Remodulin (treprostinil sodium) Injection is a sterile sodium salt formulated for subcutaneous administration. Remodulin is supplied in 20 mL multi-use vials in four strengths, containing 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL or 10.0 mg/mL of treprostinil. Each mL also contains 5.3 mg sodium chloride (except for the 10.0 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,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5- yl]oxy]acetic acid monosodium salt. Treprostinil sodium has a molecular weight of 412.49 and a molecular formula of C23H33NaO5. The structural formula of treprostinil sodium is: OH H OH

CLINICAL PHARMACOLOGY

General: The major pharmacological 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. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed.

Pharmacokinetics

The pharmacokinetics of continuous subcutaneous Remodulin are linear over the dose range of 1.25 to 22.5 ng/kg/min (corresponding to plasma concentrations of about 0.03 to 8 ug/L) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 22.5 ng/kg/min has not been studied.

Remodulin is relatively 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.

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.

The elimination of Remodulin is biphasic, with a terminal half-life of approximately 2-4 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 liters/hr for a 70 kg ideal body weight person.

Special Populations

Hepatic Insufficiency: In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency, Remodulin at a subcutaneous dose of 10 ng/kg/min for 150 minutes had a Cmax that was increased 2-fold and 4-fold, respectively, and AUC 0-[?] was increased 3-fold and 5-fold, respectively, compared to healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy adults. 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.

No studies have been performed in patients with renal insufficiency, so no specific advice about dosing in such patients can be given. Although only 4% of the administered dose is excreted unchanged in the urine, the five identified metabolites are all excreted in the urine.

Effect of Other Drugs on Remodulin: In vitro studies: Remodulin did not significantly affect the plasma protein binding of normally observed concentrations of digoxin or warfarin.

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.

Two 12-week, multicenter, randomized, double-blind studies compared Remodulin 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 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 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, described in DOSAGE AND ADMINSTRATION, 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. The two studies were identical in design and conducted simultaneously, and the results were analyzed both pooled and individually.

Hemodynamic Effects

As shown in Table 1, chronic therapy with Remodulin resulted in small hemodynamic changes consistent with pulmonary and systemic vasodilation.

Table 1: Hemodynamics During Chronic Administration of Remodulin in Patients with PAH

*Denotes statistically significant difference between Remodulin and placebo, p<0.05.

CI = cardiac index; PAPm = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance indexed;

RAPm = mean right atrial pressure; SAPm = mean systemic arterial pressure; SVRI = systemic vascular resistance indexed; SvO2 = mixed venous oxygen saturation; HR = heart rate.

Clinical Effects

The effect of Remodulin on 6-minute walk, the primary end point of the studies, was small and did not achieve conventional levels of statistical significance. For the combined populations, the median change from baseline on Remodulin was 10 meters and the median change from baseline on placebo was 0 meters. Although it was not the primary endpoint of the study, the Borg dyspnea score was significantly improved by Remodulin during the 6-minute walk, and Remodulin also had a significant effect, compared with placebo, on an assessment that combined walking distance with the Borg dyspnea score. Remodulin also consistently improved indices of dyspnea, fatigue and signs and symptoms of pulmonary hypertension, but these indices were difficult to interpret in the context of incomplete blinding to treatment assignment resulting from infusion site symptoms.

CONTRAINDICATIONS

Remodulin is contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

WARNINGS

PRECAUTIONS

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. Subcutaneous 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. Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be decreased for excessive pharmacological effects or for unacceptable infusion site symptoms (see DOSAGE AND ADMINISTRATION). Abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of PAH symptoms and should be avoided.

Patients receiving Remodulin should be given the following information: Remodulin is infused continuously through a subcutaneous catheter, via an infusion pump. Therapy with Remodulin will be needed for prolonged periods, possibly years, and the patient's ability to accept, place, and care for a subcutaneous catheter and to use an infusion pump should be carefully considered. Additionally, patients should be aware that subsequent disease management may require the initiation of an intravenous therapy.

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.

studies: Remodulin did not significantly affect the plasma protein binding of normally observed concentrations of digoxin or warfarin.

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.

Remodulin has not been studied in conjunction with Flolan (epoprostenol sodium) or Tracleer (bosentan).

In vivo studies: Warfarin - Remodulin does not affect the pharmacokinetics or pharmacodymamics 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.

Caution should be used in patients with hepatic or renal impairment (see SPECIAL POPULATIONS).

Long-term studies have not been performed to evaluate the carcinogenic potential of treprostinil. In vitro and in vivo mutagenicity studies did not demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not affect fertility or mating performance of male or female rats given continuous subcutaneous infusion at rates of up to 450 ng treprostinil/kg/min [about 59 times the recommended starting human rate of infusion (1.25 ng/kg/min) and about 8 times the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m2 basis]. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6.

Pregnancy Category B - In pregnant rats, continuous subcutaneous infusion of treprostinil sodium during the period of 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 infusion 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.

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.

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.

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.

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.

ADVERSE REACTIONS

Patients receiving Remodulin 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 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 infusion site adverse events

	Reaction		Pain
	Placebo	Remodulin	Placebo	Remodulin
Severe	1	38	2	39
Requiring narcotics *	NA * *	NA * *	1	32
Leading to discontinuation	0	3	0	7

* based on prescriptions for narcotics, not actual use

* *medications used to treat infusion site pain were not distinguished from those used to treat site reactions

Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea. 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 Remodulin than with placebo in controlled trials in PAH.

Table 3: Adverse Events in Controlled Studies of Patients with PAH, Occurring with at Least 3% Incidence and More Common on Remodulin than on Placebo.

Adverse Event	Remodulin (N=236) Percent of Patients	Placebo (N=233) Percent of Patients
Infusion Site Pain	85	27
Infusion Site Reaction	83	27
Headache	27	23
Diarrhea	25	16
Nausea	22	18
Rash	14	11
Jaw Pain	13	5
Vasodilatation	11	5
Dizziness	9	8
Edema	9	3
Pruritus	8	6
Hypotension	4	2

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 PAH Controlled Trials

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. Most delivery system complications were easily managed (e.g., replace syringe or battery, reprogram pump, straighten crimped infusion line). 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. Adverse events resulting from problems with the delivery system did not lead to clinical instability or rapid deterioration.

OVERDOSAGE

Signs and symptoms of overdose with Remodulin during clinical trials are extensions of its dose-limiting pharmacological 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).

DOSAGE AND ADMINISTRATION

Remodulin(tm) is supplied in 20 mL vials in concentrations of 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL and 10.0 mg/mL. Remodulin is meant to be administered without further dilution.

Remodulin is administered by continuous subcutaneous 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.

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacological effects of Remodulin (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction). The infusion rate should be increased in increments of no more than 1.25 ng/kg/min per week for the first four weeks and then no more than 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. There is little experience with doses >40 ng/kg/min. Abrupt cessation of infusion should be avoided (see PRECAUTIONS).

Remodulin is administered by continuous subcutaneous 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. Infusion rates are calculated using the following formula.

Infusion Rate =

Dose x Weight x [0.00006/Remodulin dosage strength concentration ]

Tables 4 through 7 provide Remodulin infusion delivery rates for doses up to 100 ng/kg/min, based on patient weight, drug delivery rate and concentration. These tables may be used to select the most appropriate concentration and infusion rate for Remodulin. No dilution is necessary.

The infusion rate for 1.0 mg/mL can be calculated using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.00006.

The infusion rate for 2.5 mg/mL can be calculated using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.000024.

The infusion rate for the 5 mg/mL concentration can be calculated by using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.000012.

The infusion rate for the 10 mg/mL concentration can be calculated by using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.000006

HOW SUPPLIED

Remodulin(tm) 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 treprostinil, as sterile solutions in water for injection, individually packaged in a carton. Each mL contains treprostinil sodium equivalent to 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, or 10.0 mg/mL treprostinil. Unopened vials of Remodulin are stable until the date indicated when stored at 15 to 25degC (59 to 77degF). Store at 25degC (77degF), with excursions permitted to 15-30degC (59-86degF) [see USP Controlled Room Temperature]. During use, a single reservoir (syringe) of Remodulin can be administered up to 72 hours at 37degC. A single vial of Remodulin should be used for no more than 14 days after the initial introduction into the vial. 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. 20-mL vial containing treprostinil sodium equivalent to 1.0 mg treprostinil per mL, carton of 1 (NDC 66302-101-01). 20-mL vial containing treprostinil sodium equivalent to 2.5 mg treprostinil per mL, carton of 1 (NDC 66302-102-01). 20-mL vial containing treprostinil sodium equivalent to 5.0 mg treprostinil per mL, carton of 1 (NDC 66302-105-01). 20-mL vial containing treprostinil sodium equivalent to 10.0 mg treprostinil per mL, carton of 1 (NDC 66302-110-01). US Patent No. 5,153,222 (Use Patent) United Therapeutics Corp. Research Triangle Park, NC 27709

Baxter Pharmaceutical Solutions LLC Bloomington, IN 47403 For United Therapeutics Corp. Research Triangle Park, NC 27709

---------------------------------------------------------------------------------------------------------------------

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.