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{{Infobox drug |
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{{Drugbox |
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| Verifiedfields = changed |
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| verifiedrevid = 445723422 |
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| verifiedrevid = 447578248 |
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| IUPAC_name = |
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| image = |
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| width = |
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| alt = |
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| caption = |
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| JAN = defibrotide sodium |
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| USAN = defibrotide sodium |
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<!--Clinical data--> |
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<!-- Clinical data --> |
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| tradename = |
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| pronounce = |
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| tradename = Defitelio |
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| Drugs.com = {{drugs.com|international|defibrotide}} |
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| Drugs.com = {{drugs.com|monograph|defibrotide-sodium}} |
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| pregnancy_category = X |
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| MedlinePlus = |
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| legal_status = Rx only (where available) |
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| DailyMedID = Defibrotide |
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| routes_of_administration = oral, i.m., i.v. |
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| pregnancy_AU = D |
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| pregnancy_AU_comment = <ref name="Defitelio APMDS" /> |
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| pregnancy_category = |
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| routes_of_administration = ] |
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| class = |
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| ATC_prefix = B01 |
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| ATC_suffix = AX01 |
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| ATC_supplemental = |
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<!--Pharmacokinetic data--> |
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<!-- Legal status --> |
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| bioavailability = 58 - 70% orally (i.v. and i.m. = 100%) |
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| legal_AU = S4 |
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| legal_AU_comment = <ref name="Defitelio APMDS" /> |
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| protein_bound = |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| metabolism = |
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| legal_BR_comment = |
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| elimination_half-life = t1/2-alpha = minutes; t1/2-beta = a few hours |
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| legal_CA = Rx-only |
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| legal_CA_comment = <ref>{{cite web | title=Blood health (non-cancer) | website=] | date=11 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/blood-health-non-cancer.html | access-date=13 April 2024}}</ref><ref>{{cite web | title=Regulatory Decision Summary - Defitelio | website=Drug and Health Product Register | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?linkID=RDS00270 | access-date=13 April 2024}}</ref> |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = POM |
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| legal_UK_comment = <ref name=UKlabel /> |
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| legal_US = Rx-only |
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| legal_US_comment = <ref name=USlabel /> |
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| legal_EU = Rx-only |
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| legal_EU_comment = <ref name="Defitelio EPAR" /> |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = Rx-only |
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<!--Identifiers--> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = 58 - 70% by mouth (i.v. and i.m. = 100%) |
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| CAS_number = 83712-60-1 |
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| protein_bound = |
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| ATC_prefix = B01 |
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| metabolism = |
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| ATC_suffix = AX01 |
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| metabolites = |
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| ATC_supplemental = |
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| PubChem = |
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| onset = |
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| elimination_half-life = < 2 hours<ref name=USlabel/> |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| duration_of_action = |
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| DrugBank = DB04932 |
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| excretion = |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 438HCF2X0M |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D07423 |
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<!--Chemical data--> |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| chemical_formula = |
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| CAS_number = 83712-60-1 |
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| CAS_supplemental = |
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| PubChem = 135565962 |
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| IUPHAR_ligand = |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DBSALT001719 |
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| DrugBank2 = DB04932 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = none |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = L7CHH2B2J0 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D07423 |
