DEFITELIO

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Prior to dilution, the solution should appear as a clear, light yellow to brown solution. Depending on the type and amount of diluent used, the color of the diluted solution may vary from colorless to light yellow.
Intravenous Administration
Dilution
-Determine the dose and number of defibrotide vials based on patient's baseline weight, defined as the weight prior to the preparative regimen for hematopoietic stem-cell transplantation (HSCT).
-Withdraw the calculated dose from the vial(s) and add to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection to make a final concentration of 4 to 20 mg/mL.
-Gently mix the solution.
-Storage: Discard partially used vials. Use diluted solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. Up to 4 doses of defibrotide may be prepared at one time, if refrigerated.

IV Infusion
-Confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than 1 vasopressor.
-Use an infusion set equipped with a 0.2 micron in-line filter.
-Flush the IV line (central or peripheral) with 5% Dextrose Injection or 0.9% Sodium Chloride Injection immediately before and after administration.
-Administer the diluted defibrotide solution over a 2-hour period.
-Do not administer with other intravenous medications in the same line.

The safety of defibrotide was evaluated in 176 adult and pediatric patients (median age: 25 years, range: 1 month to 72 years) with hepatic veno-occlusive disease (VOD) with pulmonary and/or renal dysfunction after hematopoietic stem-cell transplantation (HSCT); 37% of these patients were 16 years of age or younger. Adverse reactions were not required to be reported if they were related to hepatic VOD or if they were expected to occur after HSCT, unless they were considered serious or Grade 4 to 5 (life-threatening or fatal). Data regarding adverse reactions resulting in permanent discontinuation was available for 102 patients; 35 (34%) of these patients had an adverse reaction related to defibrotide that resulted in permanent discontinuation. Such reactions included pulmonary hemorrhage (3%), low blood pressure (3%), catheter site hemorrhage (3%), multi-organ failure (3%), cerebral hemorrhage (2%), and sepsis (2%).

Hypersensitivity reactions, including rash (unspecified), urticaria, and angioedema, were reported in < 2% of defibrotide-treated patients during clinical trials. In addition, anaphylaxis/anaphylactoid reactions were reported in 1 patient with previous exposure to defibrotide. Monitor patients for hypersensitivity reactions, especially if the patient has previously received defibrotide. If a serious hypersensitivity reaction occurs, discontinue defibrotide, treat the reaction according to the standard of care, and monitor the patient until symptoms have resolved. Permanently discontinue defibrotide if a severe or life-threatening hypersensitivity reaction (e.g., anaphylaxis) occurs.

The use of defibrotide may increase the risk of bleeding. During clinical trials, hemorrhagic events of any type and severity were reported for 59% of patients; 20% of patients experienced a bleeding-related event that was considered Grade 4 or 5 (life-threatening or fatal). Specific reactions reported in defibrotide-treated patients include epistaxis (14%; Grade 4 or 5, 0%), pulmonary alveolar hemorrhage (9%; Grade 4 or 5, 7%), pulmonary hemorrhage (4%; Grade 4 or 5, 2%), GI bleeding (9%; Grade 4 or 5, 3%), intracranial bleeding (3%; Grade 4 or 5, 2%), and cerebral hemorrhage (2%; Grade 4 or 5, 2%). Monitor all patients for signs of bleeding during defibrotide therapy. If persistent, severe, or potentially life-threatening bleeding occurs, discontinue defibrotide, treat the underlying cause of bleeding, and provide supportive care as necessary. Consider resuming defibrotide (at the same dose and infusion volume) when the bleeding has stopped and the patient is hemodynamically stable. If significant bleeding recurs, discontinue defibrotide permanently. There is no reversal agent for the profibrinolytic effects of defibrotide.

Hypotension (37%) was one of the most common adverse reactions reported in defibrotide-treated patients during clinical trials. Grade 4 or 5 (life-threatening or fatal) hypotension occurred in 7% of patients.

Diarrhea (24%), vomiting (18%), and nausea (16%) were among the most commonly reported adverse reactions during defibrotide clinical trials. No Grade 4 or 5 (life-threatening or fatal) gastrointestinal adverse reactions were observed.

Sepsis (7%), pneumonia (5%), and unspecified infection (3%) were reported in defibrotide-treated patients during clinical trials; these reactions were considered Grade 4 or 5 (life-threatening or fatal) in 5%, 3%, and 2% of patients, respectively. Lung infiltration (6%) was also reported during clinical trials and was considered a Grade 4 or 5 reaction in 3% of defibrotide-treated patients.

Hyperuricemia was reported in 2% of patients receiving defibrotide during clinical trials; all hyperuricemia was considered Grade 4 or 5 (life-threatening or fatal).

Graft-versus-host disease (GVHD) was reported in 6% of defibrotide-treated patients during clinical trials; Grade 4 or 5 (life-threatening or fatal) GVHD occurred in 4% of patients.

Defibrotide is contraindicated in patients with a known hypersensitivity to defibrotide or to any of its excipients. Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported with defibrotide use. In addition, anaphylaxis has been reported in 1 patient with previous exposure to defibrotide. Monitor patients for hypersensitivity reactions, especially if the patient has previously received defibrotide. If a serious hypersensitivity reaction occurs, discontinue the drug, treat the reaction according to the standard of care, and monitor the patient until symptoms have resolved. Permanently discontinue defibrotide if a severe or life-threatening hypersensitivity reaction (e.g., anaphylaxis) occurs.

