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`
`
`
`Exhibit C
`
`

`
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`NDA 21-272/S-005
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`PRODUCT INFOR1\-1A TION
`
`REMODULI:-.1'"' (treprostinil sodium) Injection
`
`DESCRIPTION
`
`Remoduim~' (treprostinil sodium) Injection is a sterile sodium salt formulated for subcutaneous or mtravenous
`administration. Remodulin is supplied 111 20 mL multi-use vials in four strengths, containing l mg/mL,
`2 5 mg/mL, 5 mg/mL or 10 mg/mL oftreprostinil. Each mL also contams 5.3 mg sodmm chlonde (except tor
`the 10 mg/mL strength which contains 4.0 mg sodium chloride), 3.0 mg metacresol, 6.3 mg sodium citrate, and
`water for injection. Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2.
`
`Treprostinil is chemically stable at room temperature and neutral pH.
`
`Treprostinil sodium is ( 1 R,2R,3aS,9aS)-[[2,3 ,3a,4 .9 ,9a-Hexahydro-2-hydroxy-l-[ (3S )-3-hydroxyoctyl j-!H(cid:173)
`benz[f]indcn-5-yl]oxy]acetic acid monosodium salt Treprostinil sodium has a molecular weight of 412.49 and
`a molecular fonnula ofC:JH33NaOs.
`
`The structural fom1Ula oftreprostinil sodium is:
`
`OH
`
`+
`Na
`
`CLINICAL PHARMACOLOGY
`General: TI1c major phannacologic actions of treprostinil are direct vasodilation of pulmonary and systemic
`artcnal vascular beds and mhibition of platelet aggregation. In animals, the vasodilatoG· effects reduce right and
`left ventricular aftcrload and mcreasc cardiac output and stroke volume. Other studies have shown that
`treprostinil causes a dose-related negati\'C motrop1c ~md lus!tropic effect. No maJor effects on cardiac conductiOn
`have been observed.
`
`Pharmacokinetics
`The pharmacokinetics of continuous subcutaneous Remodulin arc linear over the dose range of I .25 to 22.5
`nglkg/min (corresponding to plasma concentrations of about 0.03 to 8 mcg/L) and can be described by a two(cid:173)
`compartment model. Dose proportionality at infusion rates gre:..tter than 22.5 nglkg/min has not been studied.
`
`Subcutaneous and mtravenous adnunistration of Rcmodulin demonstrated biocquivalencc at stcadv state at a
`dose or I 0 ng/kg/min
`
`Absomtion: Rcmodulin JS rclativeh rapidlY and completeh absorbed after subcutaneous mfus10n. With an
`absolute bioavailabilit~ approximating I 00°0. Swady-statc conccntrauons occurred Ill approximately 10 hours
`Concentrations in patients treated with an average dose of lJ. 3 ng/kgmun \\ere approximate! y 2 mcg/L
`
`Distribution TI1e volume of distribution or tbe drug in the central compartment IS approximately l4L/70 kg
`Ideal body weight Remodulin at m vi rro concentrations ranging from 3 30-1 0, 000 mcg/L was 91 'Yo bound to
`human plasma protein.
`
`EXHIBIT
`
`Miller 14
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`Metabolism: Remodulin is substantially metabolized by the liver, but the precise enzymes responsible are
`unkno·wn. Five metabolites have been described (HUl through HU5). The biological activity and metabolic fate
`ofthese metabolites are unknown. The chemical structure ofHUl is unknown. HU5 is the glucuronide
`conJugate of trcprostinil. The other metabolites arc formed by oxidation ofthc 3-hydroxyoctyl side chain (HU2)
`and subsequent additional oxidation (HU3) or dehydration (HU4). Based on the results ofm vitro human hepatic
`cy1ochrome P450 studies, Remodulin does not inhibit CYP-1A2. 2C9. 2Cl9, 2D6, 2El, or 3A. Whether
`Rcmodulin induces these enzymes has not been studied.
`
`ExcretiotL The elimination of Remodulin is biphasic, with a terminal half-life of approximate!: 4 hours.
`Approximately 79% of an administered dose is excreted in the urine as tmchanged drug (4%) and as the
`identified metabolites ( 64%). Approximately 13% of a dose is excreted in the feces. Systemic clearance is
`approximately 30 literslhr for a 70 kg ideal body weight person.
