Belinostat (Monograph)

Brand name: Beleodaq
Drug class: Antineoplastic Agents
- HDAC Inhibitors
- Histone Deacetylase Inhibitors
Chemical name: N-Hydroxy-3-[3-[(phenylamino)sulfonyl]phenyl]-2-propenamide
Molecular formula: C₁₅H₁₄N₂O₄S
CAS number: 414864-00-9

Introduction

Antineoplastic agent; a histone deacetylase (HDAC) inhibitor.

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 cancer ). Efficacy determined based on overall response rate and duration of response in a noncomparative, open-label study in patients with relapsed or refractory PTCL.

Belinostat Dosage and Administration

General

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

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

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion through a 0.22-µm inline filter.

Belinostat powder for injection must be reconstituted and diluted prior to administration. (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. Swirl vial to ensure dissolution.

Dilution

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

Rate of Administration

Administer over 30 minutes.

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

Dosage

Adults

Peripheral T-cell Lymphoma

IV

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

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.

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%.

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%.

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

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%.

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

Reduced UGT1A1 Activity

IV

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

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Geriatric Patients

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

Cautions for Belinostat

Contraindications

• No known contraindications.

Warnings/Precautions

Hematologic Effects

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

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

Infectious Complications

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

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

Patients with active infection should not receive belinostat.

Hepatic Toxicity

Fatal hepatotoxicity and liver function test abnormalities may occur.

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

Tumor Lysis Syndrome

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

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

GI Effects

Nausea, vomiting, and diarrhea occur frequently.

Antiemetic and antidiarrheal therapy may be necessary.

Fetal/Neonatal Morbidity and Mortality

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

Impairment of Fertility

Animal studies suggest belinostat may impair male fertility.

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

Safety and efficacy not established.

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. No substantial differences in overall response rate in patients ≥75 years of age relative to younger adults.

No clinically important differences in safety relative to younger adults.

Hepatic Impairment

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

Renal Impairment

Systemic exposure not affected by Cl_cr >39 mL/minute.

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

Common Adverse Effects

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

Drug Interactions

Metabolized principally (80–90%) by UGT1A1.

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

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

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)

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

Specific Drugs

Belinostat Pharmacokinetics

Distribution

Extent

Not known whether belinostat is distributed into milk.

Plasma Protein Binding

92.9–95.8%.

Special Populations

Systemic exposure not affected by Cl_cr >39 mL/minute.

Elimination

Metabolism

Extensively metabolized in the liver, principally (80–90%) by UGT1A1. 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.

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).

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

Half-life

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

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.

Stability

Storage

Parenteral

Powder for Injection

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

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

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

Compatibility

Parenteral

Solution Compatibility

Actions

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

• 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.

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

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

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

Advice to Patients

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

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

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

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

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

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

• Risk of tumor lysis syndrome.

• 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).

• Importance of informing patients of other important precautionary information. (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.

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