DEFITELIO 80mg / ml perfusive solution concentrate medication leaflet

Defitelio 80 mg/mL concentrate for solution for infusion

One mL of concentrate contains defibrotide* 80 mg corresponding to a quantity of 200 mg in 2.5 mLin 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.

Each vial contains 0.89 mmol (equivalent to 20.4 mg) sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

The solution is clear light yellow to brown, free from particulate matter or turbidity.

Defitelio is indicated for the treatment of severe hepatic veno-occlusive disease (VOD) also known assinusoidal 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.

Defitelio must be prescribed and administered to patients by specialised physicians experienced in thediagnosis and treatment of complications of 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 notrecommended to increase the dose above 25 mg/kg/day.

The treatment should be administered for a minimum of 21 days and continued until the symptomsand signs of severe VOD resolve.

Dose adjustment is not required for patients with renal impairment or who are on intermittenthaemodialysis (see section 5.2).

No formal pharmacokinetic studies have been performed in patients with hepatic impairment;however, the medicinal product has been used in clinical studies of patients developing hepaticimpairment without dose adjustment with no safety issues identified. No dose adjustment is thereforerecommended but careful monitoring of patients should be undertaken (see section 5.2).

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.

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 infusionor sodium chloride 9 mg/mL (0.9%) solution for infusion to a suitable concentration to permit infusionover 2 hours. The total volume of infusion should be determined based on the individual’s patientweight. 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 (seesection 6.6)

For instructions on dilution of the medicinal product before administration, see section 6.6.

− 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).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Use of medicinal products that increase the risk of haemorrhage within 24 hours of Defitelioadministration (within 12 hours in the case of unfractionated heparin) is not recommended.

Concomitant systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors anddirect factor Xa inhibitors) (see section 4.5), except for routine maintenance or reopening of centralvenous line, requires careful monitoring. Consideration should be given to discontinuation of Defitelioduring 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 isrecommended in patients who undergo surgery or invasive procedures at significant risk of majorbleeding.

Administration of defibrotide to patients who have haemodynamic instability, defined as inability tomaintain 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 20.4 mg sodium per vial, equivalent to 1.02% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Potential interactions with recombinant t-PA

In a mouse model of thromboembolism, recombinant t-PA potentiated the antithrombotic effect ofdefibrotide when given intravenously and thus co-administration may present an increased risk ofhaemorrhage 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 activityof 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 thrombininhibitors (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 thecoagulation parameters (see section 4.4).

Potential interactions with other medicinal products

Defibrotide does not inhibit or induce CYP450s (see section 5.2).

Effective contraception is required for patients and partners of patients during exposure to Defitelioand for one week subsequent to discontinuation.

There are no studies using defibrotide in pregnant women. Embryo-foetal developmental toxicologystudies in pregnant rats and rabbits of defibrotide doses close to the recommended therapeutic humandose, 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 requirestreatment with Defitelio.

It is not known whether defibrotide is excreted in human milk. Considering the nature of the medicinalproduct, a risk to the newborns/infants is not expected. Defitelio may be used during breastfeeding.

There are no studies investigating the effects of defibrotide on human fertility.

Defitelio has no or negligible influence on the ability to drive and use machines. However, patientswould not be expected to drive or operate machinery due to the nature of the underlying disease.

The safety evaluation of defibrotide is based on the safety pooled data set, which included patientswho received 25 mg/kg/day of defibrotide for the treatment of VOD, from 4 clinical studies: The

Phase 3 pivotal treatment study (2005-01), the Treatment-IND study, the dose-finding study (99-118),and a controlled randomised prophylaxis study (2004-000592-33). In the Phase 3 pivotal treatmentstudy, the overall incidence of adverse events was similar in the defibrotide treatment group and in thecontrol group (historical). The tabulated list of adverse reactions incorporates the ADRs observed inthe safety pooled data set [ADR = any event reported as possibly related on at least two occasions] and

TEAEs observed in the final completed Treatment-IND 2006-05 study [TEAE = any AE that startedor worsened in severity after the first dose of defibrotide]. For the adverse reactions reported thehighest frequency was used in the table below. The safety data from the pivotal study are supportedand 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) andhypotension.

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 formulationof defibrotide, consequently hypersensitivity is included as an ADR.

Adverse reactions observed are listed below, by system organ class and frequency. Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequenciesare 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).

Common Coagulopathy

Uncommon Hypersensitivity

Common Cerebral haemorrhage

Uncommon Cerebral haematoma

Uncommon Conjunctival haemorrhage

Very common Hypotension

Common Haemorrhage

Common Pulmonary haemorrhage

Epistaxis

Uncommon Haemothorax

Common Gastrointestinal haemorrhage

Nausea

Haematemesis

Mouth haemorrhage

Uncommon Melaena

Common Rash

Pruritus

Petechiae

Uncommon Ecchymosis

Common Haematuria

Common Catheter site haemorrhage

Uncommon Injection site haemorrhage

In the treatment studies over 50% of the patients were children. In doses above the recommended doseof 25 mg/kg/day there was a higher proportion of patients with bleeding events in the high dose groupbut since many events occurred in the follow-up period, a clear relationship with defibrotide treatmentcould not be determined. In the paediatric prevention study at 25 mg/kg/day there was an increasedincidence 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 fataloutcome.