`
`Special Populations
`
`with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic
`-'-""¥""~~~""""~~In
`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 an AUC n.~ that \Vas increased 3-fold and 5-fold, respectively, compared to
`healthy subjects. Clearance in patients \Vith hepatic insufficiency was reduced by up to 80% compared to
`healthy adults.
`
`In patients with mild or moderate hepatic insufficiency, the initial dose ofremodulin 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 lnsufficiencv: No studies have been perfom1ed 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.
`
`f,ffect of Other Drugs on Remodulin: In vitro studies: Remodulin did not stgnificantly affect the plasma protein
`binding of nom1ally observed concentrations of digoxin or vvarfarin.
`
`In vivo studies: Acetaminophen -Analgesic doses of acetaminophen, 1000 mg every 6 hours for seven doses,
`did not affect the pham1acokinetics of Remodulin, at a subcutaneous infusion rate of 15 nglkg/min.
`
`Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`
`Two 12-week, multicenter, randomized, double-blind studies compared continuous subcutaneous infusion of
`Remodulin to placebo in a total of 470 patients with N'YHA Class TI-N 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 nght shunts in 23%. The mean age -..vas 45 (range 9 to 75 years). About 81% were female and
`84'% were Caucasian. Pulmonary hypertension had been diagnosed for a mean of3.8 years. The primary
`endpoint of the studies was change in 6-minute walking distance, a standard measure of exercise capacity 1l1ere
`were many assessments of symptoms related to heart failure, but local discomfort and pain associated with
`Remoduhn 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) vvcre
`admimstered by a person not participating 111 other aspects of the study. Remodulin was administered as a
`subcutaneous infusion. described in DOSAGE AND ADMINSTRATION, and the dose averaged 9.3 nglkg/min
`at Week 12. Few subjects received doses> 40 ng/kg/min. Background therapy, detennined by the investigators.
`could include anticoagulants. oral vasodilators. diuretics. digoxin, and oxygen but not an endothelin receptor
`antagonist or epoprostenol. 1l1c two studies were identical in design and conducted simultaneously. and the
`results were analyzed both pooled and individually.
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`Hemodynamic Effects
`
`As shown in Table l. chronic therapy with Remodulin resulted in small hemody11amic changes consistent with
`pulmonary and systemic vasodilation.
`
`Table 1: Hemodynamics During Chronic Administration ofRemodulin in Patients with PAH in 12-Week
`Studies
`
`I
`
`I
`I
`
`I 2.4±088
`
`Baseline
`Remodulin
`Placebo
`(N=204-231)
`(N=215-235)
`
`Mean change from baseline at Week 12
`Remodulin
`Placebo
`(N=163-199)
`(N=l82-215)
`
`2.2 ± 0.74
`
`I +0.12 ± 0.58*
`I
`
`I
`
`-0.06 ± 0.55
`
`i
`
`Hemodynamic
`Parameter
`CT
`(Liminlm")
`PAPm
`(mmHg)
`RAPm
`(mmHg)
`PVR.l
`~ (mmHg/Limin/m 2
`II
`SVR.l
`I i (mmHg/Limin/m 2
`Sv02
`I!
`(%)
`I
`I
`SAPm
`I
`I
`(mmHg)
`I
`HR
`I
`(bpm)
`'
`l
`I
`*Denotes statistically significant difference between Remodulin and placebo. p<0.05.
`CI
`cardiac index: PAPm =mean pulmonary arterial pressure: PVRI pulmonary Yascular resistance
`indexed: RAPm =mean right atrial pressure: SAPm mean systemic arterial pressure: SVRI = systemic
`vascular resistance indexed: SvO: mixed venous oxygen saturation: HR heart rate.
