Beleodaq

6 ADVERSE REACTIONS 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 )] The most common adverse reactions (>25%) are nausea, fatigue, pyrexia, anemia, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Acrotech Biopharma Inc at 1-888-292-9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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) 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 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.

4 CONTRAINDICATIONS None None. ( 4 )

11 DESCRIPTION Beleodaq is a histone deacetylase inhibitor with a sulfonamide-hydroxamide structure. The chemical name of belinostat is (2E)- N -hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide. The structural formula is as follows: The molecular formula is C 15 H 14 N 2 O 4 S and the molecular weight is 318.35 g/mol. Belinostat is a white to off-white powder. It is slightly soluble in distilled water (0.14 mg/mL) and polyethylene glycol 400 (about 1.5 mg/mL), and is freely soluble in ethanol (> 200 mg/mL). The pKa values are 7.87 and 8.71 by potentiometry and 7.86 and 8.59 by UV. Beleodaq (belinostat) for injection is supplied as a sterile lyophilized yellow powder containing 500 mg belinostat as the active ingredient. Each vial also contains 1000 mg L-Arginine, USP as an inactive ingredient. The drug product is supplied in a single-dose clear glass vial with a coated stopper and aluminum crimp seal with “flip-off” cap. Beleodaq is intended for intravenous administration after reconstitution with 9 mL Sterile Water for injection, and the reconstituted solution is further diluted with 250 mL of sterile 0.9% Sodium Chloride injection prior to infusion [see Dosage and Administration ( 2) ] . Structure

2 DOSAGE AND ADMINISTRATION Recommended dosage of Beleodaq is 1,000 mg/m 2 administered over 30 minutes by intravenous infusion once daily on days 1-5 of a 21-day cycle. Cycles can be repeated until disease progression or unacceptable toxicity. ( 2.1 ) Treatment discontinuation or interruption with or without dosage reductions by 25% may be needed to manage adverse reactions ( 2.2 ) 2.1 Dosing Information The recommended dosage of Beleodaq is 1,000 mg/m 2 administered over 30 minutes by intravenous infusion once daily on Days 1-5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. 2.2 Dosage Modification for Hematologic and Non-Hematologic Toxicities Table 1 displays the recommended Beleodaq dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy. • Absolute neutrophil count (ANC) should be greater than or equal to 1.0 x 10 9 /L and the platelet count should be greater than or equal to 50 x 10 9 /L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Beleodaq according to the guidelines described in Table 1 below. Discontinue Beleodaq in patients who have recurrent ANC nadirs less than 0.5 x 10 9 /L and/or recurrent platelet count nadirs less than 25 x 10 9 /L after two dosage reductions. • Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment. Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle. Table 1: Dosage Modifications for Hematologic and Non-Hematologic Toxicities Dosage Modification Dosage Modifications due to Hematologic Toxicities Platelet count ≥ 25 x 10 9 /L and nadir ANC ≥ 0.5 x 10 9 /L No Change Nadir ANC < 0.5 x 10 9 /L (any platelet count) Decrease dosage by 25% (750 mg/m 2 ) Platelet count < 25 x 10 9 /L (any nadir ANC) Dosage Modifications due to Non-Hematologic Toxicities Any CTCAE Grade 3 or 4 adverse reaction For nausea, vomiting, and diarrhea, only dose modify if the duration is greater than 7 days with supportive management Decrease dosage by 25% (750 mg/m 2 ) Recurrence of CTCAE Grade 3 or 4 adverse reaction after two dosage reductions Discontinue Beleodaq 2.3 Patients with Reduced UGT1A1 Activity Reduce the starting dose of Beleodaq to 750 mg/m 2 in patients known to be homozygous for the UGT1A1*28 allele [see Clinical Pharmacology ( 12.5 )] . 2.4 Preparation and Administration Precautions As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Beleodaq. 2.5 Reconstitution and Infusion Instructions a) 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). b) Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient’s BSA [m 2 ]) 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. c) Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed. d) Connect the infusion bag containing drug solution to an infusion set with a 0.22 µm in-line filter for administration. e) 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.

1 INDICATIONS AND USAGE Beleodaq is indicated for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response [ see Clinical Studies ( 14 )]. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. Beleodaq is a histone deacetylase inhibitor indicated for the treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.( 1 )

10 OVERDOSAGE No specific information is available on the treatment of overdosage of Beleodaq. There is no antidote for Beleodaq and it is not known if Beleodaq is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The elimination half-life of belinostat is 1.1 hours [see Clinical Pharmacology ( 12.3) ] .

7 DRUG INTERACTIONS 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 ) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Beleodaq 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). 12.2 Pharmacodynamics Cardiac Electrophysiology Multiple clinical trials have been conducted with Beleodaq, in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Beleodaq on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes. 12.3 Pharmacokinetics The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m 2 . The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent). Distribution The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL. Elimination Metabolism Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known. Excretion Following a single dose of [ 14 C]-labelled belinostat (100 μCi, 1500 mg) administered as a 30-minute intravenous infusion in patients with recurrent or progressive malignancy (N=6), fecal excretion accounted for a mean (± SD) of 9.7% (± 6.5%) of the administered radioactive belinostat dose over 168 hours. The mean (± SD) of the administered radioactive belinostat dose that was excreted in urine over 168 hours was 84.8% (± 9.8%), of which unchanged belinostat accounted for only 1.7%. Drug Interaction Studies 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. In cancer patients, co-administration of Beleodaq (1,000 mg/m 2 ) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or C max of either R- or S-warfarin. Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp. 12.5 Pharmacogenomics UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 20% of the black population, 10% of the white population, and 2% of the Asian population are homozygous for the UGT1A1*28 allele. Additional reduced function alleles may be more prevalent in specific populations. Because belinostat is primarily (80 -90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A1*28 allele). Reduce the starting dose of Beleodaq to 750 mg/m 2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities.

12.1 Mechanism of Action Beleodaq 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).

12.2 Pharmacodynamics Cardiac Electrophysiology Multiple clinical trials have been conducted with Beleodaq, in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Beleodaq on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes.

12.3 Pharmacokinetics The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m 2 . The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent). Distribution The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL. Elimination Metabolism Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known. Excretion Following a single dose of [ 14 C]-labelled belinostat (100 μCi, 1500 mg) administered as a 30-minute intravenous infusion in patients with recurrent or progressive malignancy (N=6), fecal excretion accounted for a mean (± SD) of 9.7% (± 6.5%) of the administered radioactive belinostat dose over 168 hours. The mean (± SD) of the administered radioactive belinostat dose that was excreted in urine over 168 hours was 84.8% (± 9.8%), of which unchanged belinostat accounted for only 1.7%. Drug Interaction Studies 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. In cancer patients, co-administration of Beleodaq (1,000 mg/m 2 ) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or C max of either R- or S-warfarin. Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp.

20221230

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3 DOSAGE FORMS AND STRENGTHS For injection: 500 mg, lyophilized powder in single-dose vial for reconstitution For injection: 500 mg, lyophilized powder in single-dose vial for reconstitution ( 3 )

Beleodaq Belinostat BELINOSTAT BELINOSTAT ARGININE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Beleodaq 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Beleodaq 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.

NDA206256

Beleodaq

Belinostat

72893-002

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Carton Label NDC 72893-002-01 Beleodaq® (belinostat) for injection 500 mg/vial For Intravenous Infusion Only Single-Dose Vial Vial Label NDC 72893-002-01 Beleodaq® (belinostat) for injection 500 mg/vial For Intravenous Infusion Only Single-Dose Vial carton label vial label