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| ChEBI_Ref = |
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| ChEBI = |
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| ChEMBL_Ref = |
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| ChEMBL = 3707226 |
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| ChEMBL2 = 2108396 |
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| NIAID_ChemDB = |
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| PDB_ligand = |
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| synonyms = STA-1474, JZP-381 |
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<!-- Chemical and physical data --> |
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| molecular_weight = |
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| IUPAC_name = |
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| chemical_formula = |
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| C= | H= | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I= |
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| K= | Li= | Mg= | Mn= | N= | Na= | O= | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge= |
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| molecular_weight = |
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| SMILES = |
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| StdInChI = |
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| StdInChI_comment = |
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| StdInChIKey = |
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| density = |
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| density_notes = |
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| melting_point = |
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| melting_high = |
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| solubility = |
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| specific_rotation = |
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}} |
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}} |
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'''Defibrotide''' is a ] derivative (single-stranded) derived from cow ] or porcine ]. It is an ] with a multiple mode of action (see below). |
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'''Defibrotide''', sold under the brand name '''Defitelio''', is a mixture of single-stranded ]s that is purified from the ] of pigs. It is used to treat ] of the liver of people having had a ], with different limitations in the US and the European Union. It works by protecting the cells lining blood vessels in the liver and preventing ]; the way it does this is not well understood.<ref name=USlabel>{{cite web | title=Defitelio- defibrotide sodium injection, solution | website=DailyMed | date=30 March 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2c3db989-d7ad-41ed-9ebf-698dcf6c24ec | access-date=16 August 2020}}</ref><ref name=UKlabel>{{cite web|title=Defitelio 80 mg/mL concentrate for solution for infusion - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/medicine/31111|publisher=UK Electronic Medicines Compendium|access-date=20 July 2017|date=26 May 2016}}</ref><ref name="Defitelio EPAR">{{cite web | title=Defitelio EPAR | website=] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/defitelio | access-date=16 August 2020}}</ref> |
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It has been used with ].<ref name="pmid16769582">{{cite journal |author=Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T |title=Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy |journal=Haematologica |volume=91 |issue=6 |pages=795–800 |year=2006 |month=June |pmid=16769582 |doi= |url=http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=16769582}}</ref> |
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The most common side effects include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects that were identified include bleeding (hemorrhage) and allergic reactions. Defibrotide should not be used in people who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body's ability to form clots.<ref name="FDA PR" /><ref name="Defitelio EPAR" /> Use of the drug is generally limited by a strong risk of life-threatening bleeding in the brain, eyes, lungs, gastrointestinal tract, urinary tract, and nose. Some people have hypersensitivity reactions.<ref name=UKlabel/> |
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==Pharmacokinetics== |
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Defibrotide is available as an oral, ], and ] formulation. Its oral ] is in the range of 58-70% of the ] forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral ] defibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug's short ], it is necessary to give the daily dose divided in 2 to 4 doses (see below). |
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Defibrotide was approved for medical use in the European Union in October 2013, in the United States in March 2016, and in Australia in July 2020.<ref name="FDA Approval">{{cite web | title=Defitelio Injection | website=U.S. ] (FDA) | date=10 May 2016 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208114Orig1s000TOC.cfm | access-date=16 August 2020}}</ref><ref name="Defitelio EPAR" /><ref name="Defitelio APMDS">{{cite web | title=Defitelio Australian Prescription Medicine Decision Summary | website=Therapeutic Goods Administration (TGA) | date=31 July 2020 | url=https://www.tga.gov.au/apm-summary/defitelio | access-date=16 August 2020}}</ref> Defibrotide is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.<ref name="FDA PR" /> |
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==Mode of action== |
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The drug appears to prevent the formation of ] and to help dissolve blood clots by increasing levels of ] I2, E2, and ], altering ], 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 ]. 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). |
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==Medical uses== |
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Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g., hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision. |
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In the European Union defibrotide is indicated for the treatment of severe hepatic veno-occlusive disease (VOD) also known as sinusoidal obstructive syndrome (SOS) in hematopoietic stem-cell transplantation (HSCT) therapy for adults, adolescents, children, and infants over one month of age.<ref name="Defitelio EPAR" /> |
