PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 21 SPECIAL HANDLING INSTRUCTIONS 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION 23

PHARMACEUTICAL INFORMATION 23 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 28 TOXICOLOGY 29 REFERENCES 36

PART III: CONSUMER INFORMATION. 37

REMODULIN(r)

(treprostinil sodium) Injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Remodulin is contraindicated in patients with known hypersensitivity to the drug, any of its excipients, or to structurally related compounds. For a complete listing of Remodulin excipients, see the Dosage Forms, Composition and Packaging section of the product monograph.

WARNINGS AND PRECAUTIONS

General

Remodulin is a potent pulmonary and systemic vasodilator. Remodulin is indicated for subcutaneous or intravenous use only. Remodulin should be used only by clinicians experienced in the diagnosis and treatment of PAH. Initiation of Remodulin must be performed in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Remodulin is infused continuously through a subcutaneous or surgically placed indwelling central venous catheter. In order to reduce the risk of infection, aseptic technique must be used in the preparation and administration of Remodulin. Dosage adjustments in clinical trials were based on the patient's signs and symptoms of PAH and side effects of Remodulin. Dosage of Remodulin should be adjusted at the first sign of recurrence or worsening of symptoms attributable to PAH or the occurrence of intolerable adverse events associated with Remodulin. (See DOSAGE and ADMINISTRATION.) The decision to initiate therapy with Remodulin should be based on the understanding that there is a high likelihood that subcutaneous or intravenous therapy with Remodulin will be needed for prolonged periods, possibly years, and the patient's ability to administer Remodulin and care for an infusion system should be carefully considered. As with any potent vasodilator, abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of PAH symptoms. Abrupt withdrawal of Remodulin should be avoided if at all possible. Although in clinical trials, no patient death from discontinuation of Remodulin was judged directly attributable to the interruption of the drug, 2 of 11 patients who abruptly discontinued subcutaneous Remodulin therapy died within 24 hours. Although their death may have been related to their deteriorating clinical condition, it seems most appropriate to wean patients from Remodulin. Only 3 of 55 (5%) patients with abrupt disruption of Remodulin developed increased symptoms of PAH, and no patients developed hemodynamic instability. In addition, among patients who discontinued Remodulin abruptly, no relationship has been established between abrupt discontinuation and rebound pulmonary hypertension.

DRUG INTERACTIONS

Overview

Additional reductions in blood pressure may occur when Remodulin is administered with diuretics, antihypertensive agents, or other vasodilators. When antiplatelet agents or anticoagulants are used concomitantly with Remodulin there is the potential for increased risk of bleeding due to the antiplatelet effect of Remodulin. However, patients receiving Remodulin in clinical trials were maintained on anticoagulants without evidence of increased bleeding. Treprostinil investigated in healthy volunteers had no effect in vivo on warfarin pharmacodynamics as measured by the effect on INR. Treprostinil also had no effect on pharmacokinetics of either the R- or S-enantiomer of warfarin. No untoward clinical manifestations have been observed in patients in whom Remodulin was used concurrently with the following classes of drugs: Anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti- inflammatory drugs, opioids and corticosteroids. Interaction potential with alcohol has not been established.

Effect of Treprostinil on Cytochrome P450 Isoenzymes:

Results from an in vitro study in human hepatic microsomes demonstrated that treprostinil does not significantly inhibit the following P450 isoforms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

Drug-Drug Interactions

The effects of large daily doses of acetaminophen (4 g/day) on the pharmacokinetics of treprostinil were investigated in healthy volunteers. Acetaminophen did not have any clinically important effects on the pharmacokinetics of treprostinil. Treprostinil did not significantly affect the plasma protein binding of digoxin or warfarin when evaluated in human plasma at physiologic concentrations. Modest interaction was observed between treprostinil and furosemide. Remodulin dose reduction in patients receiving furosemide is not recommended, although patients should be monitored for excess adverse effects of Remodulin.

Drug-Food Interactions

As Remodulin is administered parenterally, interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Patients with hepatic impairment (See Recommended Dose and Dosage Adjustment).

Recommended Dose and Dosage Adjustment

Remodulin is supplied in 20 mL multi-use vials in concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, and 10.0 mg/mL. Remodulin can be administered as supplied or diluted for intravenous infusion with 0.9% Sodium Chloride Injection or Sterile Water for Injection at concentrations as low as 0.004 mg/mL prior to administration.

Initial Dose:

Remodulin is administered by continuous subcutaneous or intravenous infusion. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated, the infusion rate should be reduced to 0.625 ng/kg/min.

