NDA 21-272
`Page 4
`
`PRODUCT INFORMATION
`
`REMODULIN (treprostinil sodium) Injection
`
`DESCRIPTION
`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
`
`OH
`
`H
`
`H
`
`OCH 2CO2
`
`Na
`
`
`
`
`
`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 µg/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.
`
`Absorption: 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 µg/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 µg/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
`
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`

`NDA 21-272
`Page 5
`
`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 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.
`
`Renal 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.
`
`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.
`
`Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`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.
`
`
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`NDA 21-272
`Page 6
`
`
`62 ± 17.6
`
`60 ± 14.8
`
`10 ± 5.7
`
`26 ± 13
`
`38 ± 15
`
`62 ± 100
`
`90 ± 14
`
`82 ± 13
`
`10 ± 5.9
`
`25 ± 13
`
`39 ± 15
`
`60 ± 11
`
`91 ± 14
`
`82 ± 15
`
`Table 1: Hemodynamics During Chronic Administration of Remodulin in Patients with PAH
`
`Baseline
`Mean change from baseline at Week 12
`Hemodynamic
`Remodulin
`Placebo
`Remodulin
`Placebo
`Parameter
`(N=204-231)
`(N=215-235)
`(N=163-199)
`(N=182-215)
`CI
`2.4 ± 0.88
`2.2 ± 0.74
`+0.12 ± 0.58*
`-0.06 ± 0.55
`(L/min/m2)
`PAPm
`(mmHg)
`RAPm
`(mmHg)
`PVRI
`(mmHg/L/min/m2)
`SVRI
`(mmHg/L/min/m2)
`SvO2
`(%)
`SAPm
`(mmHg)
`HR
`(bpm)
`*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.
`
`
`-2.3 ± 7.3*
`
`-0.5 ± 5.0*
`
`-3.5 ± 8.2*
`
`-3.5 ± 12*
`
`+2.0 ± 10*
`
`-1.7 ± 12
`
`-0.5 ± 11
`
`+0.7 ± 8.5
`
`+1.4 ± 4.8
`
`+1.2 ± 7.9
`
`-0.80 ± 12
`
`-1.4 ± 8.8
`
`-1.0 ± 13
`
`-0.8 ± 11
`
`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.
`
`INDICATIONS AND USAGE
`Remodulin is indicated as a continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension in
`patients with NYHA Class II-IV symptoms (see CLINICAL PHARMACOLOGY: Clinical Effects) to diminish symptoms
`associated with exercise.
`
`CONTRAINDICATIONS
`
`Remodulin is contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.
`
`WARNINGS
`Remodulin is indicated for subcutaneous use only.
`
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`

`NDA 21-272
`Page 7
`
`PRECAUTIONS
`
`General
`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.
`
`Information for Patients
`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.
`
`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.
`
`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.
`
`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.
`Remodulin has not been studied in conjunction with Flolan (epoprostenol sodium) or Tracleer (bosentan).
`
`Effect of Remodulin on Other Drugs
`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.
`
`Hepatic and Renal Impairment
`Caution should be used in patients with hepatic or renal impairment (see SPECIAL POPULATIONS).
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`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.
`
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`NDA 21-272
`Page 8
`
`Pregnancy
`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.
`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.
`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.
`
`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.
`
`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.
`
`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
`1
`38
`2
`39
`Severe
`NA**
`NA**
`1
`32
`Requiring narcotics*
`0
`3
`0
`7
`Leading to discontinuation
`* 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.
`
`
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`

`NDA 21-272
`Page 9
`
`
`
`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
`
`Placebo
`Remodulin
`(N=233)
`(N=236)
`Percent of Patients
`Percent of Patients
`27
`85
`Infusion Site Pain
`27
`83
`Infusion Site Reaction
`23
`27
`Headache
`16
`25
`Diarrhea
`18
`22
`Nausea
`11
`14
`Rash
`5
`13
`Jaw Pain
`5
`11
`Vasodilatation
`8
`9
`Dizziness
`3
`9
`Edema
`6
`8
`Pruritus
`2
`4
`Hypotension
`Reported adverse events (at least 3%) are included except those too general to be informative, and those not plausibly
`attributable to the use of the drug, because they were associated with the condition being treated or are very common in the
`treated population.
`
`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™ 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.
`
`Initial Dose
`
`
`
`

