CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-2 72
`
`APPROVED LABELING
`
`
`
`
`

`

`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 m1. 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 betuwen 6.0 and 7.2.
`
`Treprostinil is chemically stable at room temperature and neutral pH.
`
`Treprostinil sodium is (l R,2R,3aS,9aS)—[[2,3,3a,4,9,9a~Hexahydro—2-hydroxy-l -[(3 S)-3-hydroxyoctyl]-lH-benz[flinden—S-
`yl]oxy]acetic acid monosodium salt. Treprostinil sodium has a molecular weight of 412.49 and a molecular formula of
`CanNaOs-
`
`The structural formula of treprostinil sodium is:
`
`
`
`CLINICAL PHARMACOLOGY
`
`General: The major pharmacological actions oftrcprostinil are direct vasodilation of pulmonary and systemic arterial
`vascular beds and inhibition of platelet aggregation. in animals, the vasodilatory effects mduce right and lea ventricular
`afierload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related
`negative inotropic and Iusitropic effect. Nomajor 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.
`
`Am Remodulin is relatively rapidly and completely absorbed after subcutaneous infirsion, 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.
`
`Mung); The volume of distribution of the drug in the central compartment is approximately 14U70 kg ideal body
`weight. Rernodulin at in vitro concentrations ranging fi'orn 330-10,000 ug/L was 91% bound to human plasma protein.
`
`‘1
`
`\.
`
`mm; Remodulin is substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five
`metabolites have been described (HUI through HUS). The biological activity and metabolic fate of these metabolites are
`unknown. The chemical structure ofW1 is unknown. HUS is the glucuronide conjugate of treprostinil. The other
`metabolites are formed by oxidation ofthe 3-hydroxyoctyl side chain (HUZ) and subsequent additional oxidation (HU3) or
`
`
`
`

`

`NDA 21-272
`
`Page 5
`
`(w
`
`.
`dehydration (HU4). Based on the results of in vitro human hepatic cytochrome P450 studies, Remodulin does not inhibit
`CYP-lAZ, 2C9, 2Cl9, 2D6, 2B], or 3A. Whether Remodulin induces these enzymes has not been studied.
`
`W The elimination ofRemodulin is biphasic, with a terminal half-life of approximately 2-4 hours. Approximately
`79% ofan 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
`
`W In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic
`insufficiency, Remodulin at a subcutaneous dose of 10 ng/kg/rnin for 150 minutes had a C“... 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.
`
`W 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 dase is excreted unchanged in the urine, the five
`identified metabolites are all excreted in the urine.
`
`WI): vitro studies: Remodulin did not significantly affect the plasma protein binding of
`normally observed concentrations of digoxin or warfarin.
`
`/
`
`f
`
`In viva studies: Acetaminophen - Analgesic doses ofacetuninophen, 1000 mg every 6 hours for seven doses, did not affect
`the pharmacokinetics of Remodulin, at a subcutaneous infirsion 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 ll-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 ofthe study. Remodulin was administered as a subcutaneous infusion, described in DOSAGE AND
`ADMINSTRATION, and the dose averaged 9.3 ng/kymin 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.
`
`
`W 'W
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`NDA 21-272
`
`Page 6
`
`Table l: Hemod namics Durin Chronic Administration of Remodulin in Patients with PAH
`
`Hctnodynamic
`Parameter
`Cl
`
`Remodulin
`(N=204-231)
`
`Placebo
`(N=215-235)
`
`Mean change from baseline at Week 12
`Remodulin
`Placebo
`(N=163-199)
`('N=182-215)
`
`PAPm
`
`(
`
`Wm
`8)
`H
`PVRI
`
`.
`
`14.
`
`-2.
`
`. ‘
`
`.
`
`.
`
`101:57
`.
`
`10:1:59
`.
`
`~0.
`
`5:1:50
`. ‘
`
`14148
`.
`+ .
`
`
`
`
`
`
`
`
`
`
`
`
`
`SVRI
`-0.80 i 12
`-3.5 d: 12‘
`39 :l: 15
`33 i 15
`(mmHg/L/min/m’)
`4.413.:
`+2.0: 10*
`60:1: 11
`62:1:100
`5&3;
`SAPm
`(m1--_
`-1.
`13
`-1.7
`911:”
`21:14
`HR
`82il3
`82:1:15
`415111
`~08:l:11
`(bpm)
`'
`'
`'Denotes statistically significant difference between Remodulin and pm p<0.0$.
`Cl‘wdhchdemPAhn-mnpuhmuamhlmsmeWVthdmmvucuhrmm indexed;
`RAPmtmeanrightatrialpressme;SAPm-mansynemicamrialpeasm;SVRl=systanvasaduresisnnceindexcd;
`SvO;*mhedmmoxypnsatmatim;HR=heartnte.
`
`Clinical Eflects
`
`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 md signs and symptoms of pulmonary hypertension, but
`these indices were difiicult to interpret in the context of incomplete blinding to treatment assignment resulting liom infusion
`site symptoms.
`
`INDICATIONS AND USAGE
`
`Remodulin” is indicated as a continuous subcutaneous infusion for the treatment ofpulmonary arterial hypertension in
`patients with NYI-IA Class II-IV symptoms (see CLINICAL PHARMACOLOGY: Clinical Efl‘ects) to diminish symptoms
`associated with exercise.
`
`CONTRAINDICATIONS
`
`Remodulin is contraindicated in patients with known hypersensitivity to the drug or to su'ucturally related compounds.
`
`WARNINGS
`
`Remodulin is indicated for subcutaneous use only.
`
`I
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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 carefirlly 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/or Pafients
`
`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.
`
`Efl'ect 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 TracleerT" (bosentan).
`
`Effect ofRemodulin 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 l0 ng/kg/min.
`
`Hepatic and Renal Impairment
`
`Caution should be used in patients with hepatic or renal impairment (see SPECIAL POPULATIONS).
`
`Carcinogenesis, Muragenesis, Impairment ofFutility
`
`Long-term studies have not been performed to evaluate the carcinogenic potential of treprostinil. In vitro and in viva
`mutagenicity studies did not demonstrate any mutagenic or clastogenic effects oftreprostinil. 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 (l.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 fiom 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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`