Dosage Adjustments:

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while achieving an acceptable side effect profile. The infusion rate should be adjusted based on PAH signs and symptoms and Remodulin side effects. Dose-related symptoms may necessitate a decrease in infusion rate; however, the event may resolve without dosage adjustment. Should an adverse event worsen and/or become intolerable, the infusion rate should be reduced, or infusion should be discontinued.

Dosage in Patients with Hepatic Impairment:

Remodulin should be increased more conservatively in patients with hepatic dysfunction, and these patients should be closely monitored for signs and symptoms or emergence of adverse events due to excess Remodulin. No experience is available in patients with severe hepatic impairment.

Missed Dose

As with any potent vasodilator, abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of PAH symptoms. Abrupt withdrawal of Remodulin should be avoided if at all possible. Although in clinical trials, no patient death from discontinuation of Remodulin was judged directly attributable to the interruption of the drug, 2 of 11 patients who abruptly discontinued Remodulin therapy died within 24 hours. Although their death may have been related to their deteriorating clinical condition, it seems most appropriate to wean patients from Remodulin. Only 3 of 55 (5%) patients with abrupt disruption of Remodulin developed increased symptoms of PAH, and no patients developed hemodynamic instability. In addition, among patients who discontinued Remodulin abruptly, no relationship has been established between abrupt discontinuation and rebound pulmonary hypertension. 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.

Administration

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 should have 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 able to adjust infusion rates in 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 37degC. The Subcutaneous Infusion rate is calculated using the following formula:

Subcutaneous Infusion Rate

Dose

(ng/kg/min) x

=

Weight

(kg) x 0.00006 *

Remodulin Vial Strength

(mg/mL) *Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng 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)

x 60 x 0.00006

ng/kg/min

kg

mg/mL

= 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 Vial Strength, the infusion rate would be calculated as follows:

Subcutaneous Infusion Rate =

(mL/hr)

x 65 x 0.00006

ng/kg/min

kg

mg/mL

= 0.031

mL/hr

Intravenous Infusion: Diluted Remodulin is administered intravenously by continuous infusion, via a surgically placed indwelling central venous catheter, using an infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of Remodulin. Use of a peripheral intravenous infusion for more than a few hours may be associated with an increased risk of thrombophlebitis. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. The ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of +-6% or better of the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene or glass. The infusion set should also contain 0.2 mm in-line filter and an anti-siphon valve. 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 with 0.9% Sodium Chloride Injection or Sterile Water for Injection as the diluent. Intravenous ad-mixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, discoloration, or leakage should not be used. Discard unused portion. 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 changes. 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:

Diluted Intravenous

Dose

(ng/kg/min) x

Weight

(kg) x 0.00006

Remodulin

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:

Amount of Remodulin Injection

(mL)

Diluted Intravenous Remodulin Concentration

= (mg/mL) x

Remodulin Vial Strength

(mg/mL)

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 (0.9% Sodium Chloride Injection or Sterile Water 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:

Diluted Intravenous Remodulin Concentration

(mg/mL)

5 ng/kg/min x 60 kg x 0.00006

= 1 = 0.018

mL/hr

mg/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:

Amount of Remodulin Injection

=

(mL)

mg/mL

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:

Diluted Intravenous Remodulin Concentration

(mg/mL)

30 ng/kg/min x 75 kg x 0.00006

= 2 = 0.0675

mL/hr

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:

Amount of Remodulin Injection

=

(mL)

mg/mL

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.

OVERDOSAGE

Signs and symptoms of overdose with Remodulin(r) 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 chronic, 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 incorrect dose. The amount of excess Remodulin actually administered varied in each patient. Three placebo patients in controlled clinical trials were inadvertently administered Remodulin with doses initiated at 8.5, 10 and 15 ng/kg/min, respectively. Six patients received excess Remodulin due to incorrect pump settings (excess doses ranged from two to forty-six times their prescribed dose). The remaining five patients received excess Remodulin as a result of accidental bolus administration while in the process of changing syringes or tubing. Typical symptoms elicited were expected pharmacologic effects and included flushing, headache, hypotension, nausea, vomiting and diarrhea. The symptoms resolved with reduction of Remodulin dose or withholding Remodulin for a short time. In only two cases did excess delivery of Remodulin produce an event of substantial hemodynamic concern (hypotension, near-syncope). No deaths occurred as a result of overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Treprostinil is a tricyclic benzindene analogue of prostacyclin (PGI2). The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of treprostinil on heart rate in animals varies with dose. No major effects on cardiac conduction have been observed.

