`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` REMODULIN safely and effectively. See full prescribing information for
`
` REMODULIN.
`
` REMODULIN® (treprostinil) Injection, for subcutaneous or intravenous
`
`use
`
`Initial U.S. Approval: May 2002
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`
`
`Dosage and Administration (2.1, 2.5)
`12/2014
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`
`
`Remodulin is a prostacyclin vasodilator 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)
`Patients who require transition from Flolan®, to reduce the rate of
`
`clinical deterioration. The risks and benefits of each drug should be
`
`
`
`
`
`carefully considered prior to transition. (1.2)
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`PAH in patients with NYHA Class II-IV symptoms:
`
`
`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, 2.3)
`
`
`
`
`• Mild to moderate hepatic insufficiency: Decrease initial dose to 0.625
`
`
`ng/kg/min.
`
`Severe hepatic insufficiency: No studies performed. (2.4)
`
`
`Administration:
`
`
`
`Continuous subcutaneous infusion (undiluted) is the preferred mode. Use
`
`
`
`
`intravenous (IV) infusion (dilution required) if subcutaneous infusion is not
`
`
`tolerated. (2.1, 2.5)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`
`
`
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg
`
`•
`
`
`
`
`of treprostinil (1, 2.5, 5 or 10 mg/mL). (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`None
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`
`For intravenous infusion use an indwelling central venous catheter. This
`
`•
`
`
`
`
`route is associated with the risk of blood stream infections (BSIs) and
`
`
`sepsis, which may be fatal. (5.1)
`
`
`Do not abruptly lower the dose or withdraw dosing. (5.2)
`
`•
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`
`Most common adverse reactions (incidence >3%) reported in clinical studies
`
`
`
`with Remodulin: subcutaneous infusion site pain and reaction, headache,
`
`
`
`
`diarrhea, nausea, jaw pain, vasodilatation, edema, and hypotension. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`
`
`
`
`Therapeutics Corp. at 1-866-458-6479 or contact FDA at 1-800-FDA-1088
`
`or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`
`
`Blood pressure lowering drugs (e.g., diuretics, antihypertensive agents,
`
`•
`
`
`
`or vasodilators): Risk of increased reduction in blood pressure (7.1)
`
`
`Remodulin inhibits platelet aggregation. Potential for increased risk of
`
`
`
`bleeding, particularly among patients on anticoagulants. (7.2)
`
`
`Remodulin dosage adjustment may be necessary if inhibitors or inducers
`
`
`of CYP2C8 are added or withdrawn. (7.6)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`Revised: 12/2014
`
`
`
`Transition from Flolan:
`
`
`
`
`Increase the Remodulin dose gradually as the Flolan dose is decreased, based
`
`
`on constant observation of response. (2.6)
`
`_________________________________________________________________________________________________________________________
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1. INDICATIONS AND USAGE
`
`
`1.1 Pulmonary Arterial Hypertension
`
`
`
`1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from
`Flolan®
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General
`
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`
`2.3 Dosage Adjustments
`
`2.4 Patients with Hepatic Insufficiency
`
`2.5 Administration
`
`
`2.6 Patients Requiring Transition from Flolan
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Catheter-Related Bloodstream Infection
`
`
`
`5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose
`
`
`
`Reduction
`
`5.3 Patients with Hepatic or Renal Insufficiency
`
`
`
`5.4 Effect of Other Drugs on Treprostinil
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Post-Marketing Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Antihypertensive Agents or Other Vasodilators
`
`
`7.2 Anticoagulants
`
`
`7.3 Bosentan
`
`7.4 Sildenafil
`
`7.5 Effect of Treprostinil on Cytochrome P450 Enzymes
`
`7.6 Effect of Cytochrome P450 Inhibitors and Inducers on Treprostinil
`
`
`7.7 Effect of Other Drugs on Treprostinil
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Patients with Hepatic Insufficiency
`
`8.7 Patients with Renal Insufficiency
`
`
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`
`14.2 Flolan-To-Remodulin Transition Study
`
`16 HOW SUPPLIED / STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`_________________________________________________________________________________________________________________________
`
`Reference ID: 3677009
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
` 1. INDICATIONS AND USAGE
`
`
`
`
`
`
`
` 1.1 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 (14.1)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 are
`
`
`
`
`
`
`
`
`
`
` considered warranted [see Warnings and Precautions 5.1].
