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Defitelio
Sponsor
Device/Product name
Defitelio
Active Ingredient
Defibrotide
Date of decision
Published
Submission type
New biological entity
ATC codes
B01AX01
Decision
Approved
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Defitelio was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
| Description | Date |
|---|---|
| Designation (Orphan) | 22 February 2019 |
| Submission dossier accepted and first round evaluation commenced | 31 July 2019 |
| First round evaluation completed | 4 February 2020 |
| Sponsor provides responses on questions raised in first round evaluation | 21 February 2020 |
| Second round evaluation completed | 22 May 2020 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 12 May 2020 |
| Sponsor's pre-Advisory Committee response | 26 May 2020 |
| Advisory Committee meeting | 4 June 2020 |
| Registration decision (Outcome) | 15 July 2020 |
| Completion of administrative activities and registration on ARTG | 23 July 2020 |
| Number of working days from submission dossier acceptance to registration decision* | 223 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. This product will remain in the scheme for 5 years, starting on the date the product is first supplied in Australia
Dose forms
Concentrated solution for infusion
Strength
200 mg/2.5 mL
Other ingredients
Sodium citrate dihydrate, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injections
Containers
Vial
Pack sizes
10
Routes of administration
Intravenous infusion
Dosage
Defitelio must be prescribed and administered to patients by specialised physicians experienced in the diagnosis and treatment of complications of haematopoietic stem-cell transplantation (HSCT).
The recommended dose is 6.25 mg/kg body weight every 6 hours (25 mg/kg/day).
There is limited efficacy and safety data on doses above this level and consequently it is not recommended to increase the dose above 25 mg/kg/day.
The treatment should be administered for a minimum of 21 days and continued until the symptoms and signs of severe veno‑occlusive disease (VOD) resolve.
For further information refer to the Product Information.
Pregnancy category
DDrugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Defitelio (defibrotide) was approved for the following therapeutic use:
Defitelio is indicated for the treatment of severe hepatic veno-occlusive disease (VOD) also known as sinusoidal obstruction syndrome (SOS) in haematopoietic stem-cell transplantation (HSCT) therapy.
It is indicated in adults and in adolescents, children and infants of 1 month of age and above.
What is this medicine and how does it work
Defibrotide is an oligonucleotide mixture with demonstrated antithrombotic, fibrinolytic, antiadhesive and anti-inflammatory actions. The mechanism of action is multifactorial. It primarily acts through reducing excessive endothelial cell (EC) activation (endothelial dysfunction), thereby modulating endothelial homeostasis and maintaining the thrombo-fibrinolytic balance. However, the exact mechanism of action of defibrotide is not fully elucidated.Defibrotide has demonstrated antithrombotic and fibrinolytic effects in vitro and in vivo by: increasing systemic tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) and thrombomodulin (TM) expression; decreasing von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression; and enhancing the enzymatic activity of plasmin to hydrolyse fibrin clots.In vitro and in vivo studies have demonstrated that defibrotide inhibits leukocyte and platelet adhesion to endothelium by: suppressing P-selectin and vascular cell adhesion molecule-1 (VCAM-1); interfering with lymphocyte function-associated antigen 1-intercell adhesion molecule (LFA-1-ICAM) mediated leukocyte transmigration; and increasing nitric oxide (NO), prostaglandin I2 (PGI2) and prostaglandin E2 (PGE2).In vitro defibrotide demonstrates anti-inflammatory effects that attenuates the release and production of reactive oxygen species and inflammatory mediators such as interleukin 6, thromboxane A2, leukotriene B4 and tumour necrosis factor-α (TNF-α).In vitro and in vivo studies have shown that defibrotide protects ECs from damage and promotes tissue homeostasis by decreasing fludarabine-mediated apoptosis of EC while maintaining its anti-leukemic effect and by inhibiting the expression of heparanase.
What post-market commitments will the sponsor undertake
- Defitelio (defibrotide) is to be included in the Black Triangle Scheme. The Product Information (PI) (including the PI as package insert) and the Consumer Medicines Information (CMI) for Defitelio must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date that the sponsor notifies the TGA of supply of the product.
- The Defitelio European Union-Risk Management Plan (EU-RMP; version 7.0, dated 19 December 2019, data lock point 18 October 2019), with Australian specific Annex (version 1.0, dated June 2020), included with submission PM-2019-01763-1-3, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of risk management plans is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Reports are to be provided in line with the current published list of European Union reference dates and frequency of submission of PSURs until the period covered by such reports is not less than three years from the date of the approval letter.
- All batches of Defitelio (defibrotide) imported into Australia must comply with the product details and specifications approved during evaluation and detailed in the Certified Product Details (CPD).
- Up to five (5) initial batches of Defitelio (defibrotide) imported into Australia is not released for sale until samples and/or the manufacturer's release data have been assessed and endorsed for release by the TGA Laboratories Branch. Outcomes of laboratory testing are published biannually in the TGA Database of Laboratory Testing Results.
The sponsor should be prepared to provide product samples, reference materials and documentary evidence as defined by the TGA Laboratories branch. The sponsor must contact Biochemistry.Testing@health.gov.au for specific material requirements related to the batch release testing/assessment of the product. More information is available at Testing of biological medicines
This batch release condition will be reviewed and may be modified on the basis of actual batch quality and consistency. This condition remains in place until the sponsor is notified in writing of any variation.
- Certified Product Details
The CPD, as described in Guidance 7: Certified Product Details of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM), in PDF format, for the products should be provided upon registration of these therapeutic goods. In addition, an updated CPD should be provided when changes to finished product specifications and test methods are approved in a Category 3 application or notified through a self-assessable change.
CPDs should be emailed to Biochemistry.Testing@health.gov.au as a single PDF document.
- For all injectable products the Product Information must be included with the product as a package insert.