Pharmacodynamics

Clinical Trials in Pulmonary Arterial Hypertension (PAH)

Hemodynamic Effects: Acute infusion of Remodulin at 10 ng/kg/min intravenously for 75 minutes followed by a 10 ng/kg/min infusion subcutaneously for 150 minutes, in patients with primary pulmonary hypertension produced increases in cardiac index (CI) and mixed venous oxygen saturation (SvO2), and decreases in mean pulmonary arterial pressure (PAPm), mean right atrial pressure (RAPm) and pulmonary vascular resistance indexed (PVRI), with little effect on mean systemic arterial pressure (SAPm), or heart rate (HR). Chronic continuous, subcutaneous infusion of Remodulin in NYHA Class II, III, or IV patients with PAH was studied in two identical, 12-week, double-blind, placebo- controlled, multicenter, parallel-group, randomized trials comparing Remodulin plus conventional therapy to conventional therapy alone. Dosage of Remodulin averaged 9.3 ng/kg/min at Week 12. The hemodynamic effects from the two placebo-controlled studies are shown in Table 3. The hemodynamic effects after chronic therapy with Remodulin were generally consistent with the pharmacological effects seen acutely. There were statistically significant increases in CI and SvO2, and statistically significant decreases in PAPm, RAPm, PVRI, and SVRI in patients treated with Remodulin for 12 weeks compared to patients treated with placebo. Heart rate and SAPm were unchanged. In patients with pulmonary hypertension, elevated RAPm and PAPm, and reduced CO and SvO2 are predictive of mortality.

Table 3

Hemodynamics During Chronic Subcutaneous Administration of Subcutaneous Remodulin in Patients with PAH

*Denotes statistically significant difference between Remodulin and placebo, p<0.0005.

CI = cardiac index; PAPm = mean pulmonary arterial pressure; PVRI = pulmonary vascular pressure indexed; RAPm = mean right atrial pressure, SAPm = mean systemic arterial pressure; SVRI = systemic vascular resistance indexed; SvO2 = mixed venous oxygen saturation, HR = heart rate.

Pharmacokinetics

Table 4 provides data from a randomized, two-period, cross-over study of Remodulin in normal volunteers. In this study, subcutaneous and intravenous administration of Remodulin (10 ng/kg/min) for 72 hours demonstrated bioequivalence at steady-state, between 48 and 72 hours.

Table 4

Summary of Pharmacokinetic Parameters of Treprostinil

Steady-state (ss) comparisons were made based on extensive plasma sampling between 48 and 72 hours.

In a [14C] treprostinil mass balance and metabolic fate study in healthy volunteers, 78.6% and 13.4% of the subcutaneous radioactive dose were recovered in the urine and feces, respectively, over a period of 224 hours. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% of the dose administered. These five metabolites accounted for a combined total of 64.4%. Three metabolites are products of oxidation of the 3-hydroxyloctyl side chain, one is glucuronide conjugate (treprostinil glucuronide) and one is unidentified. Only 3.7% of the dose was recovered in the urine as unchanged parent drug. In a chronic pharmacokinetic study in normal volunteers with chronic subcutaneous Remodulin doses ranging from 2.5 to 15 ng/kg/min, steady-state plasma treprostinil concentrations achieved peak levels twice (at 1 a.m. and 10 a.m., respectively) and achieved trough levels twice (at 7 a.m. and 4 p.m., respectively). The peak concentrations were ~20% to 30% higher than trough concentrations. Dose adjustments are not deemed to be necessary due to diurnal variation.

Absorption:

Remodulin is rapidly and completely absorbed after subcutaneous infusion, with an absolute bioavailability approximating 100%. Steady-state concentrations occurred in approximately 10 hours. Concentrations in patients treated with an average dose of 9.3 ng/kg/min were approximately 2 ug/L.

Distribution:

The volume of distribution of the drug in the central compartment is approximately 14L/70 kg ideal body weight. Remodulin at in vitro concentrations ranging from 330-10,000 ug/L was 91% bound to human plasma protein.

Metabolism:

Remodulin is substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five metabolites have been described (HU1 through HU5). The biological activity and metabolic fate of these metabolites are unknown. The chemical structure of HU1 is unknown. HU5 is the glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3) or dehydration (HU4). Based on the results of in vitro human hepatic cytochrome P450 studies, Remodulin does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether Remodulin induces these enzymes has not been studied.

Excretion:

The elimination of Remodulin is biphasic, with a terminal half-life of approximately 4 hours. Approximately 79% of an administered dose is excreted in the urine as unchanged drug (4%) and as the identified metabolites (64%). Approximately 13% of a dose is excreted in the feces. Systemic clearance is approximately 30 L/h for a 70 kg ideal body weight person.