Do not initiate defibrotide in patients with active bleeding. Defibrotide increases the activity of fibrinolytic enzymes in vitro and may increase the risk of bleeding. Monitor all patients for signs of bleeding. If persistent, severe, or potentially life-threatening bleeding occurs, discontinue defibrotide, treat the underlying cause of bleeding, and provide supportive care as necessary. Consider resuming defibrotide (at the same dose and infusion volume) when the bleeding has stopped and the patient is hemodynamically stable. If significant bleeding recurs, discontinue defibrotide permanently. There is no reversal agent for the profibrinolytic effects of defibrotide. Discontinue defibrotide at least 2 hours prior to surgery or other invasive procedures. Treatment may be resumed as soon as any procedure-related risk of bleeding is resolved. Defibrotide is contraindicated in patients receiving systemic fibrinolytic or anticoagulant therapy. Concomitant use of defibrotide and anticoagulants or fibrinolytics (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulant and fibrinolytic agents prior to initiation of defibrotide. Consider delaying the initiation of defibrotide until the effects of the anticoagulant or fibrinolytic have subsided.

Description: Defibrotide, a polydeoxyribonucleotide with fibrinolytic properties, is indicated for the treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome (SOS), with renal or pulmonary dysfunction after hematopoietic stem-cell transplantation (HSCT). VOD is a common and potentially fatal complication after HSCT, with an incidence rate highest in children. VOD typically develops within 30 days of transplantation. Severe VOD is defined by the presence of multiorgan failure and associated with a more than 85% mortality by +100 days after HSCT. Defibrotide has been shown to improve survival in patients with VOD and multi-organ failure at day +100 after HSCT. In a historically controlled, open-label, multicenter, phase 3 trial, survival at day +100 post-HSCT was 38.2% in those receiving defibrotide (n = 102; age range 1 month to 72 years) compared to 25% in the historical control group (n = 32; age range 1 to 57 years) (23% estimated difference; 95% CI 5.2 to 40.8, p = 0.0109, using propensity-adjusted analysis). Complete response at day +100 post-HSCT was observed in 25.5% of defibrotide-treated patients compared to 12.5% of patients in the control group (19% estimated difference; 95% CI 3.5 to 34.6, p = 0.016). Although defibrotide was generally well tolerated with adverse reactions similar to the historical control group, 10.7% of patients discontinued treatment prematurely for possible drug-related toxicity. Defibrotide has also been studied for the prevention of VOD in high risk pediatric patients. Due to an increased risk of bleeding, defibrotide is contraindicated with concomitant systemic anticoagulant or fibrinolytic therapy. Do not initiate therapy in patients with active bleeding; there is no known reversal agent for defibrotide's profibrinolytic effects. Defibrotide is FDA-approved for use in pediatric patients 1 month and older.

For the treatment of hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction after hematopoietic stem-cell transplantation (HSCT):
Intravenous dosage:
Infants, Children, and Adolescents: 6.25 mg/kg/dose IV every 6 hours for a minimum of 21 days. Utilize the patient's baseline weight, defined as the weight prior to the preparative hematopoietic stem-cell transplantation (HSCT) regimen, for dosing. Prior to administration, confirm the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than 1 vasopressor. If after 21 days, signs and symptoms of hepatic VOD have not resolved, continue treatment until resolution of VOD or up to a maximum of 60 days.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
25 mg/kg/day IV.
-Children
25 mg/kg/day IV.
-Adolescents
25 mg/kg/day IV.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The exact mechanism of action of defibrotide is not fully understood. In vitro data indicate defibrotide enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Defibrotide also increases tissue plasminogen activator and thrombomodulin expression while decreasing von Willebrand factor and plasminogen activator inhibitor-1 expression, which reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis. In addition, defibrotide protects endothelial cells from damage caused by chemotherapy, tumor necrosis factor alpha, serum starvation, and perfusion.

Pharmacokinetics: Defibrotide is administered intravenously. Defibrotide is highly bound (93%) to plasma proteins and has a Vd of approximately 8 to 9 L in adult patients. The precise pathway of defibrotide metabolism has not been fully elucidated; it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to free 2'-deoxyribose sugar, purine, and pyrimidine bases. Defibrotide does not undergo appreciable metabolism by human hepatocyte cells. Metabolism followed by urinary excretion is probably the main route of elimination. The estimated total clearance is 3.4 to 6.1 L/hour. After administration of 6.25 to 15 mg/kg doses as 2-hour infusions, approximately 5% to 15% of the total dose was excreted in urine as defibrotide, with the majority of the dose excreted during the first 4 hours. Elimination half life is less than 2 hours. No accumulation is expected after multiple-dose administration.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
After intravenous administration, peak plasma concentrations occur approximately at the end of each infusion.


-Special Populations
Pediatrics
Although defibrotide is FDA-approved for use in pediatric populations, sufficient pharmacokinetic data are not available to draw conclusions.

Renal Impairment
The pharmacokinetics of defibrotide 6.25 mg/kg as a 2-hour IV infusion were evaluated in patients with severe renal disease and end stage renal disease (ESRD) both requiring and not requiring hemodialysis. AUC was 50% to 60% higher in patients with severe renal impairment or ESRD compared to healthy individuals; Cmax was approximately 35% higher after both single- and multiple-dose administration. Defibrotide was not removed by hemodialysis, and it had no notable effect on the drug's plasma clearance. Terminal half-life was consistently less than 2 hours, with no drug accumulation after repeated dosing.