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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`SUPPLEMENT APPROVAL
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`NDA 21-272/S-009
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`United Therapeutics Corporation
`Attention: Kerry McKenzie
`P.O. Box 14186
`One Park Drive
`Research Triangle Park, NC 27709
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`Dear Mr. McKenzie:
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`Please refer to your supplemental new drug application (NDA) dated January 24, 2008, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Remodulin (treprostinil sodium)
`Injection 1, 2.5, 5, and 10 mg/mL.
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`We also refer to our supplement request letter dated February 27, 2007 and related meeting minutes
`dated January 22, 2008.
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`This supplemental new drug application provides for the following revisions to the package insert:
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`1. To make the following changes in the INDICATIONS AND USAGE section
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`FROM
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`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.
`
`TO
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`Remodulin is indicated 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. It may be administered as a
`continuous subcutaneous infusion or continuous intravenous infusion; however, because
`of the risks associated with chronic indwelling central venous catheters, including
`serious blood stream infections, continuous intravenous infusion should be reserved for
`patients who are intolerant of the subcutaneous route, or in whom these risks are
`considered warranted.
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`

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`NDA 21-272/S-009
`Page 2
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`2. To make the following changes in the WARNINGS section
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`FROM
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`Remodulin is indicated for subcutaneous or intravenous use only.
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`TO (note: in last sentence of second paragraph, “one BSI” has been changed to “1 BSI”)
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`Adverse Events Attributable to the Intravenous Drug Delivery System
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`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.
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`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.
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`3. In the ADVERSE REACTIONS section, to delete the statement “In addition, generalized
`rashes, sometimes macular or papular in nature, and cellulitis have been infrequently
`reported in postmarketing experience” as well as to change the following text
`
`FROM
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`Adverse Events Attributable to the Drug Delivery System
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`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.
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`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.
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`TO (italics show differences from last approved labeling dated March 2006)
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`Adverse Events Attributable to the Drug Delivery System
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`

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`NDA 21-272/S-009
`Page 3
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`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. In addition to these adverse events due to the drug
`delivery system during subcutaneous administration, the following adverse events may
`be attributable to the IV mode of infusion including arm swelling, paresthesias,
`hematoma and pain (see WARNINGS).
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`Adverse Events Observed During Clinical Practice
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`In addition to adverse reactions reported from clinical trials, the following events have
`been identified during post-approval use of Remodulin. Because they are reported
`voluntarily from a population of unknown size, estimates of frequency cannot be made.
`The following events have been chosen for inclusion due to a combination of their
`seriousness, frequency of reporting, and potential connection to Remodulin. These
`events are thrombophlebitis associated with peripheral intravenous infusion,
`thrombocytopenia and bone pain. In addition, generalized rashes, sometimes macular
`or papular in nature, and cellulitis have been infrequently reported.
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`4. To make the following changes in the DOSAGE AND ADMINISTRATION section
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`FROM
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`Initial Dose for Patients New to Prostacyclin Infusion Therapy
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`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.
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`Dosage Adjustments
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`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).
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`

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`NDA 21-272/S-009
`Page 4
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`TO (italics show differences from last approved labeling dated March 2006)
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`Initial Dose for Patients New to Prostacyclin Infusion Therapy
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`Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only. 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.
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`Dosage Adjustments
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`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).
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`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 ng/kg/min. Abrupt cessation of
`infusion should be avoided (see PRECAUTIONS). 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.
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`5. To make the following changes in the DOSAGE AND ADMINISTRATION section
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`FROM
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`Intravenous Infusion
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`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.
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`TO (italics show differences from last approved labeling dated March 2006)
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`Intravenous Infusion
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`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
`
`

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`NDA 21-272/S-009
`Page 5
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`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.
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`We have completed our review of this application, and it is approved, effective on the date of this
`letter, for use as recommended in the enclosed agreed-upon electronic labeling text. We will transmit
`the SPL version of the labeling with minor edits submitted on January 24, 2008 to the National Library
`of Medicine for public dissemination.
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`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
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`Marketing the product with labeling that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
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`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
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`If you have any questions, please call Dan Brum, Pharm.D., Regulatory Project Manager,
`at (301)796-0578.
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`MEDWATCH
`Food and Drug Administration
`5515 Security Lane
`HFD-001, Suite 5100
`Rockville, MD 20852
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`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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`cc: Enclosed 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.
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` /s/
`---------------------
`Norman Stockbridge
`2/4/2008 08:29:42 AM
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