Special Populations and Conditions

Hepatic Insufficiency:

(See WARNINGS and PRECAUTIONS, Hepatic/Biliary/Pancreatic)

Renal Insufficiency:

(See WARNINGS and PRECAUTIONS, Renal)

STORAGE AND STABILITY

Remodulin should be stored at room temperature at 15deg to 30degC. Remodulin Injection should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. A single vial of Remodulin should be used for no more than 30 days after the initial puncture of the rubber stopper. During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 37degC. Diluted Remodulin Solution can be administered up to 48 hours at 37degC when diluted to concentrations as low as 0.004 mg/mL in Sterile Water for Injection or 0.9% Sodium Chloride Injection. Intravenous ad-mixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, discoloration, or leakage should not be used. Discard unused portion.

SPECIAL HANDLING INSTRUCTIONS

Avoid contact with skin or eyes. For skin contact, wash affected area immediately with soap and water and contact physician. For eye contact, flush eyes immediately with large amounts of water and contact physician.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Remodulin(r) (treprostinil sodium) Injection is supplied in 20 mL multi-use vials at concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, and 10.0 mg/mL of treprostinil for subcutaneous or intravenous use. Each mL of Remodulin Injection, 1.0 mg/mL, contains 1.0 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 5.3 mg sodium chloride, 3.0 mg metacresol, 0.24 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH. Each mL of Remodulin Injection, 2.5 mg/mL, contains 2.5 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 5.3 mg sodium chloride, 3.0 mg metacresol, 0.32 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH. Each mL of Remodulin Injection, 5.0 mg/mL, contains 5.0 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 5.3 mg sodium chloride, 3.0 mg metacresol, 0.62 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH. Each mL of Remodulin Injection, 10.0 mg/mL, contains 10.0 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 4.0 mg sodium chloride, 3.0 mg metacresol, 1.2 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Treprostinil (treprostinil sodium, the soluble sodium salt of treprostinil, is formed during the finished product manufacturing process) Chemical name: [[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1- [(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (IUPAC) Molecular formula and molecular mass: C23H34O5 390.52 Structural formula:

OH H

7 8 9 9a 1

2 OH

6 5 4 3a 3

H OCH2CO2H Physicochemical properties: Description: White to cream-colored powder, practically insoluble in water and low pH buffers. pKa: 4.5 (aqueous titration with 20% ethanol as co- solvent). Partition Coefficient: Distribution coefficient of treprostinil in various buffer solutions at various pHs indicates distribution into octanol layers at all pHs (2-10). Melting Range: NLT 120.0degC and NMT 126.0degC

CLINICAL TRIALS

Study Demographics and Trial Design

Table 5

Summary of Patient Demographics for Study P01:04/05 in Patients with PAH

PAH = Pulmonary Arterial Hypertension

Two 12-week, multicenter, randomized, double-blind studies compared continuous subcutaneous infusion of Remodulin(r) (treprostinil sodium) to placebo in a total of 470 patients with NYHA Class II-IV pulmonary arterial hypertension (PAH). PAH was primary in 58% of patients, associated with collagen vascular disease in 19%, and the result of congenital left to right shunts in 23%. The mean age was 45 (range 9 to 75 years). About 81% were female and 84% were Caucasian. Pulmonary arterial hypertension had been diagnosed for a mean of 3.8 years. The primary endpoint of the studies was change in 6-minute walking distance, a standard measure of exercise capacity. There were many assessments of symptoms related to heart failure, but local discomfort and pain associated with subcutaneous Remodulin may have substantially unblinded those assessments. The 6-minute walking distance and an associated subjective measurement of shortness of breath during the walk (Borg dyspnea score) were administered by a person not participating in other aspects of the study. Remodulin was administered as a subcutaneous infusion, and the dose averaged 9.3 ng/kg/min at Week 12. Few subjects received doses > 40 ng/kg/min. Background therapy, determined by the investigators, could include anticoagulants, oral vasodilators, diuretics, digoxin, and oxygen but not an endothelin receptor antagonist or epoprostenol.

Study Results

Table 6

Results of Study P01:04/05 in Patients with PAH

Clinical Effects:

As the two 12-week studies were identical in design and conducted simultaneously, results were analyzed both pooled and individually. Exercise capacity, as measured by the Six-Minute Walk Test, improved significantly in Class II, III, and IV patients receiving continuous subcutaneous Remodulin plus conventional therapy (N=232) for 12 weeks, with a median increase of 10 meters in this group compared to those receiving conventional therapy plus placebo (N=236) (p=0.0064). Table 6 specifies the improvements in Six-Minute Walk distance at Week 12 for Remodulin patients with NYHA Class III and IV PAH, for which Remodulin is indicated. Improvements, although not statistically significant, were apparent as early as Week 6 of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Dyspnea-Fatigue Rating and Borg Scale. Signs and symptoms of PAH also improved, as did the Physical Dimension component of a Quality of Life Scale. Remodulin was shown to be effective for the treatment of PAH, either primary (PPH), or secondary to the scleroderma spectrum of diseases or associated with congenital systemic-to-pulmonary shunts (repaired or unrepaired), in NYHA Class III and IV patients who did not respond adequately to conventional therapy.

