DEFITELIO (Page 2 of 5)

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 Reactionsa ≥10% or Grade 4-5 Adverse Reactions ≥2%

DEFITELIO

(n=176)

Adverse Reaction a

Any grade

Grade 4-5b

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 hemorrhagec

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

7 DRUG INTERACTIONS

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)].

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