Chemical formula: C₁₅H₁₄N₂O₄S Molecular mass: 318.35 g/mol PubChem compound: 6918638
Based on its mechanism of action, belinostat can cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells. There are no available data on belinostat use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. No animal reproduction studies were conducted with belinostat. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
There are no data on the presence of belinostat in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with belinostat, and for 2 weeks after the last dose.
Carcinogenicity studies have not been performed with belinostat.
Belinostat was genotoxic in a bacterial reverse mutation test (Ames assay), an in vitro mouse lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay.
Belinostat may impair male fertility. Fertility studies using belinostat were not conducted. However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose dog toxicology study included reduced organ weights of the testes/epididymides that correlated with a delay in testicular maturation.
Clinically significant adverse reactions:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of belinostat may not reflect the rates observed in practice.
The safety of belinostat was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered belinostat at a dosage of 1,000 mg/m 2 administered over 30 minutes by IV infusion once daily on Days 1-5 of a 21-day cycle. The median duration of treatment was 2 cycles (range 1–33 cycles).
The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with belinostat were nausea, fatigue, pyrexia, anemia, and vomiting. The following table summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL.
Adverse Reactions Occurring in ≥10% of Patients with Relapsed or Refractory PTCL (NCI-CTC Grade 1-4):
| Adverse Reactions | Percentage of Patients (%) (N=129) | |
|---|---|---|
| All Grades | Grade 3 or 4 | |
| All Adverse Reactions | 97 | 61 |
| Nausea | 42 | 1 |
| Fatigue | 37 | 5 |
| Pyrexia | 35 | 2 |
| Anemia | 32 | 11 |
| Vomiting | 29 | 1 |
| Constipation | 23 | 1 |
| Diarrhea | 23 | 2 |
| Dyspnea | 22 | 6 |
| Rash | 20 | 1 |
| Peripheral Edema | 20 | 0 |
| Cough | 19 | 0 |
| Thrombocytopenia | 16 | 7 |
| Pruritus | 16 | 3 |
| Chills | 16 | 1 |
| Increased Blood Lactate Dehydrogenase | 16 | 2 |
| Decreased Appetite | 15 | 2 |
| Headache | 15 | 0 |
| Infusion Site Pain | 14 | 0 |
| Hypokalemia | 12 | 4 |
| Prolonged QT | 11 | 4 |
| Abdominal pain | 11 | 1 |
| Hypotension | 10 | 3 |
| Phlebitis | 10 | 1 |
| Dizziness | 10 | 0 |
Note: Adverse reactions are listed by order of incidence in the “All Grades” category first, then by incidence in “the Grade 3 or 4” category; Measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0
Sixty-one patients (47.3%) experienced serious adverse reactions while taking belinostat or within 30 days after their last dose of belinostat. The most common serious adverse reactions (>2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial.
One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with belinostat. ECG analysis did not identify QTc prolongation.
Twenty-five patients (19.4%) discontinued treatment with belinostat due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure.
In the trial, dosage adjustments due to adverse reactions occurred in 12% of belinostat-treated patients.
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