C15H14N2O4S
CAS Number: 414864-00-9
Brands: Beleodaq

Introduction

Antineoplastic agent; a histone deacetylase (HDAC) inhibitor.1

Uses for Belinostat

Peripheral T-cell Lymphoma

Treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) (designated an orphan drug by FDA for treatment of this cancer4 ).1 2 3 10 Efficacy determined based on overall response rate and duration of response in a noncomparative, open-label study in patients with relapsed or refractory PTCL.1

Belinostat Dosage and Administration

General

  • Obtain CBC prior to initiation of therapy and weekly during therapy.1 Perform serum chemistry tests, including hepatic and renal function tests, before the first belinostat dose of each treatment cycle.1 (See Dosage Modification under Dosage and Administration.)

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion through a 0.22-mcm inline filter.1

Belinostat powder for injection must be reconstituted and diluted prior to administration.1 (See Storage under Stability.)

Reconstitution

Reconstitute vial containing 500 mg of belinostat with 9 mL of sterile water for injection to provide a solution containing 50 mg/mL.1 Swirl vial to ensure dissolution.1

Dilution

Dilute appropriate dose in 250 mL of 0.9% sodium chloride injection.1

Rate of Administration

Administer over 30 minutes.1

If infusion site reactions (e.g., pain) occur, may administer over 45 minutes.1

Dosage

Adults

Peripheral T-cell Lymphoma
IV

1 g/m2 daily on days 1–5 of each 21-day cycle.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification
Hematologic Toxicity
IV

For nadir ANC ≥500/mm3 and nadir platelet count ≥25,000/mm3, interrupt therapy until ANC ≥1000/mm3 and platelet count ≥50,000/mm3, and then resume at the same dosage.1

For nadir ANC <500/mm3 with any platelet count, interrupt therapy until ANC ≥1000/mm3 and platelet count ≥50,000/mm3; upon resumption, reduce dosage by 25%.1

For nadir platelet count <25,000/mm3 with any ANC, interrupt therapy until ANC ≥1000/mm3 and platelet count ≥50,000/mm3; upon resumption, reduce dosage by 25%.1

If ANC <500/mm3 and/or platelet count <25,000/mm3 recurs following 2 dosage reductions, discontinue therapy.1

Nonhematologic Toxicity
IV

For prolonged grade 3 or 4 nausea, vomiting, and/or diarrhea (persisting for >7 days despite supportive management) or for other grade 3 or 4 nonhematologic toxicity, interrupt therapy until toxicity resolves to grade 2 or less; upon resumption, reduce dosage by 25%.1

If grade 3 or 4 nonhematologic toxicity recurs following 2 dosage reductions, discontinue therapy.1

Reduced UGT1A1 Activity
IV

In patients who are homozygous for the UGT1A1*28 allele, reduce initial dose to 750 mg/m2.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Special Populations

Hepatic Impairment

Moderate or severe hepatic impairment: Insufficient data to provide dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Clcr ≤39 mL/minute: Insufficient data to provide dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Belinostat

Contraindications

  • No known contraindications.1

Warnings/Precautions

Hematologic Effects

Thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia may occur.1

Monitor CBC weekly during therapy.1 (See Dosage Modification under Dosage and Administration.)

Infectious Complications

Serious and sometimes fatal infections, including pneumonia and sepsis, reported.1

Risk for life-threatening infections may be increased in patients with history of extensive or intensive chemotherapy.1

Patients with active infection should not receive belinostat.1

Hepatic Toxicity

Fatal hepatotoxicity and liver function test abnormalities may occur.1

Perform liver function tests prior to initiation of therapy and prior to each cycle.1 (See Dosage Modification under Dosage and Administration.)

Tumor Lysis Syndrome

Tumor lysis syndrome, including at least 1 death, reported.1

Increased risk of tumor lysis syndrome in patients with advanced stage disease and/or large tumor burden.1 Monitor closely and take appropriate precautions.1

GI Effects

Nausea, vomiting, and diarrhea occur frequently.1

Antiemetic and antidiarrheal therapy may be necessary.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Based on mechanism of action, embryo and fetal lethality and teratogenicity may occur.1 Avoid pregnancy during therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Impairment of Fertility

Animal studies suggest belinostat may impair male fertility.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether belinostat is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In patients with PTCL, overall response rate was 36% in patients ≥65 years of age compared with 16% in patients <65 years of age.1 No substantial differences in overall response rate in patients ≥75 years of age relative to younger adults.1

No clinically important differences in safety relative to younger adults.1

Hepatic Impairment

Data lacking in patients with moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN).1 (See Elimination under Pharmacokinetics.)

Renal Impairment

Systemic exposure not affected by Clcr >39 mL/minute.1

Data lacking in patients with Clcr ≤39 mL/minute.1 (See Elimination under Pharmacokinetics.)

Common Adverse Effects

Nausea,1 3 fatigue,1 pyrexia,1 anemia,1 vomiting,1 3 constipation,1 diarrhea,1 dyspnea,1 rash,1 peripheral edema,1 cough,1 thrombocytopenia1 , pruritus,1 chills,1 elevated concentrations of serum LDH,1 decreased appetite,1 headache,1 infusion site pain,1 3 hypokalemia,1 prolonged QT interval,1 abdominal pain,1 hypotension,1 phlebitis,1 dizziness.

