Defitelio Drug Information

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).

• 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

• Antithrombotic Agents DEFITELIO may enhance the pharmacodynamic activity of antithrombotic/fibrinolytic drugs such as heparin or alteplase. Concomitant use of DEFITELIO with antithrombotic or fibrinolytic drugs is contraindicated because of an increased risk of hemorrhage [see Contraindications (4) ] .
• DEFITELIO may enhance the activity of antithrombotic/fibrinolytic drugs. ( 7 )

Pregnancy Risk Summary There are no available data on DEFITELIO use in pregnant women. When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, defibrotide sodium decreased the number of implantations and viable fetuses. Advise pregnant women of the potential risk of miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses.

Pregnant rats were administered defibrotide sodium from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 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.

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 . 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.

• The use of DEFITELIO is contraindicated in the following conditions:
• Concomitant administration with systemic anticoagulant or fibrinolytic therapy [see Warnings and Precautions (5.1) ]
• Known hypersensitivity to DEFITELIO or to any of its excipients [see Warnings and Precautions (5.2) ]
• Concomitant administration with systemic anticoagulant or fibrinolytic therapy. ( 4 )
• Known hypersensitivity to DEFITELIO or to any of its excipients. ( 4 )

There are no known cases of overdose with DEFITELIO. There is no known antidote for DEFITELIO, and DEFITELIO is not dialyzable. If an overdose occurs, institute general supportive measures.