"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
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), reserve continuous intravenous infusion for patients who are intolerant of the subcutaneous route, or in whom these risks areconsidered 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. Consider the risks and benefits of each drug prior to transition.
DOSAGE AND ADMINISTRATION
Remodulin can be administered without further dilution for subcutaneous administration, or diluted for intravenous infusion with Sterile Diluent for Remodulin or similar approved high-pH glycine diluent (e.g. Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1 below for storage and administration time limits for the different diluents.
Table 1: Selection of Diluent
|Route||Diluent||Storage limits||Administration limits|
|SC||None||See HOW SUPPLIED Section||72 hours at 37°C|
|IV||Sterile Diluent for Remodulin Sterile Diluent for Flolan Sterile Diluent for Epoprostenol Sodium||14 days at room temperature||48 hours at 40 °C|
|Sterile water for injection 0.9% Sodium Chloride for injection||4 hours at room temperature or 24 hours refrigerated||48 hours at 40°C|
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.
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]. 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, 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, Use In Specific Populations and CLINICAL PHARMACOLOGY].
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.
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 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:
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 Infusion Rate (mL/hr) =||1.25 ng/kg/min x 60 kg x 0.00006||= 0.005 mL/hr|
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 Infusion Rate (mL/hr) =||40 ng/kg/min x 65 kg x 0.00006||= 0.031 mL/hr|
Diluted Remodulin 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 when stored for up to 14 days using high-pH glycine diluent 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:
|Diluted Intravenous Remodulin Concentration (mg/mL) =||Dose (ng/kg/min) x Weight (kg) x 0.00006|
|Intravenous Infusion Rate (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:
|Volume of Remodulin Injection (mL) =||Diluted Intravenous Remodulin Concentration (mg/mL)||x Total Volume of Diluted Remodulin Solution in Reservoir (mL)|
|Remodulin Vial Strength (mg/mL)|
The calculated volume of Remodulin Injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir.
Example calculations for Intravenous Infusion are as follows:
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:
|Diluted Intravenous Remodulin Concentration (mg/mL)=||5 ng/kg/min x 60 kg x 0.00006||= 0.018mg/mL (18,000 ng/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:
|Amount of Remodulin Injection (mL) =||0.018 mg/mL 1 mg/mL||x 50 mL = 0.9 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.
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:
|Diluted Intravenous Remodulin Concentration (mg/mL)||30 ng/kg/min x 75 kg x 0.00006||= 0.0675 mg/mL (67,500 ng/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:
|Amount of Remodulin Injection(mL) =||0.0675 mg/mL 2.5 mg/mL||x 100 mL = 2.7 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). Initiate Remodulin at a recommended dose of 10% of the current Flolan dose, and then escalate as the Flolan dose is decreased (see Table 2 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 2: 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|
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 as sterile solutions in water for injection, individually packaged in cartons. Unopened vials of Remodulin are stable until the date indicated when stored at 25°C (77°F), with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. 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 mg / 20 mL||1 mg/ mL||101-01|
|50 mg / 20 mL||2.5 mg/ mL||102-01|
|100 mg / 20 mL||5 mg/ mL||105-01|
|200 mg / 20 mL||10 mg/ mL||110-01|
Sterile Diluent for Remodulin is supplied separately as:
50 mL vial, carton of 1 (NDC 66302-150-50).
REMODULIN manufactured for: United Therapeutics Corp., Research Triangle Park, NC 27709. Revised: Dec 2014This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 2/5/2016
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