Medicinal Products

EPOPROSTENOL SANDOZ 0.5 mg

Flolan Generic Drug
Therapeutic class: Cardiology and angiology
active ingredients: Epoprostenol
laboratory: Sandoz

Powder and solvent for solution for IV infusion
Box of 1 bottle of powder + 50 ml solvent bottle
All forms

Indication

Epoprostenol is indicated for continuous intravenous infusion therapy, pulmonary arterial hypertension (PAH):

· Idiopathic pulmonary arterial hypertension - familial or sporadic

· Pulmonary arterial hypertension associated with systemic collagenosis

in patients with functional clinical stage III or IV in the New York Heart Association (NYHA) severity scale.

Treatment should only be initiated and followed by experienced clinicians in the treatment of pulmonary arterial hypertension. Treatment should be initiated under close medical supervision in departments with an intensive care unit and an invasive cardiological exploration unit.

Dosage EPOPROSTENOL SANDOZ 0.5 mg Powder and solvent for solution for infusion IV Box of 1 vial of powder + vial of solvent of 50 ml

Epoprostenol is indicated only as a continuous intravenous infusion. It should not be administered as a bolus.

Dosage:

adults

Vasodilation test in acute:

This test is not intended to establish the long-term epoprostenol infusion dose. Its only interest is to screen responders for oral vasodilators (such as calcium channel blockers). It can easily be replaced by an inhaled nitric oxide (NO) test, which is simpler and has no systemic repercussions.

The infusion will be initiated at a rate of 2 ng / kg / min, then increased in increments of 2 ng / kg / min every 15 minutes or less frequently until a maximal hemodynamic response or the appearance of limiting pharmacological effects ( eg, nausea, vomiting, headache, hypotension or tachycardia).

As an indication, during clinical trials, the maximum dose administered in acute without such effects being observed was on average 8.6 ± 0.3 ng / kg / min.

Continuous infusion in the long run:

Continuous continuous infusion of epoprostenol will be administered with a central venous catheter. Temporarily, before the establishment of a central approach, epoprostenol may be administered intravenously. Long-term infusions will be initiated with a lower dose of 4 ng / kg / min than the maximum tolerated infusion rate. If the maximum tolerated infusion rate is less than 5 ng / kg / min, long-term infusion will be started at a rate of half the maximum tolerated rate.

Adjustments of doses infused during long-term treatment:

The long-term infusion rate will be adjusted according to the persistence, recurrence or worsening of symptoms of pulmonary arterial hypertension, or the occurrence of adverse events that would be due to an excessive dose of epoprostenol.

In the majority of cases, the required dose increases gradually over time compared to the dose used at the initiation of long-term treatment. Dose augmentation should be considered if symptoms of pulmonary arterial hypertension persist or recur after improvement. The infusion rate will be increased in increments of 1 to 2 ng / kg / min, with sufficient interval to allow evaluation of the clinical response; in most cases this interval is 12 to 24 hours. After any change in perfusion rate, the patient will be kept under observation for several hours, including monitoring the systemic blood pressure while standing / lying and heart rate, to verify that the new dose is well tolerated.

The occurrence during long-term treatment of dose-related adverse pharmacological effects, such as those observed in an acute test, may require a reduction in the infusion rate; it is also possible that an effect of this type disappears without dose adjustment.

Decreases in dose until dose-limiting effects are resolved should be gradual, in increments of 2 ng / kg / min every 15 minutes or at longer intervals.

It is imperative to avoid abrupt interruption of epoprostenol infusion or abrupt reduction of infusion rate due to the major risk of a significant rebound effect. Except in situations where the vital prognosis is engaged in the short term (coma, collapse, etc.), the adjustments of the infusion rate of epoprostenol will have to be made progressively to mitigate by avoiding any too abrupt modification.

Use in children:

There is limited data on the use of epoprostenol in the treatment of pulmonary arterial hypertension in children.

Use in elderly subjects:

There is limited data on the use of epoprostenol in subjects over 65 years of age. In general, in these patients, the choice of a dosage should be careful, because of a greater risk of hepatic, renal, cardiac dysfunction, and associated pathologies or treatments.

Administration mode

For long-term intravenous infusion, the epoprostenol solution will be administered via an indwelling central venous catheter using a portable continuous infusion pump for ambulatory use.

In order to avoid possible interruptions in the administration of the drug in the event of an accidental malfunction, the patient must be able to access an infusion pump and a replacement infusion set.

The ambulatory pump used to administer epoprostenol must:

· Be light and small,

· Allow adjustments to the infusion rate in increments of 1 ng / kg / min,

· Be equipped with an alarm system that triggers if there is an obstruction in the tubing, at the end of the infusion, and when the batteries expire,

· Allow a programmed flow accuracy of at least 6%,

· Work by positive pressure (continuous or pulsatile), the interval between outbreaks not to exceed 3 minutes with the flow rates used for the administration of epoprostenol,

· Be equipped with a refrigerant pocket system.

The tank must be made of polyvinyl chloride, polypropylene or glass.

The preparation of the infusion solution and the calculation of the infusion rate should be made with the greatest attention.

The preparation must be carried out following the procedures described below.

Reconstitution and dilution of the solution should be performed under sterile conditions and immediately before administration.

For reconstitution of the solution, the powder will be diluted only with the sterile glycine buffer solution provided.

Reconstitution:

1. Use only the glycine buffer solution provided as diluent to reconstitute the solution.

2. Extract approximately 10 ml of glycine buffer solution into a sterile syringe, inject the contents of the syringe into the EPOPROSTENOL SANDOZ 0.5 mg vial containing the powder and shake gently until dissolved.

3. Extract the solution thus produced into the syringe, then reinject it into the remaining volume of glycine buffer solution and mix well.

Dilution:

The reconstituted epoprostenol solution may be used in the treatment of pulmonary arterial hypertension either directly or in diluted form. The reconstituted solution should be diluted only with the glycine buffer solution provided. Do not use a solution of sodium chloride for infusion (commonly referred to as saline) for the dilution of epoprostenol used for the treatment of pulmonary arterial hypertension.

The most commonly used concentrations in the treatment of pulmonary arterial hypertension are:

30, 000 ng / ml - 1.5 mg of reconstituted epoprostenol in a total volume of 50 ml of glycine buffer used as diluent.

15, 000 ng / ml - 1.5 mg of reconstituted epoprostenol diluted in a total volume of 100 ml of glycine buffer used as diluent.

10, 000 ng / ml - 2 vials of 0.5 mg of reconstituted epoprostenol diluted in a total volume of 100 ml of glycine buffer used as diluent.

5000 ng / ml - 1 vial of 0.5 mg of reconstituted epoprostenol diluted in a total volume of 100 ml of glycine buffer as diluent.

The maximum concentration recommended for use in the treatment of pulmonary arterial hypertension is 60, 000 ng / ml.

Filtration step:

Filtration of the solution is necessary before administration in concentrated or diluted form. To perform the filtration, extract the reconstituted product into a large syringe and attach the sterile filter provided to the syringe.

Transfer the concentrated solution directly into the chosen infusion solution, exerting firm and continuous pressure on the plunger; in practice, it takes about 70 seconds to filter 50 ml of concentrated solution.

Remove the filter from the syringe and fill it with the volume of glycine buffer needed to obtain the desired dilution.

Re-attach the filter to the syringe, and transfer the additional buffer through the filter into the concentrated solution contained in the cassette. Mix well.

The filter should be used once, then discarded.

Administration

The solution should be prepared just before administration and used immediately.

After reconstitution and dilution according to the recommendations mentioned above, the solution for infusion of epoprostenol is at a pH of about 10 and will remain stable to retain 90% of its effectiveness for about 12 hours, if maintained at 25 ° C. C.

Also, the reconstituted solution should not be used for more than 12 hours when administered at room temperature (between + 15 ° C and + 25 ° C). It must not be exposed to temperatures exceeding 25 ° C and must be kept out of the light.

From a microbiological point of view, if the reconstituted solution is not used immediately, compliance with the storage conditions prior to its administration is the responsibility of the user and they should not normally exceed 24 hours with temperatures. of storage is between 2 ° C and 8 ° C. Under these conditions, the maximum infusion time will be 8 hours at room temperature.

Before use, the solution will be inspected and discarded if there is abnormal coloring or if there are solid particles in suspension.

Calculation of the infusion rate:

The perfusion rate Δ (ml / h) will be calculated using the following formula:

Δ (ml / h) = [D (ng / kg / min) x P (kg) x 60 min]

________________________

[F (ng / ml) x 1 (h)]

D represents the prescribed dose of epoprostenol expressed in ng / kg / min.

P represents the body weight of the patient expressed in kg.

F represents the concentration of epoprostenol expressed in ng / ml and calculated on the basis of the following formula: F (ng / ml) = Q (ng) / VD (ml) where VD represents the dilution volume of the solvent expressed in ml and Q the amount of epoprostenol expressed in ng.

Examples of infusion rates:

Perfusion rates (ml / h) for a solution of epoprostenol concentrated at 15, 000 ng / ml:

Concentration = 15, 000 ng / ml epoprostenol

Dosage (ng / kg / min)

Body weight (kg)

30

40

50

60

70

80

90

100

4

1.0

1.1

1.3

1.4

1.6

6

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

Perfusion rates in ml / h.

Perfusion rates (ml / h) for a solution of epoprostenol concentrated at 5, 000 ng / ml:

Concentration = 5, 000 ng / ml epoprostenol

Dosage (ng / kg / min)

Body weight (kg)

30

40

50

60

70

80

90

100

2

1.0

1.2

1.4

1.7

1.9

2.2

2.4

4

1.4

1.9

2.4

2.9

3.4

3.8

4.3

4.8

6

2.2

2.9

3.6

4.3

5.0

5.8

6.5

7.2

8

2.9

3.8

4.8

5.8

6.7

7.7

8.6

9.6

10

3.6

4.8

6.0

7.2

8.4

9.6

10.8

12.0

12

4.3

5.8

7.2

8.6

10.1

11.5

13.0

14.4

14

5.0

5.7

8.4

10.1

11.8

13.4

15.1

16.8

16

5.8

7.7

9.6

11.5

13.4

15.4

17.3

19.2

Perfusion rates in ml / h.

Against indications

Epoprostenol is contraindicated:

· If there is known hypersensitivity to epoprostenol or to any of the excipients;

· In patients with congestive heart failure due to severe dysfunction of the left ventricle;

· In the event of pulmonary edema during the adjustment phase of the dose.

· In the event of pulmonary edema occurring at the start of treatment evoking the underlying existence of pulmonary veno-occlusive disease.

Adverse effects Epoprostenol Sandoz

Adverse effects are classified below by organ system and frequency. The frequency of adverse events is defined as follows:

Very common (≥ 1/10)

Frequent (≥ 1/100 to <1/10);

Uncommon (≥ 1/1000 to <1/100);

Rare (≥ 1/10 000 to <1/1000);

Very rare (<1 / 10, 000)

Not known (can not be estimated from the available data).

The clinical features of the underlying disease being treated may make it difficult to interpret the adverse events that occur during the long-term administration of epoprostenol.

Infections and infestations

Frequent: sepsis, sepsis (most often related to the system of administration of epoprostenol).

Hematologic and lymphatic system disorders

Frequent: thrombocytopenia, various bleeding (epistaxis, pulmonary bleeding, gastrointestinal, intracranial, postoperative or retroperitoneal bleeding).

Metabolism and nutrition disorders

Not known: increased blood glucose.

Psychiatric disorders

Common: anxiety, nervousness

Very rare: agitation.

Nervous system disorders

Very common: headache.

Cardiac disorders

Common: Cases of tachycardia have been reported with doses of 5 ng / kg / min or lower.

Bradycardia, sometimes with orthostatic hypotension, occurred in healthy volunteers receiving epoprostenol doses greater than 5 ng / kg / min. Bradycardia, associated with a marked drop in systolic and diastolic blood pressure, followed intravenous administration of a dose of epoprostenol equivalent to 30 ng / kg / min in healthy volunteers.

Vascular disorders

Very common: flushing of the face (including anesthetized patients).

Very rare: pallor.

Respiratory, thoracic and mediastinal disorders

Not known: pulmonary edema.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhea.

Common: abdominal colic, sometimes reported as abdominal discomfort / pain.

Uncommon: dryness of the mouth.

Skin and subcutaneous tissue disorders

Common: rash

Very rare: hypersudation.

Not known: photosensitivity reaction

Musculoskeletal and connective tissue disorders

Very common: pain in the mandibles.

Common: arthralgia

General disorders and administration site conditions

Very common: pain (without further details).

Common: pain and edema of the lower extremities sometimes associated with ascites, chest pain, injection site pain *.

Rare: local infection *.

Very rare: chest tightness, redness at the infusion site *, intravenous catheter occlusion, fatigue.

* Material effect and method of administration.

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