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Epoprostenol (Veletri®) - Paediatrics

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For inpatient initiation of therapy in PICU or Ward 23b Intensive Observation Area, up titration on Ward 23b and transition to community therapy

Purpose of guideline

  • This guideline is for the Veletri® brand of epoprostenol ONLY 
  • This guideline is presented in several sections covering the initiation of epoprostenol (Veletri®) and the titration of medication, the transition to CADD pump administration for ongoing out-of-hospital use and the preparation of the CADD cassettes in the home setting.
  • A printable pdf version of the guideline can be downloaded here - please remember to check it is the latest version before use.

Action of medication

Epoprostenol (Veletri®) is a therapy for severe pulmonary hypertension delivered via continuous intravenous infusion. Mechanisms of action include:

  • Strong vasodilator of pulmonary and systemic vascular arterial beds
  • Inhibits platelet aggregation
  • Slows the process of scarring and rapid growth of new cells in lung vessels

It has a very short half-life (minutes) and interruption of infusion or rapid decrease in dose may precipitate pulmonary hypertensive crisis.

Indications

For long-term treatment in World Health Organisation (WHO) Functional Class III or Class IV patients with pulmonary arterial hypertension (PAH) who have failed to respond to alternative PAH agents

Criteria for access to epoprostenol (Veletri®):

  • Epoprostenol (Veletri®) is currently listed on the Hospital Medicines List with the following criteria "for use in patients with a valid Special Authority approval for epoprostenol in pulmonary arterial hypertension" or "For in-hospital stabilisation in emergency situations"
  • Epoprostenol (Veletri®) is currently listed on the Community Pharmaceutical Schedule with funding available via Special Authority on approval by the Pulmonary Arterial Hypertension panel. The criteria for funding are as follows:

    Epoprostenol may only be applied for when patients meet one of the following criteria:
    • Patients presenting acutely with idiopathic pulmonary arterial hypertension (IPAH) in New York Heart Association/World Health Organization (NYHA/WHO) Functional Class IV; or
    • Patients deteriorating rapidly to NYHA/WHO Functional Class IV who may be lung transplant recipients in the future, if their disease is stabilised; or
    • Patients with PAH associated with the scleroderma spectrum of diseases (APAHSSD) who have no major morbidities and are deteriorating despite combination therapy, or
    • For use as a bridge to transplant for patients with pulmonary arterial hypertension who are on the active waiting list for lung transplantation.
  • All patients electively commenced on epoprostenol require Special Authority approval before the initiation of therapy. This can take some time to obtain, so apply well in advance of initiation. Further details of the current application criteria and process are available on the Pharmac website: www.pharmac.govt.nz
  • Domicilie District Health Board (DHB) funding is required for consumables for community use.
  • Liaison with the paediatric congenital cardiac service (PCCS) multi-disciplinary team (MDT) is necessary to ensure the home situation is suitable for long-term therapy and that requisite supplies are obtained and training is undertaken.

Administration

  • Administer by continuous intravenous infusion ONLY. Epoprostenol (Veletri®) infusions must never be flushed and are incompatible with other medications.
  • No antibiotics can be administered via the line used for epoprostenol (Veletri ®) administration. If intravenous antibiotics are required, a separate peripherally inserted venous cannula (PIVC) must be established.
  • Programmable pump with dedicated administration set (with integrated 0.22micron filter) to be used when delivering epoprostenol (Veletri ®):
    Alaris Syringe Driver (GH) for up to 50 mL, for in hospital initiation or emergency situations
    CADD Solis pump for up to 100 mL for long term ambulatory use

Reconstitution of the vial

Epoprostenol (Veletri®) must be reconstituted and diluted before use:

  • Dissolve the contents of one 500 microgram vial epoprostenol (Veletri®) with 5 mL of water for injection or sodium chloride 0.9% to achieve a concentration of 100 micrograms in 1 mL.
    Note: this dilution is for the 500 microgram vial of epoprostenol (Veletri®) - see Presentation, for other vial strengths.
  • The reconstituted solution of epoprostenol (Veletri®) is stable only when reconstituted as directed using sterile water for injection or sodium chloride 0.9% injection.
  • Reconstituted epoprostenol (Veletri®) is stable at room temperature (25°C) for up to 48 hours (but Starship recommends 24 hourly syringe/cassette changes)
  • At temperatures between 25°C - 30°C epoprostenol (Veletri®) can infuse for up to 24 hours
  • Stability outside of these temperature ranges is both temperature and concentration-dependent. Consult the data sheet for further information.
  • The reconstituted solution must also be protected from direct sunlight. The solution cannot be frozen.

Delivery via Alaris syringe driver

  •  A new syringe of epoprostenol (Veletri®) must be prepared every 24 hours prior to previous syringe running out or being disconnected. Epoprostenol (Veletri®) has a very short half-life of 2-6 minutes, so withdrawal symptoms can occur rapidly if the infusion runs out or is disconnected for any length of time.
  • If possible consider making up two syringes for the patient from one vial of epoprostenol (Veletri®). The second syringe can be stored in the fridge for use within the next 24 hours. Take out of fridge one hour prior to changing syringe to bring to room temperature.

For long term epoprostenol (Veletri®) use once the patient is stable and the volume has reached more than 50 mL/day transition to a 100 mL cassette for use with the CADD Solis pump.

Delivery via CADD Solis pump

  • Epoprostenol (Veletri®) is administered via 100 mL medication cassette and portable CADD Solis pump for long term therapy for pulmonary hypertension.
  • Target dose for discharge from hospital is generally 7-10 nanograms/kg/min, subject to individual requirements and tolerance.
  •  Cardiac monitoring and frequent vital signs can be ceased once the patient transitions on to the CADD Solis pump for long term therapy.
  • For epoprostenol (Veletri®) for home use parents are instructed to make up to 4 cassettes at one time, and to store the extra cassettes in a designated container in the fridge. Remove each cassette up to one hour prior to being used to bring to room temperature.

Dose

  • Start epoprostenol (Veletri®) infusion at 2 nanograms/kg/minute, titrated up every 8-12 hours by 0.5 nanograms/kg/minute, as tolerated by the patient until there is maximum haemodynamic benefit without dose-limiting side effects1 See: possible adverse effects below.
  • Target discharge dose is generally 7-10 nanograms/kg/minute. Dosing is obviously subject to individual requirements and tolerance1 and will be directed by the lead cardiologist

Long term epoprostenol (Veletri®) dosing

  • Due to tachyphylaxis (rapidly diminishing response to epoprostenol rendering it less effective), the epoprostenol infusion will need to be continually up-titrated over time depending on individual needs1
  • Usual dose range 25-30 nanograms/kg/min by end of first year on epoprostenol therapy1
  • Other published data indicates the effective dose of epoprostenol in children is frequently higher than in adults, with a broad optimal dosing range from 40 to >150 nanograms/kg/minute and an average dose of ~ 80 nanograms /kg/minute4  
  • Final dose will depend on patient effect and will be decided by lead cardiologist.

Prescription

To be prescribed on the fluid balance chart with cross-reference on the medication chart stating "Epoprostenol (Veletri®) as per fluid balance chart"

The prescription must include:

  1. Amount of epoprostenol (Veletri®) to be added, in micrograms.
  2. Diluent (water for injection or sodium chloride 0.9%) and final volume of infusion.
  3. Dose in nanograms/kg/minute.
  4. Rate in mL/hour.

Rechart dose in nanograms/kg/minute and rate in mL/hour  with every dose change.

Targets for heart rate, blood pressure and respiratory rate need to be clearly documented on fluid balance chart.

Initiating therapy in hospital

Delivery via Alaris Syringe driver (GH) 50 mL for in-hospital use.

To calculate the amount of epoprostenol (Veletri®) per 50 mL syringe for an individual patient, us the following calculation:

Epoprostenol 1

Prescription to be written on fluid balance chart, as below (see example):

Add X micrograms of epoprostenol  (Veletri®) to sterile water for injection or sodium chloride 0.9% to make a final volume of 50 mL.
Run at Y mL / hr to give Z nanograms /kg /minute


Note: this method results in the following: 1mL/hour = 1 nanogram/kg/min

An example of how to calculate and write the prescription for epoprostenol (Veletri®)

An 18kg patient is commencing an epoprostenol (Veletri®) infusion at 2 nanograms/kg/minute.

One vial of epoprostenol (Veletri®) 500 microgram reconstituted with 5 mL water for injection or sodium chloride 0.9% gives a concentration of 100 micrograms in 1 mL

To achieve a concentration whereby 1 nanogram/kg/minute = 1mL/hour:
Calculate the micrograms of epoprostenol (Veletri®) required in 50 mL:

Epoprostenol (micrograms) = wt (kg) x 60 (mins) x 50 (mL)
                                                   1000 (to convert to mcg)

                                             = X micrograms (of epoprostenol (Veletri®) in 50mL)


wt x 60 (minutes) x 50 (mL)
     1000 (convert to mcg)

18 x 60 x 50
        1000

54 micrograms (of epoprostenol in 50 mL)
Calculate the volume of reconstituted epoprostenol (Veletri®) to draw up:
Reconstituted vial has concentration of 100 micrograms / mL

Volume required (mL) = Dose required (micrograms)
                                   Concentration (micrograms / mL)
 

Dose required (micrograms)
 Concentration (micrograms / mL)

54
  100

= 0.54 mL of reconstituted epoprostenol (Veletri®)
Dilute with Sterile water for injection
or
Sodium chloride 0.9 %
Make up to a final total volume of 50 mL
Rate (mL/hour) 1 mL/hour = 1 nanogram/kg/minute
Therefore run infusion at 2 mL/hour
2 nanograms/kg/minute
Prescription to be written on fluid balance chart for this patient of 18Kg:

Add 54 micrograms of epoprostenol  (Veletri®) to sterile water or sodium chloride 0.9% for injection to make a final volume of 50 mL, so that 1 mL/hour = 1 nanogram/kg/minute.
.
Run infusion at 2 mL / hr = 2 nanograms /kg /minute


Add cross reference on medication chart "epoprostenol  (Veletri®) as per fluid balance chart"
Double check the calculation for the above example.
To confirm the dose of epoprostenol  (Veletri®) in 50 mL syringe running at 1 mL/hour = 1 nanogram/kg/minute
Equation
Total amount of epoprostenol in 50 mL syringe
÷ total fluid volume (50 mL)
= amount of epoprostenol in micrograms running at 1 mL/hour
÷ patient weight (kg)
= dose/kg in micrograms at 1 mL/hour
X 1000
= dose/kg in nanograms at 1 mL/hour
÷ 60 (minutes)
= dose in nanograms/kg/minute at 1 mL/hour
Example above
54 micrograms
÷ 50
= 1.08 micrograms running at 1 mL/hour
÷ 18
= 0.06 micrograms/kg at 1 mL/hour
X 1000
= 60 nanograms/kg at 1 mL/hour
÷ 60 (minutes)
= 1 nanogram/kg/minute at 1 mL/hour 

Delivery of long term epoprostenol  (Veletri®) via CADD Solis pump, 100ml Cassette