The frequency nature and severity of adverse reactions in children are otherwise the same as in adults.

No special precautions are indicated.

Reporting suspected adverse reactions after authorization of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for overdose and treatment should be symptomatic. Defibrotide is notremoved by dialysis (see section 5.2).

Pharmacotherapeutic group: other antithrombotic agents; ATC code: B01AX01.

Defibrotide is an oligonucleotide mixture with demonstrated antithrombotic, fibrinolytic, anti-adhesiveand anti-inflammatory actions. The mechanism of action is multifactorial. It primarily acts throughreducing excessive endothelial cell (EC) activation (endothelial dysfunction), modulating endothelialhomeostasis as well as restoring thrombo-fibrinolytic balance. However, the exact mechanism ofaction of defibrotide is not fully elucidated.

Defibrotide has demonstrated antithrombotic and fibrinolytic effects in vitro and in vivo by: increasingsystemic tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) andthrombomodulin (TM) expression; decreasing von Willebrand factor (vWF) and plasminogenactivator inhibitor-1 (PAI-1) expression; and enhancing the enzymatic activity of plasmin to hydrolysefibrin clots.

In vitro and in vivo studies have demonstrated that defibrotide inhibits leukocyte and platelet adhesionto 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 ofreactive 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 decreasingfludarabine-mediated apoptosis of EC while maintaining its anti-leukemic effect and by inhibiting theexpression of heparanase, shown in in vitro and in vivo studies respectively.

Treatment of VOD

The efficacy and safety of defibrotide in the treatment of severe VOD were studied in a pivotal Phase3 historical-controlled study (2005-01). Forty-four children and 58 adult patients with severe VODpost-HSCT, were treated with Defitelio 25 mg/kg/day intravenous by infusion, and compared with32 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 completeresponse 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 historicalcontrol (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-findingstudy (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 atday+100

Individual studies

Dose-finding Open label Historically controlled trial(25mg/kg/day treatment IND (25mg/kg/day)arm) (25mg/kg/day) Defibrotide Historicaltreated group control

Completeresponse by 43% 39.3% 23.5% 9.4%

Day+100 (32/75) (201/512) (24/102) (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 fornon-severe and severe VOD post-transplant, are consistent with the controlled clinical studies, withcomplete response rate 24% (51/212) and survival 37% (78/212) in the subset of patients with severe

VOD.

Coppell et al in 2010 reported data from a large meta-analysis of 235 patients with severe VODshowing a background mortality rate of severe VOD of 84.3% and that this mortality rate hasremained constant over several decades.

Data derived from an independent US registry have shown a beneficial effect of Defitelio in routineclinical 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 defibrotidewas 69%, and 61% in those patients who received defibrotide. These data are from an open labelregistry and the subjects were not randomised.

Additional information is shown in the following Table 2.

Table 2: US Registry data

Non-defibrotide treated Defibrotide treated55 41

Alive at Day +100 17 (31%) 16 (39%)

VOD resolved by Day +100 16 (29%) 21 (51%)

A controlled randomised prophylaxis study (Study 2004-000592-33) was conducted in the paediatricpatients undergoing HSCT. Patients (n=356) were randomised to receive 25 mg/kg/day from the startof 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 thecontrol arm to 12.2% in the Defitelio arm), has been shown. The use of Defitelio rescue treatment forall patients who developed VOD meant that the study was not designed to assess any survivaladvantage and none was seen in this study.

In secondary analyses on the subset of patients undergoing allogeneic transplants, Defitelioprophylaxis was also associated with a lower incidence and less Grade 2 to 4 severity of acute graftversus host disease (aGvHD) by Day+100.

A separate prophylaxis study (Study 15-007) using the same dose of Defitelio 25 mg/kg/day byintravenous infusion was conducted in paediatrics (n=198) as well as adults (n=174) post HSCT. Themost common primary diseases of patients were acute lymphoblastic leukemia (n=100) 26.9%, acutemyelogenous leukemia (n=96) 25.8%, or neuroblastoma (n=57) 15.3%. Patients were randomised to

Defitelio plus best supportive (BSC) care or BSC alone.

The primary endpoint of VOD-free survival by Day +30 post-HSCT was not met; there was nodifference when Defitelio plus BSC was compared with BSC alone. The Kaplan-Meier estimates(95% CIs) of VOD-free survival by Day +30 post-HSCT were 66.8% in the Defitelio prophylaxis arm(57.8%, 74.4%) and 72.5% (62.3%, 80.4%) in the BSC alone. The p-value from the stratified log ranktest that compared VOD-free survival over time between the two treatment arms was 0.8504. By

Day +30 post-HSCT, there were 10/190 or 5.7% deaths in Defitelio plus BSC and 5/182 or 2.9%deaths in the BSC alone.

Similar proportions of participants in the Defitelio plus BSC against the those receiving BSC aloneonly experienced TEAEs (99.4% vs 100%, respectively), serious TEAEs (40.9% vs 35.1%,respectively).

In the clinical studies performed in the treatment of VOD, over 55% (780 patients) were under the ageof 18 years. Safety and efficacy information in children are available from three clinical studies for thetreatment of VOD: the Phase 3 pivotal treatment study (2005-01), the Treatment-IND study (2006-05)and the dose-finding study (99-118). Safety in paediatric patients was also investigated in twoadditional prophylaxis studies (Study 2004-000592-33 & 15-007) described in section ‘Prophylaxis’above.

Safety and efficacy in children aged less than 1 month have not yet been established.

Based on the results of the QTc study, conducted in healthy subjects at therapeutic andsupra-therapeutic doses, it can be concluded that Defitelio has no significant or clinically relevant

QTc-prolonging potential at doses up to 2.4 times higher than therapeutically indicated. Defiteliomight be considered free of proarrhythmic toxicity related to QT changes.

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease and for ethical reasons preventing to perform a placebo-controlled study, it hasnot been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

In 52 healthy volunteers, after a single 6.25 mg/kg dose of Defitelio given as a 2-hour infusion, thepharmacokinetic parameters were as follows:

Table 3: Defitelio pharmacokinetic parameters after intravenous infusion of 6.25 mg/kg tohealthy subjects

Parameter Defitelio PK Parameters

Mean ± SD

Cmax (µg/mL) 17.3 ± 3.83tmax (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 ± 0.66t1/2 (h) 0.71 ± 0.35# median (min-max)

Maximum plasma concentrations peaked at the end of the infusion period and declined thereafter witha 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 notaccumulate 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 toplasma proteins.

After administration of the therapeutic dose (6.25 mg/kg) to healthy subjects, an average of 9.48% ofthe total dose administered is excreted in urine as unchanged defibrotide in 24 hours, with the majorityexcreted during the first collection interval of 0-4 hours (approximately 98%).

Defibrotide does not inhibit or induce CYP450s.

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 to6 healthy subjects with similar baseline demographics. Defitelio 6.25 mg/kg was administeredintravenously over 2 hours to subjects every 6 hours. Compared to healthy controls, subjects withrenal impairment demonstrated 1.6- and 1.4-fold increases in AUC and Cmax, respectively and ahalf-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 administeredin 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 doseswas not found. Difference in exposure is not considered clinically relevant and so dose adjustment isnot 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)

No formal pharmacokinetic studies have been performed in hepatic impaired patients. Defitelio hasbeen used in clinical studies in patients with hepatic impairment without dose adjustment with nomajor safety issues identified (see section 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity or carcinogenicity.

In both species, the main findings were accumulation of vacuolated macrophages in liver of dogs andin 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 byinducing a high rate of haemorrhagic abortion when infused intravenously over two hours at all doselevels tested including doses close to the human dose. Due to this maternal toxicity, no conclusion canbe drawn regarding the effects of defibrotide on embryo-foetal development. PAI-2 is known to beuniquely up-regulated in the placenta.

Juvenile toxicity

Repeated intravenous administration of defibrotide, at doses below and close to the human therapeuticdose, to juvenile rats resulted in a delay in the mean age of preputial separation, suggesting a delay inthe onset of male puberty in rats. However, the clinical relevance of these findings is unknown.

Sodium citrate, dihydrate

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vials3 years

In-use stability after first opening and/or dilution

From a microbiological point of view, after dilution, the reconstituted medicinal product should beused immediately. However, chemical and physical in-use stability has been demonstrated for72 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.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and would not normally be expected to exceed 24 hours at 2-8 °C.

Store below 25 °C. Do not freeze.

For storage conditions after dilution of the medicinal product, see section 6.3.

2.5 mL vials (Type I clear glass), closed with a stopper (butyl rubber) and seal (aluminium).

Pack size of 10 vials.

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% glucosesolution for infusion (see section 6.3 for concentration range and stability of the diluted solution) to asuitable concentration to permit 2 hour 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 theliquid 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. Thefinal 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% solutionfor infusion from the infusion bag should be withdrawn and discarded, equal to the total volumeof 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 solutionswithout visible particles should be used. Depending on the type and amount of diluent thecolour of the diluted solution may vary from colourless to light yellow. It is recommended thatthe diluted Defitelio solution be administered to patients using an infusion set equipped with a0.2 μm in-line filter.

9. After the infusion is complete, the intravenous line should be flushed with sodium chloride9 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 localrequirements.

Gentium S.r.l

Piazza XX Settembre, 222079 Villa Guardia (Como)

Italy

EU/1/13/878/001

Date of first authorisation: 18 October 2013

Date of latest renewal: 26 May 2023

Detailed information on this medicinal product is available on the website of the European Medicines

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