Defitelio

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Defitelio 80 mg/mL concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One mL of concentrate contains defibrotide* 80 mg corresponding to a quantity of 200 mg in 2.5 mL 
in a vial, and corresponding to a concentration in the range of 4 mg/mL to 20 mg/mL after dilution. 
* produced from porcine intestinal mucosa. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
The solution is clear light yellow to brown, free from particulate matter or turbidity. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indication 
 
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 over 1 month of age. 
 
4.2 Posology and method of administration 
 
Defitelio must be prescribed and administered to patients by specialised physicians experienced in the 
diagnosis and treatment of complications of HSCT.  
 
Posology 
 
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 VOD resolve. 
 
Renal impairment 
 
Dose adjustment is not required for patients with renal impairment or who are on intermittent 
haemodialysis (see section 5.2).  
 
 



 

 
Hepatic impairment 
 
No formal pharmacokinetic studies have been performed in patients with hepatic impairment; 
however, the medicinal product has been used in clinical trials of patients developing hepatic 
impairment without dose adjustment with no safety issues identified. No dose adjustment is therefore 
recommended but careful monitoring of patients should be undertaken (see section 5.2). 
 
Paediatric population 
 
The recommended dose for children aged 1 month to 18 years is the same mg/kg dose as for adults i.e. 
6.25 mg/kg body weight every 6 hours. 
 
The safety and efficacy of defibrotide in children aged less than 1 month has not yet been established. 
No data are available. The use of Defitelio in children aged less than one month is not recommended. 
 
Method of administration  
 
Defitelio is for intravenous use. It is administered by intravenous infusion, over two hours. 
 
Defitelio should always be diluted prior to use. It can be diluted with 5% glucose solution for infusion 
or sodium chloride 9 mg/mL (0.9%) solution for infusion, to a suitable concentration to permit 
infusion over 2 hours. The total volume of infusion should be determined based on the individual’s 
patient weight. The final concentration of Defitelio should be in the range of 4 mg/mL to 20 mg/mL. 
 
Vials are intended for a single use and unused solution from a single dose must be discarded (see 
section 6.6) 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 
− Concomitant use of thrombolytic therapy (e.g. t-PA) (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded in the patient file. 
 
Use of medicinal products that increase the risk of haemorrhage within 24 hours of Defitelio 
administration (within 12 hours in the case of unfractionated heparin) is not recommended. 
 
Concomitant systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and 
direct factor Xa inhibitors) (see section 4.5), except for routine maintenance or reopening of central 
venous line, requires careful monitoring. Consideration should be given to discontinuation of Defitelio 
during use of such therapy.  
 
Medicinal products that affect platelet aggregation (e.g. non–steroidal anti-inflammatory agents) 
should be administered with care, under close medical supervision, during Defitelio administration. 
 
In patients who have or develop clinically significant acute bleeding requiring blood transfusion, 
Defitelio is not recommended or should be discontinued. Temporary discontinuation of Defitelio is 
recommended in patients who undergo surgery or invasive procedures at significant risk of major 
bleeding. 
 



 

Administration of defibrotide to patients who have haemodynamic instability, defined as inability to 
maintain mean arterial pressure with single pressor support, is not recommended. 
 
A bolus administration of Defitelio may cause flushing or a sensation of “generalised heat”. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 
“sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Potential interactions with recombinant t-PA 
 
In a mouse model of thromboembolism, recombinant t-PA potentiated the antithrombotic effect of 
defibrotide when given intravenously and thus co-administration may present an increased risk of 
haemorrhage and is contraindicated (see section 4.3).  
 
Potential interactions with antithrombotic fibrinolytic agents 
 
Defibrotide has a profibrinolytic effect (see section 5.1) and this may potentially enhance the activity 
of antithrombotic/fibrinolytic medicinal products. 
 
There is currently no reported experience in patients on the concomitant treatment with Low 
Molecular Weight Heparins (LMWHs), warfarin or the concomitant treatment with direct thrombin 
inhibitors (e.g., dabigatran) or direct Factor Xa inhibitors (e.g., rivaroxaban and apixaban). Therefore, 
the use of defibrotide with antithrombotic/fibrinolytic medicinal products is not recommended.  
However, if used, in exceptional cases, caution should be exercised by closely monitoring the 
coagulation parameters (see section 4.4). 
 
