central venous lines) may increase the risk of bleeding. discontinue anticoagulants and fibrinolytic agents prior to defitelio treatment, and consider delaying the start of defitelio administration until the effects of the anticoagulant have abated [see contraindications (4) ] . 5.2 hypersensitivity reactions hypersensitivity reactions have occurred in less than 2% of patients treated with defitelio. these reactions include rash, urticaria and angioedema. one case of an anaphylactic reaction was reported in a patient who had previously received defitelio. monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. if a severe hypersensitivity reaction occurs, discontinue defitelio, treat according to the standard of care, and monitor until symptoms resolve [see dosage and administration (2.3) ] .

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.

wing 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

mg/kg/day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. pregnant rabbits were administered defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from gd 6 to 18 by 2-hour infusions 4 times per day. in another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. the dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m 2 basis. subgroup 1 was dosed from gd 6 to 10, subgroup 2 was dosed from gd 10 to 14, and subgroup 3 was dosed from gd 14 to 18. an increased incidence of unilateral implantation was observed in defibrotide sodium-treated animals. treatment with defibrotide sodium resulted in a decreased number of implantations and viable fetuses. 8.2 lactation risk summary there is no information regarding the presence of defitelio in human milk, the effects on the breastfed infant, or the effects on milk production. because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with defitelio. 8.4 pediatric use the safety and effectiveness of defitelio have been established in pediatric patients. use of defitelio is supported by evidence from an adequate and well-controlled study and a dose finding study of defitelio in adult and pediatric patients with vod with evidence of renal or pulmonary dysfunction following hsct. the clinical trials enrolled 66 pediatric patients in the following age groups: 22 infants (1 month up to less than 2 years), 30 children (2 years up to less than 12 years), and 14 adolescents (12 years to less than 17 years). the efficacy and safety outcomes were consistent across pediatric and adult patients in the clinical trials [see adverse reactions (6) and clinical studies (14) ] . juvenile animal toxicity data a juvenile toxicity study in 21-day-old rats was conducted with intravenous bolus administration of defibrotide sodium at 40, 150, or 320 mg/kg/day for 4 weeks. a delayed mean age of preputial separation was observed at all doses, suggesting a delay in onset of male puberty. the dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m 2 basis for a child. the relevance of this finding for the onset of male puberty in humans is unknown. 8.5 geriatric use clinical studies of defitelio did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients.

venous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. pregnant rabbits were administered defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from gd 6 to 18 by 2-hour infusions 4 times per day. in another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. the dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m 2 basis. subgroup 1 was dosed from gd 6 to 10, subgroup 2 was dosed from gd 10 to 14, and subgroup 3 was dosed from gd 14 to 18. an increased incidence of unilateral implantation was observed in defibrotide sodium-treated animals. treatment with defibrotide sodium resulted in a decreased number of implantations and viable fetuses.

elay in onset of male puberty. the dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m 2 basis for a child. the relevance of this finding for the onset of male puberty in humans is unknown.

ent. pai-1 inhibition plasma concentrations of pai-1 were assessed on an exploratory basis as a potential pharmacodynamic marker for efficacy in study 2. pai-1 is an inhibitor of t-pa and therefore of fibrinolysis. mean pai-1 levels on days 7 and 14 were lower than those at baseline in patients with complete response (cr) and in those who were alive at day+100, but this trend did not reach statistical significance. there were no statistically significant differences in mean pai-1 levels by treatment or outcome. 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) ] .

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) ] .

tial thromboplastin time (aptt) at 1200 and 4800 mg/kg/day administered as a continuous infusion in rats and at 300 and 1600 mg/kg/day administered in 2-hour infusions 4 times daily in dogs. prothrombin time (pt) was also transiently increased at 4800 mg/kg/day in rats. these findings were observed at doses at least 6 times higher on a mg/m 2 basis than the clinical dose of 25 mg/kg/day. the effects on aptt and pt may be due to direct effects on coagulation based on the dose-dependent response observed.

agnosis of hepatic vod and multi-organ dysfunction following hsct, with 75 patients treated with defitelio at a dose of 6.25 mg/kg infused every 6 hours. the planned minimum duration of treatment was 14 days. the treatment could be continued until signs of hepatic vod resolved. study 3 is an expanded access program for defitelio for the treatment of adult and pediatric patients with hepatic vod. the efficacy of defibrotide was evaluated in 351 patients who had received a hsct and developed hepatic vod with renal or pulmonary dysfunction. all patients received defitelio at a dose of 6.25 mg/kg infused every 6 hours. baseline demographic information and details for patients treated in these studies are provided below in table 3. table 3: baseline demographics of patients treated with defitelio at 6.25 mg/kg every 6 hours data source study 1 study 2 study 3 design prospective prospective expanded access study number of patients 102 75 351 median age (years) (range) 21 years (<1, 72) 32 years (<1, 61) 15 years (<1, 69) age, n(%) < 17 years ≥ 17 years 44 (43%) 58 (57%) 22 (29%) 53 (71%) 189 (54%) 162 (46%) race, n(%) white black/african american asian other 77 (75%) 6 (6%) 4 (4%) 15 (15%) 61 (81%) 6 (8%) 2 (3%) 6 (8%) 237 (68%) 21 (6%) 15 (4%) 78 (22%) gender, n(%) male female 64 (63%) 38 (37%) 41 (55%) 34 (45%) 184 (52%) 167 (48% ) median number of days on treatment (days) (range) 21.5 days (1,58) 19.5 days (3,83) 21.0 days a (1,93) type of graft, n(%) allograft autograft 90 (88%) 12 (12%) 67 (89%) 8 (11%) 317 (90%) 34 (10%) ventilator or dialysis dependent at study entry, n(%) 34 (33%) 8 (11%) 149 (42%) a duration of treatment from first dose to last dose is presented because days without treatment were not captured for the expanded access study. the efficacy of defitelio was based on survival at day + 100 after hsct. in study 1, the survival rate was 38% (95% ci: 29%, 48%) at 100 days after transplantation. in study 2 the survival rate was 44% (95% ci: 33%, 55%) at 100 days after transplantation. in study 3, the day + 100 survival was 45% (95% ci: 40%, 51%). based on published reports and analyses of patient level data for individuals with hepatic vod with renal or pulmonary dysfunction who received supportive care or interventions other than defitelio, the expected day +100 survival rates are 21% to 31%.