`
`li
`
`11
`
`li
`II
`
`1:
`
`II
`I
`I
`
`II
`
`I
`
`)
`
`)
`
`I
`I
`
`i
`
`I
`I
`I
`
`I
`
`62± 17.6
`
`60 ± 14.8
`
`-2.3 ± 7.3*
`
`+0.7 ± 8.5
`
`10±5.7
`
`10 ± 5.9
`
`-0.5 ± 5.0*
`
`+1.4±4.8
`
`26± 13
`
`25 ± 13
`
`-3.5 ± 8.2*
`
`-'-1.2±7.9
`
`38 ± 15
`
`39 ± 15
`
`-3.5 ± 12*
`
`-0.80 ± 12
`
`62±100
`
`I
`
`90± 14
`
`60 ± 11
`
`+2.0 ± 10*
`
`-1.4±8.8
`
`91±14
`
`-1.7± 12
`
`-1.0 ± 13
`
`II
`i
`I
`
`82 ± 13
`
`82 ± 15
`
`-0.5 ± 11
`
`-0.8 ± ll
`
`Clinical Effects
`
`The effect of Remodulin on 6-minute walk. the primary end point of the 12-wcck studies, was small and did not
`achieve conventional levels of statistical significance. For the combined populations. the median change from
`baseline on Remodulin \\'as l 0 meters and the median change from baseline on placebo was 0 meters from a
`baseline of approximately 345 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.
`
`Flolan-to-Remodulin Transition Study
`
`In an 8-week. multicenter. r<mdomized. double-blind. placebo-controlled study. patients on stable doses of
`Flolan were randomly withdrawn from Flolan to placebo or Remodulin. Fourteen Remodulin and 8 placebo
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`patients completed the study. TI1e primary endpoint of the study was the time to clinical deterioration, defined as
`either an increase in Flolan dose. hospitalization due to PAH. or death. No patients died during the study.
`
`During the study period, Remodulin effectively prevented clinical deterioration in patients transitioning from
`Flolan therapy compared to placebo (Figure 1 ). Thirteen of 14 patients in the Remodulin arm were able to
`transition from Flolan successfully, compared to only 1 of 8 patients in the placebo ann (p=0.0002).
`
`Figure 1: Time to Clinical Deterioration for P AH Patients Transitioned from Flo Ian to Remodulin or
`Placebo in an 8-Week Study
`
`100
`
`90
`
`80
`
`70
`
`60
`
`i
`&l
`=
`.Sl
`~
`.!3
`'"' il
`Q ...
`..
`:5
`u
`"'
`'S
`=
`..s
`20
`~ 10
`'1.
`
`50
`
`40
`
`30
`
`0
`
`p=0.000228
`
`"---- -----
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`Days on Study
`
`INDICATIONS AND LSAGE
`
`Remodulin'"' is indicated as a continuous subcutaneous mfuswn or intravenous infusion (for those not able to
`tolerate a subcutaneous infusion) for the treatment of pulmonary arterial hypertension in patients with NYK.<\
`Class II-IV symptoms (see CLINICAL PHARMACOLOGY: Clinical Effects) to diminish sv1nptoms
`associated with exercise
`
`Remodulin is indicated to diminish the rate of clinical deterioration in patients requiring transition from Flolan"";
`the risks and benefits of each drug should be carefullY considered prior to transition.
`
`CONTRATNDICA TIONS
`Remodulin is contraindicated in patients vvith known hypersensitivity to the drug or to structurally related
`compounds.
`
`WARNINGS
`
`Remodulin is indicated for subcutaneous or intravenous use only.
`
`PRECAUTIONS
`
`General
`
`Remoclulin should be used only by clinicians experienced in the diagnosis and treatment ofPAH
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`Remodulin is a potent pulmonary and systemic vasodilator. Initiation of Remodulin must be performed in a
`setting with adequate personnel and equipment for physiological monitoring and emergency care. Therapy with
`Remodulin may be used for prolonged periods, and the patient's ability to administer Remodulin and care for an
`infusion system should be carefully considered.
`
`Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be decreased for
`infusion site symptoms (see DOSAGE AND
`excessive pham1acologic effects or for unacceptable
`ADMINISTRATION)
`
`Abrupt withdrawal or suddt:n largt: reductions in dosage of Remodulin may result in worsening of PAH
`symptoms and should be avoided.
`
`Information for Patients
`
`Patients receiving Rcmodulin should be given the follovving information: Remodulin is infused continuously
`through a subcutaneous or surgically placed indwelling central venous catheter, via an infusion pump. Therapy
`with Remodulin will be needed for prolonged periods. possiblY vears. and the patient's ability to accept and care
`for a catheter and to use an infusion pump should be carefully considered. In order to reduce the risk of
`infection, aseptic technique must be used in the preparation and administration ofRemodulin. Additionally,
`patients should be av,:are that subsequent disease management may require the initiation of an alternative
`intravenous prostacyclin therapy, Flolan~ (epoprostenol sodium).
