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Remodulin

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Remodulin

INDICATIONS

Pulmonary Arterial Hypertension

Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) [see Clinical Studies].

It may be administered as a continuous subcutaneous infusion or continuous intravenous (IV) infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections (BSIs), continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted [see WARNINGS AND PRECAUTIONS].

Pulmonary Arterial Hypertension in Patients Requiring Transition from Flolan®

In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol sodium), Remodulin is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition.

DOSAGE AND ADMINISTRATION

General

Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). Remodulin can be administered as supplied or diluted for intravenous infusion with Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium prior to administration.

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, the infusion rate should be reduced to 0.625 ng/kg/min.

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. Abrupt cessation of infusion should be avoided [see WARNINGS AND PRECAUTIONS]. 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.

Patients with Hepatic Insufficiency

In patients with mild or moderate hepatic insufficiency, the initial dose of Remodulin should be decreased to 0.625 ng/kg/min ideal body weight and should be increased cautiously. Remodulin has not been studied in patients with severe hepatic insufficiency [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY].

Patients with Renal Insufficiency

No studies have been performed in patients with renal insufficiency. No specific advice about dosing in patients with renal impairment can be given. [see CLINICAL PHARMACOLOGY].

Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, Remodulin should not be administered.

Subcutaneous Infusion

Remodulin is administered subcutaneously by continuous infusion, via a self-inserted 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.

For subcutaneous infusion, Remodulin is delivered without further dilution at a calculated Subcutaneous Infusion Rate (mL/hr) based on a patients 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 Infusion Rate (mL/hr) = Dose (ng/kg/min) x Weight (kg) x 0.00006*
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 Vial Strength, the infusion rate would be calculated as follows:

Subcutaneous Infusion Rate (mL/hr) = 1.25 ng/kg/min x 60 kg x 0.00006 = 0.005 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 Vial Strength, the infusion rate would be calculated as follows:

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

Intravenous Infusion

Remodulin must be diluted with either Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium and is administered intravenously by continuous infusion, via a surgically placed indwelling central venous catheter, using an 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).

When using an appropriate infusion pump and reservoir, a predetermined intravenous infusion rate should first be selected 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 Intravenous Remodulin Concentration (mg/mL) = Dose (ng/kg/min) x Weight (kg) x 0.00006
Intravenous Infusion Rate (mL/hr)

The Amount 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

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

The calculated amount of Remodulin Injection is then added to the reservoir along with the sufficient volume of diluent (Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium) 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 Solution Concentration would be calculated as follows:

Step 1

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

The Amount 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 Remodulin Injection (mL) = 0.018 mg/mL 1 mg/mL x 50 mL = 0.9 mL
1 mg/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 Solution Concentration would be calculated as follows:

Step 1

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

The Amount 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

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

Patients Requiring Transition from Flolan

Transition from Flolan to Remodulin is accomplished by initiating the infusion of Remodulin and increasing it, while simultaneously reducing the dose of intravenous Flolan. 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). During the transition, Remodulin is initiated at a recommended dose of 10% of the current Flolan dose, and then escalated as the Flolan dose is decreased (see Table 1 for recommended dose titrations).

Patients are individually titrated to a dose that allows transition from Flolan 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 Flolan.

Table 1: Recommended Transition Dose Changes

Step Flolan Dose Remodulin Dose
1 Unchanged 10% Starting Flolan Dose
2 80% Starting Flolan Dose 30% Starting Flolan Dose
3 60% Starting Flolan Dose 50% Starting Flolan Dose
4 40% Starting Flolan Dose 70% Starting Flolan Dose
5 20% Starting Flolan Dose 90% Starting Flolan Dose
6 5% Starting Flolan Dose 110% Starting Flolan Dose
7 0 110% Starting Flolan Dose + additional 5-10% increments as needed

HOW SUPPLIED

Dosage Forms And Strengths

20-mL vial containing 20 mg treprostinil (1 mg per mL).
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).

Storage And Handling

Remodulin is supplied in 20 mL multidose vials containing 20, 50, 100, or 200 mg of treprostinil at concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10 mg/mL treprostinil, respectively, as sterile solutions in water for injection, individually packaged in cartons. Unopened vials of Remodulin are stable until the date indicated when stored at 15 to 25°C (59 to 77°F). Store at 25°C (77°F), with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 37°C. Diluted Remodulin Solution can be administered up to 48 hours at 37°C when diluted to concentrations as low as 0.004 mg/mL in Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium . A single vial of Remodulin should be used for no more than 30 days after the initial introduction into the vial.

Remodulin Injection is supplied as:

20-mL vial containing 20 mg treprostinil (1 mg treprostinil per mL), carton of 1 (NDC 66302-101-01).
20-mL vial containing 50 mg treprostinil (2.5 mg treprostinil per mL), carton of 1 (NDC 66302-102-01).
20-mL vial containing 100 mg treprostinil (5 mg treprostinil per mL), carton of 1 (NDC 66302-105-01).
20-mL vial containing 200 mg treprostinil (10 mg treprostinil per mL), carton of 1 (NDC 66302-110-01).

REMODULIN manufactured for: United Therapeutics Corp. Research Triangle Park, NC 27709. Revised: Sep 2013

Last reviewed on RxList: 10/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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