Hemodynamic Effects: As shown previously in Table 3, and the ACTION and CLINICAL PHARMACOLOGY, Pharmacodynamics Section, hemodynamic effects after chronic subcutaneous therapy with Remodulin were generally consistent with the pharmacological effects seen acutely. There were statistically significant increases in CI and SvO2, and statistically significant decreases in PAPm, RAPm, PVRI, and SVRI in patients treated with Remodulin for 12 weeks compared to patients treated with placebo. Heart rate and SAPm were unchanged. In patients with pulmonary hypertension, elevated RAPm and PAPm, and reduced CO and SvO2 are predictive of mortality.

Comparative Bioavailability Studies

Study REM01:14 was a randomized, open-label, two-period crossover bioequivalence study comparing intravenous versus subcutaneous administration of Remodulin in healthy adult volunteers. The objective of the study was to demonstrate steady-state bioequivalence. Subjects were to receive 72 hours of Remodulin infusion (10 ng/kg/min) by both the intravenous and subcutaneous routes for pharmacokinetic comparisons. Steady-state comparisons were made based on extensive plasma sampling between 48 and 72 hours, for each respective route of administration. A total of 55 adult volunteers (60% male, mean age 36.2 years mean body weight was 73.9 kg) received study drug and were included in the safety population for the study. Fifty-one volunteers received at least 24 hours of Remodulin infusion by both routes and were included in the primary pharmacokinetic analyses. The primary analysis results are shown in Tables 7 and 8.

Table 7

Summary of Primary Steady State Pharmacokinetic Parameters (n=51)

1 Point Estimate (90% Confidence Interval)

The 90% confidence intervals for the ratios of adjusted geometric means (IV/SC) are well within the bioequivalence boundaries (confidence intervals between 80% - 125%) for both AUCss and Cmaxss. Therefore, intravenous and subcutaneous Remodulin are bioequivalent at steady state. Other pharmacokinetic assessments included AUC0-96h, AUCinf, Cmax, observed time to maximal plasma concentration (Tmax), apparent plasma clearance (CL), apparent volume of distribution (Vz), elimination rate constant of the terminal disposition phase (lz), and elimination half-life (T1/2). As shown in Table 9, these parameters were comparable between the two routes of administration. Of note, the apparent mean elimination half- life following cessation of IV infusion of Remodulin was 4.4 hours compared to 4.6 hours for SC.

Table 8

Summary of Pharmacokinetic Parameters Related to the Full Profile

IV Infusion (N=51)

SC Infusion (N=51)

