Defibrotide

Identification

Name
Defibrotide
Accession Number
DB04932
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Nucleic Acid Based Therapies
Oligonucleotides
Description

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.

Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Defibrotide sodiumL7CHH2B2J0Not AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DefitelioInjection, solution80 mg/mLIntravenousJazz Pharmaceuticals2016-03-30Not applicableUs
DefitelioSolution80 mgIntravenousJazz Pharmaceuticals Ireland Limited2017-09-06Not applicableCanada
International/Other Brands
Dasovas / Noravid / Prociclide
Categories
UNII
Not Available
CAS number
83712-60-1

Pharmacology

Indication

Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others.

Structured Indications
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 AvailableHuman
UAdenosine receptor A2aNot AvailableHuman
UAdenosine receptor A2bNot AvailableHuman
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
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AbciximabDefibrotide may increase the anticoagulant activities of Abciximab.Approved
AcenocoumarolDefibrotide may increase the anticoagulant activities of Acenocoumarol.Approved
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Defibrotide is combined with Acetylsalicylic acid.Approved, Vet Approved
AloxiprinThe risk or severity of adverse effects can be increased when Defibrotide is combined with Aloxiprin.Experimental
AlprostadilAlprostadil may increase the anticoagulant activities of Defibrotide.Approved, Investigational
AlteplaseDefibrotide may increase the anticoagulant activities of Alteplase.Approved
Aminosalicylic AcidThe risk or severity of adverse effects can be increased when Defibrotide is combined with Aminosalicylic Acid.Approved
AnagrelideAnagrelide may increase the anticoagulant activities of Defibrotide.Approved
AncrodDefibrotide may increase the anticoagulant activities of Ancrod.Investigational
AndrographolideAndrographolide may increase the anticoagulant activities of Defibrotide.Investigational
AnistreplaseDefibrotide may increase the anticoagulant activities of Anistreplase.Approved
Antithrombin III humanDefibrotide may increase the anticoagulant activities of Antithrombin III human.Approved
ApixabanThe risk or severity of adverse effects can be increased when Defibrotide is combined with Apixaban.Approved
AprotininThe therapeutic efficacy of Defibrotide can be decreased when used in combination with Aprotinin.Approved, Withdrawn
ArdeparinDefibrotide may increase the anticoagulant activities of Ardeparin.Approved, Investigational, Withdrawn
ArgatrobanDefibrotide may increase the anticoagulant activities of Argatroban.Approved, Investigational
AstaxanthinDefibrotide may increase the anticoagulant activities of Astaxanthin.Investigational
AzelastineAzelastine may increase the anticoagulant activities of Defibrotide.Approved
BalsalazideThe risk or severity of adverse effects can be increased when Defibrotide is combined with Balsalazide.Approved, Investigational
BatroxobinDefibrotide may increase the anticoagulant activities of Batroxobin.Experimental
BecaplerminDefibrotide may increase the anticoagulant activities of Becaplermin.Approved, Investigational
BemiparinDefibrotide may increase the anticoagulant activities of Bemiparin.Approved, Investigational
BeraprostDefibrotide may increase the anticoagulant activities of Beraprost.Investigational
BivalirudinDefibrotide may increase the anticoagulant activities of Bivalirudin.Approved, Investigational
BrinaseDefibrotide may increase the anticoagulant activities of Brinase.Experimental
BuflomedilBuflomedil may increase the anticoagulant activities of Defibrotide.Experimental
ButylphthalideButylphthalide may increase the anticoagulant activities of Defibrotide.Investigational
CangrelorDefibrotide may increase the anticoagulant activities of Cangrelor.Approved
CaplacizumabDefibrotide may increase the anticoagulant activities of Caplacizumab.Investigational
Carbaspirin calciumThe risk or severity of adverse effects can be increased when Defibrotide is combined with Carbaspirin calcium.Experimental, Investigational
CertoparinDefibrotide may increase the anticoagulant activities of Certoparin.Approved, Investigational
CilostazolCilostazol may increase the anticoagulant activities of Defibrotide.Approved
Citric AcidDefibrotide may increase the anticoagulant activities of Citric Acid.Approved, Nutraceutical, Vet Approved
ClopidogrelClopidogrel may increase the anticoagulant activities of Defibrotide.Approved
CloricromenDefibrotide may increase the anticoagulant activities of Cloricromen.Experimental
ClorindioneDefibrotide may increase the anticoagulant activities of Clorindione.Experimental
Collagenase clostridium histolyticumThe risk or severity of adverse effects can be increased when Defibrotide is combined with Collagenase clostridium histolyticum.Approved, Investigational
Dabigatran etexilateDefibrotide may increase the anticoagulant activities of Dabigatran etexilate.Approved
DalteparinDefibrotide may increase the anticoagulant activities of Dalteparin.Approved
DanaparoidDefibrotide may increase the anticoagulant activities of Danaparoid.Approved, Withdrawn
DarexabanDefibrotide may increase the anticoagulant activities of Darexaban.Investigational
DasatinibDasatinib may increase the anticoagulant activities of Defibrotide.Approved, Investigational
Deoxycholic AcidThe risk or severity of adverse effects can be increased when Defibrotide is combined with Deoxycholic Acid.Approved