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`NDA 21-272
`
`Page 8
`
`Pregnancy
`
`{ga‘
`
`Pregnancy Category B - In pregnant rats, continuous subcutaneous infusion oftreprostinil sodium during the period of
`organogenesis and late gestational development, at rates as high as 900 ng treprostinil/kg/min (about I 17 times the starting
`human rate of infusion, on a ng/rrl2 basis and about l6 times the average rate achieved in clinical trials), resulted in no
`evidence of harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infiision of treprostinil during
`organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right mdimentary n'b on
`lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at an infusion rate of 150 ng
`treprostinillkg/min (about 4] 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 oftreprostinil from implantation to the end of lactation, at rates of
`up to 450 ng ueprostiniI/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 nwded.
`
`Labor and delivery
`
`No treprostinil sodium treatment-related efl‘ects 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 afier 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 516 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 bleedinybruising at the infusion site and included symptoms such as erytherna, induration
`or- rash. Infusion site reactions were sometimes severe and could lead to discontinuation oftreatment.
`
`Table 2. Percentaes of sub eets re urtin infusion site adverse events
`
`
`
`’basedonpreacriptionsfornsreotics,notactualuse
`”medicationsusedtotreatinfusionsitepainwercnotdistinguishedfrornthosemedtotreatsitereactions
`
`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 Evens in Controlled Studies of Patients with PAH,
`Occurring with at Least 3% Incidence and More Common on Remodulin than
`on Placebo.
`
`Adverse Event
`
`Remodulin
`
`Placebo
`
`(N=236)
`Percent of Patients
`
`(N=233)
`Percent of Patients
`
`27
`N\l
`
`NNI
`
`Infusion Site Pain
`
`Infusion Site Reaction
`
`Headache
`
`Diarrhe
`
`Nausea
`
`Jaw Pain
`
`Vasodilatation
`
`Dininess -__-
`
`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 ofthese patients (4 Rernodulin, 4 Placebo) reported non—serious adverse events
`resulting from infusion system complications. Adverse events resulting from problem with the delivery systems were
`typically related to either symptoms ofexcess 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 ofoverdose with Remodulin during clinical trials are extensions ofits dose-limiting pharmacological
`effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and
`resolved with reduction or withholding ofRemodulin.
`
`In controlled clinical trials, seven patients received some level ofoverdose 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 ofadministration, and prescription of an incorrect dose. In only two cases did excess
`delivery of Remodulin produce an event of substantial hemodynarnic 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 mymL. Remodulin is meant to be administered without further dilution.
`
`(m
`
`Initial Dose
`
`