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Defibrotide is used to treat ] of the liver of people having had a ], with different limitations in the US and the European Union.<ref name=USlabel/><ref name=UKlabel/> As of 2016, however, ] have not been done.<ref>{{cite journal | vauthors = Dalle JH, Giralt SA | title = Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment | journal = Biology of Blood and Marrow Transplantation | volume = 22 | issue = 3 | pages = 400–9 | date = March 2016 | pmid = 26431626 | doi = 10.1016/j.bbmt.2015.09.024 | doi-access = free }}</ref> |
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The drug was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It is currently not approved in the USA. The manufacturer is Gentium. |
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Hematopoietic stem cell transplantation (HSCT) is a procedure performed in some people to treat certain blood or bone marrow cancers.<ref name="FDA PR" /> Immediately before an HSCT procedure, a patient receives chemotherapy.<ref name="FDA PR" /> Hepatic VOD can occur in people who receive chemotherapy and HSCT.<ref name="FDA PR" /> Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage.<ref name="FDA PR" /> In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs.<ref name="FDA PR" /> Fewer than two percent of people develop severe hepatic VOD after HSCT, but as many as 80 percent of people who develop severe hepatic VOD do not survive.<ref name="FDA PR" /> |
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==Usual indications== |
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Defibrotide is used to treat or prevent a failure of normal blood flow (], VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral ]s, ], and many others. Without intensive treatment, VOD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated. |
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It is administered by intravenous infusion in a doctor's office or clinic.<ref name=UKlabel/><ref name="Defitelio EPAR" /> |
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Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud's phenomenon. In very high doses, defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments. |
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==Contraindications== |
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It has been investigated for use in treatment of ].<ref name="pmid15507885">{{cite journal |author=Coccheri S, Andreozzi GM, D'Addato M, Gensini GF |title=Effects of defibrotide in patients with chronic deep insufficiency. The PROVEDIS study |journal=Int Angiol |volume=23 |issue=2 |pages=100–7 |year=2004 |month=June |pmid=15507885 |doi= |url=http://www.minervamedica.it/index2.t?show=R34Y2004N02A0100}}</ref> |
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Use of defibrotide for people who are already taking ] is dangerous and use of other drugs that affect platelet aggregation, like ]s, should be done with care. Defibrotide should not be given to people who have a difficult time maintaining a steady ].<ref name=UKlabel/> |
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==Adverse effects== |
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==Potential indications in the future== |
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There is a high risk of bleeding and some people have had ]s to defibrotide.<ref name=USlabel/><ref name=UKlabel/> |
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Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area. |
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Common adverse effects, occurring in between 1 and 10% of people, included impaired blood clotting, vomiting, ], ], eyes, lungs, stomach or intestines, ], and at catheterization sites.<ref name=UKlabel/> |
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Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus ], ], and ] in patients with ] have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage. |
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Other side effects have included ], nosebleeds, ], ], and pneumonia.<ref name=USlabel/> |
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==Cautions and contraindications== |
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* The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus. |
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* Pregnancy: The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist. |
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* Lactation: No human data is available. In order to avoid damage to the newborn, the nursing mother should discontinue either the drug or breastfeeding, taking into account the importance of treatment to the mother. |
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* Known Bleeding Disorders or Bleeding Tendencies having occurred recently: Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events. |
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] women should not take defibrotide and women should not become pregnant while taking it; it has not been tested in pregnant women but at normal doses it caused hemolytic abortion in rats.<ref name=UKlabel/> |
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==Side-effects== |
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Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far. |
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==Pharmacology== |
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==Drug interactions== |
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Defibrotide's mechanism of action is poorly understood. ''In vitro'' studies have shown that it protects the ] lining blood vessels from damage by ], a ] drug, and from a few other insults like serum starvation. It also appears to increase ] function and decrease ] activity.<ref name=USlabel/><ref name=UKlabel/> |
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Use of ] with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of serious bleeding will be increased considerably. |
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==Chemistry== |
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Defibrotide is a mixture of single-stranded ]s. The chemical name is polydeoxyribonucleotide, sodium salt.<ref name=USlabel/> It is purified from the ] of pigs.<ref name=UKlabel/> |
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== History == |
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The efficacy of defibrotide was investigated in 528 participants treated in three studies: two prospective clinical trials and an expanded access study.<ref name="FDA PR" /> The participants enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after hematopoietic stem cell transplantation (HSCT).<ref name="FDA PR" /> The studies measured the percentage of participants who were still alive 100 days after HSCT (overall survival).<ref name="FDA PR" /> In the three studies, 38 to 45 percent of participants treated with defibrotide were alive 100 days after HSCT.<ref name="FDA PR" /> Based on published reports and analyses of participant-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for participants with severe hepatic VOD who received only supportive care or interventions other than defibrotide.<ref name="FDA PR" /> |
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==Society and culture== |
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==References== |
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=== Legal status === |
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Defibrotide was approved in the European Union for use in treating veno-occlusive disease of the liver of people having had a bone marrow transplant in 2013;<ref name="Defitelio EPAR" /><ref name="Jazz PR">{{cite press release | publisher=Jazz Pharmaceuticals plc | title=Jazz Pharmaceuticals and Nippon Shinyaku Enter Into License Agreements for the Development and Commercialization of Defitelio and Vyxeos in Japan | via=PR Newswire | date=30 March 2017 | url=https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-and-nippon-shinyaku-enter-into-license-agreements-for-the-development-and-commercialization-of-defitelio-and-vyxeos-in-japan-300431679.html | access-date=16 August 2020}}</ref> Gentium had ] it.<ref name=genengnews20140115>{{cite news |title=Jazz Pharma Acquiring Gentium for $1B |url=http://www.genengnews.com/gen-news-highlights/jazz-pharma-acquiring-gentium-for-1b/81249275 |work=GEN Genetic Engineering & Biotechnology News |date=December 20, 2013}}</ref> At the end of that year, ] acquired Gentium.<ref name=genengnews20140115/> |
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In March 2016, the U.S. ] (FDA) approved it for a similar use.<ref name="FDA PR">{{cite press release | title= FDA approves first treatment for rare disease in patients who receive stem cell transplant from blood or bone marrow |url= https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-rare-disease-patients-who-receive-stem-cell-transplant-blood-or-bone |work=U.S. ] (FDA) |date=March 30, 2016 }} {{PD-notice}}</ref><ref name="FDA Approval" /><ref name="Jazz PR" /> Defibrotide is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.<ref name="FDA PR" /> The FDA granted the application for defibrotide ] status and ] designation.<ref name="FDA PR" /> The FDA granted approval of Defitelio to Jazz Pharmaceuticals.<ref name="FDA PR" /> |
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Defibrotide was approved for medical use in Japan in June 2019.<ref>{{cite press release | title=Marketing Approval of Defitelio by MHLW for the Treatment of Sinusoidal Obstruction Syndrome / Hepatic Veno-Occlusive Disease | publisher=Nippon Shinyaku Co., Ltd | via=CMOCRO | date=18 June 2019 | url=http://www.cmocro.com/ | access-date=16 August 2020}}</ref> |
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Defibrotide was approved for medical use in Australia in July 2020.<ref name="Defitelio APMDS" /> |
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== References == |
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{{reflist}} |
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{{reflist}} |
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== Further reading == |
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==External links== |
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* {{cite journal |vauthors=Richardson P, Aggarwal S, Topaloglu O, Villa KF, Corbacioglu S |title=Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) |journal=Bone Marrow Transplant. |volume=54 |issue=12 |pages=1951–1962 |date=December 2019 |pmid=30804485 |pmc=6957462 |doi=10.1038/s41409-019-0474-8 |doi-access=free }} |
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* Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45:259-94. |
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* {{cite journal |vauthors=Richardson PG, Carreras E, Iacobelli M, Nejadnik B |title=The use of defibrotide in blood and marrow transplantation |journal=Blood Adv |volume=2 |issue=12 |pages=1495–1509 |date=June 2018 |pmid=29945939 |pmc=6020812 |doi=10.1182/bloodadvances.2017008375 |doi-access=free }} |
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* http://www.globalrx.com/medinfo/Defibrotide.htm |
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* {{cite journal |author=Fisher J, Holland TK, Pescador R, Porta R, Ferro L |title=Study on pharmacokinetics of radioactive labelled defibrotide after oral or intravenous administration in rats |journal=Thromb. Res. |volume=81 |issue=1 |pages=55–63 |year=1996 |month=January |pmid=8747520 |doi= 10.1016/0049-3848(95)00213-8|url=http://linkinghub.elsevier.com/retrieve/pii/0049-3848(95)00213-8}} |
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* http://www.gentium.it/Defibrotide.aspx (information provided by manufacturer) |
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* {{cite web |url= http://rx.onconews.org/news/Melphalan.html |title= Melphalan: profile and news |archiveurl= http://web.archive.org/web/20070928150037/http://rx.onconews.org/news/Melphalan.html |archivedate= 2007-09-28 }} (on cytostatic combination therapy) |
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* {{cite journal |author=Beşişik SK, Oztürk GB, Calişkan Y, Sargin D |title=Complete resolution of transplantation-associated thrombotic microangiopathy and hepatic veno-occlusive disease by defibrotide and plasma exchange |journal=Turk J Gastroenterol |volume=16 |issue=1 |pages=34–7 |year=2005 |month=March |pmid=16252186 |doi= |url=http://www.turkgastro.org/text.php?id=374}} |
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{{Antithrombotics}} |
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{{Antithrombotics}} |
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{{Portal bar | Medicine}} |
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