DETAILED PHARMACOLOGY

Pharmacodynamics

Treprostinil is a tricyclic benzindene analogue of prostacyclin (PGI2, epoprostenol) with potent systemic and pulmonary vasodilatory and platelet antiaggregatory effects when studied in vitro and in vivo, and without limiting cardiac effects. Treprostinil (1-1000 nM) produces concentration-dependent relaxation of isolated rabbit precontracted mesenteric arteries and is approximately 45 times more potent than PGE2. In anesthetized rats, treprostinil produces dose-dependent decreases in mean arterial blood pressure when administered by the subcutaneous (29-60 mmHg at 25-100 mg/kg/min), or oral (35 and 55 mmHg at 1 and 5 mg/kg) routes, respectively. In anesthetized rats, intravenous treprostinil is approximately 10 times less potent than PGI2. In anesthetized rabbits, treprostinil and PGI2 (140 and 200 ng/kg/min, i.v. respectively) decrease mean arterial blood pressure 10 and 16 mmHg, respectively. In anesthetized closed-chest cats, treprostinil (3-30 mg/kg/min, i.v., 20 min each dose) produces dose-dependent decreases in diastolic blood pressure (22-74 mmHg). Maximum hypotension occurs within 5 minutes and returns to baseline within 40 minutes upon terminating the infusion. In anesthetized open-chest cats, treprostinil (0.1-3.0 mg/kg/min, i.v. 20 min each dose) produces dose-dependent decreases in mean systemic arterial and mean pulmonary arterial blood pressure with little effect on heart rate. At 0.3 to 3.0 mg/kg/min, treprostinil produces dose-dependent reductions in hypoxia-induced increments in pulmonary arterial blood pressure and pulmonary vascular resistance. Treprostinil is approximately 3 to 10 times less potent than PGI2 as a vasodilator under hypoxic and normoxic conditions. In anesthetized newborn piglets, treprostinil (6 and 12 mg/kg, i.v. bolus) abolished hypoxia-induced increases in pulmonary vascular resistance. In anesthetized dogs, intravenous boluses (0.32-3.2 mg/kg) or infusions (0.1-1.0 mg/kg/min for 10 min) of treprostinil produce dose-dependent decreases in blood pressure. Four-hour intravenous infusions of treprostinil (0.1-3.0 mg/ kg/min) produce dose-dependent decreases in mean systemic arterial and mean pulmonary arterial blood pressures mediated through decreases in vascular resistance in these circulatory beds. The vascular effects of treprostinil are rapid in onset achieving maximum effect within 5- 10 minutes with equally rapid recovery upon termination of the infusions. Treprostinil produces equivalent effects to those of PGI2 on the systemic and pulmonary vascular beds yet is approximately 10 times less potent than PGI2. Treprostinil and PGI2 treatment-related cardiac effects include modest decreases in inotropy and lusitropy and modest increases in heart rate. ECG changes observed in the dog were inconsistent (occurring predominantly post-infusion) and considered not to be related to treprostinil. The cardiac effects are not major, are not dose dependent, are not sustained throughout treatment, and are interpreted to be generally secondary to the prominent vascular effect and not due to a direct effect on the myocardium. Treprostinil treatment is associated with dose-dependent increases in plasma angiotensin II concentration, which correlate with the decreases in mean arterial blood pressure. Pretreatment of animals with enalapril blocks, digoxin attenuates, and furosemide potentiates the treprostinil treatment-related increases in plasma angiotensin II concentration without significantly affecting the hemodynamic profile of treprostinil. In conscious dogs, infusions of treprostinil (0.3-3 mg/kg/min, i.v. 10 minutes each) produce dose-related decreases in systolic (18-40 mmHg) and diastolic (13-45 mmHg) arterial blood pressures accompanied by small increases in heart rate (13-30 bpm). There were no adverse effects of treprostinil in autonomic, respiratory, gastrointestinal, uterine motility, inflammatory, or platelet aggregation secondary pharmacologic evaluations.

Pharmacokinetics

In a series of 13- and 26-week toxicological/toxicokinetic studies in rats and dogs, treprostinil was delivered to the systemic circulation when administered by continuous subcutaneous or intravenous infusion, and relatively linear kinetics were obtained with increasing doses. Linear kinetics were also observed in reproductive studies in rats and rabbits.

In vitro

binding of labeled-treprostinil in human plasma was 91.0%, with the compound having no significant effect on the plasma protein binding of digoxin or warfarin.

Tissue distribution studies in rats with tritium or carbon-labeled treprostinil indicated that radioactivity was widely distributed into tissues and was preferentially distributed to organs of the central compartment, including the stomach and intestinal tract. Metabolic studies in rats and humans indicated that less than 5% of treprostinil was eliminated unchanged. Five metabolites were identified by LC/MS in human urine with no single metabolite exceeding 15% of the dose. Balance/excretion studies of labeled-treprostinil in rats and dogs showed that the dose was found in the feces (65-80%) and urine (13-26%). In contrast, human volunteers excreted 13.4% and 78.6% of the dose in feces and urine, respectively. The reason for this difference is not known, but biliary excretion/enterohepatic recirculation may be significant in animals. Treprostinil showed no inhibitory potential toward cytochrome P450 isozymes when tested in vitro.

TOXICOLOGY

The preclinical toxicology of treprostinil has been extensively evaluated in a series of in vitro and in vivo genetic toxicology studies, reproductive toxicology studies in rats and rabbits, and single and repeated dose toxicity studies in mice, rats and dogs.

Acute Toxicity Studies

Treprostinil has low oral and intravenous acute toxicity in mice and rats (Table 9).

Table 9

Incidence of Death in Acute Toxicity Studies

MLD = Minimum lethal dose *Median lethal dose

In acute subcutaneous toxicity studies in rats and dogs, the maximum dose that did not produce adverse clinical signs was approximately 400 and 500 ng/kg/min, respectively. In the rat, slight ataxia occurred at approximately 490 ng/kg/min and reversed during the infusion period.

