Consumer medicine information

Defitelio

Defibrotide

BRAND INFORMATION

Brand name

Defitelio

Active ingredient

Defibrotide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Defitelio.

SUMMARY CMI

DEFITELIO®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I being given DEFITELIO?

DEFITELIO contains the active ingredient defibrotide. DEFITELIO is used to treat a condition called hepatic veno-occlusive disease (or VOD), in which the blood vessels in the liver become damaged and obstructed by blood clots.

For more information, see Section 1. Why am I being given DEFITELIO? in the full CMI.

2. What should I know before I am given DEFITELIO?

Do not use if you have ever had an allergic reaction to defibrotide or any of the ingredients listed at the end of the CMI.

Do not use if are using other medicines to break down blood clots such as tissue plasminogen activators (e.g. alteplase, reteplase).

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given DEFITELIO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DEFITELIO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is DEFITELIO given?

  • 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 cell transplantation.
  • The total dose of DEFITELIO that is given is calculated based on your body weight.

More instructions can be found in Section 4. How is DEFITELIO given? in the full CMI.

5. What should I know while being given DEFITELIO?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using DEFITELIO.
Driving or using machines
  • DEFITELIO is not expected to affect your ability to drive a car or operate machinery.
Looking after your medicine
  • It is unlikely that you will be asked to store DEFITELIO yourself. It will usually be stored in the pharmacy or on the ward.
  • DEFITELIO is stored below 25°C. It must not be frozen.

For more information, see Section 5. What should I know while being given DEFITELIO? in the full CMI.

6. Are there any side effects?

Possible side effects include signs of increased or unusual bleeding or bruising during or after treatment, nosebleeds, passing of blood in the urine or faeces, dark coloured faeces, bloody diarrhoea, vomiting blood or material that looks like coffee grounds, bleeding from the infusion line or catheter, bleeding at the site of injection, bleeding from the mouth, bleeding from the eye, chest pain, shortness of breath, rapid heartbeat, fever or high temperature, dizziness or light-headedness, sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing, nausea, vomiting, diarrhoea, rash, red or purple, flat, pinhead spots under the skin, and itching.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ 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. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

DEFITELIO®

Active ingredient(s): defibrotide

Consumer Medicine Information (CMI)

This leaflet provides important information about using DEFITELIO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DEFITELIO.

Where to find information in this leaflet:

1. Why am I being given DEFITELIO?
2. What should I know before I am given DEFITELIO?
3. What if I am taking other medicines?
4. How is DEFITELIO given?
5. What should I know while being given DEFITELIO?
6. Are there any side effects?
7. Product details

1. Why am I being given DEFITELIO?

DEFITELIO contains the active ingredient defibrotide.

DEFITELIO is used to treat a condition called hepatic veno-occlusive disease (or VOD), 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.

DEFITELIO 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.

This medicine is available only with a doctor's prescription.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

2. What should I know before I am given DEFITELIO?

Warnings

Do not use DEFITELIO if:

  • you are allergic to defibrotide, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • are using other medicines to break down blood clots such as tissue plasminogen activators (e.g. alteplase, reteplase).

Check with your doctor if you:

  • have any other medical conditions
  • are taking medicine that thins your blood or increases the risk of bleeding
  • have heavy bleeding and need a blood transfusion
  • are undergoing surgery
  • have problems with blood circulation because your body cannot maintain a constant blood pressure
  • have allergies to any other medicines, foods, preservatives, or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

DEFITELIO is not recommended in children less than 1 month of age.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Defitelio should not be used during pregnancy unless there is a definite need. Your doctor will discuss with you the risk and benefit involved in using DEFITELIO during pregnancy.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor can discuss with you the risk and benefits involved.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor if you are taking any of the following:

  • medicines to break down blood clots, such as tissue plasminogen activators (e.g. alteplase, reteplase).
  • medicines used to thin your blood such as aspirin, heparin sodium, warfarin, dabigatran etexilate, rivaroxaban, apixaban
  • non-steroidal anti-inflammatory medicines such as ibuprofen, naproxen, diclofenac and other non-steroidal anti-inflammatory medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DEFITELIO.

4. How is DEFITELIO given?

  • 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 cell transplantation.

How much is given

  • The total dose of DEFITELIO that is given is calculated based on your body weight.
  • The calculation of the dose in children from one month to 18 years of age is the same as in adults.

How it is given

  • DEFITELIO will be given via a drip (a slow injection into your veins) over a 2-hour period. This is also called an intravenous infusion.

When it is given

  • You will receive this treatment four times a day for at least 21 days and until your symptoms resolve.

If you miss a dose

Tell your doctor or nurse immediately if you think you have missed a dose of DEFITELIO.

As you will be given this medicine by a doctor or a nurse it is unlikely that a dose will be missed. You must not be given a double dose to make up for a missed dose.

If you are given too much DEFITELIO

As DEFITELIO is given to you under the supervision of your doctor it is unlikely that you will be given too much. However, if you experience any side effects after being given DEFITELIO, tell your doctor immediately.

5. What should I know while being given DEFITELIO?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using DEFITELIO.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DEFITELIO affects you.

DEFITELIO is not expected to affect your ability to drive a car or operate machinery.

Looking after your medicine

It is unlikely that you will be asked to store DEFITELIO yourself. It will usually be stored in the pharmacy or on the ward.

  • DEFITELIO is stored below 25°C. It must not be frozen.
  • 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 the month.

Keep it where young children cannot reach or see it.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effectsWhat to do
Bleeding-related:
  • signs of increased or unusual bleeding or bruising during or after treatment
  • nosebleeds
  • passing of blood in the urine or faeces
  • dark coloured faeces
  • bloody diarrhoea
  • vomiting blood or material that looks like coffee grounds
  • bleeding from the infusion line or catheter
  • bleeding at the site of injection
  • bleeding from the mouth
  • bleeding from the eye
Heart-related:
  • chest pain
  • rapid heartbeat
Breathing-related:
  • shortness of breath
General:
  • fever or high temperature
Head-related:
  • dizziness or light-headedness
Allergy related:
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
Gastrointestinal-related:
  • feeling sick, also called nausea
  • vomiting
  • diarrhoea
Skin-related:
  • rash
  • red or purple, flat, pinhead spots under the skin
  • itching
Tell your doctor or nurse immediately if you notice any of the following as you may require medical attention.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What DEFITELIO contains

Active ingredient
(main ingredient)		Defibrotide
Each 2.5 mL contains 200 mg defibrotide and each mL of concentrated solution contains 80 mg defibrotide.
Other ingredients
(inactive ingredients)
  • sodium citrate dihydrate
  • hydrochloric acid
  • sodium hydroxide
  • water for injections
Potential allergensN/A

Do not take this medicine if you are allergic to any of these ingredients.

What DEFITELIO looks like

DEFITELIO is a clear light yellow to brown concentrated solution for infusion, free from particulate matter or turbidity.

One carton contains 10 glass vials, each with 2.5 mL of concentrated solution for infusion.

(AUST R 319221).

Who distributes DEFITELIO

Jazz Pharmaceuticals ANZ Pty Ltd
Suite 214, Level 2
165 Phillip Street
Sydney, NSW, 2000
Australia
Phone: 1800 577 422

This leaflet was prepared in February 2024.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Defitelio

Active ingredient

Defibrotide

Schedule

S4

 

1 Name of Medicine

Defibrotide.

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 before dilution. The final concentration of the solution should be 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 List of Excipients.

3 Pharmaceutical Form

Concentrated 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 Indications

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.

4.2 Dose 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.

Dosage.

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.

Dose adjustment.

Renal impairment.

Dose adjustment is not required for patients with renal impairment or who are on intermittent haemodialysis (see Section 5.2 Pharmacokinetic Properties, Special populations).

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 Pharmacokinetic Properties, Special populations).

Paediatric population.

