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Defitelio

Generic Name: Defibrotide Sodium
Class: Antithrombotic Agents, Miscellaneous
CAS Number: 83712-60-1

Introduction

Antithrombotic agent with anti-inflammatory, anti-ischemic, and thrombolytic properties;1 3 7 15 polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts.1 3 7 15

Uses for Defitelio

Hepatic Veno-Occlusive Disease (VOD)

Treatment of hepatic VOD, also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT).1 2 3 18 Designated orphan drug by FDA for treatment of hepatic VOD.5

Improves day-100 post-HSCT survival rates compared with historical controls receiving supportive or other therapies.1 2 3 18 19 20

Defitelio Dosage and Administration

General

  • Prior to administration, confirm that patient is hemodynamically stable (i.e., receiving ≤1 vasopressor) and not experiencing clinically important bleeding.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Flush IV line with 0.9% sodium chloride or 5% dextrose injection before and after drug administration.1

Dilution

Must be diluted prior to administration.1

Withdraw appropriate dose of defibrotide sodium from vial and dilute in appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield final concentration of 4–20 mg/mL.1 Mix resulting solution gently.1 Solution may vary from colorless to light yellow depending on type and amount of diluent used.1

Use IV solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration; discard partially used vials of drug.1

Rate of Administration

Administer by IV infusion over 2 hours.1

Dosage

Available as defibrotide sodium; dosage expressed in terms of the salt.1

Pediatric Patients

Hepatic VOD
IV

6.25 mg/kg (based upon body weight prior to HSCT) every 6 hours.1

Administer for at least 21 days.1 If manifestations of hepatic VOD persist after 21 days, continue therapy until resolution of hepatic VOD or up to a maximum of 60 days.1

Adults

Hepatic VOD
IV

6.25 mg/kg (based upon body weight prior to HSCT) every 6 hours.1

Administer for at least 21 days.1 If manifestations of hepatic VOD persist after 21 days, continue therapy until resolution of hepatic VOD or up to a maximum of 60 days.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.11

Renal Impairment

Dosage adjustment not required.11 Not removed by hemodialysis.1

Cautions for Defitelio

Contraindications

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy.1 (See Hemorrhage under Cautions.)

  • Known hypersensitivity to defibrotide or any ingredient in the formulation.1

Warnings/Precautions

Hemorrhage

Defibrotide increases activity of fibrinolytic enzymes, which may increase risk of bleeding in patients with hepatic VOD following HSCT.1 4

Monitor patients for signs of bleeding; do not initiate in patients with active bleeding.1

If persistent, severe, or potentially life-threatening bleeding occurs, discontinue drug and initiate supportive care until bleeding has ceased; treat underlying cause of bleeding.1 May consider resumption of defibrotide sodium therapy (at same dosage and infusion volume) when bleeding has resolved and patient is hemodynamically stable.1

If recurrent clinically important bleeding occurs with defibrotide therapy, permanently discontinue the drug.1

Concomitant use of defibrotide and systemic anticoagulant or fibrinolytic agent (except for routine maintenance or reopening of central venous lines) may increase risk of bleeding; such use is contraindicated.1 17 Discontinue anticoagulants and fibrinolytic agents prior to initiation of therapy.1 Consider delaying initiation of defibrotide in patients receiving such agents until the anticoagulant effects have subsided.1

Invasive Procedures

No known reversal agent for profibrinolytic effects of defibrotide; discontinue IV infusions of defibrotide at least 2 hours prior to an invasive procedure.1 May resume therapy after procedure-related bleeding risks resolve.1

Sensitivity Reactions

Hypersensitivity reactions, including rash, urticaria, angioedema, and anaphylaxis, reported.1 17 If severe hypersensitivity reaction occurs, permanently discontinue the drug and initiate appropriate therapy with monitoring until manifestations resolve.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.1 In animal studies, defibrotide sodium administration during period of organogenesis associated with decrease in number of implantations and viable fetuses.1 Advise pregnant women of the potential risk of miscarriage.1

Lactation

Not known whether defibrotide is distributed into human milk.1 Breast-feeding during defibrotide treatment not recommended due to the potential for serious adverse effects, including bleeding, in a breast-fed infant.1

Pediatric Use

Safety and efficacy of defibrotide in patients 1 month to <17 years of age similar to safety and efficacy outcomes in adults.1 2 3

Geriatric Use

Numbers of geriatric patients in clinical studies of defibrotide insufficient to determine whether they respond differently than younger adults; other clinical experience has revealed no differences in response.1

Common Adverse Effects

Hemorrhage (including epistaxis, GI hemorrhage, hematuria, pulmonary alveolar hemorrhage),1 2 17 hypotension,1 2 3 diarrhea,1 2 vomiting,1 2 nausea.1 2

Interactions for Defitelio

Formal drug interaction studies lacking.1 17

Defibrotide is not a substrate, inhibitor, or inducer of any known drug metabolizing enzymes or transporters.1 11

Specific Drugs

Drug

Interaction

Comments

Antithrombotic agents (e.g., heparin, alteplase)

May enhance pharmacodynamic activity of antithrombotic or fibrinolytic agents1 17

Concomitant use contraindicated1

Defitelio Pharmacokinetics

Absorption

Peak plasma concentrations achieved at the end of each infusion.1

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 93%.1

Elimination

Metabolism

Does not undergo substantial metabolism by hepatocytes.1 Nucleases, nucleotidases, deaminases, and phosphorylases metabolize polynucleotides to oligonucleotides, nucleotides, nucleosides, and then to free 2'-deoxyribose sugar (purine and pyrimidine bases).1

Elimination Route

Excreted as parent drug in urine (5–15% of total dose).1 Not removed by hemodialysis.1

Half-life

Elimination half-life <2 hours.1

Stability

Storage

Parenteral

Injection Concentrate

20–25°C (may be exposed to 15–30°C).1

Diluted IV solutions (4–20 mg/mL): Use within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • Exact mechanism of action not fully elucidated but thought to protect endothelial cells and restore thrombotic-fibrinolytic balance, which preserves hepatic sinusoidal blood flow.1 7 9 10

  • Protects endothelial cells from damage by cancer chemotherapy agents, tumor necrosis factor (TNF; TNF-α), serum starvation, and perfusion.1 15

  • Reduces endothelial cell activation and increases endothelial cell-mediated fibrinolysis by increasing tissue plasminogen activator (t-PA) and thrombomodulin expression and decreasing von Willebrand factor and plasminogen activator inhibitor-1 (PAI-1) expression.1 7 15 16

  • Enhances enzymatic activity of plasmin to hydrolyze fibrin clots.1 4

Advice to Patients

  • Importance of advising patients and caregivers that defibrotide may increase the risk of bleeding.1 Advise patients to immediately report any signs or symptoms suggestive of hemorrhage (e.g., unusual bleeding, easy bruising, blood in urine or stool, headache, confusion, slurred speech, altered vision).1

  • Importance of informing patients about the risk and symptoms of allergic reactions, including anaphylaxis.1 Importance of asking patients if they have received previous treatment with defibrotide.1 Instruct patients to seek immediate medical attention if symptoms of hypersensitivity occur.1

  • Importance of women informing clinician if they are, or plan to become, pregnant or plan to breast-feed.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants) and OTC drugs.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 concentrate, for IV infusion only

80 mg/mL

Defitelio

Jazz

AHFS DI Essentials. © Copyright 2018, Selected Revisions January 1, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Jazz Pharmaceuticals. Defitelio (defibrotide) injection prescribing information. Palo Alto, CA; 2016 Mar.

2. Richardson PG, Riches ML, Kernan NA et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016; 127:1656-65. [PubMed 26825712]

3. Richardson PG, Soiffer RJ, Antin JH et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010; 16:1005-17. [PubMed 20167278]

4. Richardson PG, Ho VT, Giralt S et al. Safety and efficacy of defibrotide for the treatment of severe hepatic veno-occlusive disease. Ther Adv Hematol. 2012; 3:253-65. [PubMed 23606935]

5. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Dec 5

6. DeLeve LD, Valla DC, Garcia-Tsao G et al. Vascular disorders of the liver. Hepatology. 2009; 49:1729-64. [PubMed 19399912]

7. Fulgenzi A, Ferrero ME. Defibrotide in the treatment of hepatic veno-occlusive disease. Hepat Med. 2016; 8:105-113. [PubMed 27843363]

8. Kumar S, DeLeve LD, Kamath PS et al. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc. 2003; 78:589-98. [PubMed 12744547]

9. Dalle JH, Giralt SA. Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment. Biol Blood Marrow Transplant. 2016; 22:400-9. [PubMed 26431626]

10. Palomo M, Mir E, Rovira M et al. What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. Blood. 2016; 127:1719-27. [PubMed 26755708]

11. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 208114Orig1s000: Summary review. 2016 Mar 29. From FDA website

12. Coppell JA, Richardson PG, Soiffer R et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010; 16:157-68. [PubMed 19766729]

13. Richardson PG, Ho VT, Cutler C et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant. 2013; 19(1 Suppl):S88-90.

14. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2015; 168:481-91. [PubMed 25401997]

15. Pescador R, Capuzzi L, Mantovani M et al. Defibrotide: properties and clinical use of an old/new drug. Vascul Pharmacol. 2013 Jul-Aug; 59:1-10.

16. Richardson PG, Smith AR, Triplett BM et al. Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS): Interim Results From a Treatment IND Study. Biol Blood Marrow Transplant. 2017;

17. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 208114Orig1s000: Medical review. 2016 Feb 11. From FDA website

18. Strouse C, Richardson P, Prentice G et al. Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2016; 22:1306-12. [PubMed 27108694]

19. Food and Drug Administration. FDA news release: FDA approves first treatment for rare disease in patients who receive stem cell transplant from blood or bone marrow. Rockville, MD; 2016 Mar 30. From FDA web site

20. Jazz Pharmaceuticals. Dossier for Defitelio (defibrotide sodium). Palo Alto, CA; 2016 Apr 29 (version 1).

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