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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`NDA 21-272/S-011
`
`United Therapeutics Corporation
`Attention: Mr. Kerry McKenzie
`Regulatory Affairs Manager
`55 TW Alexander Drive
`Research Triangle Park, NC 27709
`
`
`Dear Mr. McKenzie:
`
`Please refer to your supplemental new drug application dated April 27, 2009, received April 27,
`2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Remodulin (treprostinil) 1, 2.5, 5, and 10 mg/mL Injection.
`
`We also acknowledge receipt of your submissions dated October 19 and December 18, 2009.
`
`This “Changes Being Effected” supplemental new drug application provides for revisions to the
`carton labeling, immediate container labels, and prescribing information as follows:
`
`
`
`
` General
`
`The vial and carton labeling for Remodulin has been revised.
`
`The established name for Remodulin has been revised:
`
`
`FROM
`
`
`treprostinil sodium
`
`
`
`
`TO
`
`
`
`treprostinil
`
`
`
`The molecular formula and molecular weight have been updated in the labeling to reflect
`
` this change.
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`
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`

`

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` NDA 21-272/S-011
`Page 2
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`
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`“Highlights of Prescribing Information”
`
`In DOSAGE AND ADMINISTRATION/Transition from Flolan, revised:
`
`
`FROM
`
`Recommended initial Remodulin dose is 10% of the current Flolan dose.
`Individualized dosage increase as Flolan dose is decreased, based on constant
`observation of response.
`
`TO
`
`Increase the Remodulin dose gradually as the Flolan dose is decreased, based on
`constant observation of response.
`
`In DOSAGE AND ADMINISTRATION/Administration, revised:
`
`
`FROM
`
`Continuous subcutaneous infusion (undiluted). Intravenous infusion (dilution
`required) if subcutaneous infusion is not tolerated.
`
`Complete dosing, dilution and administration instructions: See Full Prescribing
`
`Information.
`
`
`TO
`
`
`Continuous subcutaneous infusion (undiluted) is the preferred mode. Use
`
`intravenous infusion (dilution required) if subcutaneous infusion is not tolerated.
`
`See Full Prescribing Information.
`
`
`
`In DOSAGE FORMS AND STRENGTHS, revised:
`
`
`FROM
`
`Remodulin is supplied in 20 mL vials in concentrations of 1 mg/mL, 2.5
`mg/mL, 5 mg/mL and 10 mg/mL.
`
`TO
`
`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).
`
`
`
`In DRUG INTERACTIONS, added:
`
`
`
`

`

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` NDA 21-272/S-011
`Page 3
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`
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`Remodulin dosage adjustment may be necessary if inhibitors or inducers of
`CYP2C8 are added or withdrawn.
`
`
`
`“Full Prescribing Information”
`
`
`In DOSAGE AND ADMINISTRATION/General, revised:
`
`
`FROM
`
`Remodulin is supplied in 20 mL vials in concentrations of 1 mg/mL, 2.5 mg/mL,
`5 mg/mL and 10 mg/mL.
`
`TO
`
`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).
`
`
`In DOSAGE FORMS AND STRENGTHS, revised:
`
`
`FROM
`
`
` 20-mL vial containing treprostinil sodium equivalent to 1 mg treprostinil per mL.
`
`
`20-mL vial containing treprostinil sodium equivalent to 2.5 mg treprostinil per
`
`mL.
`
`
`20-mL vial containing treprostinil sodium equivalent to 5 mg treprostinil per mL.
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`20-mL vial containing treprostinil sodium equivalent to 10 mg treprostinil per
`
`mL.
`
`
`TO
`
`
`20-mL vial containing 20 mg treprostinil (1 mg per mL).
`
`20-mL vial containing 50 mg treprostinil (2.5 mg per mL).
`
`20-mL vial containing 100 mg treprostinil (5 mg per mL).
`
`20-mL vial containing 200 mg treprostinil (10 mg per mL).
`
`
`
`In WARNINGS AND PRECAUTIONS/Risks Attributable to the Drug Delivery
`System, added:
`
`
`Therefore, continuous subcutaneous infusion (undiluted) is the preferred mode of
`administration.
`
`
`In WARNINGS AND PRECAUTIONS/Patients with Hepatic or Renal
`Insufficiency, revised:
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`

