Defibrotide Sodium
FDA Drug Information • Also known as: Defitelio
- Brand Names
- Defitelio
- Dosage Form
- INJECTION, SOLUTION
- Product Type
- DRUG FOR FURTHER PROCESSING
Description
11 DESCRIPTION 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. chemical structure
What Is Defibrotide Sodium Used For?
1 INDICATIONS 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). 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). ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION
Administer DEFITELIO 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion. ( 2.1 ) Treat for a minimum of 21 days. If after 21 days signs and symptoms of VOD have not resolved, continue treatment until resolution. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of DEFITELIO for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT. Administer DEFITELIO for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue DEFITELIO until resolution of VOD or up to a maximum of 60 days. 2.2 Administration Instructions DEFITELIO must be diluted prior to infusion [see Dosage and Administration (2.4) ] . Prior to administration of DEFITELIO, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than one vasopressor [see Warnings and Precautions (5.1) ] . Administer DEFITELIO by constant intravenous infusion over a 2-hour period. Administer the diluted DEFITELIO solution using an infusion set equipped with a 0.2 micron in-line filter. Flush the intravenous administration line (peripheral or central) with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP immediately before and after administration. Do not co‑administer DEFITELIO and other intravenous drugs concurrently within the same intravenous line. 2.3 Treatment Modification Treatment modification, including temporary or permanent discontinuation of DEFITELIO, should follow the recommendations in Table 1. Table 1: Treatment Modifications for Toxicity or Invasive Procedures Event Recommended Action Hypersensitivity Reaction Severe or life-threatening (anaphylaxis) 1. Discontinue DEFITELIO permanently; do not resume treatment. Bleeding Persistent, severe or potentially life-threatening 1. Withhold DEFITELIO. 2. Treat the cause of bleeding and give supportive care as clinically indicated. 3. Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. Recurrent significant bleeding 1. Discontinue DEFITELIO permanently; do not resume treatment. Invasive Procedures 1. There is no known reversal agent for the profibrinolytic effects of DEFITELIO. Discontinue DEFITELIO infusion at least 2 hours prior to an invasive procedure. 2. Resume DEFITELIO treatment after the procedure as soon as any procedure-related risk of bleeding is resolved. 2.4 Preparation Instructions Dilute DEFITELIO in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP to a concentration of 4 mg/mL to 20 mg/mL. Administer the diluted solution over 2 hours. Vials contain no antimicrobial preservatives and are intended for a single-patient-use only. Partially used vials should be discarded. Use the diluted...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:
Hemorrhage [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] The most common adverse reactions (incidence ≥10% and independent of causality) with DEFITELIO treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Reactions a ≥10% or Grade 4-5 Adverse Reactions ≥2% DEFITELIO (n=176) Adverse Reaction a Any grade Grade 4-5 b 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 hemorrhage c 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...Drug Interactions
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) ] .
DEFITELIO may enhance the activity of antithrombotic/fibrinolytic drugs. ( 7 )Contraindications
4 CONTRAINDICATIONS The use of DEFITELIO is contraindicated in the following conditions:
Concomitant administration with systemic anticoagulant or fibrinolytic therapy [see Warnings and Precautions (5.1) ] Known hypersensitivity to DEFITELIO or to any of its excipients [see Warnings and Precautions (5.2) ] Concomitant administration with systemic anticoagulant or fibrinolytic therapy. ( 4 ) Known hypersensitivity to DEFITELIO or to any of its excipients. ( 4 )Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no available data on DEFITELIO use in pregnant women. 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. Advise pregnant women of the potential risk of miscarriage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses. Pregnant rats were administered defibrotide sodium from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 mg/kg/day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. Pregnant rabbits were administered defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from GD 6 to 18 by 2-hour infusions 4 times per day. In another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. The dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m 2 basis. Subgroup 1 was dosed from GD 6 to 10, subgroup 2 was dosed from GD 10 to 14, and subgroup 3 was dosed from GD 14 to 18. An increased incidence of unilateral implantation was observed in defibrotide sodium-treated animals. Treatment with defibrotide sodium resulted in a decreased number of implantations and viable fetuses.
Overdosage
10 OVERDOSAGE 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.
How Supplied
16 HOW 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).
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.