`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 021-272/S-020
`
`Remodulin Injection
`Trade Name:
`
`
`Treprostinil
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`United Therapeutics Corporation
`
`September 26, 2013
`
` Remodulin is a prostacyclin vasodilator indicated for
`the treatment of pulmonary arterial hypertension
`(PAH) (WHO Group 1) to diminish symptoms
`associated with exercise. Studies establishing
`effectiveness included patients with NYHA
`Functional Class II-IV symptoms and etiologies of
`idiopathic or heritable PAH (58%), PAH associated
`with congenital systemic-to-pulmonary shunts (23%),
`or PAH associated with connective tissue diseases
`(19%). Remodulin is also indicated for patients who
`require transition from Flolan®, to reduce the rate of
`clinical deterioration. The risks and benefits of each
`drug should be carefully considered prior to transition.
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 021-272/S-020
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Approvable Letter
`Labeling
`Labeling 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)
`
`
`
`X
`
`X
`X
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`

`

`
`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 021-272/S-020
`NDA 021-272/S-020
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 021272/S-020
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`United Therapeutics Corporation
`Attention: Rex Mauthe
`Associate VP, Regulatory Affairs
`
`55 TW Alexander Drive
`P.O. Box 14186
`Research Triangle Park, NC 27709
`
`Dear Mr. Mauthe:
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received May 23, 2013,
`submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Remodulin
`(treprostinil) 20 mg, 50 mg, 100 mg, and 200 mg for Injection.
`
`This “Prior Approval” supplemental new drug application provides for labeling revised as follows
`
`(additions are marked as underlined text and deletions are marked as strikethrough text):
`
`
`
`1. In HIGHLIGHTS, the following text was added/deleted:
`
`Dosage and Administration (2.1)
`Warnings and Precautions (5.1)
`
`
` 1/2010 09/2013
`
`
` 1/2010 09/2013
`
`
`
`2. In HIGHLIGHTS/DOSAGE AND ADMINISTRATION, the following text was
`
`deleted from the first bullet:
`
`
`
`
`
`Initial dose for patients new to prostacyclin infusion therapy: 1.25 ng/kg/min
`(or 0.625 ng/kg/min if not tolerated); dose increase based on clinical response
`(increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment,
`later 2.5 ng/kg/min per week). Limited experience with doses > 40
`mg/kg/min. Abrupt cessation of infusion should be avoided. (2.2, 2.3)
`
`
`3. In INDICATIONS AND USAGE/Pulmonary Arterial Hypertension, the following
`
`text was added to the second paragraph of the first section:
`
`
`
`
`
`
`
`
`
`
`
`It may be administered as a continuous subcutaneous infusion or continuous
`intravenous (IV) infusion; however, because of the risks associated with chronic
`indwelling central venous catheters, including serious blood stream infections
`(BSIs), continuous intravenous infusion should be reserved for patients who are
`intolerant of the subcutaneous route, or in whom these risks are considered
`warranted. [see Warnings and Precautions 5.1]
`
`
`
`
`
`
`Reference ID: 3379327
`
`

`

` NDA 021272/S-020
`Page 2
`
`
`
`4.
`
`
`
` Under DOSAGE AND ADMINISTRATION/General, the following text was
`added/deleted:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of
`treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). Remodulin can be
`administered as supplied or diluted for intravenous infusion with Sterile Water for
`
`Injection, 0.9% Sodium Chloride Injection, Sterile Diluent for Flolan, or Sterile
`Diluent for Epoprostenol Sodium for Injection prior to administration.
`
`
`5. Under DOSAGE AND ADMINISTRATION/Dosage Adjustments, the following text
`was deleted from the second paragraph:
`
`The infusion rate should be increased in increments of 1.25 ng/kg/min per week
`for the first four weeks of treatment and then 2.5 ng/kg/min per week for the
`remaining duration of infusion, depending on clinical response. Dosage
`adjustments may be undertaken more often if tolerated. There is little experience
`with doses > 40 mg/kg/min. Abrupt cessation of infusion should be avoided [see
`Warnings and Precautions (5.4)]. Restarting a Remodulin infusion within a few
`hours after an interruption can be done using the same dose rate. Interruptions for
`longer periods may require the dose of Remodulin to be re-titrated.
`
`
`6. Under DOSAGE AND ADMINISTRATION/Intravenous Administration, the
`following text was added/deleted to the first, second, and sixth paragraphs:
`
`Remodulin must be diluted with either Sterile Water for Injection, 0.9%
`
`
`Sodium Chloride Injection, or Flolan Sterile Diluent for Flolan, or Sterile
`Diluent for Epoprostenol Sodium for 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.
`If clinically necessary, a temporary peripheral intravenous cannula, preferably
`placed in a large vein, may be used for short term administration of Remodulin.
`Use of a peripheral intravenous infusion for more than a few hours may be
`associated with an increased risk of thrombophlebitis. 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.
`
`Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.
`
`
`The calculated amount of Remodulin Injection is then added to the reservoir along
`with the sufficient volume of diluent (Sterile Water for Injection, 0.9% Sodium
`
`Chloride Injection, or Flolan Sterile Diluent for Flolan, or Sterile Diluent for
`
`
`Reference ID: 3379327
`
`

