Remodulin
(Treprostinil)Dosage & Administration
Increase the Remodulin dose gradually as the epoprostenol dose is decreased, based on constant observation of response. (
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 2for recommended dose titrations).
Patients are individually titrated to a dose that allows transition from epoprostenol therapy to Remodulin while balancing prostacyclin-limiting adverse events. Treat increases in the patient's symptoms of PAH first with increases in the dose of Remodulin. Treat side effects normally associated with prostacyclin and prostacyclin analogs first by decreasing the dose of epoprostenol.
| Step | Epoprostenol Dose | Remodulin Dose |
|---|---|---|
| 1 | Unchanged | 10% Starting Epoprostenol Dose |
| 2 | 80% Starting Epoprostenol Dose | 30% Starting Epoprostenol Dose |
| 3 | 60% Starting Epoprostenol Dose | 50% Starting Epoprostenol Dose |
| 4 | 40% Starting Epoprostenol Dose | 70% Starting Epoprostenol Dose |
| 5 | 20% Starting Epoprostenol Dose | 90% Starting Epoprostenol Dose |
| 6 | 5% Starting Epoprostenol Dose | 110% Starting Epoprostenol Dose |
| 7 | 0 | 110% Starting Epoprostenol Dose + additional 5-10% increments as needed |
Continuous subcutaneous infusion is the preferred mode. Use intravenous (IV) infusion if subcutaneous infusion is not tolerated. (
Remodulin can be administered with or without further dilution with Sterile Diluent for Remodulin or similar approved high-pH glycine diluent (e.g., Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1below for storage and administration time limits for the different diluents.
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).
| Diluent | Storage Limits | Administration Limits |
|---|---|---|
| None | See Section 16 | 16 weeks at 40°C |
| Sterile Diluents for Remodulin, Flolan, or Epoprostenol | 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 |
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 by subcutaneous or intravenous infusion at a calculated rate based on a patient's dose (ng/kg/min), weight (kg), and the Remodulin concentration (mg/mL).
For administration of
Undiluted Infusion Rate (mL/hour) | = | Dose (ng/kg/min) | × | Weight (kg) | × | 0.00006 Conversion factor of 0.00006 = 60 min/hour × 0.000001 mg/ng | |
Remodulin Vial Strength (mg/mL) | |||||||
For administration of
Diluted Remodulin Concentration (mg/mL) | Dose (ng/kg/min) | × | Weight (kg) | × | 0.00006 | ||
= | |||||||
Infusion Rate (mL/hour) | |||||||
The volume of Remodulin Injection needed to make the required diluted Remodulin concentration for the given reservoir size can then be calculated using the following formula:
Volume of Remodulin Injection (mL) | = | Diluted Remodulin Concentration (mg/mL) | × | 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.
Remodulin is administered subcutaneously by continuous infusion, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. The infusion pump should: (1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better, (4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Remodulin. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.
Remodulin 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 increases the risk of thrombophlebitis. The infusion pump used to administer Remodulin should: (1) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better, (3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Remodulin. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets.
Infusion sets with an in-line 0.22- or 0.2-micron pore size filter should be used.
Use an implantable intravenous infusion pump approved for use with Remodulin, such as the Implantable System for Remodulin®(ISR). Refer to the pump manufacturer's manual for specific instructions regarding preparation, programing, implantation, and refilling.
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Remodulin Prescribing Information
Remodulin is a prostacyclin mimetic indicated for:
- 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%). ()
1.1 Pulmonary Arterial HypertensionRemodulin 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 (14.1)]. - Patients who require transition from epoprostenol, to reduce the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. ()
1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from EpoprostenolIn patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.
- Initial dose for patients new to prostacyclin infusion therapy: 1.25 ng/kg/min; increase based on clinical response (increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment, later 2.5 ng/kg/min per week). Avoid abrupt cessation. (,
2.2 Initial Dose for Patients New to Prostacyclin Infusion TherapyRemodulin 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.
)2.4 Dosage AdjustmentsThe 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. - Mild to moderate hepatic insufficiency: Decrease initial dose to 0.625 ng/kg/min.
Severe hepatic insufficiency: No studies performed. ()2.5 Patients with Hepatic InsufficiencyIn 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)].
Increase the Remodulin dose gradually as the epoprostenol dose is decreased, based on constant observation of response. (
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 2for recommended dose titrations).