`

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` NDA 21-272/S-011
`Page 4
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`
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`FROM
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`Caution should be used in patients with hepatic or renal insufficiency.
`
`TO
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`
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`Titrate slowly in patients with hepatic or renal insufficiency, because such
`patients will likely be exposed to greater systemic concentrations relative to
`patients with normal hepatic or renal function.
`
`In WARNINGS AND PRECAUTIONS/Effect of Other Drugs on Treprostinil,
`added:
`
`
`Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g.,
`gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co­
`administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease
`
`exposure to treprostinil. Increased exposure is likely to increase adverse events
`associated with treprostinil administration, whereas decreased exposure is likely
`to reduce clinical effectiveness.
`
`
`In ADVERSE REACTIONS, added:
`
`The following adverse reactions are discussed elsewhere in labeling: Infections
`associated with intravenous administration [see Warnings and Precautions (5.1)].
`
`In DRUG INTERACTIONS, revised:
`
`
`FROM
`
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`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
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`potential for increased risk of bleeding, particularly among patients maintained on
`
`anticoagulants. During clinical trials, Remodulin was used concurrently with
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`anticoagulants, diuretics, cardiac glycosides, calcium channel blockers,
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`analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids, corticosteroids,
`
`and other medications.
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`Remodulin has not been studied in conjunction with Flolan or Tracleer®
`
`(bosentan).
`
`
`Effect of Other Drugs on treprostinil
`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 treprostinil on Other Drugs
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` NDA 21-272/S-011
`Page 5
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`In vitro studies: Remodulin did not significantly affect the plasma protein binding
`of normally observed concentrations of digoxin or warfarin.
`
`TO
`
`Pharmacokinetic/pharmacodynamic interaction studies have been conducted with
`treprostinil administered subcutaneously (Remodulin) and orally (treprostinil
`diethanolamine).
`
`Pharmacodynamics
`
`7.1 Antihypertensive Agents or Other Vasodilators
`Concomitant administration of Remodulin with diuretics, antihypertensive agents
`or other vasodilators may increase the risk of symptomatic hypotension.
`
`7.2 Anticoagulants
`Since treprostinil inhibits platelet aggregation, there may be an increased risk of
`bleeding, particularly among patients receiving anticoagulants.
`
`Pharmacokinetics
`
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`7.3 Bosentan
`In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an
`oral formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic
`interactions between treprostinil and bosentan were observed.
`
`7.4 Sildenafil
`In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an
`oral formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic
`
` interactions between treprostinil and sildenafil were observed.
`
`7.5 Effect of Cytochrome P450 Inhibitors and Inducers
`In vitro studies of human hepatic microsomes showed that treprostinil does not
`inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8,
`CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Additionally, treprostinil
`does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9,
`CYP2C19, and CYP3A.
`
`Human pharmacokinetic studies with an oral formulation of treprostinil
`(treprostinil diethanolamine) indicated that co-administration of the cytochrome
`P450 (CYP) 2C8 enzyme inhibitor gemfibrozil increases exposure (both Cmax
`and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer
`rifampin decreases exposure to treprostinil. It has not been determined if the
`safety and efficacy of treprostinil by the parenteral (subcutaneously or
`intravenously) route are altered by inhibitors or inducers of CYP2C8 [see
`WARNINGS AND PRECAUTIONS (5.6)].
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`

`

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` NDA 21-272/S-011
`Page 6
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`
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`Remodulin has not been studied in conjunction with Flolan or Tracleer®
`(bosentan).
`
`7.6 Effect of Other Drugs on Remodulin
` Drug interaction studies have been carried out with treprostinil (oral or
`
`subcutaneous) co-administered with acetaminophen (4 g/day), warfarin (25
`mg/day), and fluconazole (200 mg/day), respectively in healthy volunteers. These
`studies did not show a clinically significant effect on the pharmacokinetics of
`treprostinil. Treprostinil does not affect the pharmacokinetics or
`pharmacodynamics 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 infusion of treprostinil at an infusion rate of 10
`ng/kg/min.
`
`
`In USE IN SPECIFIC POPULATIONS/Patients with Hepatic Insufficiency, revised:
`
`
`FROM
`
`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.
`
`TO
`
`In patients with mild or moderate hepatic insufficiency, decrease the initial dose
`of Remodulin to 0.625 ng/kg/min ideal body weight, and monitor closely.
`
`
`In DESCRIPTION, revised:
`
`FROM
`
`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.
`
`Treprostinil sodium has a molecular weight of 412.49 and a molecular formula of
`C23H33NaO5. The structural formula of treprostinil sodium is:
`
`TO
`
`Remodulin (treprostinil) Injection is a sterile solution of treprostinil formulated
`for subcutaneous or intravenous administration. Remodulin is supplied in 20 mL
`
`multidose vials in four strengths, containing 20 mg, 50 mg, 100 mg, or 200 mg
`
`(1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL) of treprostinil. Each mL also
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`