`
`
`
`
` 1.2 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.
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 General
`
`
` Storage limits
`
` See section 16
`
` 14 days at room
`
`
`
` temperature
`
`
`
` Administration limits
`
`
`
` 72 hours at 37°C
`
` 48 hours at 40 °C
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
` SC
`
`
` None
`
`
` Sterile Diluent for Remodulin
`
` IV
`
`
` Sterile Diluent for Flolan
`
`
` Sterile Diluent for Epoprostenol Sodium
`
` Sterile water for injection
`
`
`
` 0.9% Sodium Chloride for injection
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4 hours at room
` temperature or
`
`
` 24 hours
` refrigerated
`
`
`
`
`
`
`
`
` 48 hours at 40°C
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`
` 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 (5.4)]. 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 (5.5), 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
`
`Infusion Rate
`
`(mL/hr)
`
`Remodulin Vial Strength (mg/mL)
`
`
`
`
`
`*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
`
`Dose (ng/kg/min) x Weight (kg) x
`
`
`
`
`
`0.00006*
`
`
`=
`
`
`
`Example calculations for Subcutaneous Infusion are as follows:
`
`
`
`
`
`
`
`
`
`Example 1:
`
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`1.25 ng/kg/min
`
`
`
`=
`
`60 kg
`x
`
`
`1 mg/mL
`
`
`
`
`
`
`
`
`
` 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)
`
`
`
`
` x 0.00006
`
`
`
`
`= 0.005 mL/hr
`
`
`
`
`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
`
`
`Infusion Rate
`(mL/hr)
`
`
`
`=
`
`40 ng/kg/min
`
`
`65 kg
`x
`
`
`5 mg/mL
`
`
`
` x 0.00006
`
`
`
`
`
`
` = 0.031 mL/hr
`
`
`
`
`
`Intravenous Infusion
`
`
`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:
`
`
`Step 1
`
`
`
`
`Diluted
`
`Intravenous
`
`
`Remodulin
`Concentration
`
`
`(mg/mL)
`
`Dose
`
`(ng/kg/min)
`
`=
`
`
`x
`
`
`
`0.00006
`
`
`
`
`x Weight
`
`
`(kg)
` 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:
`
`
`
`
`
`
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`
`
` Step 2
`
`
`
`
`Volume of
`
`Remodulin
`
`Injection
`
`(mL)
`
`
`=
`
`
`Diluted Intravenous
`
`
`Remodulin
`
`Concentration
`
`
`(mg/mL)
`
` Remodulin Vial
`
` Strength
`
`
`(mg/mL)
`
`
`
`
` x
`
`Total Volume of Diluted
`
`Remodulin Solution in
`
`Reservoir
`
`
`(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:
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`5 ng/kg/min
`
`
`
`=
`
`60 kg
`x
`
`
`
`1 mL/hr
`
` x 0.00006
`
`
`
`
`= 0.018
`
` mg/mL
`(18,000
`
`ng/mL)
`
` Diluted
`
`
`Intravenous
`
`
` Remodulin
`
`Concentration
`
`
` (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
`
`
`
`
`Volume 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.
`
`
`
`
`
`
`
`
`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
`
`
`(67,500 ng/mL)
`
`Reference ID: 3677009
`
`
`
`

`

`
`
` Remodulin
`
`
`Concentration
`
`
`
` (mg/mL)
`
`2 mL/hr
`
`
`
`
`
`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
`
`
`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.
`
`
`
`
`
`
`
`
`
`2.6 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.
