Version May 2024
Note: Utilize baseline body weight (prior to the preparative hematopoietic stem cell transplantation regimen) to calculate the defibrotide dose. Ensure that patients are hemodynamically stable (on no more than 1 vasopressor agent) and are not experiencing clinically significant bleeding prior to defibrotide administration. Do not initiate defibrotide in patients with active bleeding.
Hepatic sinusoidal obstruction syndrome (formerly called veno-occlusive disease), treatment: IV: 6.25 mg/kg every 6 hours for at least 21 days and up to a maximum of 60 days (until sinusoidal obstruction syndrome resolution or hospital discharge) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling. Defibrotide is not removed by hemodialysis.
There are no dosage adjustments provided in the manufacturer’s labeling.
|
Event |
Severity |
Recommended Action |
|---|---|---|
|
Bleeding |
Persistent, severe, or potentially life-threatening |
Withhold defibrotide. Treat the cause of bleeding and provide supportive care as clinically indicated. Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. |
|
Recurrent significant bleeding |
Discontinue defibrotide permanently; do not resume. Provide supportive care. | |
|
Hypersensitivity reaction |
Severe or life-threatening (anaphylaxis) |
Discontinue defibrotide permanently; do not resume. |
|
Invasive procedures |
There is no known reversal agent for defibrotide profibrinolytic effects. Discontinue defibrotide infusion at least 2 hours prior to an invasive procedure. Resume defibrotide treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved. |
Refer to adult dosing.
(For additional information see "Defibrotide: Pediatric drug information")
Note: Utilize baseline body weight (prior to the preparative hematopoietic stem cell transplantation regimen) to calculate the defibrotide dose. Ensure that patients are hemodynamically stable (on no more than one vasopressor agent) and are not experiencing clinically significant bleeding prior to defibrotide administration.
Hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]), treatment:
Infants, Children, and Adolescents: IV: 6.25 mg/kg/dose every 6 hours for at least 21 days; if signs and symptoms of SOS have not resolved, continue until SOS resolution or up to a maximum of 60 days. Based on trial experience, may round doses to the nearest 5 mg for patients ≤35 kg, and to the nearest 10 mg for patients >35 kg (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Infants, Children, and Adolescents:
|
Event |
Severity |
Recommended Action |
|---|---|---|
|
Bleeding |
Persistent, severe, or potentially life-threatening |
Withhold defibrotide. Treat the cause of bleeding and provide supportive care as clinically indicated. Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. |
|
Recurrent significant bleeding |
Discontinue defibrotide permanently; do not resume. Provide supportive care. | |
|
Hypersensitivity reaction |
Severe or life-threatening (anaphylaxis) |
Discontinue defibrotide permanently; do not resume. |
|
Invasive procedures |
There is no known reversal agent for defibrotide profibrinolytic effects. Discontinue defibrotide infusion at least 2 hours prior to an invasive procedure. Resume defibrotide treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved. |
There are no dosage adjustments provided in the manufacturer's labeling. Defibrotide is not removed by hemodialysis.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in pediatric patients and adults.
>10%:
Cardiovascular: Hypotension (37%; severe hypotension: 11%)
Gastrointestinal: Diarrhea (24%), nausea (16%), vomiting (18%)
Hematologic & oncologic: Hemorrhage (59%; grade 4: ≤20%)
Respiratory: Epistaxis (14%)
1% to 10%:
Endocrine & metabolic: Hyperuricemia (2%)
Gastrointestinal: Gastrointestinal hemorrhage (9%)
Hypersensitivity: Hypersensitivity reaction (<2%; including anaphylaxis and angioedema)
Immunologic: Graft versus host disease (6%)
Infection: Infection (3%), sepsis (7%)
Nervous system: Cerebral hemorrhage (2%), intracranial hemorrhage (3%)
Respiratory: Pneumonia (5%), pulmonary alveolar hemorrhage (9%), pulmonary hemorrhage (4%), pulmonary infiltrates (6%)
Postmarketing: Genitourinary: Hematuria (Nauffal 2022)
Known hypersensitivity to defibrotide or any component of the formulation; concomitant administration with systemic anticoagulant or fibrinolytic therapy.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Hemorrhage: Defibrotide may increase the risk of bleeding (based on increased activity of fibrinolytic enzymes in vitro).
