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 sodium) Injection
`Initial U.S. Approval: May 2002
`
`•
`
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`DOSAGE AND ADMINISTRATION, General (2.1)
`9/2008
`
`DOSAGE AND ADMINISTRATION, Administration (2.6)
`9/2008
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Remodulin is a prostacyclin vasodilator indicated for:
`
`•
`
`Treatment of pulmonary arterial hypertension (PAH) in patients with
`NYHA Class II-IV symptoms, to diminish symptoms associated with
`exercise (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 in concentrations of 1 mg/mL,
`
`
`2.5 mg/mL, 5 mg/mL and 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. (5.1)
`
`
`
`• 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)
`
`• Remodulin inhibits platelet aggregation. Potential for increased risk of
`
`
`bleeding, particularly among patients on anticoagulants. (7)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: [9/2008]
`
`
`
`
`
`
`
`
`
`----------------------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). Limited experience
`with doses >40 ng/kg/min. 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:
`
`
`Recommended initial Remodulin dose is 10% of the current Flolan dose.
`
`
`Individualized dosage increase as Flolan dose is decreased, based on constant
`
`observation of response. (2.7)
`
`
`Administration:
`
`
`Continuous subcutaneous infusion (undiluted). Intravenous infusion (dilution
`
`required) if subcutaneous infusion is not tolerated. (2.1, 2.6)
`
`
`
`Complete dosing, dilution and administration instructions: See Full
`
`Prescribing Information.
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`INDICATIONS AND USAGE
`
`1.1 Pulmonary Arterial Hypertension in Patients With NYHA Class II­
`IV Symptoms
`
`
`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
`In 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 Hepatic And Renal Insufficiency Impairment
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Post-Marketing Experience
`
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`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
`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 sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`FULL PRESCRIBING INFORMATION
`
`
`
`REMODULIN® (treprostinil sodium) Injection
`
`
`1 INDICATIONS AND USAGE
`
`1.1 Pulmonary Arterial Hypertension In Patients With NYHA Class II-IV Symptoms
`
`Remodulin is indicated for the treatment of pulmonary arterial hypertension in patients with NYHA
`Class II-IV symptoms [see CLINICAL STUDIES (14.1)] to diminish symptoms associated with
`
`exercise. It may be administered as a continuous subcutaneous infusion or continuous
`intravenous infusion; however, because of the risks associated with chronic indwelling central
`
`venous catheters, including serious blood stream infections, continuous intravenous infusion
`should be reserved for patients who are intolerant of the subcutaneous route, or in whom these
`risks are considered warranted.
`
`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 in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL and
`
`10 mg/mL. Remodulin can be administered as supplied or diluted for intravenous infusion with
`
`Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Flolan® Sterile Diluent for Injection
`
`
`
`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.
`There is little experience with doses >40 ng/kg/min. 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.
`
`
`
`
` Page 2 of 16
`
`

`

`
`
` REMODULIN® (treprostinil sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`
`
` 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
`
`=
`
`
`
`
`
`
`
` Page 3 of 16
`
`

`

`1.25 ng/kg/min
`
`=
`
`x 0.00006
`
`
`
`= 0.005 mL/hr
`
`60 kg
`x
`
`1 mg/mL
`
`
`
`
` REMODULIN® (treprostinil sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`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, or Flolan® Sterile Diluent for Injection 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.
`
`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
`Concentration
`
`(mg/mL)
`
`
`
`Dose
`(ng/kg/min)
`
`=
`
`
`
`x
`
`x
`
`0.00006
`
`
`Weight
`
`(kg)
`Intravenous Infusion Rate
`
`
`(mL/hr)
`
`
`
` Page 4 of 16
`
`

`

`REMODULIN® (treprostinil sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`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, or Flolan®
`
`Sterile Diluent for Injection) 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:
`
`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:
`
`
`
` Page 5 of 16
`
`

`

`
`
` REMODULIN® (treprostinil sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`
`Step 1
`
`
`
`Diluted
`
`Intravenous
`
`Remodulin
`Concentration
`
`(mg/mL)
`
`=
`
`30 ng/kg/min x 75 kg x 0.00006
`
`
`
`
`2 mL/hr
`
`= 0.0675 mg/mL
`
`(67,500 ng/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 14 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 14: 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
`
`0
`
`110% Starting Flolan Dose + additional 5-10%
`increments as needed
`
`Step
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`
`
` Page 6 of 16
`
`