DersalazineThe risk or severity of adverse effects can be increased when Defibrotide is combined with Dersalazine.Investigational
DesirudinDefibrotide may increase the anticoagulant activities of Desirudin.Approved
DesmoteplaseDefibrotide may increase the anticoagulant activities of Desmoteplase.Investigational
DextranDefibrotide may increase the anticoagulant activities of Dextran.Approved, Vet Approved
Dextran 40Defibrotide may increase the anticoagulant activities of Dextran 40.Approved
Dextran 70Defibrotide may increase the anticoagulant activities of Dextran 70.Approved
Dextran 75Defibrotide may increase the anticoagulant activities of Dextran 75.Approved
DicoumarolDefibrotide may increase the anticoagulant activities of Dicoumarol.Approved
DiflunisalThe risk or severity of adverse effects can be increased when Defibrotide is combined with Diflunisal.Approved
DiphenadioneDefibrotide may increase the anticoagulant activities of Diphenadione.Experimental
DipyridamoleDipyridamole may increase the anticoagulant activities of Defibrotide.Approved
DitazoleDefibrotide may increase the anticoagulant activities of Ditazole.Approved, Withdrawn
Drotrecogin alfaDefibrotide may increase the anticoagulant activities of Drotrecogin alfa.Approved, Investigational, Withdrawn
Edetic AcidDefibrotide may increase the anticoagulant activities of Edetic Acid.Approved, Vet Approved
EdoxabanDefibrotide may increase the anticoagulant activities of Edoxaban.Approved
EnoxaparinDefibrotide may increase the anticoagulant activities of Enoxaparin.Approved
EpinastineEpinastine may increase the anticoagulant activities of Defibrotide.Approved, Investigational
EplivanserinDefibrotide may increase the anticoagulant activities of Eplivanserin.Investigational
eplivanserineDefibrotide may increase the anticoagulant activities of eplivanserine.Investigational
EpoprostenolEpoprostenol may increase the antiplatelet activities of Defibrotide.Approved
EptifibatideEptifibatide may increase the anticoagulant activities of Defibrotide.Approved, Investigational
Ethyl biscoumacetateDefibrotide may increase the anticoagulant activities of Ethyl biscoumacetate.Withdrawn
Ferulic acidDefibrotide may increase the anticoagulant activities of Ferulic acid.Experimental
FibrinolysinDefibrotide may increase the anticoagulant activities of Fibrinolysin.Investigational
FluindioneDefibrotide may increase the anticoagulant activities of Fluindione.Investigational
FondaparinuxDefibrotide may increase the anticoagulant activities of Fondaparinux.Investigational
Fondaparinux sodiumDefibrotide may increase the anticoagulant activities of Fondaparinux sodium.Approved, Investigational
GabexateDefibrotide may increase the anticoagulant activities of Gabexate.Investigational
GlucosamineGlucosamine may increase the antiplatelet activities of Defibrotide.Approved
GuacetisalThe risk or severity of adverse effects can be increased when Defibrotide is combined with Guacetisal.Experimental
Hemoglobin crosfumarilThe risk or severity of adverse effects can be increased when Defibrotide is combined with Hemoglobin crosfumaril.Experimental
HeparinDefibrotide may increase the anticoagulant activities of Heparin.Approved, Investigational
HigenamineDefibrotide may increase the anticoagulant activities of Higenamine.Investigational
HydroxytyrosolHydroxytyrosol may increase the anticoagulant activities of Defibrotide.Investigational
Ibritumomab tiuxetanThe risk or severity of adverse effects can be increased when Defibrotide is combined with Ibritumomab tiuxetan.Approved
IbrutinibThe risk or severity of adverse effects can be increased when Ibrutinib is combined with Defibrotide.Approved
IbudilastIbudilast may increase the anticoagulant activities of Defibrotide.Approved, Investigational
Icosapent ethylIcosapent ethyl may increase the anticoagulant activities of Defibrotide.Approved, Nutraceutical
IdraparinuxDefibrotide may increase the anticoagulant activities of Idraparinux.Investigational
IfenprodilIfenprodil may increase the anticoagulant activities of Defibrotide.Approved, Investigational, Withdrawn
IfetrobanIfetroban may increase the anticoagulant activities of Defibrotide.Investigational
IloprostIloprost may increase the antiplatelet activities of Defibrotide.Approved, Investigational
IndobufenDefibrotide may increase the anticoagulant activities of Indobufen.Investigational
KetanserinKetanserin may increase the anticoagulant activities of Defibrotide.Investigational
LepirudinDefibrotide may increase the anticoagulant activities of Lepirudin.Approved
LetaxabanDefibrotide may increase the anticoagulant activities of Letaxaban.Investigational
LimaprostThe risk or severity of adverse effects can be increased when Limaprost is combined with Defibrotide.Approved, Investigational
LinsidomineLinsidomine may increase the anticoagulant activities of Defibrotide.Experimental
MelagatranDefibrotide may increase the anticoagulant activities of Melagatran.Experimental
MesalazineThe risk or severity of adverse effects can be increased when Defibrotide is combined with Mesalazine.Approved
Methyl salicylateThe risk or severity of adverse effects can be increased when Defibrotide is combined with Methyl salicylate.Approved, Vet Approved
MilrinoneMilrinone may increase the anticoagulant activities of Defibrotide.Approved
NadroparinDefibrotide may increase the anticoagulant activities of Nadroparin.Approved
NafamostatDefibrotide may increase the anticoagulant activities of Nafamostat.Approved, Investigational
NaftopidilNaftopidil may increase the anticoagulant activities of Defibrotide.Investigational
