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去纤苷酸浓缩液输液 Defitelio 80mg/ml Infusionslösung
Defitelio 80 mg/ml Infusionslösung 去纤苷酸浓缩液输液
Defitelio 80 mg/ml Konzentrat zur Herstellung einer Infusionslösung - OP(10x2.5ml); Infusionslösung; Gentium S.p.A.
Allgemeine Angaben
Eingangsnummer : 2709527
Arzneimittelname: Defitelio 80 mg/ml Konzentrat zur Herstellung einer Infusionslösung - OP(10x2.5ml）
Darreichungsform : Infusionslösung
Administrative Daten
Antragsteller: Gentium S.p.A.
Verkehrsfähig : ja
Zulassungs-/Reg-Nr.(AMG76) : EU/1/13/878/001
Zusammensetzung
Arzneilich wirksame Bestandteile
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ASK-Nr. |
Stoffname |
Stoffmenge |
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Defibrotid |
200.mg |
AM-Klassifikation
Antrag auf Zulassung gem. § 21 AMG wurde am bzw. nach dem 30.10.2005 gestellt (Parallelimporte werden hierbei nicht betrachtet)
AM mit besonderer Überwachung gem. Art. 23 vom 27.11.2013 - Authorised under exceptional circumstances
Information
Generic Name: defibrotide
Trade Name: Defitelio
Synonym: Noravid, Prociclide
Entry Type: New molecular entity
Developmental Status
UK: Launched
EU: Launched
US: Phase III Clinical Trials
UK launch Plans: Available only to registered users
Actual UK launch date: June 2014
Comments
Jun 14: Launched in the UK [26].
09/06/2014 15:53:18
Mar 14: Launched in Germany & Austria. Jazz Pharmaceuticals, which gained ownership of Defitelio via its purchase of Gentium earlier in 2014, expects to continue launch in 27 additional European countries on a rolling basis during 2014 & 2015 [25].
15/04/2014 17:22:31
Oct 13: European Commission has granted a Marketing Authorization for Defitelio® (defibrotide) for the treatment of severe hepatic veno-occlusive disease in adults and children undergoing hematopoietic stem cell transplantation therapy. [23]
23/10/2013 16:47:45
Jul 13: EU positive opinion for Defitelio to be used for the treatment of severe hepatic veno-occlusive disease (VOD) also known as sinusoidal obstructive syndrome (SOS) in haematopoietic stem-cell transplantation (HSCT) therapy. It is indicated in adults and in adolescents, children and infants aged 1 month to 18 years. After re-examining their original negative opinion, the CHMP concluded that, in view of results from a US patient registry showing pts with severe VOD who received Defitelio plus standard care had better outcomes, including a higher survival rate after 100 days following transplantation, than those given standard care alone, along with other available data, the benefits of Defitelio outweigh its risks. A risk management plan will be put in place & the applicant will be required to provide further data on the medicine through a registry to be set up in the EU. The CHMP recommended that Defitelio be authorised in the EU under ‘exceptional circumstances’ [22].
26/07/2013 14:26:49
Jun 13: The Company has filed the documentation requesting a re-examination of the negative opinion given by the CHMP. A final recommendation may be made by the end of July [21].
10/06/2013 10:29:23
Mar 13: CHMP issues a negative opinion for defibrotide, having concluded that results from the prevention study did not provide sufficiently convincing evidence of benefit & there were problems with the way the study was conducted, including problems with documentation and reporting of data [20].
22/03/2013 12:45:23
Feb 13: Following a meeting between Gentium and the EMA’s CHMP regarding the marketing authorization application, the company expects a negative opinion for defibrotide to treat and prevent hepatic veno-occlusive disease in adults and children undergoing hematopoietic stem cell transplantation therapy [19].
21/02/2013 21:49:17
Jan 13: Gentium announces that defibrotide will be discussed at the CHMP´s Feb meeting [18].
21/01/2013 08:55:05
Dec 12: Gentium announced that it has submitted responses to the second List of Outstanding Issues to the EMA [17].
19/12/2012 10:49:08
Sep 12: CHMP has decided to adopt a second List of Outstanding Issues following company oral explanations [16]
11/12/2012 15:44:55
Sep 12: Gentium announced today that it has been asked to present Oral Explanations on September 19, 2012 to the EMA CHMP"as part of the review process of the Company´s Marketing Authorization Application (MAA) [15].
