Consumer medicine information

Veletri

Epoprostenol

BRAND INFORMATION

Brand name

Veletri

Active ingredient

Epoprostenol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Veletri.

What is in this leaflet

This leaflet answers some common questions about VELETRI. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What VELETRI is used for

VELETRI is used to treat some types of pulmonary arterial hypertension (PAH). PAH is characterised by high blood pressure in the blood vessel that carries blood from the heart to the lungs, and increased resistance in the blood vessels of the lung. The cause of PAH is not known however there are a number of diseases such as scleroderma that are associated with PAH. VELETRI belongs to a group of medicines called prostaglandins.

VELETRI works by widening the blood vessels in the lungs and so lowering the blood pressure in your lungs (known as a vasodilator action).

Your doctor however, may prescribe VELETRI for another purpose.

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

VELETRI is not addictive.

Before you use VELETRI

When you must not use VELETRI

Do not use VELETRI if you have ever had an allergic reaction to epoprostenol or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.

Do not use VELETRI if you have heart disease with shortness of breath, and swelling of the feet or legs due to fluid build-up.

Do not use VELETRI after the expiry date [EXP.] printed on the pack. If you use it after the expiry date has passed, it may not work as well.

Do not use VELETRI if the packaging is torn or shows signs of tampering.

If you're not sure whether you should be using VELETRI, talk to your doctor.

Before you start to use VELETRI

You must tell your doctor if:

  • you are allergic to foods, dyes, preservatives or any other medicines.
  • you have heart disease
  • you are pregnant, trying to become pregnant, or breastfeeding.
  • you are taking any medicine to prevent blood clots, such as heparin, warfarin, aspirin or other anti-inflammatory pain killers (NSAIDs).
  • you are taking any medicines that are used to treat high blood pressure, or a group of medicines known as nitrates that are used to treat angina.
  • you are taking digoxin, a medicine used to treat heart failure.
  • you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when using VELETRI with other medicines.

If you develop pulmonary oedema (water on the lungs) during this time, your doctor may choose not to treat you with VELETRI.

How to use VELETRI

VELETRI will be given as an intravenous infusion only, normally through a permanently fitted intravenous catheter (during initial treatment a 'peripheral line' may be used which is a non-permanent catheter). Before VELETRI is used, it must be dissolved only in sterile water for injection or Sodium Chloride 0.9% solution for injection.

How much to use

Initial treatment with VELETRI will be carried out in a hospital. Your doctor will start you on an infusion and slowly increase the dose (every 15 minutes) to find the most effective or highest dose you can tolerate.

During this part of the treatment you will also learn about how your body reacts to VELETRI.

Your doctor will then continue the infusion based on this dose, and may increase or decrease your infusion rate depending on your response to the treatment. All changes should be done gradually and under the direction of a doctor, except in emergency situations.

How to use VELETRI

Your VELETRI infusion will be given to you as continuous intravenous infusion only, normally through a permanently fitted intravenous catheter through a pump. There are only certain pumps which can be used. Your doctor will make sure you are using the right one.

Your doctor or nurse will have shown you how to keep your catheter clean, and the area around it clean and free from infection. They will also show you how to prepare and administer VELETRI and how to stop treatment if necessary. It is very important you follow their instructions carefully.

VELETRI contains no preservative. Use a vial once only and then discard.

How long to use it

Use VELETRI for as long as your doctor advises you to. VELETRI is generally used over a prolonged period of time, possibly years. It should not be stopped suddenly. Symptoms of suddenly stopping VELETRI include dizziness, weakness and difficulty breathing.

If you use too much (overdose)

As VELETRI has vasodilatory action, overdose may lead to low blood pressure, loss of consciousness, nausea, diarrhoea, vomiting, facial flushing, headache and fast heart beat.

In hospital, the effects of VELETRI are monitored carefully by your doctor. In the unlikely event that you receive too much, appropriate action, such as reducing the dose can be taken promptly.

If you are using VELETRI at home and you think you have used too much, immediately telephone your doctor or the nearest hospital casualty department, even if there are no signs of discomfort. You may need urgent medical attention.

Poison Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Keep telephone numbers for these places handy.

While you are using VELETRI

Things you must do

Tell your doctor or pharmacist that you are using VELETRI if you are about to start on any new medicines.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Tell your doctor if, for any reason, you have not used your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

It is very important to keep the area around the intravenous catheter clean, otherwise infection of the skin at the site of injection may result, which can then spread into your blood (known as septicaemia).

During administration of VELETRI the intravenous catheter may become blocked. Tell your doctor or pharmacist if this happens.

Things you must not do

Do not stop using or change the dose without first checking with your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use VELETRI to treat any other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how VELETRI affects you. If you are affected, do not drive or operate machinery. As with many other medicines, VELETRI may cause dizziness/ drowsiness/tiredness in some people.

Side Effects

Check with your doctor as soon as possible if you have any problems while taking VELETRI, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, VELETRI can cause side effects in some people.

