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
`Initial U.S. Approval: May 2002
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`
`Dosage and Administration (2.1) 09/2013
`Warnings and Precautions (5.1) 09/2013
`
`----------------------------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 FORMS AND STRENGTHS----------------------
`
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg
`
`
`of treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). (3)
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`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.
`
`
`Remodulin should be used only by clinicians experienced in the
`diagnosis and treatment of PAH. (5.2)
`
`Adjust dosage based on clinical response, including infusion site
`symptoms. (5.3)
`
`
`Do not abruptly lower the dose or withdraw dosing. (5.4)
`
`
`
`------------------------------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, dizziness, edema, pruritus and
`hypotension. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`
`
`Therapeutics Corp. at 1-866-458-6479 or via e-mail at
`
`drugsafety@unither.com, 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.
`
`
`
`
`
`
`
`
`
`
`----------------------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 (or 0.625 ng/kg/min if not tolerated); dose 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). Abrupt cessation of
`infusion should be avoided. (2.2, 2.3)
`
` Mild to moderate hepatic insufficiency: Initial dose should be decreased
`
`to 0.625 ng/kg/min ideal body weight; cautious dosage increase.
`
`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. (2.7)
`
`
`Administration:
`
`
`Continuous subcutaneous infusion (undiluted) is the preferred mode. Use
`
`
`intravenous (IV) infusion (dilution required) if subcutaneous infusion is not
`
`tolerated. (2.1, 2.6)
`
`See Full Prescribing Information.
`
`_________________________________________________________________________________________________________________________
`
`
`Revised: 09/2013
`
`
`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 Patients with Renal Insufficiency
` 
`2.6 Administration
` 
`2.7 Patients Requiring Transition from Flolan
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
`4 CONTRAINDICATIONS
` 
`5 WARNINGS AND PRECAUTIONS
` 
`5.1 Risks Attributable to the Drug Delivery System
` 
`5.2 General Conditions of Use
` 
`5.3 Dose Modification
` 
`5.4 Abrupt Withdrawal or Sudden Large Dose Reduction
` 
`5.5 Patients with Hepatic or Renal Insufficiency
` 
`5.6 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
` 
`
`Reference ID: 3379327
`
`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.
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`REMODULIN® (treprostinil) Injection
`
`
`
`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), continuous intravenous infusion
`
`should be reserved for patients who are intolerant of the subcutaneous route, or in whom these
`risks are considered warranted [see Warnings and Precautions 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. The risks and
`benefits of each drug should be carefully considered prior to transition.
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 General
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of treprostinil (1 mg/mL,
`2.5 mg/mL, 5 mg/mL or 10 mg/mL). Remodulin can be administered as supplied or diluted for
`
`intravenous infusion with Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile
`Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium prior to administration.
`
`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, the infusion rate should be reduced to 0.625 ng/kg/min.
`
`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.
`Abrupt cessation of infusion should be avoided [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.
`
`
`Reference ID: 3379327
`
`
`
` Page 2 of 17
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
` 2.4 Patients with Hepatic Insufficiency
`
`In patients with mild or moderate hepatic insufficiency, the initial dose of Remodulin should be
`decreased to 0.625 ng/kg/min ideal body weight and should be increased cautiously. Remodulin
`has not been studied in patients with severe hepatic insufficiency [see Warnings and Precautions
`(5.5), Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`2.5 Patients with Renal Insufficiency
`No studies have been performed in patients with renal insufficiency. No specific advice about
`
`dosing in patients with renal impairment can be given.
`[see Clinical Pharmacology (12.3)].
`
`2.6 Administration
`Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration whenever solution and container permit. If either particulate matter or
`discoloration is noted, Remodulin should not be administered.
`
`Subcutaneous Infusion
`
`Remodulin is administered subcutaneously by continuous infusion, via a self-inserted
`subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To
`avoid potential interruptions in drug delivery, the patient must have immediate access to a backup
`infusion pump and subcutaneous infusion sets. The ambulatory infusion pump used to administer
`Remodulin should: (1) be small and lightweight, (2) be adjustable to approximately 0.002 mL/hr,
`(3) have occlusion/no delivery, low battery, programming error and motor malfunction alarms,
`(4) have delivery accuracy of ±6% or better and (5) be positive pressure driven. The reservoir
`should be made of polyvinyl chloride, polypropylene or glass.