`
`Drug Interactions
`
`Reduction in blood pressure caused by Remodulin may be exacerbated by drugs that by themselves alter blood
`pressure, such as diuretics, antihypertensive agents, or vasodilators. Since Remodulin inhibits platelet
`aggregation, there is also a potential for increased risk of bleeding, particularly among patients maintained on
`anticoagulants. During clinical trials, Remodulin was used concurrently with anticoagulants, diuretics, cardiac
`glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids,
`corticosteroids. and other medications.
`
`Remodulin has not been studied in conjunction with Flolan or Tracleer'"' (bosentan)
`
`Effect of Other Drugs on Remodulin
`In vivo studies: Acetaminophen - Analgesic doses of acetaminophen, I 000 mg every 6 hours for seven doses,
`did not affect the phannacokinctics of Remodulm, at a subcutaneous infusion rate of 15 ng/kg/min
`
`Effect of Remodulin on Other Drugs
`
`In vitro studies: Remodulin did not sigmficantly affect the plasma protein binding of nom1ally observed
`concentrations of digoxin or \varfarin.
`
`In vivo studies: Warfarin Remodulin does not affect the phannokinetics or phannacodymamies of warfann
`The pham1acokinetics of R-and S- \varfarin and the INR in healthy subjects given a single 25 mg dose of
`vvarfarin \Yere unaffected by continuous subcutaneous Re!'nodulin at an infusion rate of 10 ng/kg/min.
`
`Hepatic and Renal Impairment
`
`Caution should be used in patients w1th hepatic or renal impam11ent (see Special Populations).
`
`Carcinogenesis, Mutagenesis, Impai1·ment ofF ertility
`
`Long-tcm1 studies have not been pcrfonncd to evaluate the carcinogenic potential of trcprostinil. In vztro and 111
`vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic effects oftreprostinil.
`Treprostinil sodium did not affect fertility or mating perfom1ar1ce of male or female rats given continuous
`subcutar1eous infusions at rates of up to 450 ng trcprostinil/kg/min [about 59 times the recommended starting
`human rate of infusion (I .25 ng/kg/min) ar1d about 8 times the average rate (9 .3 ng/kg/min) achieved in clinical
`
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`trials, on a ng/m2 basis]. In this study, males \Vere dosed from l 0 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
`
`Pregnancy Category B -In pregnant rats, continuous subcutaneous infusions oftreprostinil sodium during
`organogenesis and late gestational development, at rates as high as 900 ng treprostinillkg/min (about 117 times
`the starting human rate of infusion, on a ng/m: basis and about 16 times the average rate achieved in clinical
`trials), resulted in no evidence of han11 to the fetus. In pregnant rabbits, effects of continuous subcutaneous
`infusions of treprostinil during organogenesis were lim1ted to an increased incidence of fetal skeletal variations
`(bilateral full rib or right rudimentary rib on lumbar 1) associated v.:ith 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 oftreprostinil from implantation to the end oflactation, at rates of up to 450 ng
`treprostinillkg/min, did not affect the grov,th and development of offspring. Because animal reproduction
`studies are not
`of human response, Remodulin should be used
`pregnancy only if deariy
`needed.
`
`Labor and delivery
`No treprostinil sodium treatment-related effects on labor and delivery were seen in animal studies. TI1e effect of
`treprostinil sodium on labor and delivery in hwnans is unknown.
`
`Nursing mothers
`It is not known whether treprostinil is excreted 111 human milk or absorbed systemically after ingestion. Because
`many dmgs are excreted in human milk, caution should be exercised when Rcmodulin is administered to
`nursing women.
`
`Pediatric use
`Safety and effectiveness in pediatric patients have not been established. Clinical studies of Remodulin did not
`mclude sufficient numbers of patients aged :::_16 years to detem1ine 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 detennine
`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
`drsease or other drug therapy.