`

`‘
`
`C
`
`NDA 21-272
`
`Page 10
`
`,
`
`Remodulin is administered by continuous subcutaneous infitsion. The infusion rate is initiated at 1.25 ng/kg/min. Ifthis
`
`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 infiision, 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 infiision pump used to
`administer Remodulin should: (I) be small and lightweight, (2) be adjustable to approximately 0.002 mL/hr, (3) have
`occlusion/no delivery, low battery, programing error and motor malfimction 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/kymin) x Weight (kg) x [0.00006IRemodulin dosage strength concentration (mg/mL)l
`
`C
`
`Tables 4 through 7 provide Remodulin infiision delivery rates fordoses upto 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 infilsion rate for
`Remodulin. No dilution is necessary.
`
`I"
`
`...,.
`
`.
`
`. v..- qr... \'~“' "'"““".‘7"‘ --....q.:_...- .-.—...._¢~m.-..._~7_~...Team's." _._...,,-
`
`
`
`

`

`Table 4
`
`Dose
`
`1.0 mgImL Concentration of Remodulinm
`
`Pumn Infusion Rate Setting (mLIhr) for 1.0 mglmL Remodulln
`Patient Wei ht k
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`75
`
`80
`
`85
`
`90
`
`95
`
`100
`
`0.004 0.004 0.005
`0.008 0.008 0.009
`0.011 0.012 0.014
`0.015 0.017 0.018
`0.019 0.021 0.023
`0.023 0.025 0.027
`
`0.026 0.029 0.032
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`
`
`0.030 0.033 0.036
`0.034 0.037 0.041
`0.038 0.041 0.045
`0.041 0.045 0.050
`0.045 0.050 0.054
`0.049 0.054 0.059
`
`0.053 0.058 0.063
`0.056 0.062 0.068
`0.060 0.066 0.072
`0.064 0.070 0.077
`0.068 0.074 0.081
`0.071 0.078 0.086
`0.075 0.083 0.090
`0.083 0.091 0.099
`0.090 0.099 0.108-
`0.098 0.107 0.117
`0.105 0.116 0.126
`0.113 0.124 0.135
`0.120 0.132 0.144
`.
`.
`.
`.
`.
`0.128 0.140 0.153
`.
`.
`.
`Thomluuon ratator1.0mglmLennbocalculatod udngmofouowimfotmnn: Pathntweign1(kg)xdooo(nglkynin)x0.00006.
`
`.
`
`.
`
`,
`.
`3
`f
`'
`
`'
`
`
`
`--p-........7.-.....v-..~...q—-n—.,-v—-v-.-...___.,..,r._.-v“:‘"‘1“:
`
`
`
`
`
`l
`
`r
`
`1
`
`
`
`

`

`2.5 mglmL Concentration of RemodulinT"
`Pump infusion Rate Setting (mLIhr) for 2.5 mgImL Remodulln
`Patient Wei 2 ht k -
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`75
`
`80
`
`85
`
`90
`
`95
`
`100
`
`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
`
`(nglkglmin 25
`
`Table 5
`
`Dose
`
`
`
`
`
`
`0.004 0.005 0.005 0.006 0.007 0.008 0.008 0.009 0.010
`
`0.005 0.005 0.008 0.007 0.008 0.009 0.010 0.011 0.012
`
`0.005 0.006 0.007 0.008 0.009 0.011 0.012 0.013 0.014
`
`
`
`0.006 0.007 0.008 0.010 0.011 0.012 0.013 0.014 0.016
`
`0.007 0.008 0.009 0.011 0.012 0.014 0.015 0.016 0.018
`
`0.008 0.009 0.011 0.012 0.014 0.015 0.017 0.018 0.020
`
`
`0.011 0.011 0.012 0.013 0.014 0.014 0.015.
`
`0.013 0.014 0.014 0.015 0.016 0.017 0.018
`
`
`
`
`0.015 0.016 0.017 0.018 0.019 0.020 0.021
`
`0.017. 0.018 0.019 0.020 0.022 0.023 0.024
`
`0.019 0.020 0.022 0.023 0.024 0.026 0.027
`
`0.021 0.023 0.024 0.026 0.027 0.029 0.030
`0.023 0.025 0.026 0.028 0.030 0.031 0.033
`
`0.025 0.027 0.029 0.031 0.032 0.034 0.036
`
`0.027 0.029 0.031 0.033 0.035 0.037 0.039
`0.029 0.032 0.034 0.036 0.038 0.040 0.042
`0.032 0.034 0.036 0.038 0.041 0.043 0.045
`0.034 0.036 0.038 0.041 0.043 0.046 0.048
`0.036 0.038 0.041 0.043 0.046 0.048 0.051
`0.038 0.041 0.043 0.046 0.049 0.051 0.054
`0.040 0.043 0.046 0.048 0.051 0.054 0.057
`0.042 0.045 0.048 0.051 0.054 0.057 0.060
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.046 0.050 0.053 0.056 0.059 0.063 0.066
`0.050 0.054 0.058 0.061 0.065 0.068 0.072
`0.055 0.059 0.062 0.066 0.070 0.074 0.078
`0.059 0.063 0.067 0.071 0.076 0.080 0.084
`0.063 0.068 0.072 0.077 0.081 0.086 0.090
`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 lnluoion me lo: 2.5 mglmL can be calculated using the following lormula: Patient weight (kg) x dose (W) x 0.000024.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.008 0.010 0.012 0.013 0.015 0.017 0.018 0.020 0021
`
`0.009 0.011 0.013 0.014 0.016 0.018 0.020 0.022 0.023
`
`0.010 0.012 0.014 0.016 0.018 0.020 0.021 0.023 0.025
`
`0.011 0.013 0.015 0.017 0.019 0.021 0.023 0.025 0.027
`
`0.011 0.014 0.016 0.018 0.020 0.023 0.025 0.027 0.029
`
`0.012 0.014 0.017 0.019 0.022 0.024 0.026 0.029 0.031
`0.013 0.015 0.018 0.020 0.023 0.026 0.028 0.031 0.033
`
`0.014 0.016 0.019 0.022 0.024 0.027 0.030 0.032 0.035
`
`0.014 0.017 0.020 0.023 0.026 0.029 0.031 0.034 0.037
`
`0.015 0.018 0.021 0.024 0.027 0.030 0.033 0.036 0.039
`
`0.017 0.020 0.023 0.026 0.030 0.033 0.036 0.040 0.043
`0.018 0.022 0.025 0.029 0.032 0.036 0.040 0.043 0.047
`
`0.020 0.023 0.027 0.031 0.035 0.039 0.043 0.047 0.051
`
`0.021 0.025 0.029 0.034 0.038 0.042 0.046 0.050 0.055
`0.023 0.027 0.032 0.036 0.041 0.045 0.050 0.054 0.059
`
`0.024 0.029 0.034 0.038 0.043 0.048 0.053 0.058 0.062
`
`