12/09/2012 10:07:10
Jun 12: Gentium has submitted its response to the Day 120 list of outstanding issues & is hopeful for a positive opinion in 3Q 12 [14].
05/07/2012 16:59:27
Dec 11: Following a clarification meeting recently held with the Company´s Rapporteurs, Gentium anticipates submitting a response to the Day 120 List of Questions from the CHMP in the first quarter of 2012. [13]
30/12/2011 08:31:08
Oct 11: Company has received and reviewed the Day 120 List of Questions (LoQs) from the European Medicines Agency´s Committee for Medical Products for Human Use and anticipates that it will submit its responses by the end of December. [12]
21/10/2011 08:23:49
Aug 11: New Drug Application (NDA) for defibrotide voluntarily withdrawn following recent correspondence from the US FDA identifying numerous "Refuse to File" issues. I FDA raised concerns regarding the completeness of the datasets for both the treatment and prevention studies and requested that additional quality reviews of the original datasets and databases are conducted. The FDA also requested additional details regarding the conduct and monitoring of the trials by the independent review committee. [11]
19/08/2011 08:22:05
Jul 11: Filed in US to treat adults and children with hepatic veno-occlusive disease, who are undergoing hematopoietic stem-cell transplantation (HSCT) [10].
14/07/2011 21:38:01
June 11: EU assessment under accelerated assessment procedures effectively reducing review time by two months [9].
15/06/2011 10:11:29
May 11: Filed in the EU for treatment & prevention of hepatic veno-occlusive disease (VOD) in haematopoietic stem-cell transplantation therapy, in adults & children [8].
12/05/2011 11:28:39
Feb 11: Company plan to file for regulatory approval in EU and US by the end of 2Q 2011 [7].
10/02/2011 09:01:48
PIII in EU in adolescents and children (5)
02/04/2009 11:06:23
Orphan drug status in Eu and US for prevention and treatment. Fast track in US for treatment following stem cell transplanation (5)
02/04/2009 11:04:23
PIII trials initiated. Granted fast track designation in US(1).
Trial or other data
Dec 13: Jazz Pharmaceuticals is to buy Gentium [24]
23/12/2013 08:52:58
Feb 12: Results published in the Lancet (Lancet, early online publication, 23 February 2012) of an RCT by the European Group for Blood and Marrow Transplantation that compared defibrotide prophylaxis vs standard of care in 356 paediatric patients at high risk of developing veno-occlusive disease after HSCT. 12% vs 20%, respectively, had veno-occlusive disease by 30 days after HSCT (primary endpoint); (risk difference −7.7%, p=0.0507). Patients in either group who developed veno-occlusive disease received defibrotide for treatment. Adverse events to 180 days after HSCT were similar in both groups (87 vs 88%).
24/02/2012 16:45:22
VOD is a potentially life-threatening condition which typically occurs as a significant complication of stem cell transplantation. Defibrotide has been used in its treatment as part of a large compassionate use program & ongoing named patient programs. The EU MAA is supported by several clinical trials, & includes data from the compassionate use program. If approved by the EMA, it will be the first drug licensed in the EU for treatment of VOD in either the treatment or prevention setting [8].
12/05/2011 11:30:09
Dec 09: The final results of the PII/III Pediatric Prevention trial and PIII Treatment trial were presented at the American Society of Hematology Conference (ASH). The company claim that both trials strongly trended toward statistical significance. The Prevention trial demonstrated a 40% reduction in the incidence of VOD at day 30 (p=0.0488 Competing Risk; p=0.0507 Kaplan-Meier) and the Treatment trial showed an improvement in complete response from 9% in the historical control arm to 24% in the defibrotide arm (p=0.0148). In the prevention trial, although not powered to assess mortality, a composite score measured as a secondary endpoint, incorporating VOD-associated morbidity (including respiratory failure, renal failure, encephalopathy) and mortality, significantly favored defibrotide prophylaxis (p=0.0340). Additionally, the incidence and severity of acute GvHD by day 100 in the allogeneic SCT recipients (246 patients) was reduced from 63% for the control arm to 45% for the prophylaxis arm (p=0.0044 for incidence of GvHD and p=0.0032 for severity). Defibrotide was well tolerated in both studies [6].
09/12/2009 10:16:27
Aug 09: Top-line results announced from an open label PIII trial to eva luate 25 mg/kg/day defibrotide for the treatment of severe veno-occlusive disease (sVOD) in haematopoietic stem cell transplant (SCT) patients. The results did not reach the protocol-specified levels of significance. On ITT analysis, 24% of 102 patients in the defibrotide arm vs 9% of patients in the historical control arm achieved the primary endpoint of complete response at 100 days (p-value 0.015), and 38% vs 25% respectively, demonstrated the secondary endpoint of survival at 100 days (p-value=0.051) [5].
