BELEODAQ Powder for solution for injection Ref.[9943] Active ingredients: Belinostat

5.1 Hematologic Toxicity

Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

5.2 Infections

Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections [see Adverse Reactions (6.1)].

5.3 Hepatotoxicity

Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity [see Dosage and Administration (2.2)].

5.4 Tumor Lysis Syndrome

Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL [see Clinical Studies (14)]. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see Adverse Reactions (6.1)].

5.5 Gastrointestinal Toxicity

Nausea, vomiting and diarrhea occur with Beleodaq [see Adverse Reactions (6.1)] and may require the use of antiemetic and antidiarrheal medications.

5.6 Embryo-fetal Toxicity

Based on its mechanism of action and findings of genotoxicity, Beleodaq can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with Beleodaq and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3). Advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose.

The following clinically significant adverse reactions are described in more detail in other sections of the prescribing information.

• Hematologic Toxicity [see Warnings and Precautions (5.1)]
• Infection [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
• Gastrointestinal Toxicity [see Warnings and Precautions (5.5)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Beleodaq may not reflect the rates observed in practice.

Adverse Reactions in Patients with Peripheral T-Cell Lymphoma

The safety of Beleodaq was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Beleodaq 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 [see Clinical Studies (14)]. 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 Beleodaq were nausea, fatigue, pyrexia, anemia, and vomiting [see Clinical Studies (14)]. Table 2 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with Relapsed or Refractory PTCL (NCI-CTC Grade 1-4):

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

Serious Adverse Reactions

Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq. 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 Beleodaq. ECG analysis did not identify QTc prolongation.

Discontinuations due to Adverse Reactions

Twenty-five patients (19.4%) discontinued treatment with Beleodaq 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.

Dosage Modifications due to Adverse Reactions

In the trial, dosage adjustments due to adverse reactions occurred in 12% of Beleodaq-treated patients.

7.1 UGT1A1 Inhibitors

Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1 [see Clinical Pharmacology (12.3)].

Risk Summary

Based on its mechanism of action, Beleodaq can cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. There are no available data on Beleodaq 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 Beleodaq. 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.

Risk Summary

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 Beleodaq, and for 2 weeks after the last dose.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating Beleodaq.

Contraception

Females

Beleodaq can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Beleodaq and for 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on findings from animal studies, Beleodaq may impair male fertility. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1].

The safety and effectiveness of Beleodaq in pediatric patients have not been established.

In the single-arm trial, 48% of patients (n=62) were ≥65 years of age and 10% of patients (n=13) were ≥75 years of age [see Clinical Studies (14)]. The median age of the trial population was 63 years. Patients ≥65 years of age had a higher response rate to Beleodaq treatment than patients <65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients ≥75 years of age and those <75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age (<65 years compared with ≥65 years or <75 years of age compared with ≥75 years of age).

Belinostat exposure is not altered in patients with Creatinine Clearance (CLcr) >39 mL/min. There is insufficient data to recommend a dose of Beleodaq in patients with CLcr ≤39 mL/min [see Clinical Pharmacology (12.3)].

Belinostat is metabolized in the liver and hepatic impairment is expected to increase exposure to belinostat. Patients with moderate and severe hepatic impairment (total bilirubin >1.5 x upper limit of normal (ULN)) were excluded from clinical trials.

There is insufficient data to recommend a dose of Beleodaq in patients with moderate and severe hepatic impairment [see Clinical Pharmacology (12.3)].