`
`
`
`
`
`
`
`
`•
`
`•
`
`•
`
`
`
`
`
`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)
`
`
`Remodulin may cause symptomatic hypotension. (5.4)
`
`
`Remodulin inhibits platelet aggregation and increases the risk of
`
`
`bleeding. (5.5)
`
`
`------------------------------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------------------------------­
`
`Remodulin dosage adjustment may be necessary if inhibitors or inducers
`
`
`
`•
`of CYP2C8 are added or withdrawn. (7.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`
` 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
`
`----------------------------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)
`
`
`
`
`Transition from Flolan:
`
`
`
`
`Increase the Remodulin dose gradually as the Flolan dose is decreased, based
`
`
`on constant observation of response. (2.6)
`
`
`Revised: 06/2018
`
`
`_________________________________________________________________________________________________________________________
`
`
`
`
`7.1 Effect of CYP2C8 Inhibitors and Inducers on Treprostinil
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`8 USE IN SPECIFIC POPULATIONS
`1 INDICATIONS AND USAGE
`
`
`
`8.1 Pregnancy
`1.1 Pulmonary Arterial Hypertension
`
`
`8.2 Labor and Delivery
`1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from
`
`
`
`8.3 Nursing Mothers
`Flolan®
`
`
`8.4 Pediatric Use
`2 DOSAGE AND ADMINISTRATION
`
`
`8.5 Geriatric Use
`
`2.1 General
`
`
`8.6 Patients with Hepatic Insufficiency
`
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`
`
`8.7 Patients with Renal Impairment
`
`2.3 Dosage Adjustments
`10 OVERDOSAGE
`
`2.4 Patients with Hepatic Insufficiency
`
`11 DESCRIPTION
`
`2.5 Administration
`
`12 CLINICAL PHARMACOLOGY
`
`
`2.6 Patients Requiring Transition from Flolan
`
`3 DOSAGE FORMS AND STRENGTHS
`
`12.1 Mechanism of Action
`
`4 CONTRAINDICATIONS
`
`12.2 Pharmacodynamics
`
`5 WARNINGS AND PRECAUTIONS
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`5.1 Risk of Catheter-Related Bloodstream Infection
`
`
`5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`Reduction
`
`
`
`
`5.3 Patients with Hepatic or Renal Insufficiency
`
`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`
`
`5.4 Risk of Symptomatic Hypotension
`
`14.2 Flolan-To-Remodulin Transition Study
`
`16 HOW SUPPLIED / STORAGE AND HANDLING
`
`
`5.5 Risk of Bleeding
`
`6 ADVERSE REACTIONS
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Post-Marketing Experience
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`7 DRUG INTERACTIONS
`
`listed.
`
`_________________________________________________________________________________________________________________________
`
`Reference ID: 4274798
`
`

`

`
`
`
`
` 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 PAH 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
`
`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
`
`
`
`
`
`
`
`
` Storage Limits
` See section 16
`
` 14 days at room
`
` temperature
`
`
`
`
`
` Administration
` Limits
`
`
`
` 72 hours at 37°C
`
`
` 48 hours at 40°C
`
`
`
`
`
` 48 hours at 40°C
`
`
`
`
`
`
` Route
`
` SC
`
` IV
`
`
`
` Diluent
`
`
`
` None
`
`
` Sterile Diluent for Remodulin
`
` 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
`
`
`
`
`
`
`
`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: 4274798
`
`
`
`

`

`
`
`
`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
`
`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*
`
`
`
`
`
`
`
`Reference ID: 4274798
`
`

`

`
`
`
`
`
`
`
`
` 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
`Infusion Rate =
`
`
`(mL/hr)
`
`
`
`
` 1.25 ng/kg/min
`
`
` 60 kg
` x
`
`
` 1 mg/mL
`
`
`
` 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)
`
`
`
` x 0.00006
`
`
`
`
`
` = 0.031 mL/hr
`
`
`
` 40 ng/kg/min
`
`
` 65 kg
` x
`
`
` 5 mg/mL
`
`
`
`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:
`
`
`
`
`Reference ID: 4274798
`
`
`
`

