Defibrotide Sodium

1 INDICATIONS AND USAGE DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). ( 1 )

2 DOSAGE AND ADMINISTRATION • Administer DEFITELIO 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion. ( 2.1 ) • Treat for a minimum of 21 days. If after 21 days signs and symptoms of VOD have not resolved, continue treatment until resolution. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of DEFITELIO for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT. Administer DEFITELIO for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue DEFITELIO until resolution of VOD or up to a maximum of 60 days. 2.2 Administration Instructions • DEFITELIO must be diluted prior to infusion [see Dosage and Administration (2.4) ] . • Prior to administration of DEFITELIO, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than one vasopressor [see Warnings and Precautions (5.1) ] . • Administer DEFITELIO by constant intravenous infusion over a 2-hour period. • Administer the diluted DEFITELIO solution using an infusion set equipped with a 0.2 micron in-line filter. Flush the intravenous administration line (peripheral or central) with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP immediately before and after administration. • Do not co‑administer DEFITELIO and other intravenous drugs concurrently within the same intravenous line. 2.3 Treatment Modification Treatment modification, including temporary or permanent discontinuation of DEFITELIO, should follow the recommendations in Table 1. Table 1: Treatment Modifications for Toxicity or Invasive Procedures Event Recommended Action Hypersensitivity Reaction Severe or life-threatening (anaphylaxis) 1. Discontinue DEFITELIO permanently; do not resume treatment. Bleeding Persistent, severe or potentially life-threatening 1. Withhold DEFITELIO. 2. Treat the cause of bleeding and give supportive care as clinically indicated. 3. Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. Recurrent significant bleeding 1. Discontinue DEFITELIO permanently; do not resume treatment. Invasive Procedures 1. There is no known reversal agent for the profibrinolytic effects of DEFITELIO. Discontinue DEFITELIO infusion at least 2 hours prior to an invasive procedure. 2. Resume DEFITELIO treatment after the procedure as soon as any procedure-related risk of bleeding is resolved. 2.4 Preparation Instructions Dilute DEFITELIO in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP to a concentration of 4 mg/mL to 20 mg/mL. Administer the diluted solution over 2 hours. Vials contain no antimicrobial preservatives and are intended for a single-patient-use only. Partially used vials should be discarded. Use the diluted DEFITELIO solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. Up to four doses of DEFITELIO solution may be prepared at one time, if refrigerated. Preparation Instructions: • Determine the dose (mg) and number of vials of DEFITELIO based on the individual patient’s baseline weight (weight prior to the preparative regimen for HSCT). • Calculate the volume of DEFITELIO needed, withdraw this amount from the vial(s) and add it to the infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection for each dose to make a final concentration of 4 mg/mL to 20 mg/mL. • Gently mix the solution for infusion. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only clear solutions without visible particles should be used. Depending on the type and amount of diluent, the color of the diluted solution may vary from colorless to light yellow.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions (5.1) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] The most common adverse reactions (incidence ≥10% and independent of causality) with DEFITELIO treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of DEFITELIO was determined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who were treated with DEFITELIO 6.25 mg/kg every 6 hours [see Clinical Studies (14) ] . Patients were excluded from these trials if at time of study entry they had significant acute bleeding, active grades B-D graft-versus-host disease, or a requirement for multiple vasopressors to provide blood pressure support. For the purposes of adverse event recording in the clinical trials, events were not required to be reported if they were related to the hepatic VOD, or if they were expected to occur after hematopoietic stem-cell transplantation (HSCT), unless they were serious or Grade 4-5. The median age of the safety population was 25 years (range: 1 month to 72 years), and 63% were ≥17 years of age. A total of 60% of patients were male, 78% were white, 89% had undergone allogeneic HSCT, and the underlying diagnosis was acute leukemia for 43%. At study entry, 13% were dialysis dependent and 18% were ventilator dependent. DEFITELIO was administered for a median of 21 days (range: 1 to 83 days). Information about adverse reactions resulting in permanent discontinuation of DEFITELIO was available for 102 patients, and 35 (34%) of these patients had an adverse reaction with permanent discontinuation. Adverse reactions leading to permanent discontinuation included pulmonary alveolar hemorrhage in 5 (5%) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3%) patients; and cerebral hemorrhage and sepsis, each in 2 (2%) patients. Information about adverse reactions of any grade was available for all 176 patients. The most common adverse reactions (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis. The most common serious adverse reactions (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported for 104 (59%) of the patients, and the events were grade 4-5 in 35 (20%). Table 2 presents adverse reactions independent of causality ≥10% any grade or Grade 4/5 ≥2% reported in patients treated with DEFITELIO. Table 2: Adverse Reactions a ≥10% or Grade 4-5 Adverse Reactions ≥2% DEFITELIO (n=176) Adverse Reaction a Any grade Grade 4-5 b Hypotension 65 (37%) 12 (7%) Diarrhea 43 (24%) 0 Vomiting 31 (18%) 0 Nausea 28 (16%) 0 Epistaxis 24 (14%) 0 Pulmonary alveolar hemorrhage 15 (9%) 12 (7%) Gastrointestinal hemorrhage 15 (9%) 5 (3%) Sepsis 12 (7%) 9 (5%) Graft versus host disease 11 (6%) 7 (4%) Lung infiltration 10 (6%) 5 (3%) Pneumonia 9 (5%) 5 (3%) Pulmonary hemorrhage 7 (4%) 4 (2%) Infection 6 (3%) 4 (2%) Hemorrhage intracranial 5 (3%) 4 (2%) Hyperuricemia 4 (2%) 4 (2%) Cerebral hemorrhage c 3 (2%) 3 (2%) a Excludes events considered to be due to the underlying disease: multi-organ failure, veno-occlusive disease, respiratory failure, renal failure, and hypoxia b Adverse reactions considered life-threatening or fatal c Cerebral hemorrhage has been included in the table due to clinical relevance

12.3 Pharmacokinetics Absorption After intravenous administration, peak plasma concentrations of defibrotide sodium occur approximately at the end of each infusion. Distribution Defibrotide sodium is highly bound to human plasma proteins (average 93%) and has a volume of distribution of 8.1 to 9.1 L. Elimination Metabolism followed by urinary excretion is likely the main route of elimination. The estimated total clearance was 3.4 to 6.1 L/h. The elimination half-life of defibrotide sodium is less than 2 hours. Similar plasma concentration profiles were observed in VOD patients after initial and multiple-dose administration of 6.25 mg/kg every 6 hours for 5 days. Therefore, no accumulation is expected following multiple-dose administration. Metabolism Though the precise pathway of defibrotide sodium degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2'-deoxyribose sugar, purine and pyrimidine bases. The biotransformation of defibrotide sodium was investigated in vitro by incubation with human hepatocytes from donors of different ages and showed that defibrotide sodium does not undergo appreciable metabolism by human hepatocyte cells. Excretion After administration of 6.25 mg/kg to 15 mg/kg doses of DEFITELIO as 2-hour infusions, approximately 5-15% of the total dose was excreted in urine as defibrotide sodium, with the majority excreted during the first 4 hours. Specific Populations Age: Pediatric Population Insufficient PK data were collected in pediatric patients to draw conclusions. Renal Impairment The safety, tolerability, and pharmacokinetics of 6.25 mg/kg as 2-hour intravenous infusions of DEFITELIO were evaluated in patients with Hemodialysis-dependent End Stage Renal Disease (ESRD) during hemodialysis and on days off dialysis, and in patients with severe renal disease or ESRD not requiring dialysis. Defibrotide sodium was not removed by hemodialysis, which had no notable effect on plasma clearance of defibrotide sodium. Terminal half-lives were consistently less than 2 hours, and there was no accumulation of defibrotide sodium following repeated dosing. Defibrotide sodium exposure (AUC) in patients with severe renal impairment or ESRD was 50% to 60% higher than that observed in matched healthy subjects. Peak concentration (C max ) was 35% to 37% higher following single- and multiple-dose administration of defibrotide sodium. Drug Interactions Pharmacokinetic drug-drug interactions are unlikely at therapeutic dose. Data from in vitro studies using human biomaterial demonstrate that defibrotide sodium does not induce (CYP1A2, CYP2B6, CYP3A4, UGT1A1) or inhibit (CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT2B7) the major drug metabolizing enzymes and is not a substrate or inhibitor of the major drug uptake transporters (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3) or efflux transporters (P-gp and BCRP). There is some evidence (animal studies, ex vivo human plasma, and healthy volunteers) that defibrotide sodium may enhance the pharmacodynamic activity of heparin and alteplase [see Drug Interactions (7) ] .