Treprostinil Sodium

Class: Vasodilating Agents
VA Class: CV900
Chemical Name: [[(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
Molecular Formula: C23H34O5
CAS Number: 81846-19-7
Brands: Remodulin

Introduction

Vasodilator; a synthetic analog of prostacyclin.2 3 15

Uses for Treprostinil Sodium

Pulmonary Arterial Hypertension

Used parenterally (as a continuous sub-Q or IV infusion) for treatment of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension) to reduce symptoms associated with exercise; efficacy established principally in patients with NYHA/WHO functional class II–III PAH (idiopathic, heritable, associated with connective tissue diseases or congenital systemic-to-pulmonary shunts).1 2 3 Also used parenterally to reduce rate of clinical deterioration in PAH patients who require conversion from epoprostenol therapy; carefully consider risks and benefits of each drug prior to transition.1

Slideshow: Can Prescription Drugs Lead to Weight Gain?

Used by oral inhalation to improve exercise ability in patients with PAH; efficacy established principally in patients with NYHA/WHO functional class III PAH (idiopathic, heritable, or associated with connective tissue diseases).15 16 17 Controlled clinical experience with orally inhaled treprostinil is based primarily on short-term trials in patients receiving the drug as add-on therapy to bosentan or sildenafil.13 15 16 17

Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class III or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.13 40

Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.13 40

In patients with inadequate response to initial monotherapy, may consider combination therapy with an endothelin-receptor antagonist, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially).40 By targeting different pathophysiologic pathways of the disease, combination therapy may provide additive and/or synergistic benefits.40 41 42 43

Has been designated an orphan drug by FDA for treatment of PAH.31

Treprostinil Sodium Dosage and Administration

General

Restricted Distribution

  • Both treprostinil injection (Remodulin) and treprostinil inhalation solution (Tyvaso), as well as the Tyvaso Inhalation System used to administer the drug via oral inhalation, are available only through specialty pharmacies.44 45

  • For additional information, contact the manufacturer at 1-877-864-8437.44

Administration

Administer by continuous sub-Q or IV infusion, or by oral inhalation.1 15

When administered parenterally, sub-Q route generally preferred; reserve IV use for patients who cannot tolerate sub-Q therapy (e.g., due to infusion-site pain or reaction) or in whom risks of IV therapy are considered warranted.1

Sub-Q Administration

Administer undiluted drug solution by continuous sub-Q infusion via a self-inserted sub-Q catheter, using a controlled-infusion device (ambulatory infusion pump).1 Consult manufacturer's labeling for pump specifications.1

To avoid potential interruptions in drug delivery, patient must have immediate access to backup infusion pump and sub-Q infusion sets (since abrupt withdrawal or sudden, large dosage reductions may result in worsening of PAH symptoms).1

For sub-Q use, administer as supplied without further dilution.1 A single reservoir (syringe) of undiluted treprostinil may be administered for up to 72 hours at 37°C.1

Rate of Administration

Calculate sub-Q infusion rates using the following formula:1

sub-Q infusion rate (mL/hr) = [dose (ng/kg per minute) × wt (kg) × 0.00006] ÷ treprostinil dosage strength concentration (mg/mL)

IV Administration

For solution compatibility information, see Compatibility under Stability.

Must be diluted prior to IV administration.1 14 (See Dilution under Dosage and Administration.)

Administer diluted drug solution by continuous IV infusion through a permanent indwelling central venous catheter using a controlled-infusion device (ambulatory infusion pump).1 Consult manufacturer's labeling for pump specifications.1

A peripheral IV catheter (preferably placed in a large vein) may be used temporarily until central venous access can be established.1

To avoid potential interruptions in drug delivery, patient must have immediate access to backup infusion pump and IV infusion sets (since abrupt withdrawal or sudden, large dosage reductions may result in worsening of PAH symptoms).1

Consult manufacturer's labeling for additional information on administration of IV treprostinil.1 14

