Belinostat

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Beleodaq: 500 mg (1 ea)

Pharmacology

Mechanism of Action

Belinostat is a histone deacetylase (HDAC) inhibitor which catalyzes acetyl group removal from protein lysine residues (of histone and some nonhistone proteins). Inhibition of histone deacetylase results in accumulation of acetyl groups, leading to cell cycle arrest and apoptosis. Belinostat has preferential cytotoxicity toward tumor cells versus normal cells.

Pharmacokinetics/Pharmacodynamics

Distribution

~114 L/m² (Steele 2011); mean volume of distribution approaches total body water

Metabolism

Hepatic; predominantly via UGT1A1, also by CYP2A6, CYP2C9, and CYP3A4 to the amide and acid metabolites

Excretion

Urine (84.8% ± 9.8% over 168 hours, predominantly as metabolites; <2% as unchanged drug); feces (9.7% ± 6.5% over 168 hours)

Time to Peak

At end of infusion (Steele 2011)

Half-Life Elimination

1.1 hours

Protein Binding

~93% to 96%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Belinostat exposure is expected to be increased in hepatic impairment.

Use: Labeled Indications

Peripheral T-cell lymphoma, relapsed or refractory: Treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: ANC should be ≥1,000/mm³ and platelets should be ≥50,000/mm³ prior to each cycle

Peripheral T-cell lymphoma, relapsed or refractory: IV: 1,000 mg/m² daily on days 1 to 5 every 21 days until disease progression or unacceptable toxicity (O’Connor 2013)

Dosage adjustment for patients with reduced UGT1A1 activity: Reduce initial dose to 750 mg/m² for patients known to be homozygous for UGT1A1*28 allele.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic toxicity: ANC should be ≥1000/mm³ and platelets should be ≥50,000/mm³ prior to each cycle and prior to resuming treatment following a delay due to toxicity. Resume subsequent treatment according to the following parameters:

Platelets ≥25,000/mm³ and nadir ANC ≥500/mm³: No dosage adjustment necessary (continue treatment without modification).

Nadir ANC <500/mm³ and any platelet count: Reduce dose to 75% of the usual dose (to 750 mg/m²).

Platelets <25,000/mm³ and any nadir ANC: Reduce dose to 75% of the usual dose (to 750 mg/m²).

Recurrent nadir ANC <500/mm³ and/or recurrent nadir platelets <25,000/mm³ following 2 dosage reductions: Discontinue treatment.

Nonhematologic toxicity: Nonhematologic toxicities should be grade 2 or lower prior to retreatment. Resume subsequent treatment according to the following parameters:

Any grade 3 or 4 toxicity (except nausea, vomiting, or diarrhea): Reduce dose to 75% of the usual dose (to 750 mg/m²).

Recurrent grade 3 or 4 toxicity following 2 dosage reductions: Discontinue treatment.

Grade 3 or 4 nausea, vomiting, or diarrhea: Manage with supportive care; reduce the dose only if duration is >7 days with supportive management.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Reconstitute each 500 mg vial with SWFI 9 mL to a concentration of 50 mg/mL. Swirl vial contents until there are no visible particles in the reconstituted solution. Further dilute the appropriate dose in NS 250 mL; do not use if cloudy or precipitate is present.

Administration

IV: Infuse over 30 minutes using a 0.22-micron inline filter; if infusion site pain or other symptoms associated with infusion occur, may increase infusion time to 45 minutes.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Retain in original package until use. The reconstituted solution may be stored for 12 hours at 15°C to 25°C (59°F to 77°F). Solutions diluted for infusion in NS may be stored for up to 36 hours (including infusion time) at 15°C to 25°C (59°F to 77°F).