17 PATIENT COUNSELING INFORMATION Physicians should discuss the FDA approved Patient Information Leaflet with patients prior to treatment with Beleodaq. Instruct patients to read the Patient Information Leaflet carefully. Advise the patient or the caregiver to read the FDA-approved patient labeling (Patient Information). Advise patients or their caregivers: To report symptoms of nausea, vomiting and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered [see Warnings and Precautions ( 5.5 ) ]. To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia [see Warnings and Precautions ( 5.1 ) ]. To immediately report symptoms of infection (e.g., pyrexia) [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 ) ]. Of the potential risk to the fetus and for women to avoid pregnancy and use effective contraception while receiving Beleodaq and for 6 months after the last dose [ see Warnings and Precautions ( 5.6 ) ]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose. To avoid breastfeeding while receiving Beleodaq and for 2 weeks after the last dose [see Use in Specific Populations ( 8.2 ) ]. To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.3 ) ]. Manufactured for: Acrotech Biopharma Inc East Windsor, NJ 08520 Beleodaq is a registered trademark of Acrotech Biopharma Inc. All rights are reserved. U.S. Patent: 6,888,027

14 CLINICAL STUDIES Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL) In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Beleodaq 1,000 mg/m 2 administered over 30 minutes via IV infusion once daily on Days 1-5 of a 21-day cycle. There were 120 patients who had histologically confirmed PTCL by central review evaluable for efficacy. Patients were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity. Efficacy was evaluated using response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC) (Cheson 2007). Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. Response and progression of disease were evaluated by the IRC using the IWC. Table 3 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy. Table 3 Baseline Patient Characteristics (PTCL Population) Characteristics Evaluable Patients (N=120) Age (years) Median (range) 64 (29-81) Sex, % Male Female 52 48 Race, % White Black Asian Latin Other 88 6 3 3 2 PTCL Subtype Based on Central Diagnosis, % PTCL Unspecified (NOS) Angioimmunoblastic T-cell lymphoma (AITL) ALK-1 negative anaplastic large cell lymphoma (ALCL) Other 64 18 11 7 Baseline Platelet Count, % ≥100,000/μL <100,000/μL 83 17 ECOG Performance Status, % 0 1 2 3 34 43 22 1 Median time (months) from Initial PTCL Diagnosis (Range) 12 (2.6 – 266.4) Median Number of Prior Systemic Therapies (Range) 2 (1-8) In all evaluable patients (N = 120) treated with Beleodaq, the overall response rate per central review using IWC was 25.8% (n = 31) ( Table 4 ) with rates of 23.4% for PTCL, NOS and 45.5% for AITL, the two largest subtypes enrolled. Table 4: Response Analysis per Central Assessment Using IWC in Patients with Relapsed or Refractory PTCL Evaluable Patients (N=120) Response Rate n (%) (95% CI) CR+PR 31 (25.8) 18.3-34.6 CR 13 (10.8) 5.9-17.8 PR 18 (15.0) 9.1 – 22.7 CI=confidence interval, CR=complete response, PR=partial response The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 – 29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3 - 50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Beleodaq.

15 REFERENCES 1 OSHA Hazardous Drugs. OSHA . http://www.osha.gov/SLTC/hazardousdrugs/index.html

8.5 Geriatric Use 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).

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

8.1 Pregnancy 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.

8 USE IN SPECIFIC POPULATIONS Lactation: Advised not to breastfeed. ( 8.2 ) 8.1 Pregnancy 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. 8.2 Lactation 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 8.3 Females and Males of Reproductive Potential 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 )]. 8.4 Pediatric Use The safety and effectiveness of Beleodaq in pediatric patients have not been established. 8.6 Use in Patients with Hepatic Impairment 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 )] . 8.5 Geriatric Use 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). 8.7 Use in Patients with Renal Impairment 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 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Beleodaq (belinostat) for injection is supplied in single vial cartons; each clear vial contains sterile, lyophilized powder equivalent to 500 mg belinostat. NDC 72893-002-01 : Individual carton of Beleodaq single-dose vial containing 500 mg belinostat. 16.2 Storage and Handling Store Beleodaq (belinostat) for injection at room temperature 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. [see USP Controlled Room Temperature]. Beleodaq is a cytotoxic drug. Follow special handling and disposal procedures [see References ( 15 ) 1 ].