`

`
`
` NDA 021272/S-020
`Page 3
`
`
`
`
`
` Epoprostenol Sodium Injection) to achieve the desired total volume in the
`reservoir.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`7. Under WARNINGS AND PRECAUTIONS/Risks Attributable to the Drug Delivery
`System, the following text was added to the first paragraph:
`
`In an open-label study of IV treprostinil (n=47), there were seven catheter-related
`line infections during approximately 35 patient years, or about 1 BSI event per 5
`years of use. A CDC survey of seven sites that used IV treprostinil for the
`
`treatment of PAH found approximately 1 BSI (defined as any positive blood
`culture) event per 3 years of use. Administration of IV Remodulin with a high pH
`glycine diluent such as Sterile Diluent for Flolan or Sterile Diluent for
`Epoprostenol Sodium has been associated with a lower incidence of BSIs
`compared to neutral diluents (sterile water, 0.9% sodium chloride) when used
`along with catheter care guidelines.
`
`
`
`
`8. Under ADVERSE REACTIONS/Adverse Events during Chronic Dosing, the
`following text was added:
`
`The safety of Remodulin was also studied in a long-term, open-label extension
`study in which 860 patients were dosed for a mean duration of 1.6 years, with a
`maximum exposure of 4.6 years. Twenty-nine (29%) percent achieved a dose of
`at least 40 ng/kg/min (max: 290 ng/kg/min). The safety profile during this chronic
`dosing study was similar to that observed in the 12-week placebo controlled study
`except for the following suspected adverse drug reactions (occurring in at least
`3%): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.
`
`
`
`9. Under HOW SUPPLIED/STORAGE AND HANDLING, the following text was
`added/deleted from the second paragraph:
`
`During use, a single reservoir (syringe) of undiluted Remodulin can be
`administered up to 72 hours at 37C. Diluted Remodulin Solution can be
`administered up to 48 hours at 37C when diluted to concentrations as low as
`0.004 mg/mL in Sterile Water for Injection, 0.9% Sodium Chloride Injection, or
`Flolan Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium
`
`Injection. A single vial of Remodulin should be used for no more than 30 days
`after the initial introduction into the vial.
`
`Remodulin Injection is supplied as:
`
`
`
`10. Under PATIENT COUNSELING INFORMATION, the following text was
`added/deleted:
`
`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. Patients should use an
`
`
`Reference ID: 3379327
`
`

`

`
`
` NDA 021272/S-020
`Page 4
`
`
`
`infusion set with an in-line filter. 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).
`
`US Patent No. 5,153,222 (Use Patent)
`
`
`Copyright 20112013 United Therapeutics Corp. All rights reserved.
`
`
`
`
`
`
`11. The revision date was updated.
`
`
`There are no other changes from the last approved package insert.
`
`We have completed our review of this supplemental application, and it is approved, effective on the date
`of this letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling
`
`[21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug
`registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of
`labeling must be identical to the enclosed labeling (text for the package insert), with the addition of any
`labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable
`changes not included in the enclosed labeling.
`
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry titled “SPL
`
`Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM0723
`92.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this supplemental
`application, as well as annual reportable changes and annotate each change. To facilitate review of your
`
`submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including supplement
`number(s) and annual report date(s).
`
`PROMOTIONAL MATERIALS
`
`
`
`
`You may request advisory comments on proposed introductory advertising and promotional labeling. To
`do so, submit the following, in triplicate, (1) a cover letter requesting advisory comments, (2) the
`
`proposed materials in draft or mock-up form with annotated references, and (3) the package insert(s) to:
`
`
`
`Reference ID: 3379327
`
`