If you think you are having an allergic reaction to VELETRI while you are receiving it, TELL YOUR DOCTOR IMMEDIATELY.

Symptoms usually include some or all of the following:

  • wheezing
  • swelling of the lips/mouth
  • difficulty in breathing
  • hay fever
  • lumpy rash ("hives")
  • fainting

Tell your doctor at once if you experience any of the following while you are receiving VELETRI:

  • fever
  • fatigue
  • chills/flu-like symptoms
  • facial flushing or paleness
  • fast heart beat
  • slow heart rate
  • chest pain and tightness
  • heart attack
  • shortness of breath
  • diarrhoea
  • feeling sick (nausea) or being sick (vomiting)
  • wind or tummy discomfort
  • anxiety, nervousness and agitation
  • depression/ psychotic depression
  • acute confusional state
  • dizziness, especially on standing
  • headaches
  • dry mouth
  • itchy skin rash (eczema) or hives
  • decreased or increased feeling or sensitivity, especially in the skin
  • tingling or numbness of the hands or feet
  • reddening and pain at the infusion site
  • sweating
  • pain
  • jaw, muscle and/or back pain
  • joint pain
  • loss of appetite
  • low number of platelets or red blood cells or all types of blood cells
  • bleeding: any bleeding can be serious, if this occurs you should contact your doctor
  • ulcer (sore) on the skin
  • lung infection
  • fluid collection in the chest
  • feeling very tired
  • blood clot that moves to the lungs, causes chest pain and makes you short of breath
  • air leaks into the space between lung and chest wall (collapsed lung)
  • muscle tremors
  • increased body movement
  • overactive thyroid
  • urinary tract infection
  • increase size of the spleen

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

This is not a complete list of all possible side-effects. Others may occur in some people and there may be some side-effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor if you don't understand anything in this list.

VELETRI may affect your blood sugar levels, heart rate or blood pressure during infusion. Your doctor will monitor these.

Storing VELETRI

Storage

Keep this medicine where young children cannot reach it. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Keep VELETRI powder in a cool, dry place where it stays below 25°C.

Protect from light by keeping it in the carton until use.

Do not store VELETRI powder in a bathroom or near a sink.

Do not leave VELETRI powder in the car or on window sills.

Do not freeze VELETRI powder at any time.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

The reconstituted solution should be immediately further diluted to the final concentration. VELETRI diluted to the final concentration in the drug delivery reservoir as directed can be stored for up to 8 days at 2° to 8°C. Discard any unused solution after this time.

Do not freeze. Do not expose this solution to direct sunlight.

Do not use this medicine if you notice any particles in the reconstituted solution.

Product description

What it looks like

VELETRI: A Sterile, lyophilised white to off-white powder in a clear glass vial with a rubber stopper and an aluminium flip-off cap. Each pack contains one vial. The 0.5 mg vial has a white flip-off cap and the 1.5 mg vial has a red flip-off cap.

Pack size

Each pack contains one vial.

VELETRI - 0.5 mg vial of epoprostenol

VELETRI - 1.5 mg vial of epoprostenol

Ingredients

Active ingredient:

VELETRI contains the active ingredient epoprostenol, as the sodium salt.

Inactive ingredients:

  • sucrose,
  • L-arginine,
  • sodium hydroxide (for pH adjustment)

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

NZ Office: Auckland New Zealand
Telephone: 0800 800 806

This leaflet was prepared in August 2020.

VELETRI 0.5 mg - AUST R 208316

VELETRI 1.5 mg - AUST R 207547

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Veletri

Active ingredient

Epoprostenol

Schedule

S4

 

1 Name of Medicine

Epoprostenol (as sodium).

2 Qualitative and Quantitative Composition

The reconstituted solution of Veletri has a pH of 10.8 to 12.0 and is increasingly unstable at a lower pH. Its pKa value is 4.8.
One vial of sterile, lyophilised powder containing 0.531 mg epoprostenol sodium equivalent to 0.5 mg epoprostenol.
One vial of sterile, lyophilised powder containing 1.593 mg epoprostenol sodium equivalent to 1.5 mg epoprostenol.
See Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
Veletri is a white to off-white powder that must be reconstituted with either sterile water for injection or with sodium chloride 0.9% solution for injection.
Veletri for Injection is a sterile product, formulated for intravenous administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Veletri is indicated for the long-term treatment, via continuous intravenous infusion, in WHO functional class III or class IV patients with: idiopathic pulmonary arterial hypertension; familial pulmonary arterial hypertension; pulmonary arterial hypertension associated with the scleroderma spectrum of diseases.

4.2 Dose and Method of Administration

General.

