Brand Name
Defitelio
Generic Name
Defibrotide
View Brand Information FDA approval date: March 30, 2016
Form: Injection
What is Defitelio (Defibrotide)?
DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease , also known as sinusoidal obstruction syndrome , with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation . DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease , also known as sinusoidal obstruction syndrome , with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation .
Approved To Treat
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Brand Information
DEFITELIO (defibrotide sodium)
1INDICATIONS AND USAGE
DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
2DOSAGE FORMS AND STRENGTHS
Injection: 200 mg/2.5 mL (80 mg/mL) of defibrotide sodium as a clear, light yellow to brown solution in a single-patient-use glass vial.
3CONTRAINDICATIONS
The use of DEFITELIO is contraindicated in the following conditions:
- Concomitant administration with systemic anticoagulant or fibrinolytic therapy
- Known hypersensitivity to DEFITELIO or to any of its excipients
4ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Hemorrhage
- Hypersensitivity Reactions
4.1Clinical 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
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 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
5DRUG 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
6OVERDOSAGE
There are no known cases of overdose with DEFITELIO. There is no known antidote for DEFITELIO, and DEFITELIO is not dialyzable. If an overdose occurs, institute general supportive measures.
7DESCRIPTION
Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 14-19 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The primary structure of defibrotide sodium is shown below.
DEFITELIO (defibrotide sodium) injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8.
8CLINICAL STUDIES
The efficacy of DEFITELIO was investigated in three studies: two prospective clinical trials (Study 1 and Study 2), and an expanded access study (Study 3).
Study 1 enrolled 102 adult and pediatric patients in the DEFITELIO treatment group with a diagnosis of VOD according to the following criteria (bilirubin of at least 2 mg/dL and at least two of the following findings: hepatomegaly, ascites, and weight gain greater than 5% by Day+21 post-HSCT) with an associated diagnosis of multi-organ dysfunction (pulmonary, renal, or both) by Day+28 post-HSCT. DEFITELIO was administered to the treatment group at a dose of 6.25 mg/kg infused every 6 hours for a minimum of 21 days and continued until patient was discharged from the hospital. Patients enrolled in the DEFITELIO treatment group were not permitted to receive concomitant medications such as heparin, warfarin, or alteplase because of an increased risk of bleeding.
Study 2 included adult and pediatric patients with a diagnosis of hepatic VOD and multi-organ dysfunction following HSCT, with 75 patients treated with DEFITELIO at a dose of 6.25 mg/kg infused every 6 hours. The planned minimum duration of treatment was 14 days. The treatment could be continued until signs of hepatic VOD resolved.
Study 3 is an expanded access program for DEFITELIO for the treatment of adult and pediatric patients with hepatic VOD. The efficacy of defibrotide was evaluated in 351 patients who had received a HSCT and developed hepatic VOD with renal or pulmonary dysfunction. All patients received DEFITELIO at a dose of 6.25 mg/kg infused every 6 hours.
Baseline demographic information and details for patients treated in these studies are provided below in Table 3.
Table 3: Baseline Demographics of Patients Treated with DEFITELIO at 6.25 mg/kg Every 6 Hours
- a Duration of treatment from first dose to last dose is presented because days without treatment were not captured for the expanded access study.
The efficacy of DEFITELIO was based on survival at Day + 100 after HSCT. In Study 1, the survival rate was 38% (95% CI: 29%, 48%) at 100 days after transplantation. In Study 2 the survival rate was 44% (95% CI: 33%, 55%) at 100 days after transplantation. In Study 3, the Day + 100 survival was 45% (95% CI: 40%, 51%).
Based on published reports and analyses of patient level data for individuals with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than DEFITELIO, the expected Day +100 survival rates are 21% to 31%.
9HOW SUPPLIED/STORAGE AND HANDLING
DEFITELIO (defibrotide sodium) injection is supplied in a single-patient-use, clear glass vial as a clear, light yellow to brown, sterile, preservative-free solution for intravenous infusion. Each vial (NDC 68727-800-01) contains 200 mg/2.5 mL (at a concentration of 80 mg/mL) of defibrotide sodium.
Each carton of DEFITELIO (defibrotide sodium) injection (NDC 68727-800-02) contains 10 vials.
Store DEFITELIO (defibrotide sodium) injection at 20°C-25°C (68°F-77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) (see USP controlled room temperature).
10PATIENT COUNSELING INFORMATION
- Hemorrhage: Advise patients and caregivers that DEFITELIO may increase the risk of bleeding (hemorrhage). Instruct patients to immediately report any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, or altered vision)
- Hypersensitivity Reactions: Ask patients if they have been treated with defibrotide sodium previously. Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms
11PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
This product's label may have been updated. For full prescribing information, please visit
Distributed by:
Jazz Pharmaceuticals, Inc.
Protected by U.S. Patent Nos. 11,085,043, 11,236,328 and 11,746,348
DEFITELIO