`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`21-272/S-002
`
`
`
`
`
`
`
` United Therapeutics Corporation
`
`Trade Name: Remodulin
`
`Generic Name: treprostinil sodium
`
`Sponsor:
`
`Approval Date: November 24, 2004
`
`Purpose:
`Adding the infusion of Remodulin (treprostinil
` sodium) 1, 2.5, 5 & 10 mg/ml Injection via an
` indwelling central venous catheter to the labeling
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-272/S-002
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`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)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`
`
`
`X
`X
`
`X
`
`
`X
`X
`
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`21-272/S-002
`21-272/S-002
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`NDA 21-272/S-002
`
`
`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`One Park Drive
`Research Triangle Park, NC 27709
`
`
`
`
`Dear Mr. Bunce:
`
`Please refer to your supplemental new drug application dated January 30, 2004, received
`January 30, 2004, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`Remodulin (treprostinil sodium) 1, 2.5, 5 & 10 mg/mL Subcutaneous and Intravenous Injection.
`
`We acknowledge receipt of your submissions dated March 5 and 15; April 5, May 4, 6 and 20; July 21;
`August 26; September 17; and November 11 and 18, 2004.
`
`This supplemental new drug application provides for adding the infusion of Remodulin (treprostinil
`sodium) 1, 2.5, 5 & 10 mg/mL Injection via an indwelling central venous catheter to the labeling.
`
`We have completed the review of this supplemental application, as amended, according to the
`regulations for accelerated approval, and have concluded that adequate information has been presented
`to approve Remodulin (treprostinil sodium) 1, 2.5, 5 & 10 mg/mL Subcutaneous and Intravenous
`Injection for use as recommended in the enclosed labeling text. Accordingly, the application is
`approved under 21 CFR 314 Subpart H. Approval is effective on the date of this letter. Marketing of
`this drug product and related activities are to be in accordance with the substance and procedures of the
`referenced accelerated approval regulations.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling text for the package insert,
`and immediate container and carton labels submitted on November 12, 2004 (email attachment).
`Please submit the FPL electronically according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format – NDAs (January 1999) as soon as it is available, in no
`case more than 30 days after it is printed. Alternatively, you may submit 20 paper copies of the FPL,
`ten of which are individually mounted on heavy-weight paper or similar material. For administrative
`purposes, this submission should be designated “FPL for approved NDA 21-272/S-002.” Approval
`of this submission by FDA is not required before the labeling is used.
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled studies to verify and describe clinical benefit. We remind you of your
`post marketing study (Subpart H Phase 4 commitments) specified in our letter dated August 18, 2003.
`
`
`

`

`NDA 21-272/S-002
`Page 2
`
`We also remind you that, under 21 CFR 314.550, after the initial 120 day period following this
`approval, you must submit all promotional materials, including promotional labeling as well as
`advertisements, at least 30 days prior to the intended time of initial dissemination of the labeling or
`initial publication of the advertisement.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`exempting the pediatric study requirement for this application because Remodulin (treprostinil sodium)
`indicated for the treatment of pulmonary arterial hypertension received Orphan Drug designation on
`November 2, 1999.
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, please call:
`
`
`Mr. Daryl Allis
`Regulatory Project Manager
`(301) 594-5332
`
`
`
`
`
`
`
`
`
`
`Enclosure
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Acting Director
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`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
`11/24/04 12:30:25 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`21-272/S-002
`21-272/S-002
`
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`NDA 21-272/S-002
`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.
`
`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
`
`

`

`NDA 21-272/S-002
`Page 4
`
`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.
`
`Hemodynamic Effects
`
`As shown in Table 1, chronic therapy with Remodulin resulted in small hemodynamic changes consistent with pulmonary
`and systemic vasodilation.
`
`
`
`

`

`NDA 21-272/S-002
`Page 5
`
`
`2.4 ± 0.88
`
`2.2 ± 0.74
`
`+0.12 ± 0.58*
`
`-0.06 ± 0.55
`
`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
`
`Table 1: Hemodynamics During Chronic Administration of Remodulin in Patients with PAH
`Baseline
`Mean change from baseline at Week 12
`
`Hemodynamic
`Remodulin
`Placebo
`Remodulin
`Placebo
`Parameter
`(N=204-231)
`(N=215-235)
`(N=163-199)
`(N=182-215)
`CI
`(L/min/m2)
`PAPm
`(mmHg)
`RAPm
`(mmHg)
`PVRI
`(mmHg/L/min/m2)
`SVRI
`(mmHg/L/min/m2)
`SvO2
`(%)
`SAPm
`(mmHg)
`HR
`(bpm)
`*Denotes statistically significant difference between Remodulin and placebo, p<0.05.
`CI = cardiac index; PAPm = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance indexed;
`RAPm = mean right atrial pressure; SAPm = mean systemic arterial pressure; SVRI = systemic vascular resistance
`indexed;
`SvO2 = mixed venous oxygen saturation; HR = heart rate.
`
`26 ± 13
`
`38 ± 15
`
`62 ± 100
`
`90 ± 14
`
`82 ± 13
`
`25 ± 13
`
`39 ± 15
`
`60 ± 11
`
`91 ± 14
`
`82 ± 15
`
`-3.5 ± 8.2*
`
`+1.2 ± 7.9
`
`-3.5 ± 12*
`
`-0.80 ± 12
`
`+2.0 ± 10*
`
`-1.4 ± 8.8
`
`-1.7 ± 12
`
`-0.5 ± 11
`
`-1.0 ± 13
`
`-0.8 ± 11
`
`
`Clinical Effects
`The effect of Remodulin on 6-minute walk, the primary end point of the studies, was small and did not achieve
`conventional levels of statistical significance. For the combined populations, the median change from baseline on
`Remodulin was 10 meters and the median change from baseline on placebo was 0 meters. Although it was not the primary
`endpoint of the study, the Borg dyspnea score was significantly improved by Remodulin during the 6-minute walk, and
`Remodulin also had a significant effect, compared with placebo, on an assessment that combined walking distance with the
`Borg dyspnea score. Remodulin also consistently improved indices of dyspnea, fatigue and signs and symptoms of
`pulmonary hypertension, but these indices were difficult to interpret in the context of incomplete blinding to treatment
`assignment resulting from infusion site symptoms.
`
`
`
`INDICATIONS AND USAGE
`
`Remodulin® is indicated as a continuous subcutaneous infusion 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.
`
`
`
`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.
`
`

`

`NDA 21-272/S-002
`Page 6
`
`
`
`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. 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 pharmacokinetics or pharmacodymamics of warfarin. The
`pharmacokinetics of R- and S- warfarin and the INR in healthy subjects given a single 25 mg dose of warfarin were
`unaffected by continuous subcutaneous Remodulin at an infusion rate of 10 ng/kg/min.
`
`Hepatic and Renal Impairment
`Caution should be used in patients with hepatic or renal impairment (see Special Populations).
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Long-term studies have not been performed to evaluate the carcinogenic potential of treprostinil. In vitro and in vivo
`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 trials, on a ng/m2 basis]. In this study, males were dosed from 10
`weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until
`gestational day 6.
`
`

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`NDA 21-272/S-002
`Page 7
`
`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.
`
`
`Table 2. Percentages of subjects reporting subcutaneous infusion site adverse
`events
`
`
`Reaction
`Placebo Remodulin
`1
`38
`Severe
`NA**
`NA**
`Requiring narcotics*
`0
`3
`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
`
`Pain
`Placebo Remodulin
`2
`39
`1
`32
`0
`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.
`
`
`
`

`

`NDA 21-272/S-002
`Page 8
`
`
`
`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 Studies of Patients with PAH,
`Occurring with at Least 3% Incidence and More Common on Subcutaneous
`Remodulin than on Placebo.
`Adverse Event
`
`Infusion Site Pain
`Infusion Site Reaction
`Headache
`Diarrhea
`Nausea
`Rash
`Jaw Pain
`Vasodilatation
`Dizziness
`Edema
`Pruritus
`Hypotension
`
`Remodulin
`(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
`11
`5
`5
`8
`3
`6
`2
`
`Reported adverse events (at least 3%) are included except those too general to be informative, and those not plausibly
`attributable to the use of the drug, because they were associated with the condition being treated or are very common in the
`treated population.
`
`Adverse Events Attributable to the Drug Delivery System
`
`In 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, 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.
`
`

`

`NDA 21-272/S-002
`Page 9
`
`In controlled clinical trials, seven patients received some level of overdose and in open-label follow-on treatment seven
`additional patients received an overdose; these occurrences resulted from accidental bolus administration of Remodulin,
`errors in pump programmed rate of administration, and prescription of an incorrect dose. In only two cases did excess
`delivery of Remodulin produce an event of substantial hemodynamic concern (hypotension, near-syncope).
`
`
`DOSAGE AND ADMINISTRATION
`Remodulin® is supplied in 20 mL vials in concentrations of 1 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
`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).
`
`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
`
`

`

`NDA 21-272/S-002
`Page 10
`
`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:
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`1.25 ng/kg/min
`
`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:
`
`40 ng/kg/min
`
`x
`
`0.00006
`
`65 kg
`x
`5 mg/mL
`
`
`= 0.031 mL/hr
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`
`
`
`
`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:
`
`Step 1
`Diluted
`Intravenous
` Remodulin
`Concentration
`(mg/mL)
`
`=
`
`Dose
`(ng/kg/min)
`
`x Weight
`(kg)
`
`x
`
`0.00006
`
`Intravenous Infusion Rate
`(mL/hr)
`
`
`
`
`
`
`

`

`NDA 21-272/S-002
`Page 11
`
`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:
`
`
`
`Step 2
`Amount of
`Remodulin
`Injection
`(mL)
`
`=
`
`Diluted Intravenous
`Remodulin
`Concentration
`(mg/mL)
`
`Remodulin Vial
`Strength
`(mg/mL)
`
`
`
`x
`
`Total Volume of Diluted
`Remodulin Solution in
`Reservoir
`(mL)
`
`The calculated amount of Remodulin Injection is then added to 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.
`
` 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 Remodulin Solution Concentration would be calculated as follows:
`
`5 ng/kg/min
`
`=
`
`Step 1
`Dilu