Dosing and uses of Defitelio (defibrotide)
Adult dosage forms and strengths
IV solution
- 200mg/2.5mL (80mg/mL) vial
Hepatic Veno-Occlusive Disease
Indicated for adults and children with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)
6.25 mg/kg IV q6hr infused over 2 hr
Administer for a minimum of 21 days; if after 21 days signs and symptoms of hepatic VOD have not resolved, continue defibrotide until VOD resolution or up to a maximum of 60 days
Dosage modifications
Severe or life-threatening anaphylaxis: Discontinue permanently; do not resume treatment
Bleeding
- Persistent, severe, or potentially life-threatening
- Withhold defibrotide
- Treat the cause of bleeding and give 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 permanently; do not resume treatment
Invasive procedures
- There is no known reversal agent for the profibrinolytic effects of defibrotide
- Discontinue infusion at least 2 hr prior to an invasive procedure
- Resume treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved
Dosing Considerations
Dose is based on weight prior to preparative regimen for HSCt
Pediatric dosage forms and strengths
IV solution
- 200mg/2.5mL (80mg/mL) vial
Hepatic Veno-Occlusive Disease
Indicated for adults and children with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)
6.25 mg/kg IV q6hr infused over 2 hr
Administer for a minimum of 21 days; if after 21 days signs and symptoms of hepatic VOD have not resolved, continue defibrotide until VOD resolution or up to a maximum of 60 days
Dosage modifications
Severe or life-threatening anaphylaxis: Discontinue permanently; do not resume treatment
Bleeding
- Persistent, severe, or potentially life-threatening
- Withhold defibrotide
- Treat the cause of bleeding and give 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 permanently; do not resume treatment
Invasive procedures
- There is no known reversal agent for the profibrinolytic effects of defibrotide
- Discontinue infusion at least 2 hr prior to an invasive procedure
- Resume treatment after the procedure, as soon as any procedure-related risk of bleeding is resolved
Dosing Considerations
Dose is based on weight prior to preparative regimen for HSCt
Defitelio (defibrotide) adverse (side) effects
>10%
Hypotension, any grade (37%)
Diarrhea, any grade (24%)
Vomiting, any grade (18%)
Nausea, any grade (16%)
Epistaxis, any grade (14%)
1-10%
Pulmonary alveolar hemorrhage (7-9%)
GI hemorrhage (3-9%)
Sepsis (5-7%)
GVHD (4-6%)
Lung infiltration (3-6%)
Pneumonia (3-5%)
Pulmonary hemorrhage (2-4%)
Infection (2-3%)
Hemorrhage intracranial (2-3%)
Hyperuricemia (2%)
Cerebral hemorrhage (2%)
Hypersensitivity reactions (<2%)
Warnings
Contraindications
Coadministration with systemic anticoagulant or fibrinolytic therapy
Known hypersensitivity to defibrotide or any of its excipients
Cautions
Defibrotide increases activity of fibrinolytic enzymes in vitro, and it may increase risk of bleeding in patients with VOD; monitor for bleeding
Do not initiate drug in patients with active bleeding
If bleeding occurs, discontinue drug and treat the underlying cause (also see Dosage modifications)
Do not use with systemic anticoagulants or fibrinolytic agents (except for routine maintenance or reopening of central venous lines)
Hypersensitivity reactions reported and may include rash, urticaria, and angioedema
Pregnancy
Pregnancy
There are no available data on use in pregnant women Advise pregnant women of the potential risk of miscarriage (based on animal data)
Animal data
- 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
Lactation
Unknown if distributed in human breast milk
Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Defitelio (defibrotide)
Mechanism of action
The mechanism of action has not been fully elucidated
Enhances the enzymatic activity of plasmin to hydrolyze fibrin clots
Studies evaluating the pharmacological effects of defibrotide on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line
In vitro, defibrotide increased tissue plasminogen activator (t-PA) and thrombomodulin expression and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis
Protected ECs from damage caused by chemotherapy, TNF-alpha, serum starvation, and perfusion
Absorption
Peak plasma time: At end of IV infusion
Distribution
Protein bound: 93%
Vd: 8.1-9.1 L
Metabolism
Though the precise pathway of defibrotide degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2'-deoxyribose sugar, purine, and pyrimidine bases
Elimination
Half-life: <2 hr
Total clearance: 3.4-5.1 L/hr
Excretion: 5-15% urine
Administration
IV Preparation
Dilute with D5W or 0.9% NaCl to a concentration of 4 mg/mL to 20 mg/mL
Determine the dose (mg) and number of vials based on the individual patient’s baseline weight (weight prior to the preparative regimen for HSCT)
Calculate the volume of defibrotide needed, withdraw this amount from the vial(s), and add it to the infusion bag to result in dilution of 4 mg/mL to 20 mg/mL
Gently mix the solution for infusion
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
Only clear solutions without visible particles should be used
Depending on the type and amount of diluent, the color of the diluted solution may vary from colorless to light yellow
IV Administration
Must be diluted prior to infusion
Prior to administration, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than 1 vasopressor
Administer diluted solution by constant IV infusion over 2 hr
Administer the diluted solution using an infusion set equipped with a 0.2-micron in-line filter
Flush IV line (peripheral or central) with D5W or 0.9% NaCl immediately before and after administration
Do not coadminister with other IV drugs concurrently within the same IV line
Storage
Unopened vials: 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
Vials contain no antimicrobial preservatives and are intended for a single-patient-use only
Partially used vials should be discarded
Use the diluted solution within 4 hr if stored at room temperature or within 24 hr if refrigerated
Up to 4 doses may be prepared at one time, if refrigerated