Potential interactions with other medicinal products 
 
Defibrotide does not inhibit or induce CYP450s (see section 5.2). 
 
4.6 Fertility, pregnancy and lactation 
 
Contraception in males and females 
 
Effective contraception is required for patients and partners of patients during exposure to Defitelio 
and for one week subsequent to discontinuation.  
 
Pregnancy 
 
There are no studies using defibrotide in pregnant women. Embryo-foetal developmental toxicology 
studies in pregnant rats and rabbits of defibrotide doses close to the recommended therapeutic human 
dose, revealed a high rate of haemorrhagic abortion (see section 5.3). 
 
Defitelio should not be used during pregnancy unless the clinical condition of the woman requires 
treatment with Defitelio. 
 
Breast-feeding 
 
It is not known whether defibrotide is excreted in human milk. Considering the nature of the medicinal 
product, a risk to the newborns/infants is not expected. Defitelio may be used during breastfeeding. 
 
Fertility 
 
There are no studies investigating the effects of defibrotide on human fertility.  



 

4.7 Effects on ability to drive and use machines 
 
Defitelio  has no or negligible influence on the ability to drive and operate machines. However, 
patients would not be expected to drive or operate machinery due to the nature of the underlying 
disease.  
 
4.8 Undesirable effects 
 
Summary of the Safety Profile 
 
In the Phase 3 pivotal treatment study (2005-01 Study), the overall incidence of adverse events was 
similar in the defibrotide treatment group and in the control group (historical). The tabulated list of 
adverse reactions incorporates the ADRs observed in study 2005-01 [ADR = any event reported as 
possibly related on at least two occasions] and TEAEs observed in T-IND 2006-05 study [TEAE = 
any AE that started or worsened in severity after the first dose of defibrotide]. For adverse reactions 
reported in both studies, the highest frequency was used in the table below. The safety data from the 
pivotal study are supported and confirmed with data from the completed Treatment-IND study. 
 
The most frequent adverse reactions observed during the treatment of hepatic VOD are haemorrhage 
(including but not limited to gastrointestinal haemorrhage, pulmonary haemorrhage and epistaxis) and 
hypotension.  
 
In addition, although in the defibrotide studies in VOD there have been no reports of hypersensitivity, 
cases of hypersensitivity including anaphylaxis were reported from a previously marketed formulation 
of defibrotide, consequently hypersensitivity is included as an ADR.  
 
Tabulated list of adverse reactions 
Adverse reactions observed are listed below, by system organ class and frequency. Within each 
frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies 
are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), 
rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). 
 
Blood and lymphatic system disorders   
Common Coagulopathy 
Immune system disorders  
Uncommon Hypersensitivity 
 Anaphylactic reaction 
Nervous system disorders 
Common Cerebral haemorrhage   
Uncommon Cerebral haematoma   
Eye disorders 
Uncommon Conjunctival haemorrhage 
Vascular disorders 
Very common Hypotension 
Common Haemorrhage  
Respiratory, thoracic and mediastinal disorders 
Common Pulmonary haemorrhage 
 Epistaxis   
Uncommon Haemothorax 
Gastrointestinal disorders: 
Common Gastrointestinal haemorrhage 
 Vomiting  
 Diarrhoea 



 

 Nausea 
 Haematemesis 
 Mouth haemorrhage   
Uncommon Melaena 
Skin and subcutaneous tissue disorders 
Common Rash 
 Pruritus 
 Petechiae 
Uncommon Ecchymosis 
Renal and urinary disorders 
Common Haematuria   
General disorders and administration site conditions 
Common Catheter site haemorrhage 
 Pyrexia   
Uncommon Injection site haemorrhage   
 
Paediatric population  
 
In the treatment studies over 50% of the patients were children. In doses above the recommended dose 
of 25 mg/kg/day there was a higher proportion of patients with bleeding events in the high dose group 
but since many events occurred in the follow-up period, a clear relationship with defibrotide treatment 
could not be determined. In the paediatric prevention study at 25 mg/kg/day there was an increased 
incidence of any bleeding events in the defibrotide group compared with the treatment group.  
 
However there was no difference in incidence of serious bleeding or bleeding events with fatal 
outcome. 
 