`

`
`
`
`
` Step 1
`
`
` Diluted
`
`
`Intravenous
`Remodulin
`Concentration
`
`
` (mg/mL)
`
`Dose
`
`(ng/kg/min)
`
`x
`
`
`=
`
`
`x
`
`
`
`
`
`Weight
`
`(kg)
` Intravenous Infusion Rate
`
` (mL/hr)
`
`
`0.00006
`
`
`
`
`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
`
`
`
`
`
`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:
`
`
`
`
`
`
`
`=
`
`
` 60 kg
` 5 ng/kg/min x
`
`
`
` 1 mL/hr
`
`
`
` x 0.00006
`
`
`
`
` = 0.018 mg/mL
`
` (18,000 ng/mL)
`
`
`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 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
`
`
`
`
`
`
`
`Reference ID: 4274798
`
`
`
`
`
` 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
`
`
`
`
`
` 30 ng/kg/min
`
`
`
`
`=
`
` x 75 kg x 0.00006
`
`
`
` 2 mL/hr
`
`
`
`
`
`
` = 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:
`
`
`
`
`
` Diluted
`
` Intravenous
`
`Remodulin
`Concentration
`
`
` (mg/mL)
`
`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.
`
`
`Reference ID: 4274798
`
`
`
`

`

`
`
`
`
`
`
`
`
` Table 2: Recommended Transition Dose Changes
`
`
`
`
`
` Step
`
`1
`
`
`
`2
`
`
`3
`
`
`4
`
`
`5
`
`
`6
`
`
`7
`
`
`
`
`
` Flolan Dose
`
`Unchanged
`
`
`
`80% Starting Flolan Dose
`
`
`60% Starting Flolan Dose
`
`
`40% Starting Flolan Dose
`
`
`20% Starting Flolan Dose
`
`
`5% Starting Flolan Dose
`
`
`
` Remodulin Dose
`
`10% Starting Flolan Dose
`
`
`
`
`30% Starting Flolan Dose
`
`
`50% Starting Flolan Dose
`
`
`70% Starting Flolan Dose
`
`
`90% 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).
`
`
`
`
`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.
`
`
`Reference ID: 4274798
`
`
`
`

`

`
`
`
`
` 5.3 Patients with Hepatic or Renal Insufficiency
`
`
`
` Titrate Remodulin 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), Use In Specific Populations (8.6, 8.7),
`
`
`
` and Clinical Pharmacology (12.3)].
`
`
`
` 5.4 Risk of Symptomatic Hypotension
`
`
`
`
`
`
`
` Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial
` pressure, treatment with Remodulin may produce symptomatic hypotension.
`
`
`
`
`
`
`
`
` 5.5 Risk of Bleeding
` Remodulin inhibits platelet aggregation and increases the risk of bleeding.
`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
` The following adverse reactions are discussed elsewhere in labeling: Infections associated with
`
`
`
` intravenous administration [see Warnings and Precautions (5.1)].
`
`
` 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
`
`
`
`
` Reaction
` Pain
`
` Remodulin
` Remodulin
`
` Placebo
` Severe
`
`
`
` 39
`
` 1
` 38
`
` Requiring narcotics*
`
` NA†
`
` 32
`
` NA†
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
`
` 2
`
` 1
`
` 0
`
`Reference ID: 4274798
`
`
`
`

`

`
`
`
`
`
`
`
`
` Adverse Reactions during Chronic Dosing
`
`
`
`
`
`
`
` Table 4 lists adverse reactions that occurred at 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
`
`
` Remodulin
`
` (N=236)
` Percent of Patients
`
` 85
`
`
` 83
`
` 27
`
` 25
`
` 22
`
` 14
`
` 13
`
` 11
`
` 9
`
` Adverse Reaction
`
` Infusion Site Pain
` Infusion Site Reaction
`
`
` Headache
`
` Diarrhea
`
` Nausea
`
` Rash
` Jaw Pain
`
` Vasodilatation
`
` Edema
`
`
`
`
`
`
` Placebo
`
` (N=233)
` Percent of Patients
`
` 27
`
`
` 27
`
` 23
`
` 16
`
` 18
`
` 11
`
` 5
`
` 5
`
` 3
`
`
`Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included with
`
`
`
`
`
`the exception of 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.
`
`
`
`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 versus
`
`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
`
`
`
`Reference ID: 4274798
`
`
`
`