19/08/2009 21:42:06
Mar 09: PII/III results from European Paediatric prevention trial - defibrotide in paediatrics undergoing stem cell transplantation (SCT) who are at risk for hepatic veno-occlusive disease (VOD). Intention to treat populatio n= 180 pts in treatment arm and 176 pts in control arm. 40% reduction in VOD within 30 days after SCT, p=0.0539 (ITT population). In per protocol population (164 treatment and 169 control), 40% reduction in the rate of incidence of VOD within 30 days after SCT, p=0.0366. (4)
31/03/2009 16:56:25
Nov 08: An interim review of the P3 trial by the Data Safety Monitoring Board (DSMB) suggests that the sample size needs to be increased to 160 pt in the treatment arm (currently 102) and 80 in the historical control arm in order to be 80% powered to detect a p value of 0.01, which is required by the FDA. Increased recruitment to the treatment arm is unlikely. The DSMB did not raise any safety issues or recommend that the trail is stopped due to futility (3)
13/01/2009 10:46:58
Evidence Based eva luations
SMC http://www.scottishmedicines.org.uk/SMC_Advice/Advice/967_14_defibrotide_Defitelio/defibrotide_Defitelio
LNDG http://www.medicinesresources.nhs.uk/upload/Defibrotide.pdf
NHSC/NIHR http://www.hsc.nihr.ac.uk/topics/defibrotide-defitelio-for-hepatic-veno-occlusive-d/
EMA doc http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500146652
References
Available only to registered users
Category
BNF Category: Peripheral vasodilators and related drugs (02.06.04)
Pharmacology: Cytokine modulator
Epidemiology: Hepatic VOD is caused by toxic injury leading to hepatic vein obstruction and is associated with the pre-conditioning chemotherapy regimen for HSCT. Up to 17% of patients who receive HSCT develop VOD and about 33% progress to severe VOD. Without treatment 80% of those with severe VOD die within 100 days of HSCT.
Indication: Veno-occlusive disorders
Additional Details:
Method(s) of Administration
Intravenous infusion
Company Information
Name: Jazz Pharmaceuticals
US Name: Gentium
NICE Information
Anticipated Commissioning route (England) -
In timetable: -
PBR Specified high cost drug.
Implications Available only to registered users
DEFITELIO (défibrotide), antithrombotique
Substance active (DCI)
défibrotide ((MAMMIFERE/PORC/MUQUEUSE INTESTINALE))
HEMATOLOGIE - Nouveau médicament
Avis du 09 juillet 2014
Nature de la demande
Inscription
Progrès thérapeutique mineur dans la prise en charge de la maladie veino-occlusive hépatique sévère après transplantation de cellules souches hématopoïétiques.
DEFITELIO a l’AMM pour le traitement de la maladie veino-occlusive (MVO) hépatique sévère, également appelée syndrome obstructif sinusoïdal (SOS) survenant après transplantation de cellules souches hématopoïétiques (TCSH).
C’est le premier traitement ayant une AMM dans cette indication. Néanmoins, la Commission regrette qu’aucune étude de bon niveau de preuve n’ait été réalisée.
Service Médical Rendu (SMR)
Modéré Le service médical rendu par DEFITELIO est modéré dans l’indication de l’AMM.
Amélioration du service médical rendu (ASMR)
IV (mineur) Au vu des données disponibles qui sont d’un faible niveau de preuve alors qu’il existe des schémas d’études ne nécessitant que peu de patients, en raison de la gravité de la maladie et de l’absence d’alternative, la Commission considère que DEFITELIO, apporte une amélioration du service médical rendu mineure (ASMR IV) dans la stratégie thérapeutique du traitement de la MVO hépatique sévère post-TCSH.
Documents
DEFITELIO 09072014 AVIS CT13383 ( 183,76 Ko) Écouter
DEFITELIO SYNTHESE CT13383 ( 26,53 Ko) Écouter
Code ATC
B01AX01
Laboratoire / fabricant
GENTIUM SPA
Présentation
DEFITELIO 80 mg/ml, solution concentrée à diluer pour perfusion (code CIS : 69439245)
10 flacon(s) en verre - Code CIP : 3400958579462 |
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