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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hemorrhage: Monitor patients for bleeding. Withhold or discontinue DEFITELIO if significant bleeding occurs. ( 2.3 , 5.1 ) • Hypersensitivity Reactions: If severe or life threatening allergic reaction occurs, discontinue DEFITELIO, treat according to standard of care, and monitor until signs and symptoms resolve. ( 2.3 , 5.2 ) 5.1 Hemorrhage DEFITELIO increased the activity of fibrinolytic enzymes in vitro, and it may increase the risk of bleeding in patients with VOD after hematopoietic stem-cell transplantation (HSCT). Do not initiate DEFITELIO in patients with active bleeding. Monitor patients for signs of bleeding. If patients on DEFITELIO develop bleeding, discontinue DEFITELIO, treat the underlying cause, and provide supportive care until the bleeding has stopped [see Dosage and Administration (2.3) ] . Concomitant use of DEFITELIO and a systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of 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) ] .
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