• Hypersensitivity reactions: Hypersensitivity reactions (eg, rash, urticaria, and angioedema) have been reported (rare). One patient with a history of previous defibrotide exposure experienced an anaphylactic reaction.
Other warnings/precautions:
• Porcine derived: Defibrotide is derived from porcine tissue.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as sodium [preservative free]:
Defitelio: 200 mg/2.5 mL (2.5 mL)
No
Solution (Defitelio Intravenous)
200 mg/2.5 mL (per mL): $532.80
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as sodium:
Defitelio: 200 mg/2.5 mL (2.5 mL)
IV: Infuse over 2 hours using a 0.2 micron in-line filter. Flush the IV line (peripheral or central) with D5W or NS immediately before and after administration. Do not administer with other medications concurrently via the same infusion line.
Parenteral: IV: Infuse over 2 hours using a 0.2 micron in-line filter. Flush the IV line with D5W or NS immediately before and after administration. Do not administer with other medications.
Hepatic sinusoidal obstruction syndrome, treatment: Treatment of hepatic sinusoidal obstruction syndrome (formerly called veno-occlusive disease) in adult and pediatric patients with renal or pulmonary dysfunction following hematopoietic stem cell transplant.
Defibrotide may be confused with dofetilide
Defitelio may be confused with dofetilide
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Anticoagulants: Defibrotide may enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Risk C: Monitor therapy
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Thrombolytic Agents. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Thrombolytic Agents. The risk for bleeding may be increased. Risk C: Monitor therapy
Prostacyclin Analogues: Thrombolytic Agents may enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Risk C: Monitor therapy
Protein C Concentrate (Human): May enhance the adverse/toxic effect of Thrombolytic Agents. Specifically, the risk of bleeding may be increased. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy
Thrombolytic Agents: Defibrotide may enhance the adverse/toxic effect of Thrombolytic Agents. Specifically, the risk of hemorrhage may be increased. Risk X: Avoid combination
Tranexamic Acid: May diminish the therapeutic effect of Thrombolytic Agents. Thrombolytic Agents may diminish the therapeutic effect of Tranexamic Acid. Risk X: Avoid combination
Adverse effects have been observed in animal reproduction studies.
It is not known if defibrotide is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding during defibrotide treatment is not recommended by the manufacturer.
Monitor closely for hypersensitivity reactions, particularly in patients who have received defibrotide previously; if hypersensitivity occurs, monitor until resolved. Monitor for signs and symptoms of hepatic sinusoidal obstructive syndrome; monitor closely for signs of bleeding.
Defibrotide augments plasmin enzymatic activity to hydrolyze fibrin clots. It reduces endothelial cell (EC) activation and increases EC-mediated fibrinolysis by increasing tissue plasminogen activator and thrombomodulin expression, as well as by decreasing von Willebrand factor and plasminogen activator inhibitor-1 expression.
Distribution: Vd: 8.1 to 9.1 L.
Protein binding: 93% to human plasma proteins.
Metabolism: Polynucleotides are metabolized via nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases to oligonucleotides, nucleotides, nucleosides, and then to the free 2’-deoxyribose sugar, purine and pyrimidine bases.
Half-life elimination: <2 hours.
Excretion: Urine (5% to 15% of total dose).
Clearance: 3.4 to 6.1 L/hour.
Altered kidney function: Defibrotide AUC was 50% to 60% higher in patients with severe renal impairment or ESRD as compared to patients with normal renal function. Cmax was 35% to 37% higher (following single- and multiple-dose administration) in patients with severe renal impairment versus healthy subjects.
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