`

`
`
` NDA 021272/S-020
`Page 5
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form FDA 2253,
`at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available
`at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html; instructions are provided on page 2 of
`the form. For more information about submission of promotional materials to the Division of Drug
`Marketing, Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`All promotional materials that include representations about your drug product must be promptly revised
`to be consistent with the labeling changes approved in this supplement, including any new safety
`information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials should include
`prominent disclosure of the important new safety information that appears in the revised package
`
`labeling. Within 7 days of receipt of this letter, submit your statement of intent to comply with
`21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`
`REPORTING REQUIREMENTS
`
`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:
`
`Lori Anne Wachter, RN, BSN
`
`Regulatory Project Manager for Safety
`(301) 796-3975
`
`
`
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Mary Ross Southworth, PharmD.
`Deputy Director for Safety
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation 1
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`Reference ID: 3379327
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY R SOUTHWORTH
`09/26/2013
`
`Reference ID: 3379327
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 021-272/S-020
`NDA 021-272/S-020
`
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`Remodulin safely and effectively. See full prescribing information for
`
`Remodulin.
`
`
`REMODULIN® (treprostinil) Injection
`Initial U.S. Approval: May 2002
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`
`Dosage and Administration (2.1) 09/2013
`Warnings and Precautions (5.1) 09/2013
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`Remodulin is a prostacyclin vasodilator indicated for:
`
`Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to
`
`diminish symptoms associated with exercise. Studies establishing
`effectiveness included patients with NYHA Functional Class II-IV
`symptoms and etiologies of idiopathic or heritable PAH (58%), PAH
`associated with congenital systemic-to-pulmonary shunts (23%), or PAH
`
`associated with connective tissue diseases (19%) (1.1)
`Patients who require transition from Flolan®, to reduce the rate of
`
`clinical deterioration. The risks and benefits of each drug should be
`carefully considered prior to transition. (1.2)
`
`
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg
`
`
`of treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). (3)
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Chronic intravenous infusions of Remodulin are delivered using an
`
`indwelling central venous catheter. This route is associated with the risk
`of blood stream infections (BSIs) and sepsis, which may be fatal.
`
`
`Remodulin should be used only by clinicians experienced in the
`diagnosis and treatment of PAH. (5.2)
`
`Adjust dosage based on clinical response, including infusion site
`symptoms. (5.3)
`
`
`Do not abruptly lower the dose or withdraw dosing. (5.4)
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence >3%) reported in clinical studies
`with Remodulin: subcutaneous infusion site pain and reaction, headache,
`diarrhea, nausea, jaw pain, vasodilatation, dizziness, edema, pruritus and
`hypotension. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`
`
`Therapeutics Corp. at 1-866-458-6479 or via e-mail at
`
`drugsafety@unither.com, or contact FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`
`Blood pressure lowering drugs (e.g., diuretics, antihypertensive agents,
`
`
`or vasodilators): Risk of increased reduction in blood pressure (7.1)
`
`Remodulin inhibits platelet aggregation. Potential for increased risk of
`
`bleeding, particularly among patients on anticoagulants. (7.2)
`
`
`Remodulin dosage adjustment may be necessary if inhibitors or inducers
`of CYP2C8 are added or withdrawn. (7.6)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`
`
`
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`PAH in patients with NYHA Class II-IV symptoms:
`
`Initial dose for patients new to prostacyclin infusion therapy: 1.25
`
`ng/kg/min (or 0.625 ng/kg/min if not tolerated); dose increase based on
`clinical response (increments of 1.25 ng/kg/min per week for the first 4
`weeks of treatment, later 2.5 ng/kg/min per week). Abrupt cessation of
`infusion should be avoided. (2.2, 2.3)
`
` Mild to moderate hepatic insufficiency: Initial dose should be decreased
`
`to 0.625 ng/kg/min ideal body weight; cautious dosage increase.
`
`Severe hepatic insufficiency: No studies performed. (2.4)
`
`
`Transition from Flolan:
`
`Increase the Remodulin dose gradually as the Flolan dose is decreased, based
`
`on constant observation of response. (2.7)
`
`
`Administration:
`
`
`Continuous subcutaneous infusion (undiluted) is the preferred mode. Use
`
`
`intravenous (IV) infusion (dilution required) if subcutaneous infusion is not
`
`tolerated. (2.1, 2.6)
`
`See Full Prescribing Information.
`
`_________________________________________________________________________________________________________________________
`
`
`Revised: 09/2013
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1. INDICATIONS AND USAGE
` 