NimesulideNimesulide may increase the anticoagulant activities of Defibrotide.Approved, Investigational, Withdrawn
NitroaspirinThe risk or severity of adverse effects can be increased when Defibrotide is combined with Nitroaspirin.Investigational
ObinutuzumabThe risk or severity of adverse effects can be increased when Defibrotide is combined with Obinutuzumab.Approved
OlsalazineThe risk or severity of adverse effects can be increased when Defibrotide is combined with Olsalazine.Approved
Omega-3 fatty acidsOmega-3 fatty acids may increase the antiplatelet activities of Defibrotide.Approved, Nutraceutical
OtamixabanDefibrotide may increase the anticoagulant activities of Otamixaban.Investigational
OzagrelDefibrotide may increase the anticoagulant activities of Ozagrel.Investigational
ParnaparinDefibrotide may increase the anticoagulant activities of Parnaparin.Approved, Investigational
Pentaerythritol TetranitrateDefibrotide may increase the anticoagulant activities of Pentaerythritol Tetranitrate.Approved
Pentosan PolysulfateThe risk or severity of adverse effects can be increased when Pentosan Polysulfate is combined with Defibrotide.Approved
PentoxifyllinePentoxifylline may increase the antiplatelet activities of Defibrotide.Approved, Investigational
PhenindioneDefibrotide may increase the anticoagulant activities of Phenindione.Approved, Investigational
PhenprocoumonDefibrotide may increase the anticoagulant activities of Phenprocoumon.Approved, Investigational
PicotamideDefibrotide may increase the anticoagulant activities of Picotamide.Experimental
PrasugrelPrasugrel may increase the anticoagulant activities of Defibrotide.Approved
Protein CDefibrotide may increase the anticoagulant activities of Protein C.Approved
Protein S humanDefibrotide may increase the anticoagulant activities of Protein S human.Approved
ProtocatechualdehydeDefibrotide may increase the anticoagulant activities of Protocatechualdehyde.Approved
RamatrobanRamatroban may increase the anticoagulant activities of Defibrotide.Investigational
RelcovaptanRelcovaptan may increase the anticoagulant activities of Defibrotide.Investigational
ResveratrolResveratrol may increase the anticoagulant activities of Defibrotide.Approved, Experimental, Investigational
ReteplaseDefibrotide may increase the anticoagulant activities of Reteplase.Approved
ReviparinDefibrotide may increase the anticoagulant activities of Reviparin.Approved, Investigational
RidogrelRidogrel may increase the anticoagulant activities of Defibrotide.Approved
RivaroxabanDefibrotide may increase the anticoagulant activities of Rivaroxaban.Approved
RosiglitazoneDefibrotide may increase the anticoagulant activities of Rosiglitazone.Approved, Investigational
Salicylic acidThe risk or severity of adverse effects can be increased when Defibrotide is combined with Salicylic acid.Approved, Vet Approved
SarpogrelateDefibrotide may increase the anticoagulant activities of Sarpogrelate.Investigational
SaruplaseDefibrotide may increase the anticoagulant activities of Saruplase.Experimental
SelexipagDefibrotide may increase the anticoagulant activities of Selexipag.Approved
SevofluraneSevoflurane may increase the anticoagulant activities of Defibrotide.Approved, Vet Approved
SRT501SRT501 may increase the anticoagulant activities of Defibrotide.Investigational
StreptokinaseDefibrotide may increase the anticoagulant activities of Streptokinase.Approved, Investigational
SulodexideDefibrotide may increase the anticoagulant activities of Sulodexide.Approved, Investigational
TenecteplaseDefibrotide may increase the anticoagulant activities of Tenecteplase.Approved
TesmilifeneTesmilifene may increase the anticoagulant activities of Defibrotide.Investigational
TicagrelorDefibrotide may increase the anticoagulant activities of Ticagrelor.Approved
TiclopidineTiclopidine may increase the anticoagulant activities of Defibrotide.Approved
TinzaparinDefibrotide may increase the anticoagulant activities of Tinzaparin.Approved
TioclomarolDefibrotide may increase the anticoagulant activities of Tioclomarol.Experimental
TipranavirTipranavir may increase the antiplatelet activities of Defibrotide.Approved, Investigational
TirofibanTirofiban may increase the anticoagulant activities of Defibrotide.Approved
TositumomabThe risk or severity of adverse effects can be increased when Defibrotide is combined with Tositumomab.Approved, Investigational
TranilastTranilast may increase the anticoagulant activities of Defibrotide.Approved, Investigational
TrapidilTrapidil may increase the anticoagulant activities of Defibrotide.Approved
TreprostinilTreprostinil may increase the antiplatelet activities of Defibrotide.Approved, Investigational
TriflusalDefibrotide may increase the anticoagulant activities of Triflusal.Approved, Investigational
Trolamine salicylateThe risk or severity of adverse effects can be increased when Defibrotide is combined with Trolamine salicylate.Approved
TroxerutinDefibrotide may increase the anticoagulant activities of Troxerutin.Investigational
UrokinaseDefibrotide may increase the anticoagulant activities of Urokinase.Approved, Investigational, Withdrawn
Vitamin EVitamin E may increase the antiplatelet activities of Defibrotide.Approved, Nutraceutical, Vet Approved
VorapaxarVorapaxar may increase the anticoagulant activities of Defibrotide.Approved
WarfarinDefibrotide may increase the anticoagulant activities of Warfarin.Approved
XimelagatranDefibrotide may increase the anticoagulant activities of Ximelagatran.Approved, Investigational, Withdrawn
Food Interactions
Not Available

References

General References
  1. Noseda G, Fragiacomo C, Ferrari D: Pharmacokinetics of defibrotide in healthy volunteers. Haemostasis. 1986;16 Suppl 1:26-30. [PubMed:3754833]
  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. [PubMed:7681375]
  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. [PubMed:8511753]
  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. [PubMed:17495522]
  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. [PubMed:16584299]
  6. Pescador R, Porta R, Ferro L: An integrated view of the activities of defibrotide. Semin Thromb Hemost. 1996;22 Suppl 1:71-5. [PubMed:8807733]
External Links
PubChem Substance
46508192
ChEMBL
CHEMBL2108396
PharmGKB
PA164749105
Wikipedia
Defibrotide
ATC Codes
B01AX01 — Defibrotide
AHFS Codes
  • 20:12.20 — Thrombolytic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentMultiple Myeloma (MM)1
2CompletedTreatmentVeno-Occlusive Disease1
2Not Yet RecruitingPreventionThrombotic Microangiopathies1
2Not Yet RecruitingTreatmentAcute-graft-versus-host Disease / Graft Versus Host Disease (GVHD)1
2RecruitingTreatmentSickle Cell Disorders1
2, 3CompletedPreventionHepatic Veno-Occlusive Disease1
3CompletedTreatmentHepatic Veno-Occlusive Disease1
3CompletedTreatmentSevere Hepatic Veno Occlusive Disease / Severe Hepatic Veno-Occlusive Disease1
3RecruitingPreventionVeno-Occlusive Disease1
4RecruitingBasic ScienceEndotoxaemia / Healthy Volunteers1
Not AvailableNo Longer AvailableNot AvailableHepatic Veno-Occlusive Disease1
Not AvailableNo Longer AvailableNot AvailableLiver Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous80 mg/mL
SolutionIntravenous80 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
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. [PubMed:8405101]
Kind
Protein
Organism
Human
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. [PubMed:8405101]
Kind
Protein
Organism
Human
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. [PubMed:8405101]

Drug created on October 21, 2007 16:23 / Updated on January 14, 2018 10:04