Long-term Toxicity Studies

In repeated dose toxicity studies, treprostinil was well tolerated in rats and dogs when given continuously by subcutaneous infusion for up to 6 months or intravenous infusion for up to 3 months. In dogs, dose-limiting toxicity characterized by gastrointestinal changes (emesis, loose stools, intestinal intussusception, hypoactivity, rectal prolapse) contributing to moribundity and death was observed at doses of $300 ng/kg/min. This spectrum of gastrointestinal changes has not been observed in the clinical studies. In both rats and dogs given treprostinil doses up to 450 ng/kg/min and 200 ng/kg/min, respectively, treprostinil-related toxicity was limited to reversible, dose-related reactions at the infusion site and included lumps, masses/nodules, swellings, erythema and/or intermittent pain (dogs only). Microscopic evaluation demonstrated these areas to have local inflammation (abscess or cellulitis), edema, fibrosis or hemorrhage. Although these changes were also observed in saline control animals, the higher incidence and greater severity in the vehicle control and treated groups suggested that these reactions were related to pump implantation, catheterization technique, and/or irritability of the vehicle that was enhanced when administered in combination with treprostinil. In rats given treprostinil in repeated dose toxicity studies, other treatment-related findings have included reversible redness of extremities (due to the vasodilatory pharmacological activity of treprostinil) observed at all doses and minimal, reversible increases in mean white blood cell counts, total bilirubin and splenic weights (no histological correlation) observed at 450 ng/kg/min. In dogs, there were minimal, transient and reversible decreases in body weight and food consumption, and reversible increases in mean white blood cell counts.

Table 10

Long-term Toxicity Studies Continuous Subcutaneous (s.c.)

-

or Intravenous (i.v.) Infusion

Table 10 (continued)

Long-term Toxicity Studies Continuous Subcutaneous (s.c.)

-

or Intravenous (i.v.) Infusion

S-D = Sprague-Dawley *Saline.

Mutagenicity

Treprostinil is not mutagenic or clastogenic in in vitro and in vivo genetic toxicological assays (Table 11).

Table 11

In Vivo and In Vitro Mutagenicity Studies

Reproduction and Teratology

Treprostinil had no effect on adult reproduction, conceptus, early development and growth in rats given up to 450 ng/kg/min by continuous subcutaneous infusion. Administration of treprostinil by continuous subcutaneous infusion during major organogenesis was not teratogenic in pregnant rats at doses up to 900 ng/kg/min (Table 12). In pregnant rabbits, developmental toxicity characterized by minimal increases in fetal skeletal variations/litter was observed at doses of 150 and 300 ng/kg/min and was associated with maternal toxicity. No developmental toxicity was seen in rabbits at 50 ng/kg/min. In the Pre- and Postnatal Developmental Study in rats given treprostinil by continuous subcutaneous infusion at doses of 50, 150 or 450 ng/kg/min, the F1 mating index was reduced (not statistically significant) at 450 ng/kg/min. There were no other treatment- related changes in this study and the no observable adverse effect level (NOAEL) for F0 maternal toxicity was 450 ng/kg/min, the conservative NOAEL for F1 male and female reproductive toxicity was 150 ng/kg/min, and the NOAEL for F0 reproductive toxicity and for F1 and F2 developmental toxicity was 450 ng/kg/min.

Table 12

Reproduction and Teratology Studies Continuous Subcutaneous Infusion

-

GD = Gestational Day

REFERENCES

1. Simonneau, G., Barst, R.J., Galie, N., Naeije, R., Rich, S., Bourge, R.,

Keogh, A., Oudiz, R., Frost, A., Blackburn, S., Crow, J.W., Rubin, L.J. Continuous Subcutaneous Infusion of Treprostinil, a Prostacyclin Analogue, in Patients with Pulmonary Arterial Hypertension A Double-Blind, Randomized, Placebo-Controlled Trial. Am J Respir Crit Care Med 2002; 165:800-804. Vachiery, JL., Hill, N., Zwicke, D., Barst, R.J., Blackburn, S., Naeije, R. Transitioning From IV Epoprostenol to Subcutaneous Treprostinil in Pulmonary Arterial Hypertension. Chest 2002; 121:1561-1565 IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

Remodulin(r) (treprostinil sodium) Injection

This leaflet is part III of a three-part Product Monograph published when Remodulin was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Remodulin. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Remodulin is approved for the long-term, subcutaneous (under the

skin) or intravenous (directly into a vein) treatment of pulmonary arterial hypertension (PAH) in NYHA Class III and IV patients who did not respond adequately to conventional therapy.

What it does:

Remodulin causes widening of blood vessels in the lungs and body, and prevents platelets in the blood from sticking together.

The effects of these actions may include improvement in some

measures of heart function and ability to exercise.

When it should not be used:

Remodulin should not be used in patients with known hypersensitivity (allergy) to the active ingredient, any of its non-

medicinal ingredients, or to similar compounds.

What the medicinal ingredient is:

Treprostinil sodium

What the important non-medicinal ingredients are:

Hydrochloric acid, metacresol (0.3%), sodium chloride, sodium citrate, sodium hydroxide, and water for injection.

What dosage forms it comes in:

Remodulin is supplied in 20 mL multi-use vials at concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, and 10.0 mg/mL of

treprostinil. Remodulin can be used undiluted for subcutaneous

use, but must be diluted for intravenous infusion with 0.9% Sodium Chloride Injection or Sterile Water for Injection at concentrations as low as 0.004 mg/mL prior to administration.

WARNINGS AND PRECAUTIONS

• Long term 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 (blood infection, fever, headache, fatigue), which may be fatal.

• Abrupt withdrawal or sudden large reductions in dosage of

Remodulin may result in worsening of pulmonary hypertension symptoms, and should be avoided.

Remodulin is approved for subcutaneous (undiluted) or

intravenous (diluted) use only.

In order to reduce the risk of infection, sterile technique must be used in the preparation and administration of Remodulin

Remodulin should be used only by doctors experienced in the diagnosis and treatment of pulmonary hypertension.

Remodulin therapy must be started by a health professional

with equipment for emergency care and monitoring.

Remodulin dosage should be increased cautiously in patients with liver or kidney problems.

BEFORE you use Remodulin talk to your doctor or pharmacist if:

You have liver or kidney dysfunction.

You are a pregnant or nursing female.

You are younger than 16, or older than 65 years of age.

• You have any allergies to Remodulin, including treprostinil sodium, hydrochloric acid, metacresol, sodium chloride, sodium citrate, sodium hydroxide or components of the container.

INTERACTIONS WITH THIS MEDICATION

The lowering of blood pressure and inhibition of platelet aggregation caused by Remodulin may be increased by drugs that alter blood pressure (diuretics, antihypertensive agents, vasodilators) or inhibit platelet aggregation (anticoagulants).

PROPER USE OF THIS MEDICATION

Therapy with Remodulin may be used for prolonged periods, and your ability to use Remodulin and care for a pump and needles should be carefully considered. Your health professional will decide whether Remodulin will be given to you subcutaneously or intravenously, and will teach you how to use the pump. They will determine your correct starting dose, and will instruct you when to change your Remodulin dose.

Remodulin is given subcutaneously (under the skin) by continuous infusion, through a self-inserted catheter (tube), using an infusion pump designed for subcutaneous drug delivery. Diluted Remodulin is given intravenously (into the vein) by continuous infusion, through a surgically-placed catheter, using an infusion pump designed for intravenous drug delivery.

Usual Dose:

Once you begin Remodulin therapy, your doctor will

adjust your infusion rate to establish a dose at which PAH symptoms are improved, while minimizing Remodulin side effects.

Overdose:

If you think that you received too much REMODULIN

pharmacist.

HOW TO STORE IT

due to:

• Accidental bolus

• Errors in pump program rate of administration

• Or any other reason

Contact your doctor, the regional Poison Control Centre or report to your local emergency department of the hospital.

Missed Dose:

Patients must have a second infusion pump and infusion sets available, to avoid potential interruptions of the infusion.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

The most common side effects reported with Remodulin given subcutaneously are infusion site pain and reaction (redness or rash). Other side effects include headache, diarrhea, nausea, rash, jaw pain, vasodilatation, dizziness, edema and hypotension (low blood pressure, fainting), and these are generally considered to be related to the effects of Remodulin, whether given subcutaneously or intravenously. Events potentially related to intravenous delivery include line infections (redness, tenderness, swelling, or pus at infusion site), sepsis (blood infection, fever, headache, fatigue), arm swelling, parathesias (numbness), hematoma (bruising) and pain. You should contact your health professional about treatment for any side effects you may experience.

Remodulin should be stored at room temperature and should not

be frozen or kept under hot conditions. Remodulin vials should be looked at to make sure the vial contents are clear and the vial is not damaged.

A single vial of Remodulin should be used for no more than 30 days after the initial puncture of the rubber stopper.

During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 37degC.

Diluted Remodulin solution (for intravenous use) can be

administered up to 48 hours at 37degC when diluted to concentrations as low as 0.004 mg/mL in 0.9% Sodium Chloride Injection or Sterile Water for Injection. Inspect the liquid as often as possible to make sure it is clear and free of leaks and particles. If it is hazy, shows particles or leaks, it should be discarded.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on

serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you

may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate

Health Products and Food Branch, Health Canada Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE:

Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.northernther.com

or by contacting the sponsor, Unither Biotech.at: 1-866-206-4441

This leaflet was prepared by United Therapeutics Corporation.

This is not a complete list of side effects. For any unexpected effects while taking Remodulin, contact your doctor or

Last revised: September 25, 2008