`
`
`
`
`
`
`
`
`
`
`
`Step
`
`
`Table 2: Recommended Transition Dose Changes
`
`
`
`Flolan Dose
`Remodulin Dose
`
`
`
`
`1
`
`
`2
`
`
`3
`
`
`4
`
`
`5
`
`
`6
`
`
`7
`
`
`
`
`Unchanged
`
`
`10% Starting Flolan Dose
`
`
`
`80% Starting Flolan Dose
`
`
`
`30% Starting Flolan Dose
`
`
`
`60% Starting Flolan Dose
`
`
`
`50% Starting Flolan Dose
`
`
`
`40% Starting Flolan Dose
`
`
`
`70% Starting Flolan Dose
`
`
`
`20% Starting Flolan Dose
`
`
`
`90% Starting Flolan Dose
`
`
`
`5% Starting Flolan Dose
`
`
`
`110% Starting Flolan Dose
`
`
`
`0
`
`
`110% Starting Flolan Dose + additional 5-10%
`
`
`
`
`
` increments as needed
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`20-mL vial containing 20 mg treprostinil (1 mg per mL).
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`
`
`
`
`
`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).
`
`
`
`4 CONTRAINDICATIONS
`
`
`None
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Risk of Catheter-Related Bloodstream Infection
`
`
`
`
`
`
`
`Chronic intravenous infusions of Remodulin are delivered using an indwelling central venous
`
`
`
`
`
`
`
`
`
`
`
`
`catheter. This route is associated with the risk of blood stream infections (BSIs) and sepsis, which
`
`
`
`
`
`
`
`
`may be fatal. Therefore, continuous subcutaneous infusion (undiluted) is the preferred mode of
`
`administration.
`
`
`
`
`
`
`
`
`In an open-label study of IV treprostinil (n=47), 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.
`
`
`
`
`
`
`
`
`
`5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in
`
`
`
`worsening of PAH symptoms.
`
`
`
`
`
`5.3 Patients with Hepatic or Renal Insufficiency
`
`
`
`
`
`
`
`
`
`
`Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be
`
`
`
`
`
`
`
`
`exposed to greater systemic concentrations relative to patients with normal hepatic or renal
`
`function [see Dosage and Administration (2.4, 2.5), Use In Specific Populations (8.6, 8.7), and
`
`
`
`Clinical Pharmacology (12.3)].
`
`
`
`
`
`5.4 Effect of Other Drugs on Treprostinil
`
`
`
`
`
`
`
`Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) increases
`exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer
`
`
`
`
`
`
`(e.g., rifampin) decreases exposure to treprostinil [see Drug Interactions (7.5) and Clinical
`
`
`
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`The following adverse reactions are discussed elsewhere in labeling: Infections associated with
`
`
`
`
`
`intravenous administration [see Warnings and Precautions (5.1)].
`
`
`
`
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
` observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`
`
`
`
`
`
`
` another drug and may not reflect the rates observed in practice.
`
`
`
`
`
`
`
`
` Adverse Events with Subcutaneously Administered Remodulin
`
`
`
`
`
` Patients receiving Remodulin as a subcutaneous infusion reported a wide range of adverse
`
` events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right
`
`
`
`
`
`
` ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of
`
`
`
`
`
`
`
`
`
` Remodulin, infusion site pain and reaction were the most common adverse events among those
`
`
` treated with Remodulin. Infusion site reaction was defined as any local adverse event other than
`
`
`
`
`
`
`
`
`
` pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration
`
`
`
`
`
`
` or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of
`
`
`
`
`
`
`
`
` treatment.
