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Defitelio

Generic Name: Defibrotide Sodium
Class: Antithrombotic Agents, Miscellaneous

Introduction

Defibrotide sodium is an antithrombotic agent.

Uses for Defitelio

Defibrotide sodium has the following uses:

Defibrotide sodium 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

Defitelio Dosage and Administration

General

Defibrotide sodium is available in the following dosage form(s) and strength(s):

Injection: 200 mg/2.5 mL (80 mg/mL) in a single-patient-use vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Administer defibrotide sodium 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion.1

  • Treat for a minimum of 21 days. If after 21 days signs and symptoms of VOD have not resolved, continue treatment until resolution.1

Cautions for Defitelio

Contraindications

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy.1

  • Known hypersensitivity to defibrotide sodium or to any of its excipients.1

Warnings/Precautions

Hemorrhage

Defibrotide sodium increased the activity of fibrinolytic enzymes in vitro, and it may increase the risk of bleeding in patients with VOD after hematopoietic stem-cell transplantation (HSCT). Do not initiate defibrotide sodium in patients with active bleeding. Monitor patients for signs of bleeding. If patients on defibrotide sodium develop bleeding, discontinue defibrotide sodium, treat the underlying cause, and provide supportive care until the bleeding has stopped.1

Concomitant use of defibrotide sodium and a systemic anticoagulant or fibrinolytic agent (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytic agents prior to defibrotide sodium treatment, and consider delaying the start of defibrotide sodium administration until the effects of the anticoagulant have abated.1

Hypersensitivity Reactions

Hypersensitivity reactions have occurred in less than 2% of patients treated with defibrotide sodium. These reactions include rash, urticaria, and angioedema. One case of an anaphylactic reaction was reported in a patient who had previously received defibrotide sodium. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue defibrotide sodium, treat according to the standard of care, and monitor until symptoms resolve.1

Specific Populations

Pregnancy

Risk Summary:There are no available data on defibrotide sodium 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.1

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.1

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.1

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/m2 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.1

Lactation

There is no information regarding the presence of defibrotide sodium in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with defibrotide sodium.1

Pediatric Use

The safety and effectiveness of defibrotide sodium have been established in pediatric patients. Use of defibrotide sodium is supported by evidence from an adequate and well-controlled study and a dose finding study of defibrotide sodium in adult and pediatric patients with VOD with evidence of renal or pulmonary dysfunction following HSCT. The clinical trials enrolled 66 pediatric patients in the following age groups: 22 infants (1 month up to less than 2 years), 30 children (2 years up to less than 12 years), and 14 adolescents (12 years to less than 17 years). The efficacy and safety outcomes were consistent across pediatric and adult patients in the clinical trials.1

Juvenile Animal Toxicity Data:A juvenile toxicity study in 21-day-old rats was conducted with intravenous bolus administration of defibrotide sodium at 40, 150, or 320 mg/kg/day for 4 weeks. A delayed mean age of preputial separation was observed at all doses, suggesting a delay in onset of male puberty. The dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m2 basis for a child. The relevance of this finding for the onset of male puberty in humans is unknown.1

Geriatric Use

Clinical studies of defibrotide sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.1

Common Adverse Effects

The most common adverse reactions (incidence ≥10% and independent of causality) with defibrotide sodium treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Defibrotide sodium may enhance the activity of antithrombotic/fibrinolytic drugs.1

Actions

Mechanism Of Action

The mechanism of action of defibrotide sodium has not been fully elucidated. In vitro, defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide sodium 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. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion.1

Advice to Patients

Patient Counseling Information

Hemorrhage: Advise patients and caregivers that defibrotide sodium 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).1

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.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Defibrotide Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

80 mg /1 mL

Defitelio

Jazz Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2016, Selected Revisions September 13, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Jazz Pharmaceuticals, Inc.. DEFITELIO (defibrotide sodium) INTRAVENOUS prescribing information. 2016 Mar.

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