Veletri must be reconstituted before use. Any further dilution must be performed using the recommended solutions. Infusion sets with an in-line 0.22 micron filter must be used (see Section 4.2 Dose and Method of Administration, Instructions for use/handling).
Suitable ambulatory pumps to be used for the administration of Veletri include: CADD Legacy 1, CADD Legacy Plus, CADD Solis VIP (variable infusion profile).
Manufactured by Smiths Medical.
Pump accessories found compatible with the administration of Veletri include:
CADD disposable Medication Cassette Reservoir - 50 mL; 100 mL from Smiths Medical.
CADD extension set with in-line 0.2 micron filter (CADD extension set with male luer, 0.2 micron air eliminating filter, clamp, and integral anti-siphon valve with male luer) from Smiths Medical.
To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets.
Veletri is suitable for continuous intravenous infusion only. The following schedules have been found effective.

Adults.

Short-term (acute) dose ranging.

A short-term dose ranging procedure administered via either a peripheral or central venous line is required to determine the long-term infusion rate. The infusion is initiated at 2 nanogram/kg/min and increased by increments of 2 nanogram/kg/min every 15 minutes or longer until maximum haemodynamic benefit or dose-limiting pharmacological effects are elicited.

Long-term continuous infusion.

Long-term continuous infusion of Veletri should be administered through a central venous catheter. Temporary peripheral intravenous infusions may be used until central access is established. Long-term infusions should be initiated at 4 nanogram/kg/min less than the maximum tolerated infusion rate determined during short-term dose-ranging. If the maximum tolerated infusion rate is 5 nanogram/kg/min or less, then the long-term infusion should be started at 1 nanogram/kg/min.

Dosage adjustments.

Changes in the long-term infusion rate should be based on persistence, recurrence or worsening of the patient's symptoms of pulmonary arterial hypertension (PAH) or the occurrence of adverse events due to excessive doses of Veletri.
In general, the need for increases in dose from the initial long-term dose should be expected over time. Increases in dose should be considered if symptoms of PAH persist, or recur after improving. The infusion rate should be increased by 1 to 2 nanogram/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. Following establishment of a new infusion rate, the patient should be observed, and erect and supine blood pressure and heart rate monitored for several hours to ensure that the new dose is tolerated.
In the controlled 12-week trial in PH/SSD, for example, the dose increased from a mean starting dose of 2.2 nanogram/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 nanogram/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 nanogram/kg/min. The mean incremental increase was 2 to 3 nanogram/kg/min every 3 weeks.
During long-term infusion, the occurrence of dose related pharmacological events similar to those observed during the dose-ranging period may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Dosage decreases should be made gradually in 2 nanogram/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve.
If dose-limiting pharmacologic effects occur, then the infusion rate should be decreased to an appropriate chronic infusion rate whereby the pharmacologic effects of Veletri are tolerated. If the initial infusion rate of 2 nanogram/kg/min is not tolerated, a lower dose that is tolerated by the patient should be identified.
Abrupt withdrawal of Veletri or sudden large reductions in infusion rates must be avoided. An abrupt interruption of therapy can induce a rebound of pulmonary arterial hypertension resulting in dizziness, asthenia, increase in dyspnoea and may lead to death. Except in life-threatening situations (e.g. unconsciousness, collapse, etc) infusion rates of Veletri should be adjusted only under the direction of a physician (see Section 4.4 Special Warnings and Precautions for Use).
In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.
Lack of response [persistence of (New York Heart Association) NYHA class or lack of significant improvements in haemodynamic outcomes] after 3 months of epoprostenol therapy indicates poor survival and alternative options should be considered in this group of patients.

Children.

There is limited information on the use of Veletri for primary pulmonary hypertension in children.

Elderly.

There is limited information on the use of Veletri in patients over 65. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Instructions for use/ handling.

Particular care should be taken in the preparation of the infusion and in calculating the rate of infusion. The procedure given below should be closely followed.

Reconstitution and dilution.

Reconstitution and dilution of Veletri must be carried out using aseptic conditions. The powder for solution for infusion must be reconstituted using either sterile water for injection or sodium chloride 0.9% solution for injection. Infusion sets with an in-line 0.22 micron filter must be used.
Veletri is stable only when reconstituted as directed using sterile water for injection, or sodium chloride 0.9% solution for injection. Veletri must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration. Each vial is for single use only. Contains no antimicrobial agent, use in one patient on one occasion only. Discard any unused solution.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. If either occurs, Veletri should not be administered. The reconstituted solution should be free from visible particles. Do not expose this solution to direct sunlight.

Use after reconstitution and immediate dilution to final concentration.

A concentration for the solution of Veletri should be selected that is compatible with the infusion pump being used with respect to minimum and maximum flow rates and reservoir capacity. Veletri, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Veletri diluted to the final concentration in the drug delivery reservoir as directed can be stored for up to 8 days at 2° to 8°C as detailed in Tables 4 and 5.
Outlined in Table 1 are directions for preparing different concentrations of Veletri for up to a 48-hour period. Each vial is for single use only. Contains no antimicrobial agent; use in one patient on one occasion only. Discard any unused solution.
The vial containing 0.5 mg epoprostenol must be used for the preparation of solutions with final concentrations below 15,000 nanogram/mL.
Infusion rates may be calculated using the following formula (see Equation 1):
Examples of some concentrations commonly used in PAH are shown in Table 2 and Table 3.