`
`ADVERSE REACTIONS
`
`Patients receiving Remodulin as a subcutaneous infusion reported a wide range of adverse events. many
`potentially related to the underlying disease (dyspnea. fatigue, chest pain, right ventricular heart failure. and
`pallor). During clinical trials with subcutaneous infusion of Rcmodulin. infi.1sion site pain and reaction were the
`most common adverse events among those treated \\ith Remodulin. Infusion site reaction was defined as an~
`local adverse event other than pain or bleeding/bruismg at the infi.tsion site and included symptoms such as
`erythema. induration or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of
`treatment. In addition. generalized rashes, sometimes macular or papular in nature, and cellulitis have been
`mfrequently reported in postmarketing expenence.
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`Table 2. Percentages of subjects reporting subcutaneous infusion site adverse
`events
`Reaction
`
`Placebo
`
`Pain
`Remodulin
`
`Placebo fm:duli
`
`38
`Severe
`1
`NA**
`NA**
`Requiring narcotics*
`I
`"
`Leading to discontinuation
`0
`* based on prescnptwns for narcot1cs, not actual use
`**medications used to treat infusion site pain were not distinguished from those
`used to treat site reactions
`
`2
`1
`0
`
`..)
`
`I
`
`39
`32
`7
`
`Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these arc generally
`considered to be related to the pharmacologic effects of Remoduhn, \vhether admrmstered subcutaneously or
`intravenously.
`
`Adverse Events During Chronic Dosing
`
`Table 3 lists adverse events that occurred at a rate of at least 3% and were more frequent in patients treated with
`subcutaneous Remodulin than with placebo in controlled trials in PAH
`
`Table 3: Adverse Events in Controlled 12-Week Studies of Patients with
`P AH, Occurring with at Least 3% Incidence and More Common on
`Subcutaneous Remodulin than on Placebo.
`Remodulin
`Adverse Event
`(N=236)
`Percent of Patients
`85
`83
`27
`25
`22
`14
`13
`11
`9
`9
`8
`4
`
`Placebo
`(N=233)
`Percent of Patients
`27
`27
`23
`16
`18
`II
`5
`5
`8
`3
`6
`2
`
`I
`
`lnfi.1sion Site Pain
`Infusion Site Reaction
`Headache
`· Diarrhea
`Nausea
`Rash
`Jaw Pain
`VasodilatatiOn
`Dizziness
`Edema
`Pruritus
`Hypotension
`
`Reported adverse events (<It least :1%)) arc included except those too general to he informative and those not
`plausibly attributable to the usc of the drug. because the~· were associated \vith the condition being treated or arc
`very common in the treated population.
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`Adverse Events Attributable to the Drug Delivery System
`
`In controlled studies of Rcmodulin administered subcutaneously, there -vvcrc no reports of infection related to the
`dmg delivery system. There were 187 infusion system complications reported in 28% of patients (23%
`Remodulin, 33% placebo): 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these
`patients (4 Remodulin, 4 Placebo) reported non-serious adverse events resulting from infusion system
`complications. Adverse events resulting from problems with the delivery systems were typically related to
`either symptoms of excess Remodulin (e.g., nausea) or return of P AH symptoms (e.g .. dyspnea). TI1ese events
`were general!; resolved by correcting the deli very system pump or infusion set problem such as replacing the
`syringe or battery, reprogramming the pump, or straightening a crimped infusion line. Adverse events resulting
`from problems ':vith the delivery system did not lead to clinical instability or rapid deterioration.
`
`TI1ere are no controlled clinical studies -vvith Remodulin administered intravenously. Among the subjects (n=38)
`treated for 12-weeks in an open-label study, 2 patients had either line infections or sepsis. Other events
`potentially related to the mode of infusion include arm swelling, paresthcsias, hematoma and pain.
`
`OVERDOSAGE
`
`Signs and s~mptoms of overdose with Remodulin during clinical trials are extensions of its dose-limiting
`pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea Most
`events were self-limiting and resolved with reduction or withholding ofRemodulin.
`
`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 concem (hypotension, near-syncope).
`
`One pediatric patient was accidentally administered 7.5 mg ofRemodulin via a central venous catheter.
`Symptoms included flushing, headache, nausea, vomiting, hypotension and seizure-like activity ·with loss of
`consciousness lasting several mmutes. The patient subsequently recovered.