`

`
`
` REMODULIN® (treprostinil sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`20-mL vial containing treprostinil sodium equivalent to 1 mg treprostinil per mL.
`20-mL vial containing treprostinil sodium equivalent to 2.5 mg treprostinil per mL.
`20-mL vial containing treprostinil sodium equivalent to 5 mg treprostinil per mL.
`20-mL vial containing treprostinil sodium equivalent to 10 mg treprostinil 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.
`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.
`
`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 Hepatic and Renal Insufficiency
`
`
`Caution should be used in patients with hepatic or renal insufficiency [see DOSAGE AND
`ADMINISTRATION (2.4) and (2.5), USE IN SPECIFIC POPULATIONS (8.6) and (8.7), and
`
`CLINICAL PHARMACOLOGY (12.3)].
`
`6 ADVERSE REACTIONS
`
`
`
`
`
` Page 7 of 16
`
`

`

`REMODULIN® (treprostinil sodium) Injection Package Insert
`
`
`
`
`September 2008
`
`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.
`
`
`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
`
`Adverse Event
`
`Infusion Site Pain
`Infusion Site Reaction
`Headache
`Diarrhea
`Nausea
`Rash
`Jaw Pain
`Vasodilatation
`Dizziness
`Edema
`Pruritus
`Hypotension
`
`Placebo
`(N=233)
`Percent of Patients
`27
`27
`23
`16
`18
`11
`5
`5
`8
`3
`6
`2
`
`
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` REMODULIN® (treprostinil sodium) Injection Package Insert
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`September 2008
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`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.
`
`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: Adverse Events Attributable To The Drug Delivery System,
`(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
`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
`
`Reduction in blood pressure caused by Remodulin may be exacerbated by drugs that by
`themselves alter blood pressure, such as diuretics, antihypertensive agents, or vasodilators.
`Since Remodulin inhibits platelet aggregation, there is also a potential for increased risk of
`bleeding, particularly among patients maintained on anticoagulants. During clinical trials,
`Remodulin was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium
`channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids,
`corticosteroids, and other medications.
`
`Remodulin has not been studied in conjunction with Flolan or Tracleer® (bosentan).
`
`Effect Of Other Drugs On Remodulin
`
`
`In vivo studies: Acetaminophen - Analgesic doses of acetaminophen, 1000 mg every 6 hours for
`
`seven doses, did not affect the pharmacokinetics of Remodulin, at a subcutaneous infusion rate
`of 15 ng/kg/min.
`
`Effect Of Remodulin On Other Drugs
`
`
`In vitro studies: Remodulin did not significantly affect the plasma protein binding of normally
`
`observed concentrations of digoxin or warfarin.
`
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` REMODULIN® (treprostinil sodium) Injection Package Insert
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`September 2008
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`In vivo studies: Warfarin - Remodulin 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 Remodulin 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
`sodium 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. Because animal reproduction studies are not always predictive of human response,
`
`Remodulin should be used during pregnancy only if clearly needed.
`
`8.2 Labor And Delivery
`
`
`No treprostinil sodium 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. Because many drugs are excreted in human milk, caution should be exercised when
`
`Remodulin is administered to nursing women.
`
`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. In general, dose selection should be cautious.
`
`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, 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, DOSAGE AND ADMINISTRATION (2.4),
`WARNINGS AND PRECAUTIONS (5.5) and CLINICAL PHARMACOLOGY (12.3)].
`
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` REMODULIN® (treprostinil sodium) Injection Package Insert
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`September 2008
`
`8.7 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)].
`
`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. Symptoms included flushing, headache, nausea, vomiting, hypotension and seizure-like
`activity with loss of consciousness lasting several minutes. The patient subsequently recovered.
`
`11 DESCRIPTION
`
`Remodulin (treprostinil sodium) Injection is a sterile sodium salt formulated for subcutaneous or
`intravenous administration. Remodulin is supplied in 20 mL multi-use vials in four strengths,
`containing 1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL of treprostinil. Each mL also contains 5.3
`mg sodium chloride (except for the 10 mg/mL strength which contains 4.0 mg sodium chloride),
`3.0 mg metacresol, 6.3 mg sodium citrate, and water for injection. Sodium hydroxide and
`
`hydrochloric acid may be added to adjust pH between 6.0 and 7.2.
`
`Treprostinil is chemically stable at room temperature and neutral pH.
`
`Treprostinil sodium is (1R,2R,3aS,9aS)-[[2,3,3a,4,9,