Use at room temperature (25°C).

Veletri solution reconstituted with 5 mL of sterile water for injection or sodium chloride 0.9% injection, and immediately diluted to the final concentration in the drug delivery reservoir can be administered at room temperature per the conditions of use as outlined in Table 4.

Use at higher temperatures (> 25°C up to 30°C).

A single reservoir of fully diluted solution of Veletri prepared as directed above can also be administrated as outlined in Table 5.
Do not freeze.

4.3 Contraindications

Veletri is contraindicated in patients with known hypersensitivity to the drug.
Veletri is contraindicated in patients with congestive heart failure arising from severe left ventricular dysfunction, because it was found to increase mortality in such patients.
Veletri should not be used chronically in patients who develop pulmonary oedema during dose-ranging.

4.4 Special Warnings and Precautions for Use

Veletri should be used only by clinicians experienced in the diagnosis and treatment of PAH.
Short-term dose-ranging with Veletri must be performed in a hospital setting with adequate personnel and equipment for haemodynamic monitoring and emergency care.
Some patients with primary pulmonary hypertension have developed pulmonary oedema during dose-ranging, which may be associated with pulmonary veno-occlusive disease.
Veletri must be reconstituted only as directed using either sterile water for injection or sodium chloride 0.9% solution for injection. It must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
Veletri is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with Veletri requires commitment by the patient to sterile drug reconstitution, drug administration, care of the permanent central venous catheter, and access to intense and ongoing patient education. Sterile technique must be adhered to in preparing the drug and in the care of the catheter as sepsis is a known associated risk with an indwelling central venous catheter and requires immediate access to expert medical care (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse events attributable to the drug delivery system).
Chronic infusions of Veletri must not be stopped suddenly. Even brief interruptions in the delivery of epoprostenol can lead to rapid clinical deterioration, with symptoms including dyspnoea, dizziness, and asthenia, which in some cases have been fatal. Sudden cessation of Veletri can also lead to platelet hyperaggregability. The decision to administer Veletri for PAH should be based upon the patient's understanding that there is a high likelihood that therapy with Veletri will be needed for prolonged periods, possibly years, and the patient's ability to accept and care for a permanent intravenous catheter and infusion pump should be carefully considered. Patients must receive comprehensive training in preparation of the infusion solution and care of the catheter and pump before being allowed to self-administer Veletri.
Because of the high pH of the final infusion solutions, care should be taken to avoid extravasation during administration and consequent risk of tissue damage.

Effects on blood.

Epoprostenol is a potent inhibitor of platelet aggregation, therefore, an increased risk for haemorrhagic complications should be considered, particularly for patients with other risk factors for bleeding (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Unless contraindicated, anticoagulant therapy should be administered to PAH patients receiving Veletri to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale.
Elevated serum glucose levels have been reported.

Effects on cardiovascular system.

Extreme caution is advised in patients with coronary artery disease.
Veletri generally increases heart rate. During or shortly after dose-ranging, some patients may experience sudden onset bradycardia, hypotension, nausea and sweating. If this occurs, Veletri should be immediately suspended and supportive measures instituted.
Blood pressure and heart rate should be monitored during administration of Veletri.
The effects of Veletri on heart rate may be masked by concomitant use of drugs which affect cardiovascular reflexes.
Epoprostenol is a potent pulmonary and systemic vasodilator. The cardiovascular effects during infusion disappear within 30 minutes of the end of administration.
If excessive hypotension occurs during administration of Veletri, the dose should be reduced or the infusion discontinued. Hypotension may be profound in overdose and may result in loss of consciousness (see Section 4.9 Overdose).

Use in the elderly.

There is limited information on the use of Veletri for PAH in patients over 65 years of age.

Paediatric use.

There is limited information on the use of Veletri for PAH in children.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Effects on blood.

4.5 Interactions with Other Medicines and Other Forms of Interactions

When Veletri is administered to patients receiving concomitant anticoagulants, standard anticoagulant monitoring is advisable.
The vasodilator effects of Veletri may augment or be augmented by concomitant use of other vasodilators.
Epoprostenol decreased the apparent oral clearance of digoxin by 15% within two days of starting therapy. Although digoxin clearance returned to baseline levels within 90 days, prescribers should be alert to the potential for short-term elevations of digoxin concentrations after initiation of Veletri, especially in patients prone to digoxin toxicity.
As reported with other prostaglandin analogues, Veletri may reduce the thrombolytic efficacy of tissue plasminogen activator (t-PA) by increasing hepatic clearance of t-PA.
When NSAIDs or other drugs affecting platelet aggregation are used concomitantly, there is the potential for Veletri to increase the risk of bleeding.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility was not impaired in rats given epoprostenol by subcutaneous injection at doses up to 100 microgram/kg/day [600 microgram/m2/day, 1.2 times the average human chronic dose (9.2 nanogram/kg/min or 490 microgram/m2/day, IV) based on body surface area]. However, the relevance of these animal findings in humans is unknown.
(Category B1)
Reproductive studies have been performed in pregnant rats and rabbits given epoprostenol subcutaneously at doses up to 100 microgram/kg/day [600 microgram/m2/day in rats, 1.2 times the average human dose, and 1100 microgram/m2/day in rabbits, 2.2 times the average human dose (9.2 nanogram/kg/min or 490 microgram/m2/day) based on body surface area]. These studies showed no effects of epoprostenol on pregnancy, the foetus or offspring development. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefits to the mother are considered to outweigh the possible risks to the foetus. However, the relevance of these animal findings in humans is unknown.
It is not known whether epoprostenol is excreted in human or animal milk. A risk to the breast-feeding child cannot be excluded. A decision must be made whether to discontinue/ abstain from breastfeeding or to discontinue/ abstain from epoprostenol therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