`

`NDA 21-272
`Page 10
`
`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.
`
`Dosage Adjustments
`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).
`
`Administration
`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 (mL/hr) =
`Dose (ng/kg/min) x Weight (kg) x [0.00006/Remodulin dosage strength concentration (mg/mL)]
`
`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.
`
`
`
`
`
`

`

`
`
`Table 4
`
`(ng/kg/min)
`
`Dose
`
`
`
`1.25
`2.5
`3.75
`5
`6.25
`7.5
`8.75
`10
`11.25
`12.5
`13.75
`15
`16.25
`17.5
`18.75
`20
`21.25
`22.5
`23.75
`25
`27.5
`30
`32.5
`35
`37.5
`40
`42.5
`
`
`
`30
`
`
`
`35
`
`
`
`40
`
`
`
`45
`
`
`
`50
`
`
`
`55
`
`
`
`Patient Weight (kg)
`
`Pump Infusion Rate Setting (mL/hr) for 1.0 mg/mL Remodulin
`
`1.0 mg/mL Concentration of RemodulinTM
`
`100
`25
`0.002 0.002 0.003 0.003 0.003 0.004 0.004 0.005 0.005 0.005 0.006 0.006 0.006 0.007 0.007 0.008
`0.004 0.005 0.005 0.006 0.007 0.008 0.008 0.009 0.010 0.011 0.011 0.012 0.013 0.014 0.014 0.015
`0.006 0.007 0.008 0.009 0.010 0.011 0.012 0.014 0.015 0.016 0.017 0.018 0.019 0.020 0.021 0.023
`0.008 0.009 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.030
`0.009 0.011 0.013 0.015 0.017 0.019 0.021 0.023 0.024 0.026 0.028 0.030 0.032 0.034 0.036 0.038
`0.011 0.014 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.045
`0.013 0.016 0.018 0.021 0.024 0.026 0.029 0.032 0.034 0.037 0.039 0.042 0.045 0.047 0.050 0.053
`0.015 0.018 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.060
`0.017 0.020 0.024 0.027 0.030 0.034 0.037 0.041 0.044 0.047 0.051 0.054 0.057 0.061 0.064 0.068
`0.019 0.023 0.026 0.030 0.034 0.038 0.041 0.045 0.049 0.053 0.056 0.060 0.064 0.068 0.071 0.075
`0.021 0.025 0.029 0.033 0.037 0.041 0.045 0.050 0.054 0.058 0.062 0.066 0.070 0.074 0.078 0.083
`0.023 0.027 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.090
`0.024 0.029 0.034 0.039 0.044 0.049 0.054 0.059 0.063 0.068 0.073 0.078 0.083 0.088 0.093 0.098
`0.026 0.032 0.037 0.042 0.047 0.053 0.058 0.063 0.068 0.074 0.079 0.084 0.089 0.095 0.100 0.105
`0.028 0.034 0.039 0.045 0.051 0.056 0.062 0.068 0.073 0.079 0.084 0.090 0.096 0.101 0.107 0.113
`0.030 0.036 0.042 0.048 0.054 0.060 0.066 0.072 0.078 0.084 0.090 0.096 0.102 0.108 0.114 0.120
`0.032 0.038 0.045 0.051 0.057 0.064 0.070 0.077 0.083 0.089 0.096 0.102 0.108 0.115 0.121 0.128
`0.034 0.041 0.047 0.054 0.061 0.068 0.074 0.081 0.088 0.095 0.101 0.108 0.115 0.122 0.128 0.135
`0.036 0.043 0.050 0.057 0.064 0.071 0.078 0.086 0.093 0.100 0.107 0.114 0.121 0.128 0.135 0.143
`0.038 0.045 0.053 0.060 0.068 0.075 0.083 0.090 0.098 0.105 0.113 0.120 0.128 0.135 0.143 0.150
`0.041 0.050 0.058 0.066 0.074 0.083 0.091 0.099 0.107 0.116 0.124 0.132 0.140 0.149 0.157 0.165
`0.045 0.054 0.063 0.072 0.081 0.090 0.099 0.108 0.117 0.126 0.135 0.144 0.153 0.162 0.171 0.180
`0.049 0.059 0.068 0.078 0.088 0.098 0.107 0.117 0.127 0.137 0.146 0.156 0.166 0.176 0.185 0.195
`0.053 0.063 0.074 0.084 0.095 0.105 0.116 0.126 0.137 0.147 0.158 0.168 0.179 0.189 0.200 0.210
`0.056 0.068 0.079 0.090 0.101 0.113 0.124 0.135 0.146 0.158 0.169 0.180 0.191 0.203 0.214 0.225
`0.060 0.072 0.084 0.096 0.108 0.120 0.132 0.144 0.156 0.168 0.180 0.192 0.204 0.216 0.228 0.240
`0.064 0.077 0.089 0.102 0.115 0.128 0.140 0.153 0.166 0.179 0.191 0.204 0.217 0.230 0.242 0.255
`
`60
`
`
`
`65
`
`
`
`70
`
`
`
`75
`
`
`
`80
`
`
`
`85
`
`
`
`90
`
`
`
`95
`
`
`
`
`
`
`
`
`
`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.
`
`