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` NDA 21-272/S-011
`Page 7
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`contains 5.3 mg sodium chloride (except for the 10 mg/mL strength which
`contains 4.0 mg sodium chloride), 3 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 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. Treprostinil has a molecular
`weight of 390.52 and a molecular formula of C23H34O5.
`
`
`The structural formula of treprostinil is:
`
`In CLINICAL PHARMACOLOGY/Pharmacodynamics, added:
`
`
`Treprostinil produces vasodilation and tachycardia. Single doses of treprostinil up
`to 84 mcg by inhalation produce modest and short-lasting effects on QTc, but this
`is apt to be an artifact of the rapidly changing heart rate. Treprostinil administered
`by the subcutaneous or intravenous routes has the potential to generate
`concentrations many-fold greater than those generated via the inhaled route; the
`effect on the QTc interval when treprostinil is administered parenterally has not
`been established.
`
`
`In CLINICAL PHARMACOLOGY/Pharmacokinetics/Metabolism and Excretion,
`revised:
`
`
`FROM
`
`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.
`
`
`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.
`
`TO
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`

`

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`
` NDA 21-272/S-011
`Page 8
`
`
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`Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. In a
`study conducted in healthy volunteers using [14C] treprostinil, 78.6% and 13.4%
`of the subcutaneous dose was recovered in the urine and feces, respectively, over
`10 days. Only 4% was excreted as unchanged treprostinil in the urine. Five
`metabolites were detected in the urine, ranging from 10.2% to 15.5% and
`
`representing 64.4% of the dose administered. Four of the metabolites are products
`of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated
`derivative (treprostinil glucuronide). The identified metabolites do not appear to
`have activity.
`
`The elimination of treprostinil (following subcutaneous administration) is
`biphasic, with a terminal elimination half-life of approximately 4 hours using a
`two compartment model. Systemic clearance is approximately 30 L/hr for a 70 kg
`person.
`
`Based on in vitro studies treprostinil does not inhibit or induce major CYP
`enzymes [see Drug Interactions (7.5)].
`
`In HOW SUPPLIED / STORAGE AND HANDLING, revised:
`
`
`FROM
`
`
`Remodulin is supplied in 20 mL multi-use vials at concentrations of 1 mg/mL, 2.5
`
`mg/mL, 5 mg/mL, and 10 mg/mL treprostinil, as sterile solutions in water for
`
`injection, individually packaged in a carton. Each mL contains treprostinil sodium
`
`
`
`equivalent to 1 mg/mL, 2.5 mg/mL, 5 mg/mL, or 10 mg/mL treprostinil.
`
`
`20-mL vial containing treprostinil sodium equivalent to 1 mg treprostinil per mL,
`
`
`carton of 1 (NDC 66302-101-01).
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`20-mL vial containing treprostinil sodium equivalent to 2.5 mg treprostinil per
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`mL, carton of 1 (NDC 66302-102-01).
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`20-mL vial containing treprostinil sodium equivalent to 5 mg treprostinil per mL,
`
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`carton of 1 (NDC 66302-105-01).
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`20-mL vial containing treprostinil sodium equivalent to 10 mg treprostinil per
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`mL, carton of 1 (NDC 66302-110-01).
`
`
`TO
`
`
`Remodulin is supplied in 20 mL multidose vials containing 20, 50, 100, or 200
`
`mg of treprostinil at concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10
`
`mg/mL treprostinil, respectively, as sterile solutions in water for injection,
`
`individually packaged in cartons.
`
`
`20-mL vial containing 20 mg treprostinil (1 mg treprostinil per mL), carton of 1
`
`(NDC 66302-101-01).
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`
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`

`

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` NDA 21-272/S-011
`Page 9
`
`
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`20-mL vial containing 50 mg treprostinil (2.5 mg treprostinil per mL), carton of 1
`(NDC 66302-102-01).
`
`20-mL vial containing 100 mg treprostinil (5 mg treprostinil per mL), carton of 1
`(NDC 66302-105-01).
`
`20-mL vial containing 200 mg treprostinil (10 mg treprostinil per mL), carton of 1
`(NDC 66302-110-01).
`
`
`
`We have completed our review of this application, as amended. 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, please submit the
`content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as
`described at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed
`labeling. For administrative purposes, please designate this submission, “SPL for approved
`NDA 21-272/S-011”.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and container labels that are the same as the enclosed carton and
`immediate container labels as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry titled
`Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (October 2005).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 21-272/S-011.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`
`the letter to both this NDA and to the following address:
`
`
`MedWatch
`
`Food and Drug Administration
`
`5600 Fishers Lane, Room 12B05
`
`Rockville, MD 20857
`
`
`
`
`REPORTING REQUIREMENTS
`
`
`

`

`
`
` NDA 21-272/S-011
`Page 10
`
`
`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 Dan Brum, Pharm.D., RAC, Regulatory Project Manager,
`at (301)796-0578.
`
`
`
`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
`
`
`
`
`Enclosure: Agreed-upon labeling including carton and container labeling
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21272
`
`Submission
`Type/Number
`--------------------
`SUPPL-11
`
`Submitter Name
`
`Product Name
`
`--------------------
`UNITED
`THERAPEUTICS
`CORP
`
`------------------------------------------
`REMODULIN(TREPROSTINIL
`SODIUM)1/2.5/10
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`01/08/2010
`
`