Defibrotide

{{Infobox drug | Verifiedfields = changed | verifiedrevid = 447578248 | image = | image_class = skin-invert-image | width = 200px | alt = | caption = | JAN = defibrotide sodium | USAN = defibrotide sodium

| pronounce = | tradename = Defitelio | Drugs.com = {{drugs.com|monograph|defibrotide-sodium}} | MedlinePlus = | DailyMedID = Defibrotide | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Defitelio APMDS" /> | pregnancy_category = | routes_of_administration = Intravenous | class = | ATC_prefix = B01 | ATC_suffix = AX01 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref name="Defitelio APMDS" /> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Blood health (non-cancer) | website=Health Canada | 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> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref name=UKlabel /> | legal_US = Rx-only | legal_US_comment = <ref name=USlabel /> | legal_EU = Rx-only | legal_EU_comment = <ref name="Defitelio EPAR" /> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 83712-60-1 | CAS_supplemental = | PubChem = | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DBSALT001719 | DrugBank2 = DB04932 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = none | UNII_Ref = {{fdacite|correct|FDA}} | UNII = L7CHH2B2J0 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D07423 | ChEBI_Ref = | ChEBI = | ChEMBL_Ref = | ChEMBL = 3707226 | ChEMBL2 = 2108396 | NIAID_ChemDB = | PDB_ligand = | synonyms = JZP-381

| IUPAC_name = | chemical_formula = | C= | H= | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I= | K= | Li= | Mg= | Mn= | N= | Na= | O= | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge= | molecular_weight = | SMILES = | StdInChI = | StdInChI_comment = | StdInChIKey = | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Defibrotide''', sold under the brand name '''Defitelio''', is a mixture of single-stranded oligonucleotides that is purified from the intestinal mucosa of pigs. It is used to treat veno-occlusive disease of the liver of people having had a bone marrow transplant, with different limitations in the US and the European Union. It works by protecting the cells lining blood vessels in the liver and preventing blood clotting; 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=European Medicines Agency (EMA) | date=21 April 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/defitelio | access-date=16 August 2020}}</ref>

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/>

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. Food and Drug Administration (FDA) | date=10 May 2016 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208114Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20160531094301/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208114Orig1s000TOC.cfm | url-status=dead | archive-date=May 31, 2016 | 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" />

==Medical uses== 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" />

Defibrotide is used to treat veno-occlusive disease of the liver of people having had a bone marrow transplant, with different limitations in the US and the European Union.<ref name=USlabel/><ref name=UKlabel/> As of 2016, however, randomized placebo controlled trials 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>

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" />

It is administered by intravenous infusion in a doctor's office or clinic.<ref name=UKlabel/><ref name="Defitelio EPAR" />

==Contraindications== Use of defibrotide for people who are already taking anticoagulants is dangerous and use of other drugs that affect platelet aggregation, like NSAIDs, should be done with care. Defibrotide should not be given to people who have a difficult time maintaining a steady blood pressure.<ref name=UKlabel/>

==Adverse effects== There is a high risk of bleeding and some people have had hypersensitivity reactions to defibrotide.<ref name=USlabel/><ref name=UKlabel/>

Common adverse effects, occurring in between 1 and 10% of people, included impaired blood clotting, vomiting, low blood pressure, bleeding in the brain, eyes, lungs, stomach or intestines, in the urine, and at catheterization sites.<ref name=UKlabel/>

Other side effects have included diarrhea, nosebleeds, sepsis, graft vs host disease, and pneumonia.<ref name=USlabel/>

Pregnant 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/>

==Pharmacology== Defibrotide's mechanism of action is poorly understood. ''In vitro'' studies have shown that it protects the endothelium lining blood vessels from damage by fludarabine, a chemotherapy drug, and from a few other insults like serum starvation. It also appears to increase t-PA function and decrease plasminogen activator inhibitor-1 activity.<ref name=USlabel/><ref name=UKlabel/>

==Chemistry== Defibrotide is a mixture of single-stranded oligonucleotides. The chemical name is polydeoxyribonucleotide, sodium salt.<ref name=USlabel/> It is purified from the intestinal mucosa of pigs.<ref name=UKlabel/>

== History == 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" />

==Society and culture== === Legal status === 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 developed 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, Jazz Pharmaceuticals acquired Gentium.<ref name=genengnews20140115/>

In March 2016, the U.S. Food and Drug Administration (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 |archive-url= https://web.archive.org/web/20191211202236/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-rare-disease-patients-who-receive-stem-cell-transplant-blood-or-bone |url-status= dead |archive-date= December 11, 2019 |work=U.S. Food and Drug Administration (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 priority review status and orphan drug designation.<ref name="FDA PR" /> The FDA granted approval of Defitelio to Jazz Pharmaceuticals.<ref name="FDA PR" />

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=https://www.cmocro.com/ | access-date=16 August 2020}}</ref>

Defibrotide was approved for medical use in Australia in July 2020.<ref name="Defitelio APMDS" />

== References == {{reflist}}

== Further reading == * {{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 }} * {{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 }}

Category:Anticoagulants Category:Orphan drugs