PAH and its therapeutic management may affect the ability to drive and operate machinery.
See Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 http://www.tga.gov.au/reporting-problems.
During clinical trials, adverse events were classified as follows:
1. Adverse events during acute dose-ranging.
2. Adverse events during chronic dosing.
3. Adverse events associated with the drug delivery system.

1. Adverse events during acute dose-ranging.

During acute dose-ranging, epoprostenol was administered in 2 nanogram/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to the major pharmacological effect of epoprostenol, vasodilation. Table 6 lists adverse events reported in ≥ 1% of 720 patients during acute dose-ranging.
Dose limiting adverse events occurring in 1% or more of patients during acute dose-ranging were (in descending order of frequency): headache, nausea/vomiting, flushing, hypotension, anxiety/nervousness/agitation, chest pain, dizziness, bradycardia, abdominal pain, jaw pain, tachycardia, back pain, and dyspnoea.

2. Adverse events during chronic administration.

2.1 Idiopathic or familial pulmonary arterial hypertension.

Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of epoprostenol (e.g. dizziness, syncope). Adverse events probably related to the underlying disease include dyspnoea, fatigue, chest pain, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to epoprostenol. These include headache, jaw pain, flushing, diarrhoea, nausea and vomiting, flu-like symptoms, allergic reactions, including anaphylaxis, and anxiety/nervousness. In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 7 lists adverse events that occurred at a rate at least 10% different in the two groups in controlled trials.
The following adverse events led to dose adjustment or discontinuation of epoprostenol in ≥ 1% of patients: dyspnoea, nausea, asthenia, flushing, headache, chest pain, diarrhoea, dizziness, vomiting, hypotension, pallor, myalgia, jaw pain, pain, and syncope.
Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.

2.2 Pulmonary arterial hypertension associated with scleroderma spectrum of diseases.

See Tables 8 and 9.

Adverse events reported during epoprostenol use in clinical practice.

Blood and lymphatic.

Anaemia, splenomegaly, pancytopenia, bleeding at various sites.

Cardiovascular.

Bradycardia, hypotension and pulmonary embolism.

General.

Anaphylaxis, unspecified pain, arthralgia, reddening over the infusion site, occlusion of the long IV catheter, lassitude, chest tightness.

Endocrine.

Hyperthyroidism.

Neurological.

Acute confusional state.

Skin and subcutaneous tissue disorders.

Rash and sweating.

Gastrointestinal disorders.

Diarrhoea, abdominal colic, sometimes reported as abdominal discomfort, dry mouth and hepatic failure.

Respiratory, thoracic and mediastinal disorders.

Pulmonary oedema.

3. Adverse events attributable to the drug delivery system.

Chronic infusions of epoprostenol are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PPH trials of up to 12 weeks' duration, up to 21% of patients reported a local infection and 13% of patients reported pain at the injection site. During a controlled PH/SSD trial of 12 weeks' duration, 14% of patients reported a local infection and 9% of patients reported pain at the injection site. During long-term follow-up in the clinical trial of PPH, sepsis was reported at least once in 14% of patients and occurred at a rate of 0.23 infections per patient per year in patients treated with epoprostenol. This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in oncology patients using these catheters. Malfunction in the delivery system resulting in an inadvertent bolus of or a reduction in epoprostenol were associated with symptoms related to excess or insufficient epoprostenol, respectively (see Section 4.8 Adverse Effects (Undesirable Effects), Adverse events during chronic administration).
The following serious or life-threatening adverse events related to the delivery system were reported in ≥ 1% of patients during chronic epoprostenol therapy: pain at injection site, injection site reaction, sepsis and septicaemia, catheter-related infections caused by organisms not always considered pathogenic (including micrococcus), dyspnoea, pneumothorax, cellulitis, chest pain, cyanosis, haemothorax, hypotension, hypoxia, infection, pallor, procedural complication and syncope.

Postmarketing experience.

Infections and infestations.

Common: sepsis, septicaemia (mostly related to delivery system for epoprostenol).
Catheter-related infections caused by organisms not always considered pathogenic (including micrococcus) have been reported.

Blood and lymphatic system disorders.

