Beleodaq

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Beleodaq

Classes

Small Molecule Antineoplastic Histone Deacetylase (HDAC) Inhibitors

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Low
Administer prn antiemetics as necessary.

Injectable Administration Intravenous Administration

Reconstitution:
Add 9 mL of Sterile Water for Injection, USP to each 500 mg vial of belinostat. Swirl the contents of the vial until there are no visible particles in the solution. The reconstituted solution will contain belinostat 50 mg/mL.
The reconstituted solution is stable at ambient room temperature for up to 12 hours.
Aseptically withdraw the appropriate amount of belinostat from the reconstituted vial and further dilute in 250 mL 0.9% Sodium Chloride for Injection, USP.
The final solution is stable at room temperature for up to 36 hours, including infusion time.
 
Intermittent Infusion:
Visually inspect the solution for particulate matter. Do not administer if cloudiness or particulates are observed.
Connect to an infusion set with a 0.22 micron in-line filter.
Administer belinostat as an intravenous infusion over 30 minutes. If infusion site pain or other symptoms that may be attributable to the infusion occur, extend the infusion time to 45 minutes.

Adverse Reactions
Severe

anemia / Delayed / 11.0-11.0
thrombocytopenia / Delayed / 7.0-7.0
dyspnea / Early / 6.0-6.0
fatigue / Early / 5.0-5.0
QT prolongation / Rapid / 4.0-4.0
hypokalemia / Delayed / 4.0-4.0
hypotension / Rapid / 3.0-3.0
pruritus / Rapid / 3.0-3.0
anorexia / Delayed / 2.0-2.0
diarrhea / Early / 2.0-2.0
fever / Early / 2.0-2.0
vomiting / Early / 1.0-1.0
abdominal pain / Early / 1.0-1.0
nausea / Early / 1.0-1.0
constipation / Delayed / 1.0-1.0
ventricular fibrillation / Early / 0-1.0
rash / Early / 1.0-1.0
phlebitis / Rapid / 1.0-1.0
chills / Rapid / 1.0-1.0
hepatic failure / Delayed / 0-1.0
tumor lysis syndrome (TLS) / Delayed / 0-1.0
renal failure (unspecified) / Delayed / 2.0

Moderate

peripheral edema / Delayed / 20.0-20.0
neutropenia / Delayed / 0-1.0
elevated hepatic enzymes / Delayed / 0-1.0

Mild

cough / Delayed / 19.0-19.0
headache / Early / 15.0-15.0
dizziness / Early / 10.0-10.0
infection / Delayed / 1.0-10.0

Common Brand Names

Beleodaq

Dea Class

Rx

Description

IV histone deacetylase inhibitor for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)
Accelerated FDA-approval based on tumor response rate and duration of response; no improvement in survival has been found
Myelosuppression, an increased risk of serious infections, and fatal hepatotoxicity have been reported

Dosage And Indications
For the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).
The FDA has designated belinostat as an orphan drug for the treatment of PTCL.
Intravenous dosage Adults

1,000 mg/m2 IV over 30 minutes once daily on days 1, 2, 3, 4, and 5 repeated every 21 days until disease progression or unacceptable toxicity. The initial belinostat starting dose is 750 mg/m2 in patients who are homozygous for the UGT1A1*28 allele. Interruption, dose reduction, or discontinuation of therapy may be necessary in patients who develop toxicities. The absolute neutrophil count should be 1,000 cells/mm3 or greater and the platelet count should be 50,000 cells/mm3 or greater before the start of each new cycle. The overall response rate (ORR) (primary end point) assessed by an independent review committee was 25.8% following treatment with belinostat in patients with relapsed or refractory PTCL in a multinational, single-arm, phase II trial (n = 129; the BELIEF trial). The complete response (CR) was 10.8% and the median duration of response (DOR) was 8.4 months. Additionally, the median progression-free survival and overall survival times were 1.6 months and 7.9 months, respectively. In this trial, the median number of prior therapies was 2 (range, 1 to 8 therapies); 20.8% of patients had previously had a hematopoietic stem-cell transplant. The ORR was 25% in patients with relapsed or refractory PTCL who received belinostat (median of 2 cycles of therapy; range 1 to 9 cycles) in another multinational, phase II trial (n = 24); 8.3% of these patients achieved a CR. The median DOR was 109 days, and the median time to progression was 82 days. Patients in this study had received a median of 3 prior therapies (range, 1 to 9 therapies).

Dosing Considerations
Hepatic Impairment

Baseline hepatic impairment: Specific guidelines for initial dosage adjustment of belinostat in patients with hepatic impairment are not available; however, belinostat is metabolized in the liver and hepatic impairment is expected to increase drug exposure. Patients with a total bilirubin levels greater than 1.5-times the upper limit of normal were excluded from clinical trials.
Grade 3 or 4 treatment-related hepatotoxicity: Hold therapy until the toxicity resolves to grade 2 or less; decrease the belinostat dose by 25% (e.g., from 1,000 mg/m2 to 750 mg/m2). Discontinue therapy in patients who have a recurrence of grade 3 or 4 toxicity following 2 dose reductions.

Renal Impairment

No initial dosage adjustment of belinostat is necessary in patients with a creatinine clearance (CrCl) greater than 39 mL/min. There is insufficient data to recommend a dose in patients with a CrCl of 39 mL/min or less.

Drug Interactions

Atazanavir: (Contraindicated) Avoid concomitant administration of belinostat with strong UGT1A1 inhibitors such as atazanavir, as belinostat is primarily metabolized by UGT1A1. Coadministration with strong UGT1A1 inhibitors may increase belinostat exposure and result in increased toxicities.
Atazanavir; Cobicistat: (Contraindicated) Avoid concomitant administration of belinostat with strong UGT1A1 inhibitors such as atazanavir, as belinostat is primarily metabolized by UGT1A1. Coadministration with strong UGT1A1 inhibitors may increase belinostat exposure and result in increased toxicities.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Gemfibrozil: (Moderate) Gemfibrozil may inhibit UGT1A1 in vitro; belinostat is primarily metabolized by UGT1A1. Use caution if coadministration of belinostat with gemfibrozil is necessary, as increased belinostat concentrations and toxicities may occur.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sodium Phenylbutyrate: (Major) Avoid coadministration of sodium phenylbutyrate and belinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and belinostat are inhibitors of histone deacetylase (HDAC).
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate and belinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and belinostat are inhibitors of histone deacetylase (HDAC).
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

How Supplied

Beleodaq/Belinostat Intravenous Inj Pwd F/Sol: 500mg

Maximum Dosage
Adults

1,000 mg/m2 IV daily for 5 consecutive days per cycle.

Geriatric

1,000 mg/m2 IV daily for 5 consecutive days per cycle.

Mechanism Of Action

Belinostat is a class I and II inhibitor of the histone deacetylase (HDAC) family of enzymes. HDACs are enzymes that catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. Overexpression of HDACs or an abnormal recruitment of HDACs to oncogenic transcription factors is present in some cancer cells. This causes hypoacetylation of core nucleosomal histones resulting in a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity produces an accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In many different malignant cell lines, HDAC inhibitors have been shown to activate differentiation, inhibit the cell cycle, and induce apoptosis. In vivo, HDAC inhibitors have exhibited stimulation of the immune system and blockage of angiogenesis. In vitro, belinostat has shown preferential cytotoxicity towards tumor cells compared to normal cells, inducing cell cycle arrest and/or apoptosis of some transformed cells at nanomolar concentrations (< 250 nanomolar).

Pharmacokinetics

Belinostat is administered intravenously. It has limited tissue distribution, with 92.9% to 95.8% of drug bound to plasma proteins. In pooled data from a phase I/II trial, the total mean plasma clearance was 1,240 mL/min and the elimination half-life was 1.1 hours following belinostat doses ranging from 150 to 1,200 mg/m2. The total clearance approximates average hepatic blood flow (1,500 mL/min), suggesting high hepatic extraction. Belinostat is primarily metabolized in the liver via UGT1A1. Identified metabolites include belinostat amide and belinostat acid, methyl belinostat, and 3-(anilinosulfonyl)-benzenecarboxylic acid (3-ASBA). Following a single, radiolabeled 1,500-mg dose of belinostat IV given over 30 minutes in 6 patients with recurrent or progressive malignancy, the mean percent of radioactivity recovered over 168 hours were 9.7% +/- 6.5% and 84.8% +/- 9.8% in the feces and urine, respectively. Unchanged belinostat accounted for 1.7% of the radioactivity recurred in the urine.
 
Affected cytochrome P450 isoenzymes or transporters: UGT1A1, P-gp
Belinostat is primarily metabolized by UGT1A1; avoid concomitant administration with strong UGT1A1 inhibitors. In vitro studies have demonstrated it also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 and that belinostat and its metabolites inhibit CYP2C8 and CYP2C9. Belinostat is a P-glycoprotein (P-gp) substrate; it is unlikely to inhibit P-gp.

Pregnancy And Lactation
Pregnancy

Belinostat can cause fetal harm including teratogenicity and/or embryo-fetal death if administered during pregnancy, based on its mechanism of action. Reproductive animal studies have not been conducted with belinostat and there is no data in pregnant humans; however, it is a genotoxic drug that actively targets dividing cells. Women of childbearing potential should avoid becoming pregnant during treatment with belinostat. Advise pregnant women of the potential hazard to the fetus.

Counsel patients about the reproductive risk and contraception requirements during belinostat treatment. Pregnancy testing should be performed prior to starting belinostat in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 6 months after belinostat therapy. Women who become pregnant while receiving belinostat should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during therapy and for 3 months after the last dose due to the risk of male-mediated teratogenicity. Belinostat may cause male infertility, based on data from animal studies. It is not known if infertility is reversible.