`
`For subcutaneous infusion, Remodulin is delivered without further dilution at a calculated
`Subcutaneous Infusion Rate (mL/hr) based on a patients Dose (ng/kg/min), Weight (kg), and the
`Vial Strength (mg/mL) of Remodulin being used. During use, a single reservoir (syringe) of
`
`undiluted Remodulin can be administered up to 72 hours at 37C. The Subcutaneous Infusion
`rate is calculated using the following formula:
`
`
`
`Dose (ng/kg/min) x Weight (kg) x
`
`
`
`0.00006*
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`Remodulin Vial Strength (mg/mL)
`
`*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
`
`=
`
`
`
`
`Reference ID: 3379327
`
`
`
` Page 3 of 17
`
`

`

`1.25 ng/kg/min
`
`=
`
`x 0.00006
`
`
`
`= 0.005 mL/hr
`
`60 kg
`x
`
`1 mg/mL
`
`
`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`Example calculations for Subcutaneous Infusion are as follows:
`
`
`Example 1:
`
`For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/mL
`Remodulin Vial Strength, the infusion rate would be calculated as follows:
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`
`Example 2:
`
`For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin Vial
`Strength, the infusion rate would be calculated as follows:
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`40 ng/kg/min
`
`
`65 kg
`x
`
`5 mg/mL
`
`
`x 0.00006
`
`
`
`= 0.031 mL/hr
`
`
`
`
`
`Intravenous Infusion
`
`Remodulin must be diluted with either Sterile Water for Injection, 0.9% Sodium Chloride
`
`
`Injection, Sterile Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium and is
`administered intravenously by continuous infusion, via a surgically placed indwelling central
`venous catheter, using an infusion pump designed for intravenous drug delivery. If clinically
`necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be
`used for short term administration of Remodulin. Use of a peripheral intravenous infusion for
`more than a few hours may be associated with an increased risk of thrombophlebitis. To avoid
`potential interruptions in drug delivery, the patient must have immediate access to a backup
`infusion pump and infusion sets. The ambulatory infusion pump used to administer Remodulin
`
`should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery, programming
`error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better of the hourly
`dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl chloride,
`polypropylene or glass.
`
`Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.
`
`Diluted Remodulin has been shown to be stable at ambient temperature for up to 48 hours at
`concentrations as low as 0.004 mg/mL (4,000 ng/mL).
`
`
`When using an appropriate infusion pump and reservoir, a predetermined intravenous infusion
`rate should first be selected to allow for a desired infusion period length of up to 48 hours
`between system changeovers. Typical intravenous infusion system reservoirs have volumes of 50
`or 100 mL. With this selected Intravenous Infusion Rate (mL/hr) and the patient’s Dose
`
`(ng/kg/min) and Weight (kg), the Diluted Intravenous Remodulin Concentration (mg/mL) can be
`calculated using the following formula:
`
`Step 1
`
`
`
`Diluted
`Intravenous
`Remodulin
`
`=
`
`
`Dose
`(ng/kg/min)
`
`x
`
`
`Weight
`
`(kg)
`
`x
`
`0.00006
`
`Reference ID: 3379327
`
`
`
` Page 4 of 17
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`Concentration
`
`(mg/mL)
`
`Intravenous Infusion Rate
`
`(mL/hr)
`
`
`The Amount of Remodulin Injection needed to make the required Diluted Intravenous Remodulin
`Concentration for the given reservoir size can then be calculated using the following formula:
`
`
`Step 2
`
`
`
`Amount of
`Remodulin
`Injection
`
`(mL)
`
`=
`
`Diluted Intravenous
`
`Remodulin
`
`Concentration
`
`
`(mg/mL)
`Remodulin Vial
`Strength
`
`
`(mg/mL)
`
`
`x
`
`Total Volume of Diluted
`Remodulin Solution in
`Reservoir
`
`(mL)
`
`
`The calculated amount of Remodulin Injection is then added to the reservoir along with the
`sufficient volume of diluent (Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile
`Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium) to achieve the desired total volume
`in the reservoir.
`
` Example calculations for Intravenous Infusion are as follows:
`
`
`Example 3:
`
`For a 60 kg person at a dose of 5 ng/kg/min, with a predetermined intravenous infusion
`rate of 1 mL/hr and a reservoir of 50 mL, the Diluted Intravenous Remodulin Solution
`Concentration would be calculated as follows:
`
`Step 1
`
`
`
`Diluted
`Intravenous
`Remodulin
`Concentration
`
`(mg/mL)
`
`5 ng/kg/min
`
`=
`
`60 kg
`x
`
`
`1 mL/hr
`
`x 0.00006
`
`
`= 0.018
`mg/mL
`(18,000
`
`ng/mL)
`
`
`The Amount of Remodulin Injection (using 1 mg/mL Vial Strength) needed for a total
`Diluted Remodulin Concentration of 0.018 mg/mL and a total volume of 50 mL would be
`calculated as follows:
`
`
`Step 2
`
`
`
`
`Amount of
`Remodulin Injection
`
`(mL)
`
`=
`
`0.018 mg/mL
`1 mg/mL
`
`x 50 mL = 0.9 mL
`
`
`
`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:
`
`
`Reference ID: 3379327
`
`
`
` Page 5 of 17
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion
`rate of 2 mL/hr, and a reservoir of 100 mL, the Diluted Intravenous Remodulin Solution
`Concentration would be calculated as follows:
`
`Step 1
`
`
`
`=
`
`30 ng/kg/min x 75 kg x 0.00006 = 0.0675 mg/mL
`
`
`
`
`2 mL/hr
`
`(67,500 ng/mL)
`
`Diluted
`
`Intravenous
`
`Remodulin
`Concentration
`
`(mg/mL)
`
`
`The Amount of Remodulin Injection (using 2.5 mg/mL Vial Strength) needed for a total
`Diluted Remodulin Concentration of 0.0675 mg/mL and a total volume of 100 mL would
`be calculated as follows:
`
`Step 2
`
`
`
`
`Amount of
`
`Remodulin Injection
`
`(mL)
`
`=
`
`0.0675 mg/mL
`2.5 mg/mL
`
`x 100 mL = 2.7 mL
`
`
`
`
`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.
