VELETRI Powder for solution for infusion Ref.[9383] Active ingredients: Epoprostenol

Posology

Pulmonary Arterial Hypertension

VELETRI is only indicated for continuous infusion by intravenous route.

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension.

Short-term (acute) dose ranging

This procedure should be conducted in a hospital with adequate resuscitation equipment.

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 ng/kg/min and increased by increments of 2 ng/kg/min every 15 min or longer until maximum haemodynamic benefit or dose-limiting pharmacological effects are elicited.

If the initial infusion rate of 2 ng/kg/min is not tolerated, a lower dose that is tolerated by the patient should be identified.

Long-term continuous infusion

Long-term continuous infusion of VELETRI should be administered through a central venous catheter. Temporary peripheral i.v. infusions may be used until central access is established. Long-term infusions should be initiated at 4 ng/kg/min less than the maximum tolerated infusion rate determined during short-term dose-ranging. If the maximum tolerated infusion rate is 5 ng/kg/min or less, the long-term infusion should be started at 1 ng/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 or the occurrence of adverse reactions 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 pulmonary arterial hypertension persist, or recur after improving. The infusion rate should be increased by 1 to 2 ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 min. 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.

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 reactions may occasionally resolve without dosage adjustment. Dosage decreases should be made gradually in 2 ng/kg/min decrements every 15 min or longer until the dose-limiting effects resolve. Abrupt withdrawal of VELETRI or sudden large reductions in infusion rates should be avoided due to the risk of potentially fatal rebound effect (see section 4.4). Except in life-threatening situations (e.g. unconsciousness, collapse, etc.), infusion rates of VELETRI should be adjusted only under the direction of a physician.

Renal Dialysis

VELETRI is suitable for continuous infusion only, either intravascularly or into the blood supplying the dialyser.

The following schedule of infusion has been found effective in adults:

Prior to dialysis: 4 ng/kg/min intravenously for 15 mins

During dialysis: 4 ng/kg/min into the arterial inlet of the dialyser

The infusion should be stopped at the end of dialysis.

The recommended dose for renal dialysis should be exceeded only with careful monitoring of patient blood pressure.

Elderly

There is no specific information on the use of VELETRI in patients over 65 years for renal dialysis or pulmonary arterial hypertension. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal (in the case of pulmonary arterial hypertension) or cardiac function and of concomitant disease or other medicine therapy.

Paediatric population

The safety and efficacy of VELETRI in children have not yet been established.

Method of administration

VELETRI long-term administration is administered via intravenous route through central venous catheter using an ambulatory infusion pump. The patient must be adequately trained in all aspects of care of the central venous catheter, in the aseptic preparation of the VELETRI intravenous injectable solution, and in the preparation and change of the drug delivery reservoir of the infusion pump, and the extension set.

Suitable ambulatory pumps to be used for the administration of VELETRI are provided in section 6.6.

Reduction of the risk of catheter-related blood-stream infection

Particular attention should be given to the recommendations in section 4.4 and the following as this should help to reduce the risk of catheter-related blood-stream infections.

The care of the central venous catheter and the catheter exit site should follow established medical principles.

Only extension sets with an in-line 0.22 micron filter placed between the infusion pump and the central venous catheter must be used. It is recommended to use filters with a hydrophilic polyethersulfone membrane. The extension set and the in-line filter must be changed at least every 48 hours (see section 6.6).

Preparation of VELETRI intravenous injectable solution

The reconstituted solution should be examined prior to further dilution. Its use is forbidden in the presence of discolouration or particles. Reconstituted solutions should be immediately further diluted to the final concentration.

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

VELETRI must not be administered as a bolus injection.

The main feature of overdose is likely to be hypotension.

In general, events seen after overdose of VELETRI represent exaggerated pharmacological effects of the drug (e.g. hypotension and complications of hypotension).

If overdose 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.

Shelf life: 3 years.

In use shelf life reconstituted/diluted solution for infusion:

The reconstituted solution should be immediately further diluted to the final concentration.

The diluted solution should be stored in the drug delivery reservoir in order to protect from light and can be stored for up to 8 days at 2 to 8°C.

This medicinal product (powder for solution for infusion) does not require any special temperature storage conditions. Do not freeze.

The reconstituted solution should be immediately further diluted to the final concentration. (see section 4.2, section 6.3 and section 6.6).

VELETRI diluted to the final concentration in the drug delivery reservoir as directed can be administered at room temperature (25°C) immediately after dilution or after storage for up to 8 days at 2 to 8°C as per the conditions of use outlined in Table 2 section 6.6. Do not expose the fully diluted solution to direct sunlight.

Powder for solution for infusion

10 mL colourless glass type I vial closed with a rubber stopper and an aluminium flip-off cap (with a white disc for the 0.5 mg/vial strength, and a red disc for the 1.5 mg/vial strength).

Pack presentations

Pulmonary Arterial Hypertension:

There are 2 presentations available for use in the treatment of pulmonary arterial hypertension, as follows:

• One 0.5 mg powder vial.
• One 1.5 mg powder vial.

Renal Dialysis:

There is 1 presentation available for use in the treatment of renal dialysis, as follows:

• One 0.5 mg powder vial.

Not all pack sizes may be marketed.

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 to be 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.

It is recommended that the infusion pump is not carried in permanent contact with the skin in order to avoid temperature excursions of the cassette.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The stability of solutions of VELETRI is pH dependent.

The powder for solution for infusion must be reconstituted using either Sterile Water for Injection or Sodium Chloride 0.9% Injection solution.

Further dilution should be performed with the same diluent as used for reconstitution of the sterile, lyophilised powder.

Reconstitution, dilution and calculation of infusion rate:

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 must be carried out under aseptic conditions

Renal Dialysis

There is 1 pack available for use in the treatment of renal dialysis:

• One vial containing sterile, freeze-dried VELETRI equivalent to 0.5 mg VELETRI supplied alone.

Reconstitution:

Withdraw 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9% Injection diluent into a sterile syringe, inject the contents of the syringe into the vial containing VELETRI and shake gently until the powder has dissolved. The reconstituted solution should be examined prior to further dilution. Its use is forbidden in the presence of discolouration or particles. Any unused reconstituted solution should be disposed of in accordance with local requirements.

Dilution:

The reconstituted solution should be immediately further diluted to the final concentration. Further dilution should be performed with the same diluent as used for reconstitution of the sterile, lyophilised powder.

Calculation of infusion rate:

Infusion rate (mL/min) = Dosage(ng/kg/min) x bodyweigth (kg) / Concentration of solution (ng/mL)

Infusion rates may be calculated using the following formula:

Infusion rate (mL/h) = Infusion rate (mL/min) × 60

A commonly used dilution is 2000 ng/mL VELETRI:

Pulmonary Arterial Hypertension

There are 2 packs available for use in the treatment of pulmonary arterial hypertension, as follows:

• One vial containing sterile, freeze-dried VELETRI equivalent to 0.5 mg VELETRI supplied alone.
• One vial containing sterile, freeze-dried VELETRI equivalent to 1.5 mg VELETRI supplied alone.

Reconstitution:

Withdraw 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9% Injection diluent into a sterile syringe, inject the contents of the syringe into the vial containing VELETRI and shake gently until the powder has dissolved. The reconstituted solution should be examined prior to further dilution. Its use is forbidden in the presence of discolouration or particles. Any unused reconstituted solution should be disposed of in accordance with local requirements.

Dilution:

The reconstituted solution should be immediately further diluted to the final concentration. Further dilution should be performed with the same diluent as used for reconstitution of the sterile, lyophilised powder.

VELETRI when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Only extension sets with an in-line 0.22 micron filter placed between the infusion pump and the catheter must be used. It is recommended to use filters with a hydrophilic polyethersulfone membrane. The extension set and the in-line filter must be changed at least every 48 hours (see section 4.4).

The vial containing 0.5 mg epoprostenol must be used for the preparation of solutions with final concentrations below 15,000 ng/mL.

Table 1 provides examples for preparing frequently used concentrations of VELETRI solutions. Each vial is for single use only.

Table 1. Frequently used concentrations – Examples of Reconstitution and Dilution:

* Solutions with higher final concentrations may be necessary for patients who receive long-term administration of VELETRI.

VELETRI diluted to the final concentration in the drug delivery reservoir as directed can be administered immediately at room temperature (25°C) or, if stored, for up to 8 days at 2 to 8°C as per the conditions of use outlined in Table 2.

Table 2. Maximum duration of administration (hours) at room temperature (25°C) of fully diluted solutions stored in the drug delivery reservoir:

Do not expose the fully diluted solution to direct sunlight.

Calculation of infusion rate:

Infusion rate (mL/min) = Dosage(ng/kg/min) x bodyweigth (kg) / Concentration of solution (ng/mL)

Infusion rates may be calculated using the following formula:

Infusion rate (mL/h) = Infusion rate (mL/min) × 60

Examples for some concentrations commonly used in pulmonary arterial hypertension are shown below.

Table 3. Infusion Rates for VELETRI at a Concentration of 5000 ng/mL:

Table 4. Infusion Rates for VELETRI at a Concentration of 15,000 ng/mL:

Table 5. Infusion Rates for VELETRI at a Concentration of 30,000 ng/mL:

Higher dosages, and therefore, more concentrated solutions may be necessary with long-term administration of VELETRI.