`

`
`
`
`
`Table 5
`
`(ng/kg/min
`
`Dose
`
`)
`5
`6.25
`7.5
`8.75
`10
`11.25
`12.5
`13.75
`15
`16.25
`17.5
`18.75
`20
`21.25
`22.5
`23.75
`25
`27.5
`30
`32.5
`35
`37.5
`40
`42.5
`
`
`
`25
`
`
`
`30
`
`
`
`35
`
`
`
`40
`
`
`
`45
`
`
`
`50
`
`
`
`55
`
`
`
`60
`
`
`
`65
`
`
`
`70
`
`
`
`75
`
`
`
`80
`
`
`
`85
`
`
`
`90
`
`
`
`95
`
`
`
`100
`
`
`
` Pump Infusion Rate Setting (mL/hr) for 2.5 mg/mL Remodulin
`
`2.5 mg/mL Concentration of RemodulinTM
`
`Patient Weight (kg)
`
`0.003 0.004 0.004 0.005 0.005 0.006 0.007 0.007 0.008 0.008 0.009 0.010 0.010 0.011 0.011 0.012
`0.004 0.005 0.005 0.006 0.007 0.008 0.008 0.009 0.010 0.011 0.011 0.012 0.013 0.014 0.014 0.015
`0.005 0.005 0.006 0.007 0.008 0.009 0.010 0.011 0.012 0.013 0.014 0.014 0.015 0.016 0.017 0.018
`0.005 0.006 0.007 0.008 0.009 0.011 0.012 0.013 0.014 0.015 0.016 0.017 0.018 0.019 0.020 0.021
`0.006 0.007 0.008 0.010 0.011 0.012 0.013 0.014 0.016 0.017 0.018 0.019 0.020 0.022 0.023 0.024
`0.007 0.008 0.009 0.011 0.012 0.014 0.015 0.016 0.018 0.019 0.020 0.022 0.023 0.024 0.026 0.027
`0.008 0.009 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.030
`0.008 0.010 0.012 0.013 0.015 0.017 0.018 0.020 0.021 0.023 0.025 0.026 0.028 0.030 0.031 0.033
`0.009 0.011 0.013 0.014 0.016 0.018 0.020 0.022 0.023 0.025 0.027 0.029 0.031 0.032 0.034 0.036
`0.010 0.012 0.014 0.016 0.018 0.020 0.021 0.023 0.025 0.027 0.029 0.031 0.033 0.035 0.037 0.039
`0.011 0.013 0.015 0.017 0.019 0.021 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.040 0.042
`0.011 0.014 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.045
`0.012 0.014 0.017 0.019 0.022 0.024 0.026 0.029 0.031 0.034 0.036 0.038 0.041 0.043 0.046 0.048
`0.013 0.015 0.018 0.020 0.023 0.026 0.028 0.031 0.033 0.036 0.038 0.041 0.043 0.046 0.048 0.051
`0.014 0.016 0.019 0.022 0.024 0.027 0.030 0.032 0.035 0.038 0.041 0.043 0.046 0.049 0.051 0.054
`0.014 0.017 0.020 0.023 0.026 0.029 0.031 0.034 0.037 0.040 0.043 0.046 0.048 0.051 0.054 0.057
`0.015 0.018 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.060
`0.017 0.020 0.023 0.026 0.030 0.033 0.036 0.040 0.043 0.046 0.050 0.053 0.056 0.059 0.063 0.066
`0.018 0.022 0.025 0.029 0.032 0.036 0.040 0.043 0.047 0.050 0.054 0.058 0.061 0.065 0.068 0.072
`0.020 0.023 0.027 0.031 0.035 0.039 0.043 0.047 0.051 0.055 0.059 0.062 0.066 0.070 0.074 0.078
`0.021 0.025 0.029 0.034 0.038 0.042 0.046 0.050 0.055 0.059 0.063 0.067 0.071 0.076 0.080 0.084
`0.023 0.027 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.090
`0.024 0.029 0.034 0.038 0.043 0.048 0.053 0.058 0.062 0.067 0.072 0.077 0.082 0.086 0.091 0.096
`0.026 0.031 0.036 0.041 0.046 0.051 0.056 0.061 0.066 0.071 0.077 0.082 0.087 0.092 0.097 0.102
`
`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.
`
`