Interactions for Belinostat

Metabolized principally (80–90%) by UGT1A1.1

Belinostat and its metabolites, including belinostat glucuronide, belinostat amide, and methyl belinostat, inhibit CYP2C8 and CYP2C9.1 Other metabolites, including 3-(anilinosulfonyl)-benzenecarboxylic acid (3-ASBA) and belinostat acid, inhibit CYP2C8.1

Likely substrate, but unlikely inhibitor, of P-glycoprotein (P-gp).1

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)

Potent UGT1A1 inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of belinostat).1 Avoid concomitant use.1

Specific Drugs

Drug

Interaction

Warfarin

No substantial effect on AUC and peak plasma concentration of R- or S-warfarin1

Belinostat Pharmacokinetics

Distribution

Extent

Not known whether belinostat is distributed into milk.1

Plasma Protein Binding

92.9–95.8%.1

Special Populations

Systemic exposure not affected by Clcr >39 mL/minute.1

Elimination

Metabolism

Extensively metabolized in the liver, principally (80–90%) by UGT1A1.1 Also metabolized to belinostat amide and belinostat acid by CYP2A6, 2C9, and 3A4; enzymes responsible for conversion to methyl belinostat and 3-ASBA not determined to date.1

Elimination Route

Main circulating metabolites are excreted in urine; 2 metabolites (3-ASBA and belinostat glucuronide) predominate (4.61 and 30.5% of dose, respectively).1

Minimally (<2%) excreted in urine as unchanged drug.1

Half-life

1.1 hours (over dosage range of 150–1200 mg/m2).1

Special Populations

In patients with genetic polymorphisms associated with reduced UGT1A1 activity (e.g., individuals homozygous for the UGT1A1*28 allele), clearance may be reduced.1

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 20–25°C (may be exposed to 15–30°C).1

Reconstituted drug: 15–25°C for up to 12 hours.1

Diluted infusion solution: 15–25°C for up to 36 hours (including infusion time).1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%1

Actions

  • Inhibits enzymatic activity of histone deacetylases and exhibits cytotoxic activity and induces apoptosis in various tumor cell lines at nanomolar concentrations;1 5 9 HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.1 5 6 7 8

  • Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones observed in some cancer cells.7 8

  • Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription.6 7 8

  • Inhibition of HDAC activity allows for accumulation of acetyl groups on the histone lysine residues, resulting in an open chromatin structure and transcriptional activation.7 8

  • In vitro, causes accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.1

Advice to Patients

  • Importance of instructing patients to read the manufacturer’s patient information carefully before starting therapy and before each treatment.1

  • Importance of informing patients that nausea, vomiting, and diarrhea occur frequently and antiemetic and/or antidiarrheal therapy may be necessary.1 Importance of informing clinicians if nausea, vomiting, or diarrhea occurs.1

  • Risk of cytopenias.1 Importance of informing clinician immediately if unusual bleeding or bruising, tiredness, pallor, shortness of breath, or infection occurs.1

  • Risk of infections.1 Importance of informing clinician if fever, flu-like symptoms, cough, shortness of breath, burning on urination, muscle aches, or worsening skin problems occur.1

  • Risk of fetal harm.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women of childbearing potential to avoid pregnancy.1 Apprise patient of potential fetal hazard if used during pregnancy.1

  • Risk of hepatotoxicity and importance of liver function test monitoring.1 Importance of informing clinician if icteric changes, dark urine, pruritus, or abdominal pain (particularly in right upper quadrant) occurs.1

  • Risk of tumor lysis syndrome.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Belinostat

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

500 mg

Beleodaq

Spectrum

AHFS DI Essentials. © Copyright 2016, Selected Revisions March 9, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Spectrum Pharmaceuticals, Inc. Beleodaq (belinostat) for injection prescribing information. Irvine, CA; 2014 Jul.

2. O'Connor OW, Masszi T, Savage KJ et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. J Clin Oncol. 2013; 31 (suppl): Abstract No. 8507 (presented at the 48th Annual ASCO Meeting. Chicago, IL: 2013 Jun 1).

3. Foss F, Advani R, Duvic M et al. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol. 2014; :. [PubMed 25404094]

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Jul 15.

5. Steele NL, Plumb JA, Vidal L et al. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res. 2008; 14:804-10. [PubMed 18245542]

6. Howman RA, Prince HM. New drug therapies in peripheral T-cell lymphoma. Expert Rev Anticancer Ther. 2011; 11:457-72. [PubMed 21417858]

7. Merck & Co., Inc. Zolinza (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2013 Apr.

8. Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer. 2006; 95:S2-6:

9. Plumb JA, Finn PW, Williams RJ et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther. 2003; 2:721-8. [PubMed 12939461]

10. Reimer P, Chawla S. Long-term complete remission with belinostat in a patient with chemotherapy refractory peripheral T-cell lymphoma. J Hematol Oncol. 2013; 6:69. [PubMed 24020452]

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