Posology : מינונים

2. DOSAGE AND ADMINISTRATION

2.1 General
Remodulin can be administered without further dilution for subcutaneous administration, or diluted for intravenous infusion with Sterile Water for Injection or 0.9% Sodium Chloride Injection, prior to administration.

2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy

Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated because of severe site pain or reaction.
The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.

2.3 Dosage Adjustments

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of Remodulin (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction).

The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. Dosage adjustments may be undertaken more often if tolerated.
Avoid abrupt cessation of infusion [see Warnings and Precautions (5.2)]. Restarting a Remodulin infusion within a few hours after an interruption can be done using the same dose rate.
Interruptions for longer periods may require the dose of Remodulin to be re-titrated.
2.4 Patients with Hepatic Insufficiency

In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min ideal body weight. Remodulin has not been studied in patients with severe hepatic insufficiency [see Warnings and Precautions (5.3), Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].


2.5 Administration
Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Subcutaneous Infusion

Remodulin is administered subcutaneously by continuous infusion without further dilution, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets. The ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) be adjustable to approximately 0.002 mL/hr, (3) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (4) have delivery accuracy of ±6% or better and (5) be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene or glass.

Remodulin is administered subcutaneously by continuous infusion at a calculated Subcutaneous Infusion Rate (mL/hr) based on a patient's Dose (ng/kg/min), Weight (kg), and the Vial Strength (mg/mL) of Remodulin being used. During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 37°C. The Subcutaneous Infusion rate is calculated using the following formula:


Subcutaneous                Dose (ng/kg/min)     x   Weight (kg)     x     0.00006* Infusion Rate          =
(mL/hr)                           Remodulin Vial Strength (mg/mL)
*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
Example calculations for Subcutaneous Infusion are as follows:

Example 1:

For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/mL Remodulin, the infusion rate would be calculated as follows:
Subcutaneous            1.25 ng/kg/min      x   60 kg      x    0.00006 Infusion Rate     =                                                        = 0.005 mL/hr (mL/hr)                                1 mg/mL


Example 2:
For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin, the infusion rate would be calculated as follows:

Subcutaneous             40 ng/kg/min       x   65 kg      x    0.00006 Infusion Rate     =                        5 mg/mL                         = 0.031 mL/hr (mL/hr)


Intravenous Infusion
External Intravenous Infusion Pump
Remodulin must be diluted with either Sterile Water for Injection or 0.9% Sodium Chloride Injection and is administered intravenously by continuous infusion, via a surgically placed indwelling central venous catheter using an external infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of Remodulin. Use of a peripheral intravenous infusion for more than a few hours may be associated with an increased risk of thrombophlebitis. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. The ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better of the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene or glass.

Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.

Diluted Remodulin has been shown to be stable at ambient temperature for up to 48 hours at concentrations as low as 0.004 mg/mL (4,000 ng/mL).

Select the intravenous infusion rate to allow for a desired infusion period length of up to 48 hours between system changeovers. Typical intravenous infusion system reservoirs have volumes of 50 or 100 mL. With this selected Intravenous Infusion Rate (mL/hr) and the patient’s Dose (ng/kg/min) and Weight (kg), the Diluted Intravenous Remodulin Concentration (mg/mL) can be calculated using the following formula:

Step 1

Diluted
Dose               Weight
Intravenous                            x                  x      0.00006 (ng/kg/min)            (kg)
Remodulin        =
Concentration                         Intravenous Infusion Rate
(mg/mL)                                     (mL/hr)
The Volume of Remodulin Injection needed to make the required Diluted Intravenous Remodulin Concentration for the given reservoir size can then be calculated using the following formula: 
Step 2

Diluted Intravenous
Remodulin                    Total Volume of Diluted
Volume of                 Concentration                  Remodulin Solution in Remodulin          =         (mg/mL)            x
Reservoir
Injection               Remodulin Vial                            (mL) (mL)                     Strength
(mg/mL)

The calculated volume of Remodulin Injection is then added to the reservoir along with the sufficient volume of diluent (Sterile Water for Injection or 0.9% Sodium Chloride Injection) to achieve the desired total volume in the reservoir.

Example calculations for Intravenous Infusion are as follows:

Example 3:
For a 60 kg person at a dose of 5 ng/kg/min, with a predetermined intravenous infusion rate of 1 mL/hr and a reservoir of 50 mL, the Diluted Intravenous Remodulin Concentration would be calculated as follows:

Step 1

Diluted
= 0.018
Intravenous              5 ng/kg/min          x   60 kg   x   0.00006         mg/mL Remodulin        =
1 mL/hr                         (18,000
Concentration ng/mL)
(mg/mL)

The Volume of Remodulin Injection (using 1 mg/mL Vial Strength) needed for a total Diluted Remodulin Concentration of 0.018 mg/mL and a total volume of 50 mL would be calculated as follows:

Step 2

Amount of                       0.018 mg/mL
=                            x 50 mL = 0.9 mL
Remodulin Injection                  1 mg/mL
(mL)

The Diluted Intravenous Remodulin Concentration for the person in Example 3 would thus be prepared by adding 0.9 mL of 1 mg/mL Remodulin Injection to a suitable reservoir along with a sufficient volume of diluent to achieve a total volume of 50 mL in the reservoir. The pump flow rate for this example would be set at 1 mL/hr.

Example 4:

For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion rate of 2 mL/hr, and a reservoir of 100 mL, the Diluted Intravenous Remodulin Concentration would be calculated as follows:
Step 1

Diluted
Intravenous               30 ng/kg/min     x 75 kg    x   0.00006    = 0.0675 mg/mL Remodulin           =
2 mL/hr                    (67,500 ng/mL)
Concentration
(mg/mL)

The Volume of Remodulin Injection (using 2.5 mg/mL Vial Strength) needed for a total Diluted Remodulin Concentration of 0.0675 mg/mL and a total volume of 100 mL would be calculated as follows:

Step 2

Volume of                        0.0675 mg/mL
=                        x 100 mL = 2.7 mL
Remodulin Injection                   2.5 mg/mL
(mL)

The Diluted Intravenous Remodulin Concentration for the person in Example 4 would thus be prepared by adding 2.7 mL of 2.5 mg/mL Remodulin Injection to a suitable reservoir along with a sufficient volume of diluent to achieve a total volume of 100 mL in the reservoir. The pump flow rate for this example would be set at 2 mL/hr.

2.6 Patients Requiring Transition from Epoprostenol

Transition from epoprostenol to Remodulin is accomplished by initiating the infusion of Remodulin and increasing it, while simultaneously reducing the dose of intravenous epoprostenol. The transition to Remodulin should take place in a hospital with constant observation of response (e.g., walk distance and signs and symptoms of disease progression). Initiate Remodulin at a recommended dose of 10% of the current epoprostenol dose, and then escalate as the epoprostenol dose is decreased (see Table 1 for recommended dose titrations).

Patients are individually titrated to a dose that allows transition from epoprostenol therapy to Remodulin while balancing prostacyclin-limiting adverse events. Increases in the patient’s symptoms of PAH should be first treated with increases in the dose of Remodulin. Side effects normally associated with prostacyclin and prostacyclin analogs are to be first treated by decreasing the dose of epoprostenol.

Table 1:       Recommended Transition Dose Changes

Step         Epoprostenol Dose                           Remodulin Dose 
1              Unchanged                         10% Starting Epoprostenol Dose 
80% Starting Epoprostenol
2                                                30% Starting Epoprostenol Dose
Dose

60% Starting Epoprostenol
3                                                50% Starting Epoprostenol Dose Dose

40% Starting Epoprostenol
4                                                70% Starting Epoprostenol Dose
Dose
           20% Starting Epoprostenol
5                                             90% Starting Epoprostenol Dose Dose

5% Starting Epoprostenol
6                                            110% Starting Epoprostenol Dose Dose

110% Starting Epoprostenol Dose + additional
7                    0
5-10% increments as needed

3. DOSAGE FORMS AND STRENGTHS

20-mL vial containing 50 mg treprostinil (2.5 mg per mL).
20-mL vial containing 100 mg treprostinil (5 mg per mL).
20-mL vial containing 200 mg treprostinil (10 mg per mL).