`

`
`
`Table 6
`
`(ng/kg/min)
`
`Dose
`
`10
`12.5
`15
`17.5
`20
`22.5
`25
`27.5
`30
`32.5
`35
`37.5
`40
`42.5
`45
`47.5
`50
`55
`60
`65
`70
`75
`80
`
`
`
`
`
`
`
`Pump Infusion Rate Setting (mL/hr) for 5.0 mg/mL Remodulin
`
`5.0 mg/mL Concentration of RemodulinTM
`
`Patient Weight (kg)
`
`100
`0.003 0.004 0.005 0.005 0.006 0.007 0.007 0.008 0.008 0.009 0.010 0.010 0.011 0.011 0.012
`0.004 0.005 0.006 0.007 0.008 0.008 0.009 0.010 0.011 0.011 0.012 0.013 0.014 0.014 0.015
`0.005 0.006 0.007 0.008 0.009 0.010 0.011 0.012 0.013 0.014 0.014 0.015 0.016 0.017 0.018
`0.005 0.007 0.008 0.009 0.011 0.012 0.013 0.014 0.015 0.016 0.017 0.018 0.019 0.020 0.021
`0.006 0.008 0.010 0.011 0.012 0.013 0.014 0.016 0.017 0.018 0.019 0.020 0.022 0.023 0.024
`0.007 0.009 0.011 0.012 0.014 0.015 0.016 0.018 0.019 0.020 0.022 0.023 0.024 0.026 0.027
`0.008 0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.030
`0.008 0.012 0.013 0.015 0.017 0.018 0.020 0.021 0.023 0.025 0.026 0.028 0.030 0.031 0.033
`0.009 0.013 0.014 0.016 0.018 0.020 0.022 0.023 0.025 0.027 0.029 0.031 0.032 0.034 0.036
`0.010 0.014 0.016 0.018 0.020 0.021 0.023 0.025 0.027 0.029 0.031 0.033 0.035 0.037 0.039
`0.011 0.015 0.017 0.019 0.021 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.040 0.042
`0.011 0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.045
`0.012 0.017 0.019 0.022 0.024 0.026 0.029 0.031 0.034 0.036 0.038 0.041 0.043 0.046 0.048
`0.013 0.018 0.020 0.023 0.026 0.028 0.031 0.033 0.036 0.038 0.041 0.043 0.046 0.048 0.051
`0.014 0.019 0.022 0.024 0.027 0.030 0.032 0.035 0.038 0.041 0.043 0.046 0.049 0.051 0.054
`0.014 0.020 0.023 0.026 0.029 0.031 0.034 0.037 0.040 0.043 0.046 0.048 0.051 0.054 0.057
`0.015 0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.060
`0.017 0.023 0.026 0.030 0.033 0.036 0.040 0.043 0.046 0.050 0.053 0.056 0.059 0.063 0.066
`0.018 0.025 0.029 0.032 0.036 0.040 0.043 0.047 0.050 0.054 0.058 0.061 0.065 0.068 0.072
`0.020 0.027 0.031 0.035 0.039 0.043 0.047 0.051 0.055 0.059 0.062 0.066 0.070 0.074 0.078
`0.021 0.029 0.034 0.038 0.042 0.046 0.050 0.055 0.059 0.063 0.067 0.071 0.076 0.080 0.084
`0.023 0.032 0.036 0.041 0.045 0.050 0.054 0.059 0.063 0.068 0.072 0.077 0.081 0.086 0.090
`0.024 0.034 0.038 0.043 0.048 0.053 0.058 0.062 0.067 0.072 0.077 0.082 0.086 0.091 0.096
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`75
`
`80
`
`85
`
`90
`
`95
`
`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
`
`Pump Infusion Rate Setting (mL/hr) for 10.0 mg/mL Remodulin
`
`10.0 mg/mL Concentration of RemodulinTM
`
`Patient Weight (kg)
`
`100
`0.011 0.012 0.014 0.015 0.017 0.018 0.020 0.021 0.023 0.024 0.026 0.027 0.029 0.030
`0.012 0.013 0.015 0.017 0.018 0.020 0.021 0.023 0.025 0.026 0.028 0.030 0.031 0.033
`0.013 0.014 0.016 0.018 0.020 0.022 0.023 0.025 0.027 0.029 0.031 0.032 0.034 0.036
`0.014 0.016 0.018 0.020 0.021 0.023 0.025 0.027 0.029 0.031 0.033 0.035 0.037 0.039
`0.015 0.017 0.019 0.021 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.040 0.042
`0.016 0.018 0.020 0.023 0.025 0.027 0.029 0.032 0.034 0.036 0.038 0.041 0.043 0.045
`0.017 0.019 0.022 0.024 0.026 0.029 0.031 0.034 0.036 0.038 0.041 0.043 0.046 0.048
`0.018 0.020 0.023 0.026 0.028 0.031 0.033 0.036 0.038 0.041 0.043 0.046 0.048 0.051
`0.019 0.022 0.024 0.027 0.030 0.032 0.035 0.038 0.041 0.043 0.046 0.049 0.051 0.054
`0.020 0.023 0.026 0.029 0.031 0.034 0.037 0.040 0.043 0.046 0.048 0.051 0.054 0.057
`0.021 0.024 0.027 0.030 0.033 0.036 0.039 0.042 0.045 0.048 0.051 0.054 0.057 0.060
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`75
`
`80
`
`85
`
`90
`
`95
`
`
`
`Table 7
`
`
`
`(ng/kg/min)
`
`Dose
`
`50
`55
`60
`65
`70
`75
`80
`85
`90
`95
`100
`
`

`

`NDA 21-272
`Page 15
`
`
`
`HOW SUPPLIED
`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
`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 25°C (59 to 77°F). Store at 25°C (77°F), with excursions permitted to
`15-30°C (59-86°F) [see USP Controlled Room Temperature].
`During use, a single reservoir (syringe) of Remodulin can be administered up to 72 hours at 37°C. A single vial of
`Remodulin should be used for no more than 14 days after