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Drug Monographs
Treatment Regimens

Scientific Name:
BELINOSTAT
Brand Name(s):
Beleodaq

Drug Monograph

Pharmacology

Mechanism of Action

Belinostat 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).

Pharmacokinetics

Distribution:
mean volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution
Protein binding = 92.9 to 95.8%
Metabolism: 
predominantly eliminated through metabolism
primarily metabolized by hepatic UGT1A1- strong UGT1A1 inhibitors increase exposure to belinostat
other hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes- form belinostat amide and belinostat acid
major human metabolites: methyl belinostat, belinostat amide, belinostat acid, belinostat glucuronide, and 3-ASBA
Excretion:
less than 2% of the dose recovered unchanged in urine
all metabolites are generally excreted in urine within the first 24 hours after dose administration- 3-ASBA and belinostat glucuronide are the highest fractions excreted in urine (4.61% and 30.5%, respectively)

Side Effects

IMMEDIATE ONSET (hours to days)
* Tumor Lysis Syndrome (rare- symptoms include hyperuricemia, fluid & electrolyte imbalances- may lead to acute renal failure and death)
   nausea (42%), vomiting (29%)
   infusion site pain (14%), phlebitis (10%)
EARLY ONSET  (days to weeks)
* anemia (32%; Grades 3 or 4- 11%), thrombocytopenia (16%; Grades 3 or 4- 7%)
   fatigue (37%; Grades 3 or 4- 5%), pyrexia (35%)
   constipation (23%), diarrhea (23%), anorexia (15%), abdominal pain (11%)
   dyspnea (22%), cough (19%)
   rash (20%)
   peripheral edema (20%)
   pruritus (16%), chills (16%), headache (15%), dizziness (10%)
   hypotension (10%)
   prolonged QT (11%)
   Laboratory Abnormalities: increased Lactate Dehydrogenase (16%), hypokalemia (12%), increased creatinine
* pneumonia, other infections
* multi-organ failure (rare)
* hepatic failure (rare)
* ventricular fibrillation (rare)
DELAYED/LATE ONSET (weeks to years)
   cancer (leukemia, lymphoma, skin cancer)

Therapeutics

Approved Indications

Belinostat is a histone deacetylase inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

Routes

intravenous infusion

Administration

• 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.

Dosing

Intravenous:
1,000 mg/m2 administered over 30 minutes by intravenous infusion once daily on days 1-5 of a 21-day cycle

Dose Adjustment Criteria

Dosage Modifications due to Hematologic Toxicities:
1. If Platelet count ≥ 25 x 109/L and nadir ANC ≥ 0.5 x 109/L, no change
2. If nadir counts ANC < 0.5 x 109/L (with any platelet count), reduce dose by 25% (750 mg/m2)
3. If platelet count < 25 x 109/L (any nadir ANC), reduce dose  by 25% (750 mg/m2)
4. ANC > 1.0 x 109/L and platelet count > 50 x 109/L prior to the start of each cycle and prior to resuming treatment following toxicity
5. Discontinue Belinostat in patients with recurrent ANC nadirs < 0.5 x 109/L and/or recurrent platelet count nadirs < 25 x 109/L after two dosage reductions.
Dosage Modifications due to Non-Hematologic Toxicities:
1. Any CTCAE Grade 3 or 4 adverse reaction, reduce dose by 25% (750 mg/m2)
2. Recurrence of CTCAE Grade 3 or 4 adverse reaction after two dosage reductions, discontinue Belinostat

Antiemetic Risk

Nausea, vomiting and diarrhea occur with Beleodaq and may require the use of antiemetic and antidiarrheal medications

Contraindications

None

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
Liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels] before each cycle of treatment
• Observation for hypersensitivity reaction during and for 30 minutes after injection (emergency treatment readily available)
• Observation for Tumor Lysis Syndrome usually after first injection (emergency treatment readily available)
• Toxicity ratings for Skin Rash at treatment review visit
 RASH/DESQUAMATION
0. None
1. Macular or papular eruption or erythema without associated symptoms
2. macular or papular eruption or erythema with pruritus or other associated symptoms covering <50% of body surface or localized desquamation or other lesions covering <50% of body surface area
3. symptomatic generalized erythroderma or macular, papular or vesicular eruption or desquamation covering >50% of body surface area
4. generalized exfoliative dermatitis or ulcerative dermatitis

Extravasation Hazard

Unknown

Significant Interactions

UGT1A1 Inhibitors Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1 Warfarin Co-administration of belinostat and warfarin resulted in no clinically relevant increase in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment • 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. • Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp.

Product Information

Commercial Product Description

Injection: 500 mg, lyophilized powder in single-use vial for reconstitution

Pharmaceutical Considerations

• 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.
• Beleodaq is a cytotoxic drug. Follow special handling and disposal procedures
Reconstitution 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 [m2]) 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.

Note

HANDLING RISK:
HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

Pharmacare Formulary Status- Non-Formulary Not available in Canada as at 1 Dec 2015



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