The frequency nature and severity of adverse reactions in children are otherwise the same as in adults. 
No special precautions are indicated. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorization of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no specific antidote for overdose and treatment should be symptomatic. Defibrotide is not 
removed by dialysis (see section 5.2). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: other antithrombotic agents; ATC code: B01AX01. 
 
Mechanism of action 
 
Defibrotide is an oligonucleotide mixture with demonstrated antithrombotic, fibrinolytic, anti-adhesive 
and anti-inflammatory actions. The mechanism of action is multifactorial. It primarily acts through 
reducing excessive endothelial cell (EC) activation (endothelial dysfunction), modulating endothelial 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

homeostasis as well as restoring 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 attenuate 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). 
 
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, shown in in vitro and in vivo  studies respectively. 
 
Clinical efficacy and safety 
 
The efficacy and safety of defibrotide in the treatment of severe VOD were studied in a pivotal Phase 
3 historical-controlled study (2005-01). Forty-four children and 58 adult patients with severe VOD 
post-HSCT, were treated with Defitelio 25 mg/kg/day intravenous by infusion, and compared with 
32 historical control patients. Median length of therapy in those treated with Defitelio was 22 days.   
 
A significantly higher proportion of patients in the Defitelio treated group achieved a complete 
response defined as total bilirubin less than 2 mg/dL and resolution of MOF (multiple organ failure); 
Day+100 complete response was 23.5% (24/102) with Defitelio versus 9.4% (3/32) in the historical 
control (p=0.013). In addition, Day+100 survival rate was improved in the Defitelio group with 38.2% 
(39/102) of the patients surviving versus 25.0% (8/32) in the historical control group (p=0.034).  

The efficacy data from this pivotal study are supported and confirmed with data from a dose-finding 
study (25 mg/kg arm) and the Open Label Treatment-IND study, as presented in Tables 1. 
 
Table 1: Treatment Study Results: Complete Response and Survival Rate of Severe VOD at 
Day+100  

 

Individual Studies 

Dose-Finding 
(25mg/kg/day arm) 

Open Label 
Treatment IND 
(25mg/kg/day) 

Historically Controlled Trial 
(25mg/kg/day) 

Defibrotide 
treated group 

Historical 
Control 

Complete 
Response by 

Day+100 
 

43% 
(32/75) 

39.3% 
(201/512) 

23.5% 
(24/102) 

9.4% 
(3/32) 

p= 0.0131 
Survival by 
Day+100 43.9%* 49.5%* 

38.2%* 25.0%* 
p=0.0341 

*=Kaplan Meier estimates for time-to-event analysis by Day100 
 



 

Outcome data available from 611 patients treated with Defitelio on a compassionate use basis for 
non-severe and severe VOD post-transplant, are consistent with the controlled clinical trials, with 
complete response rate 24% (51/212) and survival 37% (78/212) in the subset of patients with severe 
VOD. 
 
A controlled randomised prophylaxis study (Study 2004-000592-33) was conducted in the paediatric 
patients undergoing HSCT. Patients (n=356) were randomised to receive 25 mg/kg/day from the start 
of conditioning or were randomised to receive no prophylaxis. 
 
A 40% reduction in the overall incidence of VOD in the Defitelio prophylaxis arm (from 19.9% in the 
control arm to 12.2% in the Defitelio arm), has been shown. The use of Defitelio rescue treatment for 
all patients who developed VOD meant that the study was not designed to assess any survival 
advantage and none was seen in this study.  
 
In secondary analyses on the subset of patients undergoing allogeneic transplants, Defitelio 
prophylaxis was also associated with a lower incidence and less Grade 2 to 4 severity of acute graft 
versus host disease (aGvHD) by Day+100. 
 
Coppell et al in 2010 reported data from a large meta-analysis of 235 patients with severe VOD 
showing a background mortality rate of severe VOD of 84.3% and that this mortality rate has 
remained constant over several decades.  
 
Data derived from an independent US registry have shown a beneficial effect of Defitelio in routine 
clinical practice. At an interim analysis of the on-going registry, data from 96 patients with severe 
VOD were available. 
 
The Day+100 all-cause mortality in patients with severe VOD who were not treated with defibrotide 
was 69%, and 61% in those patients who received defibrotide. These data are from an open label 
registry and the subjects were not randomised. 
 