`

`
`
`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, dizziness, arthralgia,
`
`
`
`myalgia/muscle spasm, and pain in extremity. In addition, generalized rashes, sometimes macular
`
`
`
`or papular in nature, and cellulitis have been infrequently reported.
`
`
`7 DRUG INTERACTIONS
`
`7.1 Effect of CYP2C8 Inhibitors and Inducers on Treprostinil
`
`
`
`
`
`Dose adjustment of treprostinil may be necessary when co-administered with CYP2C8 inducers
`
`
`or inhibitors. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil
`
`
`diolamine) 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 changes in exposure of treprostinil with inhibitors or inducers of CYP2C8 observed for the
`
`
`
`
`
`
`oral administration of treprostinil would be similar for treprostinil administered via the parenteral
`
`
`
`
`route. [see Clinical Pharmacology (12.3)]
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category B - In pregnant rats, continuous subcutaneous infusions of treprostinil during
`
`
`
`
`
`organogenesis and late gestational development, at rates as high as 900 ng treprostinil/kg/min
`
`(about 117 times the starting human rate of infusion, on a ng/m2 basis 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 an infusion rate of 150 ng treprostinil/kg/min (about 41 times the starting human
`
`
`rate of infusion, on a ng/m2 basis, 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 rates
`
`
`of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring.
`
`
`Animal reproduction studies are not always predictive of human response.
`
`
`
`8.2 Labor and Delivery
`
`
`
`No treprostinil treatment-related effects on labor and delivery were seen in animal studies. The
`
`
`
`effect of treprostinil sodium on labor and delivery in humans is unknown.
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`It is not known whether treprostinil is excreted in human milk or absorbed systemically after
`
`
`ingestion. Many drugs are excreted in human milk.
`
`
`Reference ID: 4274798
`
`
`
`

`

`
`
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established. Clinical studies of
`
`
`
`
`
`Remodulin did not include sufficient numbers of patients aged ≤16 years to determine whether
`
`
`they respond differently from older patients.
`
`
`8.5 Geriatric Use
`
`Clinical studies of Remodulin did not include sufficient numbers of patients aged 65 and over to
`
`
`determine whether they respond differently from younger patients. In general, dose selection for
`
`
`an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal,
`
`or cardiac function, and of concomitant disease or other drug therapy.
`
`
`
`
`8.6 Patients with Hepatic Insufficiency
`
`
`
`Remodulin clearance is reduced in 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, and monitor closely. Remodulin has not been studied in patients with severe hepatic
`
`
`
`insufficiency [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and
`
`
`
`
`Clinical Pharmacology (12.3)].
`
`
`
`8.7 Patients with Renal Impairment
`
`
`
`No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by
`
`
`
`
`
`
`dialysis [see Clinical Pharmacology (12.3)].
`
`
`
`
`10 OVERDOSAGE
`
`Signs and symptoms of overdose with Remodulin during clinical trials are extensions of its
`
`
`dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea,
`
`
`vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or
`
`
`
`withholding of Remodulin.
`
`
`In controlled clinical trials, seven patients received some level of overdose and in open-label
`
`
`
`follow-on treatment seven additional patients received an overdose; these occurrences resulted
`
`
`
`
`
`from accidental bolus administration of Remodulin, errors in pump programmed rate of
`
`
`
`
`administration, and prescription of an incorrect dose. In only two cases did excess delivery of
`
`
`Remodulin produce an event of substantial hemodynamic concern (hypotension, near-syncope).
`
`
`
`
`
`One pediatric patient was accidentally administered 7.5 mg of Remodulin via a central venous
`
`catheter. Sy