`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`21-272/S-005
`
`Remodulin Injection 1.0, 2.5, 5.0, and 10 mg/ml.
`
`United Therapeutics Corporation
`
`Trade Name:
`
`treprostinil sodium
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`March 20, 2006
`
` Remodulin is indicated for the treatment of pulmonary
`arterial hypertension in patients with NYHA Class II-
`IV symptoms to diminish symptoms associated with
`exercise.
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-272/S-005
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
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`X
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`X
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`X
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`X
`X
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`Approval Letter
`Approvable Letter
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`21-272/S-005
`21-272/S-005
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`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
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`
`

`

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`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`NDA 21-272/S-005
`
`United Therapeutics Corporation
`Attention: Dean Bunce
`P.O. Box 14186
`One Park Drive
`Research Triangle Park, NC 27709
`
`
`Dear Mr. Bunce:
`
`Please refer to your supplemental new drug application dated October 12, 2005, received October 13,
`2005, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Remodulin
`Injection (treprostinil sodium) 1.0, 2.5, 5.0, and 10 mg/ml.
`
`We acknowledge receipt of your submissions dated February 1, 7, 8, 21 and March 6, 2006.
`
`This supplemental new drug application provides a final study report for Phase 4 commitments
`required as a condition of your May 21, 2002 Subpart H approval. Specifically, this supplement
`provides information to the labeling on the use of Remodulin Injection (treprostinil sodium) 1.0, 2.5,
`5.0, and 10 mg/ml for the treatment of patients with pulmonary arterial hypertension (PAH) requiring
`transition from Flolan®.
`
`We have completed our review of this application, as amended. This application is approved, effective
`on the date of this letter, for use as recommended in the agreed-upon labeling text.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling.
`
`The electronic labeling rule published December 11, 2003, (68 FR 69009) requires submission of
`labeling content in electronic format effective June 8, 2004. For additional information, consult the
`following guidances for industry regarding electronic submissions: Providing Regulatory
`Submissions in Electronic Format - NDAs (January 1999) and Providing Regulatory Submissions in
`Electronic Format – Content of Labeling (February 2004). The guidances specify that labeling to be
`submitted in pdf format. To assist in our review, we request that labeling also be submitted in MS
`Word format. If formatted copies of all labeling pieces (i.e., package insert, patient package insert,
`container labels, and carton labels) are submitted electronically, labeling does not need to be submitted
`in paper. For administrative purposes, designate this submission "FPL for approved supplement
`NDA 21-272/S-005.” Approval of this submission by FDA is not required before the labeling is used.
`
`We approved this NDA under the regulations at 21 CFR 314 Subpart H for accelerated approval of
`new drugs for serious or life-threatening illnesses. Approval of this supplement fulfills your
`commitments made under 21 CFR 314.510.
`
`
`

`

`NDA 21-272/S-005
`Page 2
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, please call:
`
`
`Mr. John David
`Regulatory Project Manager
`(301) 796-1059
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Enclosure: Agreed upon labeling text
`
`
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`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Norman Stockbridge
`3/20/2006 03:59:46 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`21-272/S-005
`21-272/S-005
`
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

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`NDA 21-272/S-005
`Page 3
`
`PRODUCT INFORMATION
`
`REMODULIN® (treprostinil sodium) Injection
`
`DESCRIPTION
`
`Remodulin® (treprostinil sodium) Injection is a sterile sodium salt formulated for subcutaneous or intravenous
`administration. Remodulin is supplied in 20 mL multi-use vials in four strengths, containing 1 mg/mL,
`2.5 mg/mL, 5 mg/mL or 10 mg/mL of treprostinil. Each mL also contains 5.3 mg sodium chloride (except for
`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 (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 pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic
`arterial vascular beds and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and
`left ventricular afterload and increase cardiac output and stroke volume. 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 mcg/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.
`
`Subcutaneous and intravenous administration of Remodulin demonstrated bioequivalence at steady state at a
`dose of 10 ng/kg/min.
`
`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 mcg/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 mcg/L was 91% bound to
`human plasma protein.
`
`