`
`DOSAGE AND ADMINISTRATION
`
`RemodulinCR: is supplied in 20 mL vials in concentrations of l mg/mL, 2.5 mg/mL 5 mg/mL and
`I 0 mg/mL Remodulin can be administered as supplied or diluted for intravenous infusion with Sterile Water for
`Injection or O.Y% Sodium Chlondc Injection pnorto admimstrat10n.
`
`Initial Dose for Patients New to Pmstacyclin Infusion Therapy
`
`Remodulin is administered by continuous infusion. Remodulin is preferabiy infused subcutaneously, but can be
`administered by a central intravenous line if the subcutaneous route is not tolerated, because of severe site pain
`or reaction. The mfusion rate is initiated at 1.25 ng/kg/min. If this initial dose cam10t be tolerated because of
`systemic effects. the infusion rate should be reduced to 0 625 ng/kgimin.
`
`Dosage Adjustments
`
`The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while
`minimizing excessive phannacologic effects of Remoduiin (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/mm per week for the rc:mainmg duration of infusion, depending on
`clinical response. Th~:re is little experience ·with doses >40 ng/kg/min. Abrupt cessation of infusion should be
`avoided (see PRECAUTIONS)
`
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`Case 3:14-cv-05499-PGS-LHG Document 41-7 Filed 07/07/15 Page 10 of 15 PageID: 435
`
`NDA 21-272/S-005
`Page 11
`
`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 must have immediate access to a backup infhsion pump and subcutaneous infusion sets.
`The ambulatory infusion pump used to administer Remodulin should: ( l) 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 alanns, ( 4) have delivery accuracy of ±6%) or better and ( 5) be positive pressure driven. TI1e
`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 (syrmge) of undiluted Remodulin can be administered up
`to 72 hours at 3 7°C. The Subcutaneous Infusion rate is calculated using the following fommla:
`
`Subcutaneous
`Infusion Rate
`(mL!hr)
`
`Dose
`(ng/kg/min)
`
`Weight
`(kg)
`
`X
`
`X 0.00006*
`
`Remodulin Vial Strength
`(mg/mL)
`
`*Conversion/actor ofO. 00006
`
`60 min hour x 0.000001 mgng
`
`Example calculations for Subcutaneou-5 Infusion are as follovvs:
`
`Exam pie 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:
`
`1.25 ng/kg/min
`
`x
`
`60 kg
`
`x 0.00006
`
`1 mg/mL
`
`= 0.005
`mL/hr
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`Example 2:
`
`For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin Vial Strength. the infusion
`rate would be calculated as follows:
`
`Subcutaneous
`Infusion Rate
`(mL11f)
`
`40 ng/kghmn
`
`x
`
`65 kg
`
`x
`
`0.00006
`
`5 mg/mL
`
`= 0.031
`mL/hr
`
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`Case 3:14-cv-05499-PGS-LHG Document 41-7 Filed 07/07/15 Page 11 of 15 PageID: 436
`NDA 21-272/S-005
`Page 12
`
`Intravenous Infusion
`
`Remodulin must be diluted with either Sterile Water for Injection or 0.9% Sodium Chloride Injection and
`is administered intravenously by continuous infusion. via a surgically placed indwelling central venous catheter,
`using an infusion pump designed for intravenous drug delivery. To avoid potential interruptions in drug
`delivery, the patient must have immediate access to a backup infusion pump and infusion sets. TI1c 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 alanns, (3) have delivery accuracy of ±6% or
`better of the hourly dose, and ( 4) be positive pressure driven. The reservoir should be made of polyvinyl
`chloride, polypropylene or glass.
`
`Diluted Remodulin has been shown to be stable at ambient temperature for up to 48 hours at concentrations as
`low as 0.004 mg/mL (4,000 ng/mL).
`
`When using an appropriate infusion pump and reservmr, a predetermined intravenous infusion rate should first
`be selected to allow for a desired infusion period length of up to 48 hours betv.een system changeovers. Typical
`intravenous infusion system reservoirs have volumes of 50 or 100 mL With this selected Intravenous Infusion
`Rate (mL!hr) and the patient's Dose (ng/kg/min) and Weight (kg), the Diluted Intravenous Remodulin
`Concentration (mg/mL) can be calculated using the following formula:
`
`Step 1
`Diluted
`Intravenous
`Remodulin
`Concentration
`(mg/mL)
`
`Dose
`(ng!kg/min)
`
`X
`
`Weight
`(kg)
`
`X
`
`0.00006
`
`Intravenous Infusion Rate
`(mL/hr)
`
`The Amount ofRemodulin li1Jection needed to make the required Diluted Intravenous Remodulin Concentration
`for the given reservoir size can then be calculated using the following fonnula
`
`Step 2
`Amount of
`Remodulin
`Injection
`(mL)
`
`Diluted Intravenous
`Remodulin
`Con cent ration
`(mg/mL)
`------------------- X
`Remodulin Viai
`Strength
`(mg/mL)
`
`Total Volume of Diluted
`Remodulin Solution in
`Reservoir
`(mL)
`
`The calculated amount of Remodulin InJection is then added 10 the reservoir along with the sufficient volume of
`diluent (Sterile Water for Injection or 0.9% Sodium Chloride InJection) to achieve the desired total volume in
`the reservoir.
`
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`Case 3:14-cv-05499-PGS-LHG Document 41-7 Filed 07/07/15 Page 12 of 15 PageID: 437
`
`NDA 21-272/S-005
`Page 13
`
`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 Rcmodulin Solution Concentration vYould be
`calculated as follows:
`
`Step 1
`Diluted
`Intravenous
`Remodulin
`Concentration
`(mg/mL)
`
`5 ng/kg/min
`
`X
`
`60kg
`
`X
`
`0.00006
`
`lmL/hr
`
`= 0.018 mg/mL
`
`(18,000 ng/mL)
`
`The Amount ofRemodulin Injection (using 1 mg/mL Vial StrengtJ1) needed for a total
`Remodulin Concentration of 0.018 mg/mL and a total volume of 50 mL would be calculated as follows:
`
`Step 2
`
`Amount of
`Remodulin Injection
`(mL)
`
`0.018 mg/mL
`
`1 mg/mL
`
`x 50 mL = 0.9 mL
`
`The Diluted Intravenous Remodulin Concentration for the person in Example 3 \Vould thus be prepared
`by adding 0.9 mL of I 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.
`
`Example4:
`
`For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion rate of2
`mL/hr. and a reservoir of 100 mL the Diluted Intravenous Remodulin Solution Concentration would be
`calculated as follows:
`
`Step 1
`Diluted
`Intravenous
`Remodulin
`Concentration
`(mg/mL)
`
`30 ng/kg/min
`
`X
`
`75 kg
`
`X
`
`0.00006
`
`2 mL/hr
`
`= 0.0675 mg/mL
`(67.500 ng/mL)
`
`The Amount ofRemodulin Injection (using 2.:' mg/mL Vial Strength) needed for a total Diluted
`Rcmodulin Concentration ofO 0675 mg/mL and a total volume of I 00 mL would be calculated as
`follows·
`
`Step 2
`
`Amount of
`Remodulin Injection
`(mL)
`
`0.0675 mg/mL
`
`2.5 mg/mL
`
`x 100 mL
`
`2.7 mL
`
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`Case 3:14-cv-05499-PGS-LHG Document 41-7 Filed 07/07/15 Page 13 of 15 PageID: 438
`NDA 21-272/S-005
`Page 14
`
`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.
`
`In patients requiring transition from Flolan:
`Transition from Flolan to Rcmodulin is accomplished by initiating the infusion ofRcmodulin and increasing it,
`while simultaneously reducing the dose of intravenous Flolan. The transition to Remodulin should take place in
`a hospital with constant observation of response (t:.g., v.alk distanct: and signs and symptoms of disease
`progression). During the transition, Remodulin is initiated at a recommended dose of 10% of the current Flolan
`dose, and tht:n t:scalated as the Flolan dose is decreased (st:e Table 4 for recommended dose titrations).
`
`Patients are individually titrated to a dose that allows transition from Flolan therapy to Remodulin while
`balancing prostacylin-limiting adverse events. Increases in the patient's symptoms ofPAH should be first
`treated with increases in the dose of Remodulin. Side effects normally associated with prostacyclin and
`prostacyclin anal