  • When transferring from syringe driver (i.e. 50 mL syringe) to CADD 100 mL cassette select the lowest strength that allows you to infuse the 24 hour dose within the 100 mL volume so the cassette does not need to be changed within the 24 hour period.
  • CADD cassettes can infuse no greater than 100 mL/24 hours, i.e. no greater than 4 mL/hr. If the final rate is greater than 4 mL/hr an increase in the concentration of epoprostenol (Veletri®) is required. See table below.
  • Dissolve the contents of one 500 microgram vial epoprostenol (Veletri®) with 5 mL of water for injection or sodium chloride 0.9% to achieve a concentration of 100 micrograms in 1 mL.
Using the reconstituted 500 microgram vial of epoprostenol (Veletri®) and diluent of water for injection or sodium chloride 0.9% to fill the CADD cassette
Reconstituted epoprostenol volume Diluent (water) volume Final concentration (nanograms / mL)
1 mL 99 mL 1,000 nanograms / mL
2 mL 98 mL 2,000 nanograms / mL
3 mL 97 mL 3,000 nanograms / mL
4 mL 96 mL 4,000 nanograms / mL
5 mL 95 mL 5,000 nanograms / mL
10 mL 90 mL 10,000 nanograms / mL
Prescription to be written on fluid balance chart as:

Add X micrograms of epoprostenol  (Veletri®) to sterile water for injection or sodium chloride 0.9% to make a final volume of 100 mL.

Fill the CADD cassette with this solution.
.
Run at Y mL / hr to give nanograms /kg /minute

An example of how to calculate for an 18kg child on transition to CADD Solis - 100mL

Epoprostenol CADD

Possible adverse effects

Pulmonary hypertensive crisis on sudden withdrawal of epoprostenol (Veletri®)

Dose limiting side effects

During initiation and titration of therapy the most common adverse events that limit further dose increases are generally related to the vasodilator effects of epoprostenol (Veletri®) which include;

  • Flushing, headache, nausea / vomiting
  • Jaw pain
  • Hypotension
  • Anxiety/ restlessness/agitation
  • Chest Pain
  • Dizziness
  • Bradycardia or tachycardia
  • Abdominal pain
  • Musculoskeletal pain
  • Bleeding

Side effects associated with insufficient epoprostenol (Veletri®):

  • Pallor
  • Cold extremities
  • Shortness of breath
  • Chest pain

Drug interactions

  • Digoxin: Initiation of epoprostenol (Veletri®) may cause short-term elevations in digoxin levels. Close monitoring required if on concurrent Digoxin.
  • Non steroidal anti-inflammatory drugs (NSAIDs) (eg. Ibuprofen, diclofenac, aspirin): epoprostenol inhibits platelet aggregation. Care should be taken with concomitant use of NSAIDs and other drugs that inhibit platelet aggregation as there is the potential for increased bleeding risk.

Contraindications

  • Congestive heart failure arising from severe left ventricular dysfunction.
  • Should not be continued chronically in patients who develop pulmonary oedema during initial therapy
  • Hypersensitivity to epoprostenol (Veletri®)

Intravenous (IV) access

  • Decisions regarding IV access should be made prior to initiation of therapy. Therapy will often be initiated via peripheral inserted central cannula (PICC) or good peripheral access to allow benefits of therapy to commence before the requirement for general anaesthetic for tunneled central venous line (CVL) placement.
  • A single lumen tunneled CVL is to be inserted for long term access; rationale for single lumen is to minimise the risk of other medications being delivered via the line or blood sampling taking place. The CVL will require insertion in theatre under general anaesthetic. CVL placement will necessitate discussion by cardiologist with anesthetist, surgeon and ICU team prior to initiation of therapy to ensure appropriate support will be available. Due to general anesthetic risk in patients with pulmonary hypertension ECMO standby should be considered.
  • If possible play specialist involvement should be planned to prepare and support the child and family during insertion of PICC line without the need for sedation.
  • If not able to place PICC line, two PIVCs need to be inserted. PIVCs are only for in-hospital use - patients should never be discharged with epoprostenol (Veletri®) running through a PIVC.

If infusing with PIVC:

  • An infusion of sodium chloride 0.9% at 2 mL/hour is to run simultaneously with the epoprostenol (Veletri®) infusion. This is to alleviate the symptoms of peripheral inflammation and to promote longevity of the PIVC.

    In order to maintain patency of the second PIVC line, this should also have sodium chloride 0.9% running at 2 mL/hour.

Observation and Documentation

  1. Epoprostenol (Veletri®) is a potent pulmonary and systemic vasodilator and initiation and dose adjustments must be administered in 23B  or PICU
  2. Patient must be on a continuous cardiac monitor
  3. Monitor and document vital signs at initiation and following every dose increase. Monitor heart rate, blood pressure and respiratory rate at the following intervals:
    1. Every 15 minutes (twice), then
    2. Every 30 minutes (twice), then
    3. Every hour (four times), then 
    4. Every four hours, until next dose increase.
  4. Handover between staff is important - discussion with medical staff needs to take place at both morning and evening handover and also between nursing staff at each shift change:
    1. To check the current rate of infusion
    2. To independently double check the infusion dose calculation by both nursing staff members
  5. Cardiac monitoring and frequent vital signs can be ceased once the patient transitions and is stable on the CADD-1 pump for long term therapy.

Special considerations

  • Prepare new syringe of eproprostenol (Veletri®) prior to previous syringe running out or being disconnected 
  • Abrupt withdrawal or sudden large reductions in infusion rates should be avoided due to the short half-life of epoprostenol (Veletri®). The half-life is no more than 6 minutes and possibly as little as 2-3 minutes. Therefore do not disconnect the infusion more than fleetingly as this may cause rapid clinical deterioration. 
  • Unless contraindicated, anticoagulantion therapy should be administered to PAH patients receiving epoprostenol to reduce the risk of pulmonary embolism or systemic embolism through a patent foramen ovale. 
  • Reconstituted solution is highly alkaline and an irritant to tissues.

Presentation

  • Vial of sterile powder containing epoprostenol (Veletri®) 500 micrograms
  • Vial of sterile powder containing epoprostenol (Veletri®) 1.5 milligrams

Be aware there are two strengths of epoprostenol (Veletri®) and this guideline refers to the 500 microgram vial

Storage

  • Store below 25°C. Do not freeze. Protect from light.
  • Reconstituted solution: protect from direct sunlight. Do not use if solution is discoloured.
  • Syringes/cassettes: protect from direct sunlight. Do not use if solution is discoloured. May be made in advance and stored in the refrigerator for later use as described in Administration above

For detailed information about this drug including clinical pharmacology, please see Medsafe data sheet for Epoprostenol (Veletri®) in Reference viewer.

References

  1. This Guideline is based on 'Section 6: Epoprostenol (Veletri) therapy' of the Royal Children's Hospital (Melbourne) Department of Cardiology's guideline for Pulmonary Hypertension (Issued July 2015).New Zealand Formulary for Children (NZFC). NZFC v38; Aug 2015. Available from:www.nzfchildren.org.nz (Accessed August 2015)
  2. Veletri (epoprostenol) [New Zealand data sheet]. Actelion Pharmaceuticals Australia Pty Ltd [updated 10/03/2014]. Available from URL: http://www.medsafe.govt.nz
  3. Abman S, Hansmann G, Archer S, Ivy D, Adatia I, Chung W et al. Paediatric Pulmonary Hypertension.  Guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015; 132: 1-63.

Acknowledgements

Royal Children's Hospital Melbourne - Pulmonary Hypertension Team
Great Ormond Street Hospital for Children - Pulmonary Hypertension Team

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Document Control

  • Date last published: 04 April 2018
  • Document type: Drug Dosage Guideline
  • Services responsible: Paediatric Cardiology
  • Author(s): Marion Hamer, Clare O'Donnell, Elizabeth Oliphant, Nikki Anderson
  • Editor: Marion Hamer
  • Review frequency: 2 years