Additional information is shown in the following Table 2. 
 
Table 2: US Registry data 

 

Non-defibrotide treated  Defibrotide treated 
55 41 

Alive at Day +100 17 (31%) 16 (39%) 
VOD resolved by Day +100 16 (29%) 21 (51%) 

 
Paediatric population 
 
In each of the clinical trials performed in the treatment of VOD, over 50% of patients were under the 
age of 18 years. Safety information in children are available from the prevention study conducted 
solely in children. Safety and efficacy in children aged less than 1 month have not yet been 
established. 
 
Cardiac electrophysiology 
 
Based on the results of the QTc study, conducted in healthy subjects at therapeutic and 
supra-therapeutic doses, it can be concluded that Defitelio has no significant or clinically relevant 
QTc-prolonging potential at doses up to 4 times higher than therapeutically indicated. Defitelio might 
be considered free of proarrhythmic toxicity related to QT changes. 
 
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to 
the rarity of the disease and for ethical reasons preventing to perform a placebo-controlled study, it has 
not been possible to obtain complete information on this medicinal product. 



 

The European Medicines Agency will review any new information which may become available every 
year and this SmPC will be updated as necessary 
 
5.2 Pharmacokinetic properties 
 
Absorption and Distribution 
 
In 52 healthy volunteers, after a single 6.25 mg/kg dose of Defitelio given as a 2-hour infusion, the 
pharmacokinetic parameters were as follows: 
 
Table 3. Defitelio pharmacokinetic parameters after intravenous infusion of 6.25 mg/kg to 
healthy subjects. 

Parameter Defitelio PK Parameters 
Mean ± SD 

Cmax (µg/mL) 17.3 ± 3.83 
tmax (h)# 2.00 (1.00-2.00) 

AUCt (µg/mL*h) 26.9 ± 8.53 
AUC (µg/mL*h) 48.1 ± 6.49 

Vd (mL) 9934 ± 3807 
CL (L/h) 10.4 ± 1.77 
Kel (1/h) 1.25 ± 0.66 

t1/2 (h) 0.71 ± 0.35 
# median (min-max) 

 
Maximum plasma concentrations peaked at the end of the infusion period and declined thereafter with 
a rapid clearance and most of samples were undetectable 3.5 hours after the start of the infusion. 
Pharmacokinetic modelling simulation analysis showed that Defitelio plasma concentrations do not 
accumulate upon multiple dose administration and with doses up to 4-fold the therapeutic dose. 
Volume of distribution is around 10 L. In vitro studies demonstrate that 93% of Defitelio is bound to 
plasma proteins. 
 
Elimination 
 
After administration of the therapeutic dose (6.25 mg/kg) to healthy subjects, an average of 9.48% of 
the total dose administered is excreted in urine as unchanged defibrotide in 24 hours, with the majority 
excreted during the first collection interval of 0-4 hours (approximately 98%). 
 
Metabolism 
 
Defibrotide does not inhibit or induce CYP450s. 
 
Special populations 
 
Renal impairment 
 
Six patients with an estimated  glomerular filtration rate <30 mL/min/1.73m2 (calculated using the 
Modification of Diet in Renal Disease equation) and not currently on dialysis were compared to 6 
healthy subjects with similar baseline demographics. Defitelio 6.25 mg/kg was administered 
intravenously over 2 hours to subjects every 6 hours. Compared to healthy controls, subjects with 
renal impairment demonstrated 1.6– and 1.4-fold increases in AUC and Cmax, respectively and a 
half-life of about twice that of healthy subjects. 
 
The amount of defibrotide excreted in urine over 24 hrs was about 5% of the total dose administered 
in those with renal impairment versus about 12% in healthy subjects. 
 



 

Almost all renal excretion occurs within the first 4 hours. Accumulation of defibrotide over 4 doses 
was not found. Difference in exposure is not considered clinically relevant and so dose adjustment is   
not advised for patients with renal impairment (see section 4.2). 
 
In a sub-study it was shown that haemodialysis did not remove defibrotide (see section 4.2) 
 
Hepatic impairment 
 
No formal pharmacokinetic studies have been performed in hepatic impaired patients. Defitelio has 
been used in clinical trials in patients with hepatic impairment without dose adjustment with no major 
safety issues identified (see section 4.2). 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity.  
 
In both species, the main findings were accumulation of vacuolated macrophages in liver of dogs and 
in liver, kidneys and lymph nodes of rats. Macrophages are considered the main target organ. 
 
Embryo-foetal development  
 
In the Segment II reproductive studies in rats and rabbits, defibrotide has shown maternal toxicity by 
inducing a high rate of haemorrhagic abortion when infused intravenously over two hours at all dose 
levels tested including doses close to the human dose. Due to this maternal toxicity, no conclusion can 
be drawn regarding the effects of defibrotide on embryo-foetal development. PAI-2 is known to be 
uniquely up-regulated in the placenta.  
 
Juvenile toxicity 
 
Repeated intravenous administration of defibrotide, at doses below and close to the human therapeutic 
dose, to juvenile rats resulted in a delay in the mean age of preputial separation, suggesting a delay in 
the onset of male puberty in rats. However, the clinical relevance of these findings is unknown. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium citrate, dihydrate  
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vials 
3 years  
 
In-use stability after first opening and/or dilution 



 

From a microbiological point of view, after dilution, the reconstituted medicinal product should be 
used immediately. However, chemical and physical in-use stability has been demonstrated for 
72 hours at 15-25°C for a concentration range of 4 mg/mL to 20 mg/mL in sodium chloride 9 mg/mL 
(0.9%) solution for infusion or 5% glucose solution for infusion at 15-25ºC for 72 hours. 
 
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the 
user and would not normally be expected to exceed 24 hours at 2-8°C. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
Do not freeze. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
 
6.5 Nature and contents of container 
 
2.5 mL vials (Type I clear glass), closed with a stopper (butyl rubber) and seal (aluminium). 
 
Pack size of 10 vials. 
 
6.6 Special precautions for disposal and other handling 
 
Defitelio is for single use only. 
 
The concentrate solution for infusion has to be diluted using aseptic technique. 
 
Defitelio should be diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion or 5% glucose 
solution for infusion (see section 6.3 for concentration range and stability of the diluted solution) to a 
suitable concentration to permit 2 hours infusion time (see section 4.2). 
 
Preparation of Defitelio (use aseptic technique): 
 
1. The number of vials to be diluted should be determined based on the individual patient's weight 
(see section 4.2). 
2. Before dilution, each vial should be inspected for particles. If particles are observed and/or the 
liquid in the vial is not clear, the vial must not be used. 
3. The total volume of infusion should be determined based on the individual patient's weight. The 
final concentration of Defitelio should be in the concentration range of 4 mg/mL – 20 mg/mL (see 
section 6.3). 
4. A volume of the sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 5% solution 
for infusion from the infusion bag should be withdrawn and discarded, equal to the total volume of 
Defitelio solution to be added. 
5. The required volume from the Defitelio vials should be withdrawn and combined. 
6. The combined volumes of Defitelio should be added to the sodium chloride 9 mg/mL (0.9%) 
solution for infusion or glucose 5% solution for infusion. 
7. The solution for infusion should be mixed gently. 
8. Prior to use the solution should be visually inspected for particulate matter. Only clear solutions 
without visible particles should be used. Depending on the type and amount of diluent the colour of 
the diluted solution may vary from colourless to light yellow. It is recommended that the diluted 
Defitelio solution be administered to patients using an infusion set equipped with a 0.2 μm in-line 
filter. 
9. After the infusion is complete, the intravenous line should be flushed with sodium chloride 
9 mg/mL (0.9%) solution for infusion or glucose 5% solution for infusion. 
 



 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gentium S.r.l. 
Piazza XX Settembre 2  
Villa Guardia  
22079 Italy 
Phone: +39 031 5373200  
Fax: +39 031 5373241 
info@gentium.it 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/878/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 October 2013 
Date of latest renewal: 26 July 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu./


 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE 

POST-AUTHORISATION MEASURES FOR THE 
MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 



 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Gentium S.r.l. 
Piazza XX Settembre, 2  
22079 Villa Guardia (Como) 
Italy 
 
Name and address of the manufacturer responsible for batch release 
 
Gentium S.r.l. 
Piazza XX Settembre, 2  
22079 Villa Guardia (Como) 
Italy 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal products subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 
 

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time. 
 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES  



 

 
This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation 
(EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 
 

Description Due date 
Measure 1 
In order to collect comparative safety data, the MAH will provide the final CSR and a 
report of comparative safety data from the Phase 3, randomised, adaptive study 
(15-007) of Defibrotide vs best supportive care in the prevention of hepatic veno-
occlusive disease in adult and paediatric patients undergoing hematopoietic stem cell 
transplant (HSCT). 
 
The report will also reflect on the safety data being collected during prophylactic 
treatment, and any potential safety differences related to the difference in indication (ie 
treatment vs prophylactic therapy). 

 
End of February 
2021 
 

Measure 2 
In order to provide comparative data on efficacy, the MAH will submit  

 
• Data analysis from CIBMTR for patients treated and not treated with defibrotide 
  

 
Updated analysis 
from CIBMTR 
to be submitted 
by end of 
December 2020. 

 



 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Defitelio 80 mg/mL concentrate for solution for infusion  
defibrotide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One mL of concentrate contains 80 mg defibrotide. Each 2.5 mL vial contains 200 mg defibrotide. 
200 mg/2.5 mL 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: sodium citrate dihydrate, hydrochloric acid and sodium hydroxide (for pH adjustment), 
water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
10 vials  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not freeze. 



 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gentium Srl 
Piazza XX Settembre 2 
Villa Guardia 
22079 Italy 
P: +39 031 5373200 
F: +39 031 5373241 
info@gentium.it 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/878/001  
 
 
13. BATCH NUMBER 
 
Lot:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Defitelio 80 mg/mL sterile concentrate 
defibrotide 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
2.5 mL 
 
 
6. OTHER 
 
200 mg/2.5 mL 
Gentium Srl  
 
 



 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

Package leaflet: Information for the user 
 

Defitelio 80 mg/mL concentrate for solution for infusion 
defibrotide 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
− Keep this leaflet. You may need to read it again. 
− If you have any further questions, ask your doctor. 
− If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What Defitelio is and what it is used for 
2. What you need to know before you are administered Defitelio 
3. How you will be given Defitelio. 
4. Possible side effects. 
5. How to store Defitelio. 
6. Contents of the pack and other information. 
 
 
1. What Defitelio is and what it is used for 
 
Defitelio is a medicine that contains the active substance defibrotide.  
 
It is used to treat a condition called hepatic veno-occlusive disease, in which the blood vessels in the 
liver become damaged and obstructed by blood clots. This can be caused by medicines that are given  
prior to a stem cell transplantation. 
 
Defibrotide works by protecting the cells of the blood vessels and preventing or breaking down the 
blood clots.  
 
This medicine can be used in adults, and in adolescents, children and infants over one month of age. 
 
 
2. What you need to know before you take Defitelio  
 
Do not use Defitelio 
• if you are allergic to defibrotide or any of the other ingredients of this medicine (listed in 

section 6) 
• if you are using other medicines to break down blood clots such as tissue plasminogen activator  
 
Warnings and precautions 
Talk to your doctor before using Defitelio: 
• if you are taking medicine that increases the risk of bleeding 
• if you have heavy bleeding and need a blood transfusion 
• if you are undergoing surgery 
• if you have problems with blood circulation because your body cannot maintain a constant 

blood pressure. 
 

Children and adolescents 



 

Defitelio is not recommended in children less than 1 month of age. 
 
Other medicines and Defitelio 
Tell your doctor if you are taking medicines to prevent blood clotting such as acetylsalicylic acid, 
heparins, warfarin, dabigatran, rivaroxaban or apixaban or if you are taking anti-inflammatory 
medicines (e.g., ibuprofen, naproxen, diclofenac and other non-steroidal anti-inflammatory 
medicines). 
 
Pregnancy and breast-feeding 
Do not use Defitelio if you are pregnant unless your disease requires treatment with Defitelio. 
If you are sexually active and you or your partner could become pregnant, you both must use effective 
contraception during treatment with Defitelio and for 1 week after stopping the treatment.  
 
Driving and using machines 
It is not expected that Defitelio will affect your ability to drive and operate machines. 
 
Defitelio contains sodium 
This medicine contains less than 23 mg of sodium, which means it is essentially “sodium-free”. 
 