` 1.1 Pulmonary Arterial Hypertension
`
` 
`
`1.2 Pulmonary Arterial Hypertension in Patients Requiring
`Transition from Flolan®
` 
`2 DOSAGE AND ADMINISTRATION
` 
`2.1 General
` 
`2.2 Initial Dose for Patients New to Prostacyclin Infusion
`Therapy
` 
`2.3 Dosage Adjustments
` 
`2.4 Patients with Hepatic Insufficiency
` 
`2.5 Patients with Renal Insufficiency
` 
`2.6 Administration
` 
`2.7 Patients Requiring Transition from Flolan
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
`4 CONTRAINDICATIONS
` 
`5 WARNINGS AND PRECAUTIONS
` 
`5.1 Risks Attributable to the Drug Delivery System
` 
`5.2 General Conditions of Use
` 
`5.3 Dose Modification
` 
`5.4 Abrupt Withdrawal or Sudden Large Dose Reduction
` 
`5.5 Patients with Hepatic or Renal Insufficiency
` 
`5.6 Effect of Other Drugs on Treprostinil
` 
`
`6 ADVERSE REACTIONS
` 
`6.1 Clinical Trials Experience
` 
`6.2 Post-Marketing Experience
` 
`7 DRUG INTERACTIONS
` 
`7.1 Antihypertensive Agents or Other Vasodilators
` 
`7.2 Anticoagulants
` 
`7.3 Bosentan
` 
`7.4 Sildenafil
` 
`7.5 Effect of Treprostinil on Cytochrome P450 Enzymes
` 
`
`Reference ID: 3379327
`
`7.6 Effect of Cytochrome P450 Inhibitors and Inducers on
`
`Treprostinil
`
` 
`7.7 Effect of Other Drugs on Treprostinil
` 
`8 USE IN SPECIFIC POPULATIONS
` 
`8.1 Pregnancy
` 
`8.2 Labor and Delivery
` 
`8.3 Nursing Mothers
` 
`8.4 Pediatric Use
` 
`8.5 Geriatric Use
` 
`8.6 Patients with Hepatic Insufficiency
` 
`8.7 Patients with Renal Insufficiency
` 
`10 OVERDOSAGE
` 
`11 DESCRIPTION
` 
`12 CLINICAL PHARMACOLOGY
` 
`12.1 Mechanism of Action
` 
`12.2 Pharmacodynamics
` 
`12.3 Pharmacokinetics
` 
`13 NONCLINICAL TOXICOLOGY
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
`14 CLINICAL STUDIES
` 
`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
` 
`14.2 Flolan-To-Remodulin Transition Study
` 
`16 HOW SUPPLIED / STORAGE AND HANDLING
` 
`17 PATIENT COUNSELING INFORMATION
` 
`
` *Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`REMODULIN® (treprostinil) Injection
`
`
`
`1. INDICATIONS AND USAGE
`1.1 Pulmonary Arterial Hypertension
`Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group
`
`1) to diminish symptoms associated with exercise. Studies establishing effectiveness included
`
`patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH
`
`(58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated
`with connective tissue diseases (19%) [see Clinical Studies (14.1)].
`
`It may be administered as a continuous subcutaneous infusion or continuous intravenous (IV)
`
`infusion; however, because of the risks associated with chronic indwelling central venous
`catheters, including serious blood stream infections (BSIs), continuous intravenous infusion
`
`should be reserved for patients who are intolerant of the subcutaneous route, or in whom these
`risks are considered warranted [see Warnings and Precautions 5.1]
`
`
`1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from Flolan®
`
`In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol
`sodium), Remodulin is indicated to diminish the rate of clinical deterioration. The risks and
`benefits of each drug should be carefully considered prior to transition.
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 General
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of treprostinil (1 mg/mL,
`2.5 mg/mL, 5 mg/mL or 10 mg/mL). Remodulin can be administered as supplied or diluted for
`
`intravenous infusion with Sterile Water for Injection, 0.9% Sodium Chloride Injection, Sterile
`Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium prior to administration.
`
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`
`
`Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a 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.
`
`2.3 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 1.25 ng/kg/min per week for the first four
`weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion,
`depending on clinical response. Dosage adjustments may be undertaken more often if tolerated.
`Abrupt cessation of infusion should be avoided [see Warnings and Precautions (5.4)]. Restarting
`a Remodulin infusion within a few hours after an interruption can be done using the same dose
`rate. Interruptions for longer periods may require the dose of Remodulin to be re-titrated.
`
`
`Reference ID: 3379327
`
`
`
` Page 2 of 17
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`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
` 2.4 Patients with Hepatic Insufficiency
`
`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 [see Warnings and Precautions
`(5.5), Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].
`
`
`2.5 Patients with Renal Insufficiency
`No studies have been performed in patients with renal insufficiency. No specific advice about
`
`dosing in patients with renal impairment can be given.
`[see Clinical Pharmacology (12.3)].
`
`2.6 Administration
`Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration whenever solution and container permit. If either particulate matter or
`discoloration is noted, Remodulin should not be administered.
`
`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:
`
`
`
`Dose (ng/kg/min) x Weight (kg) x
`
`
`
`0.00006*
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`Remodulin Vial Strength (mg/mL)
`
`*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
`
`=
`
`
`
`
`Reference ID: 3379327
`
`
`
` Page 3 of 17
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`