Dilution

Must be diluted with sterile water for injection, 0.9% sodium chloride injection, Flolan (epoprostenol sodium) sterile diluent for injection, or sterile diluent for generic epoprostenol sodium (e.g., Teva) prior to IV administration. Diluted solutions are stable at 37°C for ≤48 hours at concentrations as low as 0.004 mg/mL (4 mcg/mL).1

Add appropriate amount of drug to a sufficient volume of diluent to fill pump reservoir (typical IV infusion system reservoirs have a total capacity of 50 or 100 mL).1 Select an infusion rate that will allow for an infusion period of ≤48 hours, and calculate concentration and amount of treprostinil required for the dilution according to the following formulas:1

Diluted IV treprostinil concentration (mg/mL) = [dose (ng/kg per minute) × wt (kg) × 0.00006] ÷ IV infusion rate (mL/hr)

Amount of treprostinil injection (mL) = [diluted IV treprostinil concentration (mg/mL) ÷ treprostinil vial strength (mg/mL)] × total reservoir volume (mL)

Consult manufacturer's labeling for additional information on preparation of IV treprostinil.1

Oral Inhalation

Treprostinil inhalation solution is for oral inhalation only; do not ingest.15

Administer using only the Tyvaso Inhalation System (ultrasonic, pulsed delivery device and related accessories).15 Patients should have access to a back-up Tyvaso Inhalation System device in the event of equipment malfunction.15 Instruct patients on proper administration (including dosing frequency), use, and maintenance of the device.15

Administer 4 times daily during waking hours at equally spaced intervals of approximately 4 hours.15

Prior to first inhalation session, transfer entire contents of a single 2.9-mL ampul of drug into medicine cup supplied by the manufacturer.15 One ampul should contain enough drug for one day of treatment.15 19 After each inhalation session, cap inhalation device and store upright with remaining drug inside for ≤24 hours.15 Discard medicine cup and any unused solution at end of each day and clean Tyvaso Inhalation System device according to manufacturer's instructions.15

Do not mix with other drugs.15

Do not allow solution to come into contact with the eyes or skin.15

Dosage

Adults

PAH
Continuous Sub-Q or IV Infusion

Initially, 1.25 ng/kg per minute.1 If initial dosage is not tolerated, reduce infusion rate to 0.625 ng/kg per minute.1

Adjust dosage to achieve symptomatic improvement while minimizing adverse effects.1 Increase infusion rate based on clinical response in increments of 1.25 ng/kg per minute at weekly intervals for the first 4 weeks and then 2.5 ng/kg per minute at weekly intervals for the remaining duration of the infusion.1

Several months may be required to identify optimal dosage.2 8 14

Oral Inhalation

Initially, 18 mcg (3 inhalations) per treatment session 4 times daily.15 If initial dosage not tolerated, reduce to 1 or 2 inhalations per treatment session, then increase up to 3 inhalations as tolerated.15 Continue to increase dose by 3 inhalations every 1–2 weeks until target maintenance dosage of 54 mcg (9 inhalations) per treatment session attained.15 If unable to titrate to target dosage, maintain patient on highest possible tolerated dosage.15

If a treatment session is missed or interrupted, resume therapy as soon as possible at usual dosage.15

Conversion from Epoprostenol to Sub-Q or IV Treprostinil Therapy
Sub-Q or IV

Perform transition in a hospital setting where patient can be closely monitored.1

Initiate treprostinil at a dosage equivalent to 10% of the current epoprostenol dosage; gradually increase treprostinil dosage while simultaneously decreasing dosage of epoprostenol.1 Manufacturer recommends the following titration protocol:1

Step

Epoprostenol Dosage

Treprostinil Dosage

1

Unchanged

10% of starting epoprostenol dosage

2

80% of starting epoprostenol dosage

30% of starting epoprostenol dosage

3

60% of starting epoprostenol dosage

50% of starting epoprostenol dosage

4

40% of starting epoprostenol dosage

70% of starting epoprostenol dosage

5

20% of starting epoprostenol dosage

90% of starting epoprostenol dosage

6

5% of starting epoprostenol dosage

110% of starting epoprostenol dosage

7

0

110% of starting epoprostenol dosage + additional 5–10% increments as needed

Individually titrate treprostinil dosage to allow transition from epoprostenol therapy while balancing symptoms of PAH and prostacyclin-related adverse effects.1 Manage any increase in PAH symptoms (e.g., shortness of breath) by initially increasing dosage of treprostinil; manage symptoms of excess prostacyclin (e.g., facial flushing, headache, jaw pain) by initially decreasing dosage of epoprostenol.1

Other transition protocols have been used successfully.9 21 22 25 Limited data indicate that patients whose therapy is transitioned from epoprostenol to IV treprostinil appear to require higher average dosages of treprostinil to maintain the same clinical benefits.11 14 21 22 24 25

Special Populations

Hepatic Impairment

In patients with mild to moderate hepatic impairment, decrease initial dosage of sub-Q or IV treprostinil to 0.625 ng/kg per minute (based on ideal body weight).1

Titrate orally inhaled treprostinil slowly in patients with hepatic impairment because of the possibility of increased systemic exposure to the drug.15

Renal Impairment

Manufacturer makes no specific dosage recommendations for patients with renal impairment;1 titrate dosage slowly because of the possibility of increased systemic exposure to the drug.1 15

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.1 15

Cautions for Treprostinil Sodium

Contraindications

  • None known.1

Warnings/Precautions

Warnings

Risk of Infection with IV Administration

Risk of serious and potentially fatal blood stream infections and sepsis associated with drug delivery system (long-term indwelling central venous catheter).1 14 25 28 Patients must use strict aseptic technique in routine catheter care and in the preparation and administration of treprostinil.1 Sub-Q route of administration is preferred when the drug is given parenterally.1 Use of a high pH glycine diluent (e.g., Flolan [epoprostenol sodium] sterile diluent for injection, sterile diluent for generic epoprostenol sodium for injection [e.g., Teva]) with IV treprostinil associated with a lower incidence of blood stream infections compared with neutral diluents (e.g., sterile water for injection, 0.9% sodium chloride injection).1

Adequate Patient Evaluation and Monitoring

Use only under the supervision of a qualified clinician experienced in the diagnosis and management of PAH.1

Initiate therapy in a setting with adequate medical personnel and equipment for providing physiologic monitoring and emergency care.1

Therapy may be continued for prolonged periods; carefully consider patient's ability to administer the drug and care for an infusion system (when drug is given parenterally).1

Precautions Related to Inhaled Treprostinil

Safety and efficacy of orally inhaled treprostinil not established in patients with lung disease (i.e., asthma, COPD).15 Monitor patients who develop acute pulmonary infections for any worsening of lung disease and loss of drug effect.15

Withdrawal of Therapy

Avoid abrupt withdrawal or sudden, large dosage reductions; may result in worsening of PAH symptoms.1

Hematologic Effects

Possible increased risk of bleeding, particularly in patients receiving anticoagulant therapy.1 15 (See Specific Drugs under Interactions.)

Hypotensive Effects

Risk of symptomatic hypotension in patients with low systemic arterial pressure receiving orally inhaled treprostinil.15

Specific Populations

Pregnancy

Category B.1 15

Lactation

Not known whether treprostinil is distributed into milk;1 15 use with caution in nursing women.1 15

Pediatric Use

Parenteral treprostinil: Safety and efficacy not established in children or adolescents <16 years of age.1 8 Clinical studies did not include sufficient numbers of patients ≤16 years of age to determine whether pediatric patients respond differently than adults.1 Titrate dosage carefully.8

Orally inhaled treprostinil: Safety and efficacy not established in patients <18 years of age.15

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 15

Hepatic Impairment

Adjust dosage of sub-Q or IV treprostinil in patients with mild to moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with severe hepatic impairment.1 15

Renal Impairment

Not studied in patients with renal impairment.1 15 However, possibility of reduced renal clearance of the drug in such patients.15

Common Adverse Effects

Sub-Q therapy: Infusion site pain and reaction (e.g., erythema, induration, rash).1

IV therapy: Arm swelling, paresthesias, hematoma, pain.1

Sub-Q and IV therapy: Headache, diarrhea, nausea, jaw pain, vasodilation, dizziness, edema, pruritus, hypotension.1

Orally inhaled therapy: Cough and throat irritation; headache; GI effects; muscle, jaw, or bone pain; flushing; syncope.15 16

Interactions for Treprostinil Sodium

Extensively metabolized in liver, principally by CYP2C8.1 29 Does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A in vitro.1 15 Does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A in vitro.1 15 Pharmacokinetic interactions with drugs metabolized by the CYP enzyme system are considered unlikely.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Pharmacokinetics of treprostinil not substantially affected1 15

Anticoagulants

Potential for increased risk of bleeding1 15

Warfarin: No clinically important interaction observed1 15

Antihypertensive agents

Additive hypotensive effect possible1 15

Bosentan

Pharmacokinetic interaction not observed with an oral formulation of treprostinil1 15 29

Diuretics

Additive hypotensive effect possible1 15

Fluconazole

Pharmacokinetics of treprostinil not substantially affected1 15

Gemfibrozil

Increased systemic exposure to an oral formulation of treprostinil; possible increased risk of adverse effects with treprostinil1 15

Rifampin

Decreased systemic exposure to an oral formulation of treprostinil; possible reduced efficacy of treprostinil1 15

Sildenafil

Pharmacokinetic interaction not observed with an oral formulation of treprostinil1 15

Vasodilating agents

Additive hypotensive effect possible1 15

Treprostinil Sodium Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after sub-Q infusion; absolute bioavailability of 100%.1

Sub-Q and IV treprostinil are bioequivalent at steady-state dosage of 10 ng/kg per minute.1 9 30

Mean absolute systemic bioavailability following oral inhalation is approximately 64 and 72% following doses of 18 and 36 mcg, respectively.15

Plasma Concentrations

Steady-state concentrations occur in approximately 10 hours following sub-Q administration.1

Peak plasma concentrations of treprostinil achieved approximately 10–15 minutes after oral inhalation.18

Special Populations

Peak plasma concentrations increased by twofold or fourfold in patients with portopulmonary hypertension and mild or moderate hepatic impairment, respectively, compared with healthy individuals.1

Distribution

Plasma Protein Binding

91%.1 15

Elimination

Metabolism

Extensively metabolized in liver, principally by CYP2C8; 5 metabolites described thus far.1 15

Elimination Route

Following sub-Q administration, excreted in urine (79%) and feces (13%).1 15

Half-life

Biphasic; terminal half-life of approximately 4 hours.1 15

Special Populations

In patients with hepatic insufficiency, clearance was reduced by up to 80% compared with healthy adults.1 15

In patients with renal impairment, clearance may be reduced since treprostinil and its metabolites are eliminated principally by the kidneys.15

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).1

May use vial for ≤30 days after initial entry.1

May store undiluted drug in a single reservoir (syringe) for ≤72 hours at 37°C.1

Diluted solutions of treprostinil are stable at 37°C for ≤48 hours at concentrations as low as 0.004 mg/mL (4000 ng/mL).1

Oral Inhalation

25°C (may be exposed to 15–30°C) for unopened ampuls in unopened foil pouch.15

Use ampuls within 7 days after opening foil pouch; store unopened ampuls in pouch until use because drug is light-sensitive.15

Once drug solution is placed in medicine cup in inhalation device, use within 24 hours.15 Discard any unused solution at end of day.15

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1 HID

Sodium chloride 0.9%

VariableHID

Dextrose 5%

Actions

  • Pharmacologic actions (e.g., vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) similar to those of epoprostenol.2 3

  • In animals, vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume.1

  • Causes dose-related negative inotropic and lusitropic effect.1

  • Orally inhaled treprostinil exhibits high pulmonary selectivity and produces sustained pulmonary vasodilation without substantial systemic effects.18

  • Modest and temporary effects on QTc interval observed following single oral inhalation doses; possibly an artifact of the rapidly changing heart rate produced by the drug.1 15 Effects of parenteral treprostinil on QTc not studied.1

Advice to Patients

  • Importance of advising patient that treprostinil is infused continuously through a self-inserted sub-Q or surgically placed indwelling central venous catheter, via an infusion pump, which will require a long-term commitment on the part of the patient.1

  • Importance of advising patient to use sterile technique when preparing and administering drug.1

  • Importance of advising patients that subsequent management of PAH may require therapy with an alternate IV prostacyclin therapy (e.g., epoprostenol).1

  • Importance of understanding potential risks associated with therapy.1

  • Importance of patients receiving adequate training in the proper administration and dosing of orally inhaled treprostinil, and on set-up, operation, and maintenance of the Tyvaso Inhalation System device.15

  • Importance of having immediate access to a back-up pump and infusion sets (when administered parenterally) or a back-up Tyvaso Inhalation System device (when administered via oral inhalation) in order to avoid potential interruptions in drug therapy secondary to drug delivery device failure or equipment malfunction.1 15

  • Importance of advising patients that if a scheduled treatment session of orally inhaled treprostinil is missed, treatment should be resumed as soon as possible.15

  • Importance of advising patients to avoid skin or eye contact with treprostinil oral inhalation solution.15 If skin or eye contact occurs, instruct patient to immediately rinse the affected area with water.15

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Treprostinil injection (Remodulin) and treprostinil inhalation solution (Tyvaso), as well as the Tyvaso Inhalation System, are available only through specialty pharmacies.44 45 (See Restricted Distribution under Dosage and Administration.)

Treprostinil Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for continuous sub-Q or IV infusion via controlled-infusion device only

1 mg (of treprostinil) per mL

Remodulin

United Therapeutics

2.5 (of treprostinil) per mL

Remodulin

United Therapeutics

5 (of treprostinil) per mL

Remodulin

United Therapeutics

10 (of treprostinil) per mL

Remodulin

United Therapeutics

Oral Inhalation

Solution, for nebulization

0.6 mg/mL (1.74 mg)

Tyvaso (available with Tyvaso Inhalation System)

United Therapeutics

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 4, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. United Therapeutics Corp. Remodulin (treprostinil sodium) injection prescribing information. Research Triangle Park, NC; 2013 Oct.

2. Simonneau G, Barst RJ, Galie N et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002; 165:800-4. [IDIS 480255] [PubMed 11897647]

3. Fleming T, Lindenfeld J, Lipicky R et al. Report from the 93rd Cardiovascular and renal drugs advisory committee meeting, August 9-10, 2001. Circulation. 2001; 104:1742. [PubMed 11591605]

4. Vachiery JL, Hill N, Zwicke D et al. Transitioning from i.v. epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest. 2002; 121:1561-5. [IDIS 481609] [PubMed 12006444]

5. United Therapeutics Corporation. Cardiovascular and Renal drugs Advisory Committee presentation. NDA 21-272 Remodulin (treprostinil sodium) injection. Research Triangle Park, NC: 2001 Aug 21.

6. Newman JH. Treatment of primary pulmonary hypertension the next generation. N Engl J Med. 2002; 346:933-5. [IDIS 478527] [PubMed 11907295]

7. Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee meeting. Rockville, MD; Aug 2001. From FDA web site.

8. United Therapeutics Corp., Research Triangle Park, NC; Personal communication.

9. Rubenfire M, McLaughlin VV, Allen RP et al. Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial. Chest. 2007; 132:757-63. [PubMed 17400684]

10. Tapson VF, Gomberg-Maitland M, McLaughlin VV et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006; 129:683-8. [PubMed 16537868]

11. Gomberg-Maitland M, Tapson VF, Benza RL et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005; 172:1586-9. [PubMed 16151039]

12. Badesch DB, Abman SH, Simonneau G et al. Medical therapy for pulmonary arterial hypertension: Updated ACCP evidence-based clinical practice guidelines. Chest. 2007; 131:1917-28. [PubMed 17565025]

13. Barst RJ, Gibbs JS, Ghofrani HA et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S78-84.

14. Oudiz RJ, Farber HW. Dosing considerations in the use of intravenous prostanoids in pulmonary arterial hypertension: an experience-based review. Am Heart J. 2009; 157:625-35. [PubMed 19332188]

15. United Therapeutics Corp. Tyvaso (treprostinil) inhalation solution prescribing information. Research Triangle Park, NC; 2013 April.

16. McLaughlin VV, Benza RL, Rubin LJ et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010; 55:1915-22. [PubMed 20430262]

17. Channick RN, Olschewski H, Seeger W et al. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006; 48:1433-7. [PubMed 17010807]

18. Voswinckel R, Enke B, Reichenberger F et al. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol. 2006; 48:1672-81. [PubMed 17045906]

19. United Therapeutics Corp. Tyvaso inhalation system instructions for use. Research Triangle Park, NC; 2009 Aug.

20. Oudiz RJ, Schilz RJ, Barst RJ et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest. 2004; 126:420-7. [PubMed 15302727]

21. Sitbon O, Manes A, Jais X et al. Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension. J Cardiovasc Pharmacol. 2007; 49:1-5. [PubMed 17261956]

22. Ivy DD, Claussen L, Doran A. Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J Cardiol. 2007; 99:696-8. [PubMed 17317374]

23. Barst RJ, Galie N, Naeije R et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006; 28:1195-203. [PubMed 16899485]

24. Naeije R, Huez S. Expert opinion on available options treating pulmonary arterial hypertension. Expert Opin Pharmacother. 2007; 8:2247-65. [PubMed 17927481]

25. Skoro-Sajer N, Lang I. Treprostinil for the treatment of pulmonary hypertension. Expert Opin Pharmacother. 2008; 9:1415-20. [PubMed 18473715]

26. Feldman JP, Chakinala M, Torres F et al. Treprostinil sodium improves exercise capacity when added to existing oral pulmonary arterial hypertension therapy. Chest. 2007; 132 (suppl). Abstract No. 474b.

27. Gomberg-Maitland M, McLaughlin V, Gulati M et al. Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension. Am J Cardiol. 2005; 96:1334-6. [PubMed 16253609]

28. Centers for Disease Control and Prevention (CDC). Bloodstream infections among patients treated with intravenous epoprostenol or intravenous treprostinil for pulmonary arterial hypertension--seven sites, United States, 2003-2006. MMWR Morb Mortal Wkly Rep. 2007; 56:170-2. [PubMed 17332729]

29. Gotzkowsky SK, Dingemanse J, Lai A et al. Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers. J Clin Pharmacol. 2010; 50:829-34. [PubMed 20133511]

30. Laliberte K, Arneson C, Jeffs R et al. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004; 44:209-14. [PubMed 15243302]

31. US Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [August 6, 2010]. From FDA web site.

38. McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009; 53:1573-619. [PubMed 19389575]

40. Galiè N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D60-72. [PubMed 24355643]

41. Channick RN. Combination therapy in pulmonary arterial hypertension. Am J Cardiol. 2013; 111(8 Suppl):16C-20C. [PubMed 23558025]

42. Zhu B, Wang L, Sun L et al. Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis. J Cardiovasc Pharmacol. 2012; 60:342-6. [PubMed 22691882]

43. Gokhman R, Smithburger PL, Kane-Gill SL et al. Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2010; :. [PubMed 20838230]

44. United Therapeutics Corporation. How to get Tyvaso (treprostinil) inhalation solution. Research Triangle Park, NC; 2014. Available at: . Accessed 2014 May 16.

45. United Therapeutics Corporation. Support and Resources. Research Triangle Park, NC; 2014. Available at

HID. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011:1492-3.

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