`
`
`2.7 Patients Requiring Transition from Flolan
`Transition from Flolan to Remodulin is accomplished by initiating the infusion of Remodulin and
`increasing it, while simultaneously reducing the dose of intravenous Flolan. The transition to
`Remodulin should take place in a hospital with constant observation of response (e.g., walk
`distance and signs and symptoms of disease progression). During the transition, Remodulin is
`initiated at a recommended dose of 10% of the current Flolan dose, and then escalated as the
`Flolan dose is decreased (see Table 1 for recommended dose titrations).
`
`
`Patients are individually titrated to a dose that allows transition from Flolan therapy to Remodulin
`while balancing prostacyclin-limiting adverse events. Increases in the patient’s symptoms of PAH
`should be first treated with increases in the dose of Remodulin. Side effects normally associated
`with prostacyclin and prostacyclin analogs are to be first treated by decreasing the dose of Flolan.
`
`
`
`Table 1: Recommended Transition Dose Changes
`
`Flolan Dose
`Remodulin Dose
`
`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
`
`Step
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Reference ID: 3379327
`
`
`
` Page 6 of 17
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`7
`
`
`
`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 Risks Attributable to the Drug Delivery System
`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 such as Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol
`Sodium 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 General Conditions of Use
`Remodulin should be used only by clinicians experienced in the diagnosis and treatment of PAH.
`
`Remodulin is a potent pulmonary and systemic vasodilator. Initiation of Remodulin must be
`performed in a setting with adequate personnel and equipment for physiological monitoring and
`emergency care. Therapy with Remodulin may be used for prolonged periods, and the patient’s
`ability to administer Remodulin and care for an infusion system should be carefully considered.
`
`5.3 Dose Modification
`Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be
`
`decreased for excessive pharmacologic effects or for unacceptable infusion site symptoms [see
`Dosage and Administration (2)].
`
`
`
`5.4 Abrupt Withdrawal or Sudden Large Dose Reduction
`Abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of
`PAH symptoms and should be avoided.
`
`
`5.5 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
`
`Reference ID: 3379327
`
`
`
` Page 7 of 17
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`
`
` function [see Dosage and Administration (2.4, 2.5), Use In Specific Populations (8.6, 8.7), and
`Clinical Pharmacology (12.3)].
`
`5.6 Effect of Other Drugs on Treprostinil
`Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may
` increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme
`
`inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to
`increase adverse events associated with treprostinil administration, whereas decreased exposure
`is likely to reduce clinical effectiveness [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)].
`
`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 2: Percentages of subjects reporting subcutaneous infusion site adverse events
`
`Reaction
`Pain
`Placebo
`Remodulin
`Remodulin
`Severe
`38
`39
`1
`NA†
`NA†
`Requiring narcotics*
`32
` Leading to discontinuation
`
`3
`7
`0
`* 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 Events during Chronic Dosing
`
`Table 3 lists adverse events that occurred at a rate of at least 3% and were more frequent in
`patients treated with subcutaneous Remodulin than with placebo in controlled trials in PAH.
`
`
`Reference ID: 3379327
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`Table 3: Adverse Events in Controlled 12-Week Studies of Patients with PAH, Occurring
`
`with at Least 3% Incidence and More Common on Subcutaneous Remodulin than on
`Placebo.
`
`Remodulin
`(N=236)
`Percent of Patients
`85
`83
`27
`25
`22
`14
`13
`11
`9
`9
`8
`4
`
`Placebo
`(N=233)
`Percent of Patients
`27
`27
`23
`16
`18
`11
`5
`5
`8
`3
`6
`2
`
`Adverse Event
`
`Infusion Site Pain
`Infusion Site Reaction
`Headache
`Diarrhea
`Nausea
`Rash
`Jaw Pain
`Vasodilatation
`Dizziness
`Edema
`Pruritus
`Hypotension
`
`
`Reported adverse events (at least 3%) 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.
`
`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 due to a combination of their seriousness, frequency of reporting, and
`potential connection to Remodulin. These events are thrombophlebitis associated with peripheral
`
`Reference ID: 3379327
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`intravenous infusion, thrombocytopenia and bone pain. 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.
`
`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 with Flolan or Tracleer® (bosentan).
`
`7.7 Effect of Other Drugs on Treprostinil
`Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co­
`administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day),
`respectively in healthy volunteers. These studies did not show a clinically significant effect on the
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`Reference ID: 3379327
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`pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or
`pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the INR in
`healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous
`subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.
`
`
`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).