`
`
`
`Table 3: Percentages of subjects reporting subcutaneous infusion site adverse events
`
`
`
`
`
`
` Pain
`
`
`
` Reaction
`
` Remodulin
` Remodulin
`
` Placebo
` Severe
`
`
`
` 39
`
` 1
` 38
`
` NA†
`
` NA†
` Requiring narcotics*
`
`
` 32
` Leading to discontinuation
`
`
`
`
` 0
` 3
` 7
`
`
`
`
` * based on prescriptions for narcotics, not actual use
`
`
`
` † medications used to treat infusion site pain were not distinguished from those used to
`
`
`
`
` treat site reactions
`
`
`
`
`
`
`
`
` Placebo
`
` 2
`
` 1
`
` 0
`
`
`
`
`
`
`Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these
`
`
`
`
`
`
`
`are generally considered to be related to the pharmacologic effects of Remodulin, whether
`
`
`
`
`
`
`
`
`
`administered subcutaneously or intravenously.
`
`
`
`
`Adverse Reactions during Chronic Dosing
`
`
`
`
`Table 4 lists adverse reactions defined by a rate of at least 3% more frequent in patients treated
`
`
`
`
`
`
`
`
`
`
`
`with subcutaneous Remodulin than with placebo in controlled trials in PAH.
`
`
`
`
`
`
`
`Table 4: Adverse Reactions in Controlled 12-Week Studies of Subcutaneous Remodulin
`
`
`
`
`
`and at least 3% more frequent than on Placebo.
`
`
` Placebo
`
`
` Remodulin
` Adverse Reaction
`
` (N=233)
`
` (N=236)
` Percent of Patients
` Percent of Patients
`
`
` 85
` 27
`
` 83
`
` 27
`
` 27
`
` 23
`
` 25
`
` 16
`
` 22
`
` 18
`
` 14
`
` 11
`
` 13
`
` 5
`
` 11
`
` 5
`
` 9
`
` 3
`
`
`
`
`
` Infusion Site Pain
`
` Infusion Site Reaction
`
`
` Headache
`
` Diarrhea
`
` Nausea
`
` Rash
` Jaw Pain
`
`
` Vasodilatation
`
` Edema
`
`
`Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included
`
`
`
`
`
`
`
`except those too general to be informative, and those not plausibly attributable to the use of the
`
`
`
`
`
`
`
`
`
`drug, because they were associated with the condition being treated or are very common in the
`
`
`
`
`
`
`
`treated population.
`
`
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`While hypotension occurred in both groups, the event was experienced twice as frequently in the
`
`
`
`
`
`Remodulin group as compared to the placebo group (4% in Remodulin treatment group verses
`
`
`
`
`
`
`
`2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the
`
`
`administration of Remodulin.
`
`
`
`
`
`
`
`
`
`The safety of Remodulin was also studied in a long-term, open-label extension study in which 860
`
`
`
`
`
`
`
`
`
`patients were dosed for a mean duration of 1.6 years, with a maximum exposure of 4.6 years.
`
`
`
`
`
`
`
`
`
`Twenty-nine (29%) percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min). The
`
`
`
`
`
`
`
`
`
`safety profile during this chronic dosing study was similar to that observed in the 12-week placebo
`
`
`
`
`
`
`
`controlled study except for the following suspected adverse drug reactions (occurring in at least
`
`
`
`
`
`
`
`
`
`
`3% of patients): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.
`
`
`
`
`
`Adverse Events Attributable to the Drug Delivery System
`
`
`
`
`
`
`
`In controlled studies of Remodulin administered subcutaneously, there were no reports of
`
`
`
`
`
`
`
`infection related to the drug delivery system. There were 187 infusion system complications
`
`
`
`
`
`
`
`
`
`
`
`reported in 28% of patients (23% Remodulin, 33% placebo); 173 (93%) were pump related and
`
`
`
`
`
`
`
`
`
`
`14 (7%) related to the infusion set. Eight of these patients (4 Remodulin, 4 Placebo) reported
`
`
`
`
`
`
`non-serious adverse events resulting from infusion system complications. Adverse events
`
`
`
`
`
`
`
`
`
`resulting from problems with the delivery systems were typically related to either symptoms of
`
`
`
`
`
`
`
`
`
`
`excess Remodulin (e.g., nausea) or return of PAH symptoms (e.g., dyspnea). These events were
`
`
`
`
`
`
`
`
`
`generally resolved by correcting the delivery system pump or infusion set problem such as
`
`
`
`
`
`replacing the syringe or battery, reprogramming the pump, or straightening a crimped infusion
`line. Adverse events resulting from problems with the delivery system did not lead to clinical
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`instability or rapid deterioration. In addition to these adverse events due to the drug delivery
`
`
`
`
`
`
`system during subcutaneous administration, the following adverse events may be attributable to
`
`
`
`
`
`
`the IV mode of infusion including arm swelling, paresthesias, hematoma and pain [see Warnings
`
`
`and Precautions (5.1)].