Common: decreased platelet count, bleeding at various sites (e.g. pulmonary, gastrointestinal, epistaxis, intracranial, post-procedural, retroperitoneal).
Very rare: hypersplenism, splenomegaly.

Endocrine disorders.

Very rare: hyperthyroidism.

Psychiatric disorders.

Common: anxiety, nervousness.
Very rare: agitation.

Nervous system disorders.

Very common: headache.

Cardiac disorders.

Common: tachycardia has been reported as a response to epoprostenol at doses of 5 nanogram/kg/min and below.
Bradycardia, sometimes accompanied by orthostatic hypotension, has occurred in healthy volunteers at doses of epoprostenol greater than 5 nanogram/kg/min.
Bradycardia associated with a considerable fall in systolic and diastolic blood pressure has followed i.v. administration of a dose of epoprostenol equivalent to 30 nanogram/kg/min in healthy conscious volunteers.
Very rare: high output cardiac failure.

Vascular disorders.

Very common: facial flushing (seen even in the anaesthetised patient).
Common: hypotension.
Very rare: ascites, pallor.

Respiratory, thoracic and mediastinal disorders.

Uncommon: pulmonary oedema.

Gastrointestinal disorders.

Very common: nausea, vomiting, diarrhoea.
Common: abdominal colic, sometimes reported as abdominal discomfort.
Uncommon: dry mouth.

Skin and subcutaneous tissue disorders.

Common: rash.
Uncommon: sweating.

Musculoskeletal and connective tissue disorders.

Very common: jaw pain.
Common: arthralgia.

General disorders and administration site conditions.

Very common: pain (unspecified).
Common: pain at the injection site*, chest pain.
Rare: local infection*.
Very rare: reddening over the infusion site*, occlusion of the long i.v. catheter*, lassitude, chest tightness.
* Associated with the delivery system for epoprostenol.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
In general, events seen after overdosage of epoprostenol represent exaggerated pharmacological effects of the drug (e.g. hypotension and complications of hypotension). Signs and symptoms of excessive doses of epoprostenol during clinical trials are the expected dose limiting pharmacologic effects of epoprostenol, including flushing, headache, hypotension, tachycardia, nausea, vomiting and diarrhoea. If overdosage occurs reduce the dose or discontinue the infusion and initiate appropriate supportive measures as necessary; for example plasma volume expansion and/or adjustment to pump flow.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Epoprostenol has two major pharmacological actions: (1) direct vasodilatation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilator effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilatation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacological effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.

Clinical trials.

Idiopathic or familial pulmonary arterial hypertension (primary pulmonary hypertension).

Chronic continuous infusions of epoprostenol in patients with primary pulmonary hypertension (PPH) were studied in two prospective, open, randomised parallel controlled trials of 8 and 12 weeks' duration comparing epoprostenol plus standard therapy to standard therapy alone. Dosage of epoprostenol averaged 9.2 nanogram/kg per minute at study end. Standard therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half of the patients. Except for two NYHA functional class II patients, all patients were either functional class III or class IV. As results are similar in the two studies, the pooled results are described below.

Haemodynamic effects.

Cardiac index (CI), stroke volume (SV), and arterial oxygen saturation were increased, and mean pulmonary artery pressure (PAPm), right atrial pressure (RAP), total pulmonary resistance (TPR), and systemic vascular resistance (SVR) were decreased in patients who received epoprostenol chronically (n = 52) compared to those who did not (n = 54). The change from baseline values is statistically significant for CI, TPR and SVR in the 8-week study, and is statistically significant for CI, SV, PAPm, mean PVR, TPR, SVR and mean systemic arterial pressure in the 12-week study. Combined results from the two controlled studies are shown in Table 10.
These haemodynamic improvements appeared to persist for at least 18 months when epoprostenol was administered in an open, uncontrolled study.

Clinical effects.

In the two studies, exercise capacity, as measured by the 6-minute walk test, improved significantly in patients receiving continuous intravenous epoprostenol plus standard therapy compared to those receiving standard therapy alone. Improvements were apparent as early as the first week of therapy. In the second study, patients who received epoprostenol for 12 weeks had significant improvements (p < 0.05) in all 4 dimensions of the Chronic Heart Failure Questionnaire (Dyspnoea, Fatigue, Emotional Function and Mastery), as well as 2 of the 6 dimensions of the Nottingham Health Profile (Emotional Reactions and Sleep).
Survival was significantly improved in PPH patients treated with epoprostenol for 12 weeks. At the end of the treatment period, 8 of 40 patients receiving conventional therapy alone died, whereas none of the patients receiving epoprostenol in addition to conventional therapy died (p = 0.003). The improvement in survival remained significant (p < 0.01) when 6-minute walk was used as a covariate in the analysis due to the difference between the two groups at baseline (median of 312 m and 267 m for epoprostenol and conventional treatment, respectively).
In the 8-week study, although not reaching statistical significance, 90% of patients treated with epoprostenol survived, as opposed to 71% of the patients on conventional therapy alone.
In a third study, 17 patients with NYHA class III or IV PPH received continuous epoprostenol infusions for 37 to 69 months and were compared with historical controls who had received conventional therapy. The comparison was stratified according to NYHA class and transplantation status. One-, three- and five-year Kaplan-Meier survival rates in the epoprostenol-treated patients were 87%, 63% and 54%, respectively, compared with 77%, 41% and 27% in the historical controls (hazard ratio 2.9 [95% CI 1.0 to 8.0, p = 0.045]).
EPITOME-1 (AC-066A401) was an exploratory, open-label, randomised, multicentre Phase IV study conducted in the USA designed to assess the safety, tolerability, and pharmacokinetics of EFI1 compared to Flolan in injectable prostanoid treatment-naïve patients with PAH. A number of protocol deviations may have affected the results. The study was conducted in a total of 30 injectable prostanoid-naïve patients randomised to either Flolan (n = 10) or EFI1 (n = 20) for a treatment period of 28 days. Exploratory evaluation of the efficacy of EFI1 and Flolan on the basis of NYHA functional class showed that patients on both drugs were either maintained at the same functional class or improved. The results of the six-minute walk test (6MWT) were variable for the two groups and the median change from baseline after 28 days of treatment was similar in each of the treatment groups.
Blood oxygen saturation measurements were only performed in a small number of patients and after 28 days of treatment there were median decreases in both treatment groups.
EPITOME-2 (study AC-066A301) was an exploratory, prospective, multicentre, single arm, open label, Phase 3b study conducted in Europe and Canada, designed to evaluate cardiac haemodynamics, efficacy, safety and tolerability in PAH patients following switching from Flolan to Veletri. A total of 42 patients were enrolled into the study and 41 patients received study treatment and completed the study according to the protocol. Cardiac haemodynamic variables remained generally stable over the treatment period with similar mean and median values at baseline and at end of study treatment (EOT). Mean and median six minute walk distances (6MWDs) observed at baseline and at EOT were similar. At EOT, values for Borg dyspnoea scores showed a mean and median decrease from baseline. For the patients for whom a NYHA functional class evaluation was performed (n = 40), the NYHA functional class remained unchanged from baseline for the majority of patients (35 patients, 87.5%) over the treatment period. One patient had an improved NYHA functional class at EOT while worsening of NYHA functional class at EOT was reported for 4 patients.

Pulmonary arterial hypertension (PAH) associated with scleroderma spectrum of diseases.

Haemodynamic effects.

Chronic continuous infusions of epoprostenol in patients with Pulmonary Hypertension (PH) associated with the scleroderma spectrum of diseases (SSD) were studied in a prospective, open, randomised trial of 12 weeks' duration comparing epoprostenol plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional class II patients, all patients were either functional class III or class IV. Dosage of epoprostenol averaged 11.2 nanogram/kg/min at study's end. Conventional therapy varied among patients and included some or all of the following: cardiovascular medication in the majority of patients, supplemental oxygen and diuretics were taken in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. More patients took warfarin in the epoprostenol therapy group (86%) than in the conventional therapy group (67%). During the 12 week study, 53 (95%) of patients in the epoprostenol group and 41 (75%) of the conventional therapy group took at least one dose of warfarin. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not. Table 11 illustrates the treatment related haemodynamic changes in these patients after 12 weeks of treatment.

Clinical effects.

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test, in patients receiving continuous intravenous epoprostenol plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Results of the 12-week study showed that exercise capacity was improved in the 56 patients treated with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks vs 270 m at baseline), but it decreased in the 55 patients treated with conventional therapy alone (192 m at 12 weeks vs. 240 m at Baseline; p < 0.001 for the comparison of the treatment groups). Increases in exercise capacity were accompanied by statistically significant improvements in dyspnoea and fatigue, as measured by the Borg Dyspnoea Index and Dyspnoea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48% (27%) with conventional therapy alone worsened. Of the patients randomised, NYHA functional class data at 12 weeks were not available for 5 patients treated with epoprostenol and 7 patients treated with conventional therapy alone.
No statistical difference in survival over 12 weeks was observed in PH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.

5.2 Pharmacokinetic Properties

Absorption.

At normal physiological pH and temperature, epoprostenol sodium breaks down spontaneously to 6-oxo-prostaglandin F1α, although there is some enzymatic degradation to other products.
The half-life for this process in humans is expected to be no more than 6 minutes, and may be as short as 2-3 minutes, as estimated from in vitro rates of degradation of epoprostenol in human whole blood.

Distribution.

Following intravenous injection of radiolabelled epoprostenol, the highest concentrations have been found in the liver, kidneys, and small intestine. During infusions in animals, steady-state plasma concentrations of tritium-labelled epoprostenol were reached within 15 minutes and were proportional to infusion rates. Tissue levels decline rapidly with no evidence for accumulation or long-term retention of a drug-related compound.

Excretion.