The recommended dose for children aged 1 month and above 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 have 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 (see Section 6.3 for concentration range and stability of the diluted solution), to a suitable concentration to permit infusion over 2 hours. The total volume of infusion should be determined based on the individual patient's 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 Special Precautions for Disposal).
The concentrated solution for infusion must be diluted using aseptic technique.

Preparation of Defitelio (use aseptic technique).

1. The total dose and thereby, the total volume of infusion and the total number of vials to be diluted 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 Shelf Life).
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 required volume from the Defitelio vials should be withdrawn and combined.
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, equal to the total volume of Defitelio concentrated solution to be added, should be withdrawn and discarded.
5. 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.
6. The solution for infusion should be mixed gently.
7. 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 micrometer in-line filter.
8. 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.
9. Administer Defitelio as described above. Do not co-administer other drugs through the same intravenous line.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed (see Section 6.1 List of Excipients).
Concomitant use of thrombolytic therapy (e.g. t-PA) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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.

Haemorrhage.

Use of medicines 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 Interactions with Other Medicines and Other Forms of Interactions), 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.
Medicines 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.

Hemodynamic instability.

Administration of defibrotide to patients who have haemodynamic instability, defined as inability to maintain mean arterial pressure with single pressor support, is not recommended.

Bolus administration.

A bolus administration of Defitelio may cause flushing or a sensation of "generalised heat". Bolus administration of Defitelio is not recommended.
This medicinal product contains 20.4 mg sodium per vial.

Use in the elderly.

Clinical studies of Defitelio did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Paediatric use.

Defitelio is indicated for the use in adolescents, children and infants of 1 month of age and above (see Section 4.8 Adverse Effects (Undesirable Effects), Paediatric population). The use of Defitelio in children aged less than one month is not recommended.

Effects on laboratory tests.

There were no safety concerns for Defitelio revealed from clinical laboratory results. Changes in laboratory values were generally consistent with underlying disease and veno-occlusive disease diagnosis.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Contraindications).

Potential interactions with antithrombotic fibrinolytic agents.

Defibrotide has a profibrinolytic effect (see Section 5.1 Pharmacodynamic Properties, Mechanism of action) 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 etexilate) 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 Special Warnings and Precautions for Use, Haemorrhage).

Potential interactions with other medicinal products.

Defibrotide does not inhibit or induce CYP450s (see Section 5.2 Pharmacokinetic Properties, Metabolism).

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.

Effects on fertility.

There are no studies investigating the effects of defibrotide on human fertility.
Animal studies of fertility were not conducted with defibrotide administered by the intravenous route. In repeat dose general toxicology studies, when defibrotide was administered intravenously to rats and dogs for up to 13 weeks, there were no effects on male or female reproductive organs.
(Category D)
There are no studies using defibrotide in pregnant women. Embryo-fetal 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 when infused intravenously over two hours at all dose levels tested. Due to this maternal toxicity, no conclusion can be drawn regarding the effects of defibrotide on embryo-fetal development. PAI-2 is known to be uniquely up-regulated in the placenta.
Defitelio should not be used during pregnancy unless the clinical condition of the woman requires treatment with Defitelio.
 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.

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 Adverse Effects (Undesirable Effects)

Clinical trial experience.

The safety assessment of Defitelio is based on pooled data from 176 subjects in the pivotal treatment study and the dose finding study. The overall incidence of adverse events was similar in the defibrotide treatment group and in the historical control group. The safety data from pooled data are supported and confirmed with data from the completed Treatment-IND study and postmarketing experience.
Table 1 describes adverse events that occurred at a rate of more than 5% in either the treatment group or the historical control group in the defibrotide 25 mg/kg/day pooled data.
Adverse reactions of uncommon or lower frequency observed in pivotal treatment study and dose-finding study are listed below, by system organ class and frequency. 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).
List of adverse reactions of uncommon or lower frequencies in the pivotal treatment study and the dose-finding study (25 mg/kg/day) pooled data:

Gastrointestinal disorders.

Uncommon: haematemesis; upper gastrointestinal haemorrhage; gastric haemorrhage; haematochezia; melaena; mouth haemorrhage.

General disorders and administration site conditions.

Uncommon: chills; feeling hot; puncture site haemorrhage.

Investigations.

Uncommon: international normalised ratio increased.

Nervous system disorders.

Uncommon: lethargy; spinal haematoma; subarachnoid haemorrhage; subdural hygroma.

Reproductive system and breast disorders.

Uncommon: menorrhagia.

Respiratory, thoracic and mediastinal disorders.

Uncommon: haemothorax; thoracic haemorrhage.

Skin and subcutaneous tissue disorders.

Uncommon: dry skin; pruritus generalised; purpura; skin haemorrhage.

Vascular disorders.

Uncommon: flushing; haemorrhage; haematoma.

Postmarketing experience.

In addition to adverse reactions from clinical studies, the following adverse reactions were identified during post-approval use of products containing defibrotide.

Immune system disorders.

Uncommon: anaphylactic reaction, hypersensitivity.

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.
A small numerical increased incidence of fatal hemorrhagic events has been observed in pediatric subjects exposed to defibrotide at doses of 25 mg/kg/day or higher, compared to historical controls. In this treatment group, causality was difficult to determine given multiple comorbidities.
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.

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 at www.tga.gov.au/reporting-problems.

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 Pharmacokinetic Properties, Special populations, Renal impairment).
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

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), 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.

Clinical trials.

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 by intravenous infusion, and compared with 32 historical control patients. Median length of therapy in those treated with Defitelio was 22 days.
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=0.0109). In addition, 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 25.5% (26/102) with Defitelio versus 12.5% (4/32) in the historical control (p=0.016).
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 Table 2.
Outcome data available from 701 patients treated with Defitelio for VOD post-transplant in an international, open label, compassionate use program are consistent with the controlled clinical trial, with a Kaplan-Meier estimated survival at Day +100 of 57.6% in patients with VOD receiving defibrotide doses of 25 mg/kg/day.
Return of outcome data for this program was not mandated and was highly variable compared to formally conducted clinical trials.
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 with subjects not randomised and data on dose or duration of defibrotide treatment were not collected.
Additional information is shown in the following Table 3.

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 is also available from a 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 2.4 times higher than therapeutically indicated. Defitelio might be considered free of proarrhythmic toxicity related to QT changes.

5.2 Pharmacokinetic Properties

Absorption and distribution.

Defibrotide PK parameters from patients (N=10) with severe VOD receiving 6.25 mg/kg dose and participating in PK sub-study in the dose finding study (99-118) are presented in Table 4.
Maximum plasma concentrations peak at the end of the infusion period and decline thereafter with a rapid clearance. Defitelio is undetectable in most samples by 3.5 hours after the start of the infusion.
Pharmacokinetic modelling simulation analysis show 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 8.1 to 9.1 L.
In vitro studies demonstrate that 93% of Defitelio is bound to plasma proteins.

Metabolism.

Defibrotide does not inhibit or induce CYP450s.

Excretion.

Metabolism followed by urinary excretion is likely the main route of elimination. The estimated total clearance is 3.4 to 6.1 L/h.
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%).

Special populations.

Renal impairment.

Six patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m2 (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 Dose and Method of Administration, Renal impairment).
In a sub-study it was shown that haemodialysis did not remove defibrotide (see Section 4.2 Dose and Method of Administration, Renal impairment).

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 Dose and Method of Administration, Hepatic impairment).

5.3 Preclinical Safety Data

Genotoxicity.

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.

Carcinogenicity.

While there was no evidence of carcinogenic potential following 2 years of dietary defibrotide administration to mice and rats (at up to 2000 mg/kg/day), this is not the clinical route of administration and the relative defibrotide exposure would be substantially less compared to intravenous administration, allowing limited conclusions to be drawn from these studies.

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 4.2 Dose and Method of Administration, Method of administration.

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.
If not used immediately, store at 2-8°C and discard after 24 hours.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze.
For storage conditions after dilution of the medicinal product, see Section 6.3 Shelf Life.

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

Defitelio is for single use in one patient only. Discard any unused contents.
In Australia, any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

83712-60-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes