Dosing and uses of Beleodaq (belinostat)
Adult dosage forms and strengths
injection, lyophilized powder for reconstitution
- 500mg/vial
Peripherial T-Cell Lymphoma
Histone deacetylase (HDAC) inhibitor indicated for relapsed or refractory peripheral T-cell lymphoma
1000 mg/m² IV qDay on days 1-5 of a 21-day cycle
Infuse IV over 30 minutes
Cycles can be repeated every 21 days until disease progression or unacceptable toxicity
Dosage modifications
ANC should be ≥1.0 x 10^9/L and the platelet count should be ≥50 x 10^9/L prior to the start of each cycle and prior to resuming treatment following toxicity
Discontinue with recurrent ANC nadirs <0.5 x 10^9/L and/or recurrent platelet count nadirs <25 x 10^9/L after 2 dosage reductions
Other toxicities must be ≤grade 2 prior to re-treatment
Monitoring
- Monitor complete blood cell 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
Hematologic toxicities
- Platelet count ≥25 x 10^9/L and nadir ANC ≥0.5 x 10^9/L: No change
- Nadir ANC <0.5 x 10^9/L (any platelet count): Decrease dose by 25% (750 mg/m²)
- Platelet count <25 x 10^9/L (any nadir ANC): Decrease dose by 25% (750 mg/m²)
Non-hematologic toxicities
- Grade 3 or 4 adverse reaction: Decrease dose by 25% (750 mg/m²)
- Grade 3 or 4 nausea/vomiting/diarrhea >7 days: Decrease dose by 25% (750 mg/m²)
- Recurrence of Grade 3 or 4 adverse reaction after 2 dosage reductions: Discontinue
Reduced UGT1A1 activity
- Patients known to be homozygous for the UGT1A1*28 allele: Reduce starting dose to 750 mg/m²
Renal or hepatic impairment
- Metabolized in the liver and hepatic impairment is expected to increase systemic exposure; patients with moderate-to-severe hepatic impairment were excluded from clinical trials
- CrCl >39 mL/min: No dosage adjustment required
- CrCl ≤39 mL/min: Insufficient dose to recommend dosage modification
Dosing Considerations
Indication 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
Pediatric dosage forms and strengths
Safety and efficacy not established
Beleodaq (belinostat) adverse (side) effects
>10%
All toxicity grades
Nausea (42%)
Fatigue (37%)
Pyrexia (35%)
Anemia (32%)
Vomiting (29%)
Constipation (23%)
Diarrhea (23%)
Dyspnea (22%)
Rash (20%)
Peripheral edema (20%)
Cough (19%)
Thrombocytopenia (16%)
Pruritus (16%)
Chills (16%)
Increased blood lactate dehydrogenase (16%)
Decrease appetite (15%)
Headache (15%)
Infusion site pain (14%)
Hypokalemia (12%)
Prolonged QT (11%)
Abdominal pain (11%)
1-10%
Hypotension (10%)
Phlebitis (10%)
Dizziness (10%)
Warnings
Contraindications
None
Cautions
Thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia may occur; monitor blood cell counts and modify dosage for hematologic toxicities (see Dosage modifications)
Serious and fatal infections (eg, pneumonia and sepsis) reported; do not administer if patient has an active infection
May cause hepatic toxicity and liver function test abnormalities; monitor liver function tests before treatment and before each treatment cycle; omit or modify dosage for hepatic toxicities (see Dosage modifications)
Tumor lysis syndrome reported; monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions
Nausea, vomiting, and diarrhea commonly occur and may require the use of antiemetic and antidiarrheal medications
Can cause fetal harm when administered to a pregnant woman; advise women of potential harm to the fetus and to avoid pregnancy
Pregnancy and lactation
Pregnancy category: d
Lactation: Unknown if distributed in human breast milk; a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Beleodaq (belinostat)
Mechanism of action
Histone deacetylase (HDAC) inhibitor; HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins
In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells; shows preferential cytotoxicity towards tumor cells compared with normal cells
Distribution
Protein bound: 92.9-95.8%
Limited tissue distribution
Metabolism
Primarily by UGT1A1 (80-90%); also CYP2A6, CYP2C9, CYP3A4
Elimination
Half-life: 1.1 hr
Plasma clearance: 124 mL/min
Excretion: 40% urine (as metabolites); <2% urine (unchanged)
Pharmacogenomics
UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity (eg, UGT1A1*28 polymorphism) ~20% of the black population, 10% of the white population, and 2% of the Asian population are homozygous for the UGT1A1*28 allele
Because belinostat is primarily (80-90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (eg, patients with UGT1A1*28 allele)
Reduce initial dose in patients known to be homozygous for the UGT1A1*28 allele (see Dosage modifications)
Administration
IV Preparation
Aseptically reconstitute each vial by adding 9 mL of sterile water for injection; resulting concentration is 50 mg/mL
Swirl vial contents until there are no visible particles in the resulting solution
Further dilute by withdrawing volume needed for the required dosage from reconstituted vial and transfer to a 250-mL infusion bag of 0.9 % NaCL
Visually inspect the solution for particulate matter; do not use if cloudiness or particulates are observed
IV Administration
Connect the infusion bag containing drug solution to an infusion set with a 0.22-micron in-line filter for administration
Infuse IV over 30 minutes
May extend infusion time to 45 minutes if infusion site pain or other symptoms attributed to the infusion occur
Cytotoxic agent; follow special handling and disposal procedures for antineoplastic drugs
Storage
Unreconstituted vials: Store at room temperature 20-25°C (68-77°F); excursions are permitted between 15-30°C (59-86°F); retain in original package until use
Reconstituted vial: May store at ambient temperature (15-25°C; 59-77°F) for up to 12 hr
Infusion bag with dose: May be stored at ambient room temperature (15-25°C; 59-77°F) for up to 36 hr, including infusion time