 
3. How you will be given Defitelio  
 
The treatment with Defitelio can be initiated and continuously supervised only by an experienced 
doctor in a hospital or in a specialised centre for stem cells transplantation. 
 
It will be slowly injected (over a 2-hour period) into one of your veins. This is called an ‘intravenous 
infusion’ or drip. 
 
You will receive this treatment four times a day for at least 21 days or until your symptoms resolve. 
The recommended dose in children from one month to 18 years of age is the same as in adults. 
 
If a dose of Defitelio has been forgotten 
As you will be given this medicine by a doctor or a nurse it is unlikely that a dose will be missed. 
However, tell your doctor or healthcare professional if you think that a dose has been forgotten. You 
must not be given a double dose to make up for a missed dose. 
If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Defitelio can cause side effects, although not everybody gets them.  For patients 
treated with Defitelio the following side effects were reported. 
 
If you experience any of these side effects, you should contact your doctor immediately. 

Very Common (may affect more than 1 in 10 people ) 

• low blood pressure  
 

Common (may affect up to 1 in 10 people) 
• bleeding in general 
• bleeding from the nose 
• bleeding in the brain 
• bleeding in the gut 
• vomiting blood 
• bleeding in the lungs 



 

• bleeding from the infusion line 
• blood in the urine 
• bleeding from the mouth 
• bleeding into the skin 
• coagulopathy (disturbance of blood clotting) 
• nausea 
• vomiting 
• diarrhoea 
• rash 
• itching 
• fever 
 
Uncommon (may affect up to 1 in 100 people) 
• bleeding from the eye 
• blood in the stool 
• bleeding at the site of injection 
• localized blood collection out of the vessel (hematoma) in the brain 
• haemothorax (accumulation of blood in the area between the heart and the lung) 
• bruising 
• severe allergic reaction (you might experience swelling of the hands, face, lips, tongue or throat, 

difficulty in breathing). 
 
Children and adolescents 
Side effects in children (1 month to 18 years old) are expected to be similar in type, severity and 
frequency and no other special precautions are needed. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Defitelio 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Defitelio after the expiry date which is stated on the carton and vial label after EXP. The 
expiry date refers to the last day of that month.  
 
Do not freeze. 
 
Once diluted for use the infusion storage should not exceed 24 hours at 2°C -8°C unless dilution has 
taken place in controlled and validated aseptic conditions. 
 
Defitelio should not be used if the solution is cloudy or contains particles. 
 
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.  
 
 
6. Contents of the pack and other information  
 
What Defitelio contains 
• The active substance is defibrotide. Each 2.5 mL vial contains 200 mg defibrotide and each mL 

solution contains 80 mg defibrotide. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

• The other ingredients are sodium citrate dihydrate, hydrochloric acid and sodium hydroxide 
(both for pH-adjustment) and water for injections (see section 2 ‘Defitelio contains Sodium’).  

 
What Defitelio looks like and contents of the pack 
Defitelio is a clear light yellow to brown concentrate for solution for infusion, free from particulate 
matter or turbidity. 
 
One carton contains 10 glass vials with 2.5 mL of concentrate each. 
 
Marketing Authorisation Holder and Manufacturer 
Gentium Srl 
Piazza XX Settembre 2 
Villa Guardia 
22079 Italy 
P:+39 031 5373200 
F: +39 031 5373241 
info@gentium.it 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
AT – BE – BG – CY – CZ – DE – DK – EE – 
EL – ES – FI – FR – HR – HU – IE – IS – IT – 
LT – LU – LV – MT – NL – NO – PO – PT – 
RO – SE – SK – SL – UK 
 
Jazz Pharmaceuticals Ireland Limited  
Tel: +44 8450305089 
medinfo-int@jazzpharma.com 

 
 
 

 
This leaflet was last revised in:  
This medicine has been authorised under ‘exceptional circumstances’. This means that because of the 
rarity of this disease and for ethical reasons it has been impossible perform a placebo-controlled 
clinical trials and to get complete information on this medicine. 
 
The European Medicines Agency will review any new information on this medicine every year and 
this leaflet will be updated as necessary. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
<--------------------------------------------------------------------------------------------------------------> 

mailto:info@gentium.it

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET