Pharmaceutical particulars : מידע רוקחי

6.    PHARMACEUTICAL PARTICULARS
6.1   List of excipients

Powder for solution for infusion:
Mannitol
Glycine
Sodium Chloride
Sodium Hydroxide (for pH adjustment)

Solvent for parenteral use:
Glycine
Sodium Chloride
Sodium Hydroxide (for pH adjustment)
Water for Injection
6.2       Incompatibilities

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

Preparation and administration materials containing PET or PETG may become damaged when used with epoprostenol solution prepared with solvent (pH 11.7-12.3) and therefore must not be used (see section 6.6).

6.3       Shelf life

Unopened vials
The expiry date of the product is indicated on the label and packaging materials.

Stability during administration

Freshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2°C to 8°C for no longer than 8 days can be administered up to:

•    72 hours at up to 25°C or

•    48 hours at up to 30ºC or
•    24 hours at up to 35 ºC or

•    12 hours at up to 40 ºC

Discard any unused solution after this time.
Reconstituted solutions can be used immediately. Refrigerate at 2°C to 8°C if not used immediately.
Protect from light. Do not freeze reconstituted solutions.

6.4       Special precautions for storage

Powder for solution for infusion:
Do not store vials above 25°C. Protect from light. Keep dry. Do not freeze. Store in the original package.
Solvent for parenteral use:
Do not store vials above 25°C. Do not freeze. Protect from light. Keep Dry. Store in the original package.
The solvent contains no preservative; consequently a vial should be used once only and then discarded.

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

6.5       Nature and contents of container
Powder for solution for infusion:
Clear (type 1) glass vials with synthetic butyl rubber stoppers and an aluminium collar with a snap-off top.
Solvent for parenteral use:
Clear plastic vials with synthetic butyl rubber stoppers and an external aluminium collar with a purple plastic flip-top cover.

Pack sizes:

Flolan Infusion of Epoprostenol 500 mcg
There are two presentations available in 0.5 mg for use in the treatment of pulmonary arterial hypertension, as follows:
• One 0.5 mg powder vial and one solvent vial and a filter unit.
• One 0.5 mg powder vial and two solvent vials and a filter unit.

Flolan Infusion of Epoprostenol 1500 mcg
There is one presentation available in 1.5 mg for use in the treatment of pulmonary arterial hypertension, as follows:
• One 1.5 mg powder vial and two solvent vials and a filter unit.

Not all pack sizes may be marketed.

6.6     Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The stability of solutions of Flolan is pH dependent. Only the solvent supplied should be used for reconstitution of freeze-dried Flolan and only the recommended infusion solutions, in the stated ratio, should be used for further dilution, otherwise the required pH may not be maintained.

Reconstitution and dilution of Flolan must be carried out using aseptic technique.

Epoprostenol solution prepared with solvent (pH 11.7-12.3), must not be used with any preparation or administration materials containing PET or PETG (see section 6.2). Based on available data from inhouse testing and published literature, preparation and administration materials likely to be compatible include: •     Modified Acrylic
•     Acrylonitrile butadiene styrene (ABS)
•     Cyclic olefin polymer
•     Polyamide
•     Polyethersulfone
•     Polyethylene
•     Polyisoprene
•     Polyolefin
•     Polypropylene
•     Polytetrafluoroethylene (PTFE)
•     Polyurethane
•     Polyvinyl chloride (PVC) (plasticised with bis(2-ethylhexyl) phthalate [DEHP]) •     Polyvinylidene fluoride (PVDF)
•     Silicone

Suitable ambulatory pumps to be used include:
•      CADD-Legacy 1
•      CADD-Legacy PLUS
•     CADD-Solis VIP (variable infusion profile)
Manufactured by Smiths Medical.
Pump accessories found to be compatible 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. The extension set and the in-line filter must be changed at least every 48 hours.

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.

