Defibrotide

Identification

Summary

Defibrotide is a mixture of single-stranded oligonucleotides used in the treatment of severe hepatic veno-occlusive disease with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation.

Brand Names
Defitelio
Generic Name
Defibrotide
DrugBank Accession Number
DB04932
Background

Defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has been shown to have antithrombotic, anti-inflammatory and anti-ischemic properties (but without associated significant systemic anticoagulant effects). It is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. In the USA it is was approved in March, 2016 as Defitelio.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Nucleic Acid Based Therapies
Oligonucleotides
Synonyms
  • Defibrotide free acid
  • Defibrotide free acid (porcine mucosa)
  • Defibrotide free acid (porcine)

Pharmacology

Indication

Indicated for the treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).Label

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use.

Mechanism of action

The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent sudies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).

TargetActionsOrganism
UAdenosine receptor A1Not AvailableHumans
UAdenosine receptor A2aNot AvailableHumans
UAdenosine receptor A2bNot AvailableHumans
Absorption

Bioavailability is 58-70% following oral administration, compared to parenteral forms (i.v. and i.m. = 100%).

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

t1/2-alpha = minutes (10-20 minutes in rat); t1/2-beta = a few hours

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Defibrotide.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Defibrotide.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Defibrotide is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Defibrotide is combined with Acenocoumarol.
Acetylsalicylic acidAcetylsalicylic acid may increase the antiplatelet activities of Defibrotide.
Albutrepenonacog alfaThe therapeutic efficacy of Albutrepenonacog alfa can be decreased when used in combination with Defibrotide.
AlclofenacThe risk or severity of bleeding and hemorrhage can be increased when Alclofenac is combined with Defibrotide.
AldesleukinThe risk or severity of bleeding can be increased when Defibrotide is combined with Aldesleukin.
AlemtuzumabThe risk or severity of bleeding can be increased when Defibrotide is combined with Alemtuzumab.
AlteplaseThe risk or severity of bleeding can be increased when Defibrotide is combined with Alteplase.
Interactions
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Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Defibrotide sodiumL7CHH2B2J0Not AvailableNot applicable
International/Other Brands
Dasovas / Noravid / Prociclide
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DefitelioSolution80 mg / mLIntravenousJazz Pharmaceuticals Ireland Limited2017-09-06Not applicableCanada flag
DefitelioInjection, solution80 mg/1mLIntravenousJazz Pharmaceuticals, Inc.2016-03-30Not applicableUS flag

Categories

ATC Codes
B01AX01 — Defibrotide
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
568FY5I1YI
CAS number
83712-60-1

References

General References
  1. Noseda G, Fragiacomo C, Ferrari D: Pharmacokinetics of defibrotide in healthy volunteers. Haemostasis. 1986;16 Suppl 1:26-30. [Article]
  2. Palmer KJ, Goa KL: Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs. 1993 Feb;45(2):259-94. [Article]
  3. Fisher J, Johnston AM, Holland TK, McCallum J, Pescador R, Mantovani M, Prino G: Pharmacokinetics, absorption, distribution and disposition of [125I]-defibrotide following intravenous or oral administration in the rat. Thromb Res. 1993 Apr 1;70(1):77-90. [Article]
  4. Koehl GE, Geissler EK, Iacobelli M, Frei C, Burger V, Haffner S, Holler E, Andreesen R, Schlitt HJ, Eissner G: Defibrotide: an endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo. Cancer Biol Ther. 2007 May;6(5):686-90. Epub 2007 Feb 3. [Article]
  5. Kornblum N, Ayyanar K, Benimetskaya L, Richardson P, Iacobelli M, Stein CA: Defibrotide, a polydisperse mixture of single-stranded phosphodiester oligonucleotides with lifesaving activity in severe hepatic veno-occlusive disease: clinical outcomes and potential mechanisms of action. Oligonucleotides. 2006 Spring;16(1):105-14. [Article]
  6. Pescador R, Porta R, Ferro L: An integrated view of the activities of defibrotide. Semin Thromb Hemost. 1996;22 Suppl 1:71-5. [Article]
PubChem Substance
46508192
RxNav
1311089
ChEMBL
CHEMBL2108396
PharmGKB
PA164749105
Wikipedia
Defibrotide
FDA label
Download (254 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceEndotoxaemia / Healthy Subjects (HS)1
3CompletedPreventionVeno-Occlusive Disease1
3CompletedTreatmentSevere Hepatic Veno Occlusive Disease1
3CompletedTreatmentVeno Occlusive Disease, Hepatic1
2Active Not RecruitingTreatmentAcute Chest Syndrome / Sickle Cell Disease (SCD)1
2CompletedPreventionThrombotic Microangiopathies1
2CompletedTreatmentAcute Graft-Versus-Host Disease (GVHD) / Graft Versus Host Disease (cGvHD)1
2CompletedTreatmentVeno-Occlusive Disease1
2RecruitingTreatmentBone Marrow Transplant Complications / Sinusoidal Obstruction Syndrome (SOS) / Veno-Occlusive Disease1
2RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous80 mg/1mL
Injection, solution, concentrateIntravenous80 MG/ML
SolutionIntravenous80 mg / mL
Capsule
Injection, solutionIntravenous
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11085043No2012-06-222032-06-22US flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Purine nucleoside binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
ADORA1
Uniprot ID
P30542
Uniprot Name
Adenosine receptor A1
Molecular Weight
36511.325 Da
References
  1. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G: Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993 Jul 20;238(2-3):327-34. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Identical protein binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
ADORA2A
Uniprot ID
P29274
Uniprot Name
Adenosine receptor A2a
Molecular Weight
44706.925 Da
References
  1. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G: Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993 Jul 20;238(2-3):327-34. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
G-protein coupled adenosine receptor activity
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
ADORA2B
Uniprot ID
P29275
Uniprot Name
Adenosine receptor A2b
Molecular Weight
36332.655 Da
References
  1. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G: Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993 Jul 20;238(2-3):327-34. [Article]

Drug created on October 21, 2007 22:23 / Updated on October 16, 2021 12:31