`
`
`
`6.2 Post-Marketing Experience
`
`
`
`
`
`
`
`
`
`In addition to adverse reactions reported from clinical trials, the following events have been
`
`
`
`
`
`
`
`identified during post-approval use of Remodulin. Because they are reported voluntarily from a
`
`
`
`
`
`
`
`
`population of unknown size, estimates of frequency cannot be made. The following events have
`
`
`
`
`
`
`
`
`
`
`been chosen for inclusion because of a combination of their seriousness, frequency of reporting,
`
`
`
`
`and potential connection to Remodulin. These events are thrombophlebitis associated with
`
`
`
`
`
`
`peripheral intravenous infusion, thrombocytopenia bone pain, pruritus and dizziness. In addition,
`
`
`
`
`
`
`
`
`
`
`generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently
`
`reported.
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`Pharmacokinetic/pharmacodynamic interaction studies have been conducted with treprostinil
`
`
`
`
`
`
`administered subcutaneously (Remodulin) and orally (treprostinil diethanolamine).
`
`
`Pharmacodynamics
`
`
`
`
`7.1 Antihypertensive Agents or Other Vasodilators
`
`
`
`
`
`
`
`
`
`Concomitant administration of Remodulin with diuretics, antihypertensive agents or other
`
`
`
`
`
`
`
`vasodilators may increase the risk of symptomatic hypotension.
`
`
`Reference ID: 3677009
`
`
`
`

`

`
`
`
`7.2 Anticoagulants
`
`
`
`
`
`
`
`
`
`
`
`
`Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding,
`
`
`
`
`particularly among patients receiving anticoagulants.
`
`
`Pharmacokinetics
`
`
`7.3 Bosentan
`
`
`
`
`
`
`In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral
`
`
`
`
`
`
`formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between
`
`
`treprostinil and bosentan were observed.
`
`
`7.4 Sildenafil
`
`
`
`
`
`
`In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation
`
`
`
`
`
`
`
`of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between treprostinil
`
`
`and sildenafil were observed.
`
`
`
`
`
`7.5 Effect of Treprostinil on Cytochrome P450 Enzymes
`
`
`
`
`
`
`
`
`
`
`
`
`In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome
`
`
`
`
`
`
`
`
`
`
`P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1
`
`
`
`
`
`
`
`and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2,
`
`
`
`
`
`
`
`
`
`CYP2B6, CYP2C9, CYP2C19, and CYP3A. Thus Remodulin is not expected to alter the
`
`
`
`
`
`
`pharmacokinetics of compounds metabolized by CYP enzymes.
`
`
`
`
`7.6 Effect of Cytochrome P450 Inhibitors and Inducers on Treprostinil
`
`
`
`
`
`
`
`
`Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil
`
`
`
`
`
`diethanolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme
`
`
`
`
`
`inhibitor gemfibrozil increases exposure (both Cmax and AUC) to treprostinil. Co-administration of
`
`
`
`
`
`
`
`
`the CYP2C8 enzyme inducer rifampin decreases exposure to treprostinil. It has not been
`
`
`
`
`
`
`
`
`
`determined if the safety and efficacy of treprostinil by the parenteral (subcutaneously or
`
`
`
`
`
`
`
`intravenously) route are altered by inhibitors or inducers of CYP2C8 [see Warnings and
`
`Precautions (5.6)].
`
`
`Remodulin has not been studied in conjunction