Patients are individually titrated to a dose that allows transition from epoprostenol therapy to Remodulin while balancing prostacyclin-limiting adverse events. Treat increases in the patient's symptoms of PAH first with increases in the dose of Remodulin. Treat side effects normally associated with prostacyclin and prostacyclin analogs first by decreasing the dose of epoprostenol.
| Step | Epoprostenol Dose | Remodulin Dose |
|---|---|---|
| 1 | Unchanged | 10% Starting Epoprostenol Dose |
| 2 | 80% Starting Epoprostenol Dose | 30% Starting Epoprostenol Dose |
| 3 | 60% Starting Epoprostenol Dose | 50% Starting Epoprostenol Dose |
| 4 | 40% Starting Epoprostenol Dose | 70% Starting Epoprostenol Dose |
| 5 | 20% Starting Epoprostenol Dose | 90% Starting Epoprostenol Dose |
| 6 | 5% Starting Epoprostenol Dose | 110% Starting Epoprostenol Dose |
| 7 | 0 | 110% Starting Epoprostenol Dose + additional 5-10% increments as needed |
Continuous subcutaneous infusion is the preferred mode. Use intravenous (IV) infusion if subcutaneous infusion is not tolerated. (
Remodulin can be administered with or without further dilution with Sterile Diluent for Remodulin or similar approved high-pH glycine diluent (e.g., Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1below for storage and administration time limits for the different diluents.
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).
| Diluent | Storage Limits | Administration Limits |
|---|---|---|
| None | See Section 16 | 16 weeks at 40°C |
| Sterile Diluents for Remodulin, Flolan, or Epoprostenol | 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 |
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 by subcutaneous or intravenous infusion at a calculated rate based on a patient's dose (ng/kg/min), weight (kg), and the Remodulin concentration (mg/mL).
For administration of
Undiluted Infusion Rate (mL/hour) | = | Dose (ng/kg/min) | × | Weight (kg) | × | 0.00006 Conversion factor of 0.00006 = 60 min/hour × 0.000001 mg/ng | |
Remodulin Vial Strength (mg/mL) | |||||||
For administration of
Diluted Remodulin Concentration (mg/mL) | Dose (ng/kg/min) | × | Weight (kg) | × | 0.00006 | ||
= | |||||||
Infusion Rate (mL/hour) | |||||||
The volume of Remodulin Injection needed to make the required diluted Remodulin concentration for the given reservoir size can then be calculated using the following formula:
Volume of Remodulin Injection (mL) | = | Diluted Remodulin Concentration (mg/mL) | × | 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.
Remodulin is administered subcutaneously by continuous infusion, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. The infusion pump should: (1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better, (4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Remodulin. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.
Remodulin 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 increases the risk of thrombophlebitis. The infusion pump used to administer Remodulin should: (1) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better, (3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Remodulin. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets.
Infusion sets with an in-line 0.22- or 0.2-micron pore size filter should be used.
Use an implantable intravenous infusion pump approved for use with Remodulin, such as the Implantable System for Remodulin®(ISR). Refer to the pump manufacturer's manual for specific instructions regarding preparation, programing, implantation, and refilling.
20-mL vial containing 2 mg treprostinil (0.1 mg per mL).
20-mL vial containing 4 mg treprostinil (0.2 mg per mL).
20-mL vial containing 8 mg treprostinil (0.4 mg per mL).
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).
20-mL vial containing 400 mg treprostinil (20 mg per mL).
Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated with pulmonary arterial hypertension
Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality.
Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous administration and with treprostinil diolamine administered orally. In pregnant rats, continuous subcutaneous infusions of treprostinil during organogenesis and late gestational development, at doses as high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous infusion rate, on a ng/m2basis and about 16 times the average rate achieved in clinical trials), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infusions of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous infusion rate, on a ng/m2basis, and 5 times the average rate used in clinical trials). In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at doses of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. In studies with orally administered treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development (teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose tested (20 mg/kg/day), which represents about 123 and 48 times the human exposure, when based on Cmaxand AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no adverse effects were seen (0.5 mg/kg/day) represents about 7 and 5 times the human exposure, when based on Cmaxand AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. No treprostinil treatment-related effects on labor and delivery were seen in animal studies. Animal reproduction studies are not always predictive of human response.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
None
- Chronic intravenous infusions delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. ()
5.1 Risk of Catheter-Related Bloodstream InfectionChronic intravenous infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous infusion is the preferred mode of administration.
In an open-label study of IV treprostinil (n=47) using an external infusion pump, there were seven catheter-related line infections during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined as any positive blood culture) event per 3 years of use. Administration of IV Remodulin with a high pH glycine diluent has been associated with a lower incidence of BSIs when compared to neutral diluents (sterile water, 0.9% sodium chloride) when used along with catheter care guidelines.
In an open-label study of an implantable pump (n=60), there were two blood stream infections (BSIs) related to the implant procedure during approximately 265 patient years.
- Do not abruptly lower the dose or withdraw dosing. ()
5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose ReductionAvoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.
- Remodulin may cause symptomatic hypotension. ()
5.4 Risk of Symptomatic HypotensionTreprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.
- Remodulin inhibits platelet aggregation and increases the risk of bleeding. ()
5.5 Risk of BleedingRemodulin inhibits platelet aggregation and increases the risk of bleeding.