Drug Interactions

Atazanavir: May increase the serum concentration of Belinostat. Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (20%), prolonged Q-T interval on ECG (11%; grades 3/4: 4%)

Central nervous system: Fatigue (37%; grades 3/4: 5%), chills (16%; grades 3/4: 1%), headache (15%)

Dermatologic: Skin rash (20%; grades 3/4: 1%), pruritus (16%; grades 3/4: 3%)

Endocrine & metabolic: Increased lactate dehydrogenase (16%; grades 3/4: 2%), hypokalemia (12%; grades 3/4: 4%)

Gastrointestinal: Nausea (42%; grades 3/4: 1%), vomiting (29%; grades 3/4: 1%), constipation (23%; grades 3/4: 1%), diarrhea (23%; grades 3/4: 2%), decreased appetite (15%; grades 3/4: 2%), abdominal pain (11%; grades 3/4: 1%)

Hematologic & oncologic: Anemia (32%; grades 3/4: 11%), thrombocytopenia (16%; grades 3/4: 7%)

Local: Pain at injection site (14%)

Respiratory: Dyspnea (22%; grades 3/4: 6%), cough (19%)

Miscellaneous: Fever (35%; grades 3/4: 2%)

1% to 10%:

Cardiovascular: Hypotension (10%; grades 3/4: 3%), phlebitis (10%; grades 3/4: 1%)

Central nervous system: Dizziness (10%)

Infection: Infection (>2%)

Renal: Increased serum creatinine (>2%)

Respiratory: Pneumonia (>2%)

Miscellaneous: Multi-organ failure (>2%)

<1%, postmarketing, and/or case reports: Abnormal hepatic function tests, febrile neutropenia, hepatic failure, hepatotoxicity, leukopenia, sepsis, tumor lysis syndrome, ventricular fibrillation

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia. Monitor blood counts at baseline and weekly during treatment. May require dosage reduction, treatment delay, or discontinuation.
• Gastrointestinal toxicity: Nausea, vomiting, and diarrhea occur with belinostat; may require management with antiemetic and antidiarrheal medications. In a phase 1 study, nausea/vomiting generally occurred at the end of the infusion each day (rarely persisting beyond day 5 each cycle) and was managed with standard antiemetics (Steele 2011).
• Hepatotoxicity: May cause liver function test abnormalities and fatal hepatotoxicity. Monitor liver function tests at baseline and prior to each cycle. May require dosage reduction, treatment delay, or permanent discontinuation (based on the severity of the hepatotoxicity). Belinostat is metabolized hepatically and increased exposure is expected to occur in patients with hepatic impairment. Patients with moderate to severe hepatic impairment (total bilirubin >1.5 times ULN) were excluded from clinical studies.
• Infection: Serious infections (occasionally fatal), including pneumonia and sepsis, have occurred with treatment. Do not administer in patients with an active infection. Heavily pretreated patients (history of extensive or intensive prior chemotherapy) may be at higher risk for life-threatening infections.
• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has been observed; closely monitor patients with advanced disease and/or high tumor burden. If TLS occurs, initiate appropriate treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Reduced UGT1A1 activity: Belinostat is primarily metabolized by UGT1A1; the initial dose should be reduced in patients known to be homozygous for UGT1A1*28 allele.

Monitoring Parameters

Monitor CBC with platelets and differential at baseline and weekly; serum chemistries (including renal and hepatic functions tests) at baseline and before each cycle; monitor for signs/symptoms of gastrointestinal toxicity (eg, nausea, vomiting, diarrhea), tumor lysis syndrome, and infection.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and findings of genotoxicity, in utero exposure to belinostat may cause fetal harm.

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for 6 months after the last belinostat dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last dose of belinostat.

Patient Education

What is this drug used for?

• It is used to treat T-cell lymphoma.

Frequently reported side effects of this drug

• Constipation
• Diarrhea
• Nausea
• Vomiting
• Headache
• Lack of appetite
• Loss of strength and energy
• Fatigue
• Injection site pain
• Abdominal pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; menstruation; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Severe dizziness
• Passing out
• Abnormal heartbeat
• Pale skin
• Shortness of breath
• Swelling of arms or legs
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.