Flolan Infusion of Epoprostenol 500 mcg
There are two 0.5 mg packs available for use in the treatment of pulmonary arterial hypertension, as follows: 
•       One vial containing sterile, freeze-dried Flolan equivalent to 0.5 mg Flolan, supplied with one 50 mL vial of solvent and a filter unit.

•       One vial containing sterile, freeze-dried Flolan equivalent to 0.5 mg Flolan, supplied with two 50 mL vials of solvent and a filter unit.

Flolan Infusion of Epoprostenol 1500 mcg
There is one 1.5 mg pack available for use in the treatment of pulmonary arterial hypertension, as follows: 
•       One vial containing sterile, freeze-dried Flolan equivalent to 1.5 mg Flolan, supplied with two 50 mL vials of solvent and a filter unit.

Initially a pack containing solvent for parenteral use must be used. During chronic Flolan therapy higher concentrated solutions may be required. The final concentration of the solution may be increased by the addition of further 0.5 mg or 1.5 mg vials of freeze-dried Flolan.

Only vials of the same amount of freeze-dried Flolan as that included in the initial starter pack may be used to increase the final concentration of solution.

Reconstitution:

1. Use only the sterile solvent solution provided for reconstitution.
2. Withdraw approximately 10 mL of the sterile solvent solution into a sterile syringe, inject it into the vial containing the freeze-dried epoprostenol and shake gently until the powder has dissolved.

3. Draw up the resulting epoprostenol solution into the syringe, re-inject it into the remaining volume of the sterile solvent solution and mix thoroughly.

This solution is now referred to as the concentrated solution.
• Where a pack containing 0.5 mg epoprostenol is reconstituted with 50 mL sterile solvent the resultant concentration is 10,000 nanograms/mL epoprostenol.

•     Where a pack containing 1.5 mg epoprostenol is reconstituted with 50 mL sterile solvent the resultant concentration is 30,000 nanograms/mL.


Dilution:

Flolan may be used either as a concentrated solution or in a diluted form for the treatment of pulmonary arterial hypertension. Only concentrated solutions are suitable for further dilution with the sterile solvent prior to use.

Only the solvent provided may be used for the further dilution of reconstituted Flolan. Sodium chloride 0.9% w/v solution must not be used when Flolan is to be used for the treatment of pulmonary arterial hypertension as the required pH is not maintained. Flolan solutions are less stable at low pH. Flolan must not be administered with other parenteral solutions or medications when used for pulmonary arterial hypertension.

The final solution to be administered to the patient must be filtered using a 0.22 or 0.20 micron filter. Use of an in-line filter as part of the infusion set during administration is preferable. Alternatively, where in-line filtration is not possible, the final solution (either as concentrated or further diluted solution) must be filtered with the provided sterile 0.22 micron filter prior to storage in the medication cassette using firm but not excessive pressure; the typical time taken to for filtration of 50mL of solution is 70 seconds.

If an in-line filter has been used during administration, then the in-line filter should be discarded when the infusion set is exchanged.

If instead a syringe filter has been used during preparation, the syringe filter unit must be used only during preparation and then discarded.

Concentrations commonly used in the treatment pulmonary arterial hypertension are as follows: 
Flolan Infusion of Epoprostenol 500 mcg
•     5,000 nanograms/mL - One vial containing 0.5 mg Flolan reconstituted and diluted to a total volume of 100 mL in solvent.

•     10,000 nanograms/mL - Two vials containing 0.5 mg Flolan reconstituted and diluted to a total volume of 100 mL in solvent.

Flolan Infusion of Epoprostenol 1500 mcg
•     15,000 nanograms/mL - 1.5 mg Flolan reconstituted and diluted to a total volume of 100mL in solvent.

•     30,000 nanograms/mL - Two vials containing 1.5 mg Flolan reconstituted and diluted to a total volume of 100 mL in solvent.