`

`1.25 ng/kg/min
`
`=
`
`x 0.00006
`
`
`
`= 0.005 mL/hr
`
`60 kg
`x
`
`1 mg/mL
`
`
`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`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)
`
`
`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
`
`
`65 kg
`x
`
`5 mg/mL
`
`
`x 0.00006
`
`
`
`= 0.031 mL/hr
`
`
`
`
`
`Intravenous Infusion
`
`Remodulin must be diluted with either Sterile Water for Injection, 0.9% Sodium Chloride
`
`
`Injection, Sterile Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium and is
`administered intravenously by continuous infusion, via a surgically placed indwelling central
`venous catheter, using an infusion pump designed for intravenous drug delivery. If clinically
`necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be
`used for short term administration of Remodulin. Use of a peripheral intravenous infusion for
`more than a few hours may be associated with an increased risk of thrombophlebitis. 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.
`
`Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.
`
`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
`
`=
`
`
`Dose
`(ng/kg/min)
`
`x
`
`
`Weight
`
`(kg)
`
`x
`
`0.00006
`
`Reference ID: 3379327
`
`
`
` Page 4 of 17
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`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`Concentration
`
`(mg/mL)
`
`Intravenous Infusion Rate
`
`(mL/hr)
`
`
`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, 0.9% Sodium Chloride Injection, Sterile
`Diluent for Flolan, or Sterile Diluent for Epoprostenol Sodium) 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:
`
`Step 1
`
`
`
`Diluted
`Intravenous
`Remodulin
`Concentration
`
`(mg/mL)
`
`5 ng/kg/min
`
`=
`
`60 kg
`x
`
`
`1 mL/hr
`
`x 0.00006
`
`
`= 0.018
`mg/mL
`(18,000
`
`ng/mL)
`
`
`The Amount of Remodulin Injection (using 1 mg/mL Vial Strength) needed for a total
`Diluted 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 would
`thus be prepared by adding 0.9 mL of 1 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.
`
`Example 4:
`
`
`Reference ID: 3379327
`
`
`
` Page 5 of 17
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`

`

`
`
` REMODULIN® (treprostinil) Injection Package Insert
`
`
`
`
`
`For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion
`rate of 2 mL/hr, and a reservoir of 100 mL, the Diluted Intravenous Remodulin Solution
`Concentration would be calculated as follows:
`
`Step 1
`
`
`
`=
`
`30 ng/kg/min x 75 kg x 0.00006 = 0.0675 mg/mL
`
`
`
`
`2 mL/hr
`
`(67,500 ng/mL)
`
`Diluted
`
`Intravenous
`
`Remodulin
`Concentration
`
`(mg/mL)
`
`
`The Amount of Remodulin Injection (using 2.5 mg/mL Vial Strength) needed for a total
`Diluted Remodulin Concen