`

`NDA 21-272/S-005
`Page 4
`
`Metabolism: Remodulin is substantially metabolized by the liver, but the precise enzymes responsible are
`unknown. Five metabolites have been described (HU1 through HU5). The biological activity and metabolic fate
`of these metabolites are unknown. The chemical structure of HU1 is unknown. HU5 is the glucuronide
`conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2)
`and subsequent additional oxidation (HU3) or dehydration (HU4). Based on the results of in vitro human hepatic
`cytochrome P450 studies, Remodulin does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether
`Remodulin induces these enzymes has not been studied.
`
`Excretion: The elimination of Remodulin is biphasic, with a terminal half-life of approximately 4 hours.
`Approximately 79% of an administered dose is excreted in the urine as unchanged drug (4%) and as the
`identified metabolites (64%). Approximately 13% of a dose is excreted in the feces. Systemic clearance is
`approximately 30 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 an AUC 0-∞ that 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 continuous subcutaneous infusion of
`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.
`
`
`
`

`

`NDA 21-272/S-005
`Page 5
`
`
`
`Hemodynamic Effects
`
`As shown in Table 1, chronic therapy with Remodulin resulted in small hemodynamic changes consistent with
`pulmonary and systemic vasodilation.
`
`Table 1: Hemodynamics During Chronic Administration of Remodulin in Patients with PAH in 12-Week
`Studies
`
`
`Baseline
`Remodulin
`Placebo
`(N=204-231)
`(N=215-235)
`2.4 ± 0.88
`2.2 ± 0.74
`
`Mean change from baseline at Week 12
`Remodulin
`Placebo
`(N=163-199)
`(N=182-215)
`+0.12 ± 0.58*
`-0.06 ± 0.55
`
`
`Hemodynamic
`Parameter
`CI
`(L/min/m2)
`PAPm
`(mmHg)
`RAPm
`(mmHg)
`PVRI
`(mmHg/L/min/m2)
`SVRI
`(mmHg/L/min/m2)
`SvO2
`(%)
`SAPm
`(mmHg)
`HR
`-0.8 ± 11
`-0.5 ± 11
`82 ± 15
`82 ± 13
`(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.
`
`62 ± 17.6
`
`60 ± 14.8
`
`10 ± 5.7
`
`26 ± 13
`
`38 ± 15
`
`62 ± 100
`
`90 ± 14
`
`10 ± 5.9
`
`25 ± 13
`
`39 ± 15
`
`60 ± 11
`
`91 ± 14
`
`-2.3 ± 7.3*
`
`-0.5 ± 5.0*
`
`-3.5 ± 8.2*
`
`-3.5 ± 12*
`
`+2.0 ± 10*
`
`-1.7 ± 12
`
`+0.7 ± 8.5
`
`+1.4 ± 4.8
`
`+1.2 ± 7.9
`
`-0.80 ± 12
`
`-1.4 ± 8.8
`
`-1.0 ± 13
`
`Clinical Effects
`The effect of Remodulin on 6-minute walk, the primary end point of the 12-week 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 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, randomized, 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
`
`

`

`NDA 21-272/S-005
`
`Page 6
`
`patients completed the study. The 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.
`
`Dining the study period, Remodulin effectively prevented clinical deterioration in patients transitioning from
`Flolan therapy compared to placebo (Figure l). 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 arm (p=0.0002).
`
`Figure 1: Time to Clinical Deterioration for PAH Patients Transitioned from Flolan to Remodulin or
`Placebo in an 8-Week Study
`
`”WM-WWW
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`96888883885
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`INDICATIONS AND USAGE
`
`RemodulinD is indicated as a continuous subcutaneous infusion or intravenous infusion (for those not able to
`tolerate a 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.
`
`Remodulin is indicated to diminish the rate of clinical deterioration in patients requiring transition from Flolanoz
`the risks and benefits of each drug should be carefully considered prior to transition.
`
`CONTRAINDICATIONS
`
`Remodulin is contraindicated in patients with known hypersensitivity to the drug or to structurally related
`compounds.
`
`WARNINGS
`
`Remodulin is indicated for subcutaneous or intravenous use only.
`
`PRECAUTIONS
`
`General
`
`Remodulin should be used only by clinicians experienced in the diagnosis and treatment of PAH.
`
`

`

`NDA 21-272/S-005
`Page 7
`
`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
`excessive pharmacologic 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 or surgically placed indwelling central venous catheter, via an infusion pump. Therapy
`with Remodulin will be needed for prolonged periods, possibly years, 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 of Remodulin. Additionally,
`patients should be aware 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, 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.
`
`Effect of Remodulin on Other Drugs
`In vitro studies: Remodulin did not significantly affect the plasma protein binding of normally observed
`concentrations of digoxin or warfarin.
`
`In vivo studies: Warfarin – Remodulin does not affect the pharmokinetics 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 genetic toxicology 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 infusions 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
`
`

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`NDA 21-272/S-005
`Page 8
`
`trials, on a ng/m2 basis]. In this study, males were dosed from 10 weeks prior to mating and through the 2-week
`mating period. Females were dosed from 2 weeks prior to mating until gestational day 6.
`
`Pregnancy
`
`Pregnancy Category B - In pregnant rats, continuous subcutaneous infusions of treprostinil sodium during
`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
`infusions 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 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 Remodulin, 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. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been
`infrequently reported in postmarketing experience.
`
`

`

`NDA 21-272/S-005
`Page 9
`
`
`
`
`Pain
`Placebo Remodulin
`
`
`Table 2. Percentages of subjects reporting subcutaneous infusion site adverse
`events
`Reaction
`Placebo Remoduli
`n
`38
`1
`Severe
`NA**
`NA**
`Requiring narcotics*
`3
`0
`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
`
`2
`1
`0
`
`39
`32
`7
`
`Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these are generally
`considered to be related to the pharmacologic effects of Remodulin, whether administered 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
`PAH, Occurring with at Least 3% Incidence and More Common on
`Subcutaneous Remodulin than on Placebo.
`Placebo
`Remodulin
`Adverse Event
`(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.
`
`

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`NDA 21-272/S-005
`Page 10
`
`Adverse Events Attributable to the Drug Delivery System
`
`In controlled studies of Remodulin administered subcutaneously, 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. 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 such as replacing the
`syringe or battery, reprogramming the pump, or straightening a crimped infusion line. Adverse events resulting
`from problems with the delivery system did not lead to clinical instability or rapid deterioration.
`
`There are no controlled clinical studies with 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, paresthesias, hematoma and pain.
`
`OVERDOSAGE
`
`Signs and symptoms 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 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).
`
`One pediatric patient was accidentally administered 7.5 mg of Remodulin via a central venous catheter.
`Symptoms included flushing, headache, nausea, vomiting, hypotension and seizure-like activity with loss of
`consciousness lasting several minutes. The patient subsequently recovered.
`
`DOSAGE AND ADMINISTRATION
`Remodulin® is supplied in 20 mL vials in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL and
`10 mg/mL. Remodulin can be administered as supplied or diluted for intravenous infusion with Sterile Water for
`Injection or 0.9% Sodium Chloride Injection prior to administration.
`
`Initial Dose for Patients New to Prostacyclin Infusion Therapy
`Remodulin is administered by continuous infusion. Remodulin is preferably 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 infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of
`systemic effects, 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 pharmacologic 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).
`
`

`

`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 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.
`
`For subcutaneous infusion, Remodulin is delivered without further dilution at a calculated Subcutaneous
`Infusion Rate (mL/hr) based on a patients Dose (ng/kg/min), Weight (kg), and the Vial Strength (mg/mL) of
`Remodulin being used. During use, a single reservoir (syringe) of undiluted Remodulin can be administered up
`to 72 hours at 37°C. The Subcutaneous Infusion rate is calculated using the following formula:
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`Dose
`(ng/kg/min)
`
`x Weight
`(kg)
`
`x 0.00006*
`
`Remodulin Vial Strength
`(mg/mL)
`
`*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
`
` Example calculations for Subcutaneous Infusion are as follows:
`
`Example 1:
`
`For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/mL Remodulin
`Vial Strength, the infusion rate would be calculated as follows:
`
`1.25 ng/kg/min
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`60 kg
`x
`1 mg/mL
`
`
`x 0.00006
`
`= 0.005
`mL/hr
`
`Example 2:
`For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin Vial Strength, the infusion
`rate would be calculated as follows:
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`
`
`40 ng/kg/min
`
`x 0.00006
`
`65 kg
`x
`5 mg/mL
`
`
`= 0.031
`mL/hr
`
`
`
`
`
`

`

`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. The ambulatory
`infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no
`delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or
`better of the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl
`chloride, polypropylene or glass.
`
`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 reservoir, a predetermined intravenous infusion rate should first
`be selected to allow for a desired infusion period length of up to 48 hours between system 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:
`
`
`
`(ng/kg/min) x Weight Dose (kg)
`Intravenous Infusion Rate
`(mL/hr)
`
`
`
`x
`
`0.00006
`
`Step 1
`Diluted
`Intravenous
` Remodulin
`Concentration
`(mg/mL)
`
`=
`
`
`The Amount of Remodulin Injection needed to make the required Diluted Intravenous Remodulin Concentration
`for the given reservoir size can then be calculated using the following formula:
`
`
`Diluted Intravenous
`Remodulin
`Concentrati