Calculation of infusion rate:

The infusion rate may be calculated from the following formula:
Infusion rate         dosage (nanogram/kg/min) x bodyweight (kg)
=
(mL/min)            concentration of solution (nanogram/mL)
Infusion rate (mL/h) = Infusion rate (mL/min) x 60


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


Infusion rates for a concentration of 5,000 nanograms/mL
Example For Dosing Using a Concentration of 5,000 nanograms/mL
Dosage                                  Bodyweight (kg)
(nanograms/kg
/ min)
20        30       40      50       60       70     80    90          100 2        0.5       0.7     1.0      1.2      1.4      1.7    1.9  2.2           2.4
4        1.0       1.4     1.9      2.4      2.9      3.4    3.8  4.3           4.8
6        1.4       2.2     2.9      3.6      4.3      5.0    5.8  6.5           7.2 8        1.9       2.9     3.8      4.8      5.8      6.7    7.7  8.6           9.6 10        2.4       3.6     4.8      6.0      7.2      8.4    9.6 10.8          12.0 12        2.9       4.3     5.8      7.2      8.6     10.1   11.5 13.0          14.4 14        3.4       5.0     6.7      8.4     10.1     11.8   13.4 15.1          16.8 16        3.8       5.8     7.7      9.6     11.5     13.4   15.4 17.3          19.2 Flow rates in mL/h


Infusion rates for a concentration of 10,000 nanograms/mL
Example For Dosing Using a Concentration of 10,000 nanograms/mL
Dosage                                    Bodyweight (kg)
(nanograms/ kg/ min)
20      30       40       50       60       70     80       90          100 2          0.2     0.4      0.5      0.6      0.7     0.8     1.0      1.1         1.2
4          0.5     0.7      1.0      1.2      1.4     1.7     1.9      2.2         2.4
6          0.7     1.1      1.4      1.8      2.2     2.5     2.9      3.2         3.6 8          1.0     1.4      1.9      2.4      2.9     3.4     3.8      4.3         4.8 10          1.2     1.8      2.4      3.0      3.6     4.2     4.8      5.4         6.0 12          1.4     2.2      2.9      3.6      4.3     5.0     5.8      6.5         7.2 14          1.7     2.5      3.4      4.2      5.0     5.9     6.7      7.6         8.4 16          1.9     2.9      3.8      4.8      5.8     6.7     7.7      8.6         9.6 Flow rates in mL/h

Infusion rates for a concentration of 15,000 nanograms/mL

Example For Dosing Using a Concentration of 15,000 nanograms/mL
Dosage                              Bodyweight (kg)
(nanograms/ kg/ min)
30       40      50      60        70        80     90          100
4        0.5     0.6      0.8     1.0       1.1      1.3     1.4         1.6
6        0.7     1.0      1.2     1.4       1.7      1.9     2.2         2.4 8        1.0     1.3      1.6     1.9       2.2      2.6     2.9         3.2 10        1.2     1.6      2.0     2.4       2.8      3.2     3.6         4.0 12        1.4     1.9      2.4     2.9       3.4      3.8     4.3         4.8 14        1.7     2.2      2.8     3.4       3.9      4.5     5.0         5.6 16        1.9     2.6      3.2     3.8       4.5      5.1     5.8         6.4 Flow rates in mL/h

Infusion rates for a concentration of 30,000 nanograms/mL

Example For Dosing Using a Concentration of 30,000 nanograms/mL
Dosage                          Bodyweight (kg)
(nanograms/ kg/ min)
30     40     50     60      70     80     90   100
6       0.4    0.5    0.6    0.7     0.8    1.0   1.1   1.2
8       0.5    0.6    0.8    1.0     1.1    1.3   1.4   1.6
10       0.6    0.8    1.0    1.2     1.4    1.6   1.8   2.0
12       0.7    1.0    1.2    1.4     1.7    1.9   2.2   2.4
14       0.8    1.1    1.4    1.7     2.0    2.2   2.5   2.8
16       1.0    1.3    1.6    1.9     2.2    2.6   2.9   3.2
18       1.1    1.4    1.8    2.2     2.5    2.9   3.2   3.6
20       1.2    1.6    2.0    2.4     2.8    3.2   3.6   4.0
Flow rates in mL/h
Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of Flolan.