`

`Table 6
`
`Dose
`
`5.0 mg/mL Concentration of Remodulinm
`Pump Infusion Rate Setting (lehr) for 5.0 mglmL Remodulin
`Patient Wei ht k
`
`n umin
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`75
`0.009
`
`0.011
`
`0.014
`
`0.016
`
`0.018
`
`0.020
`0.023
`0.025
`
`0.010
`
`0.012
`0.014
`
`0.017_
`0.019
`
`0.022
`
`0.024
`
`0.026
`
`0.027
`
`0.029
`
`0.029
`
`0.031
`0.034
`
`80
`
`85
`
`90
`
`95
`
`100
`
`0.011 0.011 0.012
`
`0.014
`
`0.014
`
`0.016
`
`0.017
`
`0.015
`0.018
`
`0.019
`
`0.020
`
`0.021
`
`0.022
`
`0.023
`
`0.024
`
`0.024
`0.027
`
`0.030
`
`0.032
`
`0.035
`
`0.038
`
`0.026
`
`0.027
`
`0.029
`
`0.030
`
`0.031
`0.034
`
`0.037
`0.040
`
`0.033
`0.036
`
`0.039
`
`0.042
`
`
`
`
`
`0.036
`
`0.038
`
`0.038
`0.041
`
`0.041
`
`0.043
`
`0.043
`
`0.046
`
`0.045
`
`0.050
`
`0.048
`0.053
`
`0.054
`
`0.058
`
`0.059
`
`0.062
`
`0.063
`
`0.067
`
`0.068
`
`0.072
`
`0.043
`
`0.046
`
`0.048
`
`0.046
`
`0.048
`
`0.051
`
`0.049
`0.051
`
`0.051
`
`0.054
`
`0.054
`
`0.057
`
`0.054
`
`0.057
`
`0.060
`
`0.059
`
`0.063
`
`0.065
`
`0.068
`
`0.066
`0.072
`
`0.070
`
`0.074
`
`0.078
`
`0.076
`
`0.080
`
`0.084
`
`0.081
`
`0.086
`
`The infusion motor the 5 mglmL concentration can be calculated byus‘mg the toiiowing formula: Patientwcigm (kg) x dose (Mg/min) x 0.000012.
`
`0.072
`
`0.077
`
`0.086
`
`0.091
`
`0.032
`0.034
`
`0.036
`
`0.041
`
`0.043
`
`0.045
`
`
`
`A1,-._.-,..
`
`0.090
`0.096
`
`/
`
`

`

`Table 7
`
`10.0 mglmL Concentration of Remodulinm
`Pump Infusion Rate Setting (mLIhr) for 10.0 mglmL Remodulin
`ht k
`Patient Wei .
`
`n 2 Ik :. min
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`70
`
`
`
`
`
`.0..,....2...._
`
`2'”.
`
`_
`
`80
`
`85
`
`90
`
`95
`
`100
`
`0.026 0.027
`
`0.029 0.03I
`
`0.028 0.030
`0.031 0.032
`
`0.033
`
`0.036 0.038
`0.038 0.041
`
`0.041 0.043
`
`0.043 0.046
`
`0.046 0.049
`
`0.048 0.051
`0.051 0.054
`
`
`
`0.011 0.012
`
`0.012 0.013
`
`0.013 0.014
`
`0.014 0.016
`
`0.015 0.017
`
`0.016 0.018
`
`0.017 0.019
`0.018 0.020
`
`0.019 0.022
`
`0.020 0.023
`0.021 0.024
`
`0.020 0.021
`
`0.021 0.023
`
`0.023 0.025
`
`75
`0.023
`
`0.025
`0.027
`
`0.025 0.027
`
`0.029
`
`0.027 0.029
`
`0.032
`
`0.029 0.032
`0.031 0.034
`
`0.033 0.036
`0.035 0.038
`
`0.037 0.040
`0.039 0.042
`
`0.034
`0.036
`
`0.038
`0.041
`
`0.043
`0.045
`
`The infusion mm for the 10 mglmL concentration can be calculated by using the ioliowing formats: Patient weight (kg) x do“ (nglkglmin) x 0.000006
`
`\../’
`
`

`

`NDA 21-272
`
`Page 15
`
`HOW SUPPLIED
`
`Remodulinm 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 m1. contains treprostinil
`sodium equivalent to 1.0 rug/mL, 2.5 rug/mL, 5.0 mm, or 10.0 mg/mL trepnostinil. Unopened vials ofRemodulin 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 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 trepmstinil sodium equivalent to 1.0 mg treprostinil per mL, carton of l
`(NDC 66302-101—01).
`
`20-mL vial containing treprostinil sodium equivalent to 2.5 mg treprostinil per mL, carton of l
`(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 l
`(NDC 66302-110-01).
`
`US Patent No. 5,153,222 (Use Patent)
`
`United Therapeutics Corp.
`Research Triangle Park, NC 27709
`
`©Copyright 2002 United Therapeutics Corp. All rights reserved.
`
`REMODULIN manufactured by:
`
`Baxter Pharmaceutical Solutions LLC
`
`Bloomington, IN 47403
`
`For United Therapeutics Corp. '
`Research Triangle Park, NC 27709
`
`Rx only
`
`March 2002
`
`

`

`
`
`[‘x
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`-_—--———-——--———————_—
`
`Robert Temple
`5/21/02 06:01:00 PM
`
`
`
`