Urinary excretion of the metabolites of epoprostenol has been found to account for 40% of the administered dose in rats, and 90% in dogs, with biliary excretion accounting for the remainder. In both species urinary excretion was greater than 95% complete within 25 hours of dosing. In anaesthetised dogs extensive clearance by the liver has been demonstrated, with approximately 80% being removed in a single pass. Following the administration of radiolabelled epoprostenol to humans, the urinary and faecal recoveries of radioactivity were 82% and 4%, respectively. At least 16 compounds were found, 10 of which were structurally identified.
Due to the chemical instability, high potency, and short half-life of epoprostenol, no precise and accurate assay has been identified as appropriate for quantifying epoprostenol in biological fluids.

Pharmacokinetic/pharmacodynamic studies.

Two pharmacokinetic/pharmacodynamic studies (AC-066-101 and AC-066-102) were conducted; these studies were exploratory and were not designed to be bioequivalence studies.
Study AC-066-101 was a single-centre, open-label, two-period, two-treatment, cross-over, ascending dose study in healthy male subjects to assess the pharmacokinetics and pharmacodynamics of two different formulations of epoprostenol; EFI1 (the first developed formulation of Veletri containing L-arginine and mannitol as excipients) and Flolan. Twenty healthy male subjects were enrolled in the study and 18 subjects completed the study. EFI1 and Flolan were administered in sequential infusions of 2, 4, 6, and 8 nanogram/kg/min for 2 h each. Due to the very short half-life of epoprostenol, the pharmacokinetic profiles of EFI1 and Flolan were characterised via analysis of the concentration time profiles of two primary metabolites, 6-keto-prostacyclin F1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-prostacyclin F1α (enzymatically formed). The plasma concentration versus time curves of EFI 1 and Flolan with respect to these two primary metabolites, were essentially superimposable.
For 6-keto-prostacyclin F1α plasma concentrations observed at 2 hours after start of each infusion step (C2, 4, 6, 8h), and the areas under the plasma concentration-time curves (AUC0-2, 2-4, 4-6, 6-8h and AUC0-∞) obtained after infusion of EFI1 were comparable to those obtained after infusion of Flolan, with the 90% confidence intervals (CIs) of the geometric mean ratios falling within the range for exposure equivalence (0.80-1.25).
For 6,15-diketo-13,14-dihydro-prostacyclin F1α, plasma concentrations at 2 hours and AUC0-2 were not assessable after administration of EFI1 and Flolan but the other exposure parameters were comparable, with the 90% CIs of the geometric mean ratios falling within the range for exposure equivalence.
Study AC-066-102 was carried out in twenty healthy male subjects. Veletri (containing L-arginine and sucrose as excipients) and Flolan were administered in a crossover design in sequential infusions of 2, 4, 6, and 8 nanogram/kg/min for 2 h each. Overall, the comparable pharmacokinetic profiles seen in AC-066-101 were also observed with Veletri and Flolan in AC-066-102. This resulted in comparable AUC values with 90% CIs of the geometric mean ratios contained within the 0.8-1.25 equivalence range, except for AUC0-2 for 6,15-diketo-13,14-dihydro-prostacyclin F1α, which was not assessable.
In addition, in both Study AC-066-101 and Study AC-066-102, the comparisons between the formulations showed comparable haemodynamic (cardiac output and heart rate), safety, and tolerability characteristics.

5.3 Preclinical Safety Data

Genotoxicity.

Epoprostenol was negative in an in vitro assay of gene mutation and in an in vitro assay of DNA damage. However, the instability of epoprostenol in solutions used for these assays makes the significance of these tests uncertain. Epoprostenol was negative in an in vivo assay of chromosomal damage (micronucleus tests in rats).

Carcinogenicity.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of epoprostenol.

6 Pharmaceutical Particulars

6.1 List of Excipients

Veletri contains the excipients sucrose, L-arginine, and sodium hydroxide added to adjust pH.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
For reconstituted solution, see Section 4.2 Dose and Method of Administration, Use after reconstitution and immediate dilution to final concentration.

6.4 Special Precautions for Storage

Unopened vials of Veletri are stable until the date indicated on the package when stored below 25°C. Protect from light. Do not freeze.
Each vial is for single use only. Use in one patient on one occasion only. Discard any unused solution.
For reconstituted solution, see Section 4.2 Dose and Method of Administration, Use after reconstitution and immediate dilution to final concentration.

6.5 Nature and Contents of Container

Sterile, lyophilised white to off-white powder in a 10 mL/20 mm Type I, clear glass borosilicate vial with a rubber stopper and flip-off cap.
The 0.5 mg vial has a white flip-off cap and the 1.5 mg vial has a red flip-off cap.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Epoprostenol (PGI2, PGX, prostacyclin) is (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid, sodium salt.

Chemical structure.

The structural formula of epoprostenol sodium is:
Molecular formula: C20H31NaO5.
Relative molecular mass: 374.45.
Epoprostenol CAS Registry Number: 35121-78-9.

CAS number.

61849-14-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes