The Role of Prostacyclin and Prostaglandin Analogs

Respiratory Medicine (2011) 105, 818e827

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

REVIEW Treatment of pulmonary arterial hypertension: The role of prostacyclin and prostaglandin analogs

Zeenat Safdar*

Baylor College of Medicine, 6620 Main Street, Suite 11B.09, Houston, TX 77030, USA

Received 18 August 2010; accepted 20 December 2010 Available online 26 January 2011

KEYWORDS Summary Epoprostenol; Pulmonary arterial hypertension is a progressive, fatal disease characterized by elevated pulmo- Iloprost; nary arterial pressure 25 mm Hg and normal pulmonary capillary wedge pressure 15 mm Hg. Right heart failure; Physiological features of pulmonary arterial hypertension are characterized clinically by the pres- Treprostinil; ence of pre-capillary pulmonary hypertension not caused by other conditions such as lung diseases 6-Minute walk test or chronic thromboembolic pulmonary hypertension. There are several therapies currently avail- distance able that have been shown to improve hemodynamics and improve outcomes in patients with pulmonary arterial hypertension. These therapies include synthetic prostacyclin and prostaglandin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Multiple prostacyclin and prostaglandin analog formulations are currently in use (both branded and generic), available for parenteral, inhaled, or oral administration. This review discusses the pharmacology, clinical effects, and routes of administration of prostacyclin and prostaglandin analogs, empha- sizing the advantages and disadvantages of each from the clinical perspective. ª 2010 Elsevier Ltd. All rights reserved.

Contents

Introduction ...... 819 Parenteral prostacyclin and prostaglandin analogs ...... 819 Epoprostenol ...... 819 Pharmacological properties ...... 820 Clinical effects ...... 820 Administration ...... 820 Treprostinil ...... 822 Pharmacological properties ...... 822

* Tel.: þ713 798 2400; fax: þ713 798 2688. E-mail address: [email protected].

Clinical effects ...... 822 Administration ...... 822 Inhaled prostaglandin analogs ...... 822 Inhaled iloprost ...... 822 Pharmacological properties ...... 822 Clinical effects ...... 822 Administration ...... 823 Inhaled treprostinil ...... 823 Pharmacological properties ...... 823 Clinical effects ...... 823 Administration ...... 824 Oral prostaglandin analogs ...... 824 Switching between PAH therapies ...... 824 Conclusions ...... 824 Competing interests ...... 824 Author contributions ...... 824 Acknowledgements ...... 824 Conflict of interest statement ...... 824 References ...... 825

Introduction Evidence suggests that endogenous prostacyclin, which is produced by endothelial cells of blood vessels, is decreased 7,8 Pulmonary hypertension is characterized by hemodynamic in patients with PAH. Four prostanoid receptors in the lung criteria of elevated mean pulmonary arterial pressure have been identified to be involved in regulating vascular tone, platelet activation, and immunological cell responses (mPAP) 25 mm Hg. Pulmonary arterial hypertension (PAH) 11 (Diagnostic Group I) is defined by an elevated mPAP (for an in-depth review, please see KK Mubarak, 2010 ). 25 mm Hg and normal pulmonary capillary wedge pressure Thus, synthetic prostaglandin I2 (PGI2), also referred to as of 15 mm Hg.1 Other causes of pulmonary hypertension prostacyclin, and prostaglandin analogs are a logical choice such as parenchymal lung diseases, sleep disorders, and for the treatment of this disease, and current guidelines recommend their use in patients with functional class IIeIV chronic thromboembolic disease must be excluded before 12 PAH diagnosis can be made.2,3 PAH is a progressive disorder PAH. Endothelin receptor antagonists and phosphodies- 4,5 terase type-5 inhibitors are also used as treatment for that leads to right ventricular failure and death. The 12 median survival in patients with untreated PAH in the 1990s patients with PAH. In addition, sequential combination was 2.8 years.6 However, recent data suggest that 1-year therapy with these agents should be considered if adequate response with monotherapy is not achieved or if patients survival in patients with PAH (both treated and untreated) 12 enrolled in prospective registries ranges from 88% to 91%.7,8 deteriorate with monotherapy. However, data supporting the use of combination therapy are limited, and such ther- This increase in survival may be due, in part, to improved 13 recognition of the presence of PAH or a greater availability apies are the focus of current research. of drugs to treat this condition. Prostacyclin and prostaglandin analogs have been used The 4th World Symposium on pulmonary hypertension in routine clinical practice since the 1990s, although there are reports of the investigational use of prostacyclin in classified PAH as idiopathic, heritable (formerly familial) 14,15 including germline mutations in a number of genes and patients with PAH dating back to the 1980s. Currently, familial cases with or without identified germline muta- there are several different prostacyclin and prostaglandin tions, drug- and toxin-induced, persistent pulmonary analog formulations available (for intravenous [IV] use, as a subcutaneous [SC] injection, and for inhalation) in the hypertension of the newborn, and the subcategories clas- 16 sified under PAH associated with other conditions, ie, United States. This review discusses the use of prostacy- connective tissue diseases, human immunodeficiency virus clin and prostaglandin analogs (both branded and generic) infection, portopulmonary hypertension, congenital heart to treat patients with Group 1 PAH, with an emphasis on the disease, schistosomiasis, or chronic hemolytic anemia as advantages and disadvantages of the different routes of Group 1 pulmonary hypertension, and pulmonary veno- administration used for these agents. occlusive disease and/or pulmonary capillary hemangio- matosis as Group 1’ pulmonary hypertension.9 Criteria used Parenteral prostacyclin and prostaglandin to stratify patients with PAH include the 6-minute walk test analogs distance (6MWD) and World Health Organization (WHO) functional class (I through IV). Patients with functional class Epoprostenol I are essentially asymptomatic, and patients with functional class IV exhibit signs of right heart failure and experience Epoprostenol, also known as synthetic PGI2 or prostacyclin, 10 shortness of breath, fatigue (even at rest), and syncope. was the first therapy approved by the United States Food 820 Z. Safdar and Drug Administration (FDA) for the treatment of PAH in epoprostenol has considerable disadvantages due to the 1995.17,18 Derived from the metabolism of arachidonic acid, potential for rebound pulmonary hypertension, cardiovas- it is a potent pulmonary and systemic vasodilator, an cular compromise, and death in the event of a brief inter- inhibitor of platelet aggregation,18,19 and it may modulate ruption of IV administration.29,34 pulmonary vascular remodeling.20 Epoprostenol sodium, which is formulated for IV injec- Administration tion, is available as Flolan (GlaxoSmithKline, Research Because of its short systemic t1/2, epoprostenol must be Triangle Park, NC),19 Veletri (Actelion Pharmaceuticals US, administered by continuous IV infusion. The drug is Inc., South San Francisco, CA), and a generic formulation administered through a central venous catheter and by the (Teva Parenteral Medicines, Inc., Irvine, CA).21 The phar- use of an ambulatory infusion pump.19,21,22,24 Branded and macological and clinical properties of the active ingredient generic epoprostenol sodium for injection can be adminis- (epoprostenol sodium) are identical. Veletri (epoprostenol tered at room temperature for a maximum of 8 h, which sodium for injection) is formulated with extended stability; can be accomplished by using smaller pump cassettes; however, the clinical indication of this compound is identical however, if the drug is to be administered over 24 h, it must to that of Flolan.22,23 For the purposes of this article, the be kept cold via use of a cold pouch that should be replaced brand names Flolan, Veletri, and the generic formulation every 12 h depending on the ambient temperature.19,21 epoprostenol sodium for injection will be referred to as Epoprostenol with extended stability, when diluted epoprostenol sodium for injection, epoprostenol with completely and administered immediately, can be infused extended stability, and generic epoprostenol sodium for at room temperature for up to 24 h at concentrations injection, respectively. The term epoprostenol will be used ranging from 6000 ng/mL to <30,000 ng/mL without the to indicate properties that refer to all 3 drugs. use of a cold pouch or ice packs.22,23 There are several important considerations in the Pharmacological properties administration of epoprostenol. Long-term administration The systemic half-life (t1/2) of epoprostenol is 2e3 min. requires a permanent indwelling catheter and a continuous Epoprostenol metabolism in humans results in 2 major and infusion pump, which increases the risks for infection and 14 minor metabolites, which are excreted primarily via the thrombosis. Adverse events may be associated with infusion kidneys.19,21,22,24 Epoprostenol with extended stability is system malfunctions and subsequent over- or underdosing more stable upon reconstitution and administration than of the drug,35 and patients receiving the IV drug can branded or generic epoprostenol sodium for injection due experience bloodstream infections and sepsis. In addition, to the use of a buffer that lacks sodium chloride, substi- considerable patient education and instruction are required tutes arginine for glycine, and has a higher pH.19,21,22,25,26 for the care and maintenance of the catheter and pump, In addition, epoprostenol with extended stability can be both of which necessitate sterile techniques.16 diluted for delivery with Sterile Water for Injection or The 3 different epoprostenols each come in slightly Sodium Chloride 0.9% for Injection, whereas branded and different sizes and packaging, and each requires different generic epoprostenol sodium for injection require a special storage conditions (Table 1). Branded epoprostenol sodium diluent.25 Additional pharmacological properties of epo- for injection is supplied in powder form in 17 mL glass vials. prostenol are summarized in Table 1. Two different quantities are available: 0.5 mg (blue cap) and 1.5 mg (red cap). The lyophilized powder can be stored Clinical effects at room temperature.19 The drug must be reconstituted Clinical studies in patients with PAH have shown that IV using a specific sterile diluent (Flolan Sterile Diluent for epoprostenol treatment improves hemodynamic parame- Injection), which is also stored at room temperature. The ters, significantly improves symptoms of dyspnea and reconstituted solution can be stored at 2e8 C for fatigue, and increases exercise capacity (6MWD).19,24,27e33 a maximum of 48 h before use due to the unstable nature of Significant dose-dependent decreases in several hemody- the reconstituted soluble compound. namic parameters, including total pulmonary resistance, Generic epoprostenol sodium for injection is supplied in pulmonary vascular resistance (PVR), and mPAP, and powder form in 10 mL glass vials. Two different quantities increases in cardiac index and stroke volume were observed are available: 0.5 mg (blue cap) and 1.5 mg (red cap).21 The with IV epoprostenol therapy.19,24,29 The hemodynamic storage conditions of the lyophilized powder, the recon- effects of epoprostenol are similar in acute and chronic stituted solution, and the diluent (Flolan Sterile Diluent settings.19,22,24 In addition, IV epoprostenol has been shown for Injection) are identical to those indicated for branded to improve survival and is the only PAH medication to have epoprostenol sodium for injection. an indication for improved survival in its prescribing infor- Epoprostenol with extended stability is supplied in mation.19,21,29 However, in patients with PAH due to the powder form in 10 mL glass vials of 1.5 mg quantity (red scleroderma spectrum of diseases, no significant improve- cap). Unlike branded and generic epoprostenol sodium for ment in survival was observed with epoprostenol therapy injection, epoprostenol with extended stability can be relative to conventional therapy.28 reconstituted using either Sterile Water for Injection or Adverse events attributable to chronic epoprostenol Sodium Chloride 0.9% for Injection.22,23 The lyophilized administration include headache, flushing, jaw pain, powder can be stored at room temperature. When diluted anxiety/nervousness, diarrhea, flu-like symptoms, nausea, completely and administered immediately at concentra- and vomiting.19,21,22,24 Patients who receive epoprostenol tions ranging from 6000 ng/mL to <30,000 ng/mL, epo- may also experience adverse events related to the route of prostenol with extended stability can be infused for 24 h at 19,21,22,24 administration. Finally, the short systemic t1/2 of room temperature without the use of ice packs. When rsaylnadpotgadnaaosi h ramn fPAH of treatment the in analogs prostaglandin and Prostacyclin

Table 1 Properties and storage conditions of parenteral epoprostenol and treprostinil. Drug Pharmacological Vial size Concentrations Diluent Stability properties Epoprostenol Clearancea: 93 mL/kg/min Drug: 17 mL 0.5 mg, blue cap Flolan Protect from light sodium for Volume of distributiona: Diluent: 50 mL 1.5 mg, red cap Diluent: 94 mg glycine; Reconstituted: up to 8 h at RT; >8h injection (Flolan )19 357 mL/kg 73.3 mg NaCl; NaOH requires cold pack refrigeration a t1/2 : 2.7 min (to adjust for pH); and Sterile Water for Injection Generic epoprostenol As above Drug: 10 mL 0.5 mg, blue cap As above Protect from light sodium for injection21 Diluent: 50 mL 1.5 mg, red cap Reconstituted: up to 8 h at RT; >8h requires cold pack refrigeration Epoprostenol with As above Drug: 10 mL 1.5 mg, red cap Sterile Water for Injection, Protect from light extended stability Diluent: 50 mL or Sodium Chloride 0.9% Reconstituted 6000 ng/mL and (Veletri )24 for Injection <30,000 ng/mL: can be administered immediately over 24 h at RT Reconstituted 30,000 ng/mL: can be stored for 7 days at 2e8 C and then administered over 24 h at RT IV/SC treprostinil Clearanceb: w429 mL/kg/h 20 mL 1.0 mg/mL, yellow cap 5.3 mg NaCl; IV: up to 48 h at 37 C (Remodulin )37 Volume of distributionb: 2.5 mg/mL, blue cap 3.0 mg metacresol; SC: up to 72 h at 37 C w1.4 L/kg 5.0 mg/mL, green cap 6.3 mg Na citrate; Terminal t1/2 : w4h 10 mg/mL, pink cap H2O Bioavailability:100%

H2O, water; IV, intravenous; Na, sodium; NaCl, sodium chloride; NaOH, sodium hydroxide; RT, room temperature; SC, subcutaneous; t1/2 , half-life. a In animals. b For a person with an ideal body weight of 70 kg. 821 822 Z. Safdar diluted to concentrations 30,000 ng/mL, epoprostenol pump. SC treprostinil requires no dilution before use; with extended stability can be stored for up to 7 days at however, IV treprostinil must first be diluted using Sterile 2e8 C and then infused for 24 h at room temperature Water for Injection, Sodium Chloride 0.9% for Injection, or without the use of ice packs.22,23 Flolan Sterile Diluent for Injection.37 Treprostinil is supplied as a solution in multi-use, 20 mL Treprostinil vials. Four different concentrations are available, ranging from 1 to 10 mg/mL (Table 1).37 Unopened vials of tre- Treprostinil is a prostaglandin analog that is stable at room prostinil can be stored at room temperature. When used temperature and has a neutral pH.36,37 Similar to epopros- subcutaneously, treprostinil can be administered for up to 72 h at 37 C; however, the diluted solution for IV admin- tenol, treprostinil is a potent pulmonary and systemic vasodilator and an inhibitor of platelet aggregation.36e38 istration can only be used for up to 48 h at 37 C. Parenteral treprostinil is available as a branded product The basic pH and short systemic t1/2 of epoprostenol only (Remodulin; United Therapeutics Corp., Research necessitate IV infusion, whereas the neutral pH and longer 37 systemic t1/2 of treprostinil enable either IV or SC adminis- Triangle Park, NC). The manufacturer recommends that 5 treprostinil be administered via a continuous SC infusion, tration. The longer t1/2 lowers the risk for rebound PAH with with IV infusion used only in the event of intolerance to SC infusion cessation, and no cases of rebound PAH have been administration (eg, severe injection site pain/reactions).37 reported in the medical literature. In addition, because treprostinil does not require refrigeration, it has the potential to considerably improve quality of life for these patients. Pharmacological properties The pharmacological properties of treprostinil are summarized in Table 1. It is metabolized by the liver into 5 Inhaled prostaglandin analogs metabolites, which are primarily excreted in the urine. Treprostinil has linear pharmacokinetics over the dose Inhaled prostaglandin analogs were developed, in part, due to range of 1.25e125 ng/kg/min.37 the limitations of parenteral administration and are often used as a bridge to IV therapy or lung transplantation. The Clinical effects adverse event profile is similar to that seen following paren- Treatment of patients with PAH with IV or SC treprostinil teral administration, whereas complications due to contin- improves hemodynamic parameters and exercise capaci- uous parenteral administration are eliminated.5 It is thought ty.39e44 The effects of treprostinil on hemodynamics have that the incidence of adverse events associated with paren- been mixed: some studies show significant improvement in teral prostacyclin and prostaglandin analogs (ie, catheter- hemodynamics compared to baseline or placebo,39,42e44 induced sepsis or thromboembolism and infusion site pain/ whereas others do not.41 In a study comparing IV trepros- reaction) is obviated with inhaled prostaglandin analogs due e tinil with epoprostenol, the hemodynamic changes were to the direct delivery of the drug to the lung.43,49 51 similar for both of these agents.41 A study in healthy volunteers showed that IV and SC treprostinil were bio- Inhaled iloprost equivalent.45 In animal studies, the use of treprostinil reduced ventricular afterload (both right and left) and Like epoprostenol and treprostinil, inhaled iloprost is increased stroke volume and cardiac output.37 a systemic and pulmonary vasodilator that also has anti- The most frequent adverse events associated with platelet properties.52 Inhaled iloprost is available as chronic SC treprostinil administration are infusion site pain, a mixture of the 4S and 4R stereoisomers; with respect to infusion site reactions, and bleeding.5,37 Other prostacy- vasodilation, the 4S isomer is more potent than the 4R clin-related adverse events include headache, diarrhea, isomer.53 Iloprost is marketed under the brand name nausea, jaw pain, and vasodilation. Adverse events asso- Ventavis (Actelion Pharmaceuticals US, Inc., South San ciated with infusion system malfunctions include over- or Francisco, CA) in the United States.53 There are no generic underdosing of treprostinil, and patients receiving IV tre- versions of inhaled iloprost available. Despite lack of prostinil can experience bloodstream infections and supportive clinical evidence, an IV formulation of iloprost is sepsis.37 The increased risk of infections associated with approved for the treatment of PAH in New Zealand and has treprostinil may be due to its receptor affinity; unlike other been used off-label in a number of countries including prostaglandin analogs, in in vitro studies and animals, tre- Germany, Switzerland, and Australia.16,54 prostinil modulates T lymphocyte and dendritic cell func- tions in an IP receptor-independent fashion and may affect Pharmacological properties endogenous immune function.46,47 Recent preliminary The systemic t1/2 of inhaled iloprost is 20e30 min; additional results of an observational study suggest that adjusting the pharmacological properties are summarized in Table 2. pH of the buffer from neutral to basic by using Flolan Inhaled iloprost is metabolized via oxidation to produce one diluent may reduce the incidence of sepsis following major metabolite, which is excreted primarily in the urine.53 treatment with IV treprostinil.48 Clinical effects Administration Inhaled iloprost improves hemodynamic parameters, func- Patients receive SC treprostinil via a self-inserted SC tional status, and exercise capacity in patients with PAH.55e62 catheter coupled to an infusion pump. Those receiving IV Furthermore, the addition of inhaled iloprost to stable treprostinil require a central venous catheter and infusion ongoing bosentan therapy significantly delayed the time to Prostacyclin and prostaglandin analogs in the treatment of PAH 823

clinical worsening in a 12-week, randomized, double-blind trial of 67 patients with PAH.63 Hemodynamic effects of inhaled iloprost in humans include decreases in PVR and mPAP and increases in cardiac output and oxygen saturation after 12 Protect from light weeks and 2 years of treatment.58,62 Unlike parenteral epoprostenol and treprostinil, the effect of inhaled iloprost on mean systemic arterial pressure has been variable; some studies show no effect,61,64e66 whereas others demonstrate a significant reduction.58 It has also been shown that patients receiving inhaled iloprost do not experience rebound symp- None RT Not stated RT Preservatives Stability toms during the night, which may occur with interruption of parenteral infusion of epoprostenol or treprostinil.67 Adverse events associated with inhaled iloprost are similar to those seen with prostacyclin and prostaglandin analogs, ie, headache, flushing, flu-like symptoms, nausea, and vomiting. Patients receiving inhaled iloprost can also experience jaw muscle spasm. Additional adverse events include cough and tongue pain, and syncope.53,58 Notably, when iloprost was added to bosentan therapy, syncope was infrequent and less

, half-life. severe (1 patient) than in an iloprost monotherapy study in 58,63 1/2 which there were 5 cases of serious syncope. t m g/mL solution (per 1 mL): m g/mL solution (per 1 mL): O 2 Administration 10 0.81 mg ethanol; 0.121 mg tromethamine; 9.0 mg NaCl; 0.51 mg HCl 20 1.62 mg ethanol; 0.242 mg tromethamine; 9.0 mg NaCl; 0.76 mg HCl 18.3 mg Na citrate; 0.58 mg NaOH; 11.7 mg 1N HCl; H Diluent Inhaled iloprost should be administered 6e9 times a day as needed (no more frequently than once every 2 h) during waking hours using the I-neb Adaptive Aerosol Delivery (AAD) System (Philips Respironics, Respiratory Drug Delivery Ltd., Chichester, UK),53 which may be a limitation for young patients with an active lifestyle. Iloprost for inhalation is supplied in 1 mL ampules in concentrations of m g/mL, red m g/mL, purple m g/mL, gold 10 mg/mL (for patients receiving either 2.5 or 5 mg per dose) and 20 mg/mL (for patients experiencing extended treatment times when maintained on 5 mg iloprost/dose). The

m g with 10 m g with 10 m g with 20 ampules should be stored at room temperature. Properties of the inhaled iloprost solution are included in Table 2. 5.0 5.0

Inhaled treprostinil

The inhaled formulation of treprostinil is the most recent 1 mL 2.5 2.9 mL 0.6 mg/mLprostaglandin 18.9 mg NaCl; analog to be approved by the US FDA (July 2009).68 It is marketed by United Therapeutics under the brand name Tyvaso.

: Pharmacological properties a 72%

e Data available for the inhaled form of treprostinil include the following. A systemic exposure of inhaled treprostinil was 69 : 64%

a proportional to the administered dose in a single-dose study in healthy volunteers.68 In one study that included patients : 20 mL/kg/min a with PAH, 30 mg/dose (4/day) and 45 mg/dose (4/day) e 30 min e 52 min caused a maximum blood concentration of 0.33 ng/mL and :20 :44 e 0.8 L/kg 0.96 ng/mL, a time to maximum concentration of 15 min and

1/2 1/2 69 Peak serum levels: 150 pg/mL 0.7 t Clearance t Bioavailability Pharmacological properties Vial size Concentrations Volume of distribution 45 min, and a t1/2 of 44 min and 52 min, respectively. A similar dose proportionality in patients with PAH has been reported in a second study.70 The bioavailability of inhaled treprostinil was 64% after administration of 18 mg and 72%

e 70 m 53 after 36 g in healthy volunteers (Table 2). ) 68 ) Properties and storage conditions of inhaled prostacyclin and prostaglandin analogs. Clinical effects Clinical studies of inhaled treprostinil have been conducted in In healthy volunteers. O, water; HCl, hydrochloric acid; Na, sodium; NaCl, sodium chloride; NaOH, sodium hydroxide; RT, room temperature; (Tyvaso (Ventavis 2 a patients already receiving the endothelin receptor antagonist Inhaled treprostinil Inhaled iloprost Table 2 Drug H bosentan or the phosphodiesterase type-5 inhibitor sildenafil 824 Z. Safdar and have shown that inhaled treprostinil significantly hemodynamics were not reported in two additional improves hemodynamics, functional class, and exercise studies.88,90 Despite the potential worsening hemody- capacity when added to oral therapy.68e70 However, in one namics, there is little evidence that clinical deterioration study (TRIUMPH-I), inhaled treprostinil significantly improved in patients on treprostinil differs from those receiving exercise capacity (6MWD), but not functional class, when epoprostenol.87,88,90 added to oral therapy.69 Hemodynamic effects of inhaled The results of studies investigating the transition of treprostinil include decreases in mPAP and PVR.69,70 patients with PAH from prostacyclin or prostaglandin analogs Adverse events associated with inhaled treprostinil to oral agents of a different class were mixed; while generally include cough, headache, pharyngolaryngeal pain and the transitions were successful, some patients did deterio- throat irritation, nausea, flushing, and syncope.68e70 rate when switched to oral therapy, and the conclusions generally called for care when selecting patients suitable for Administration transition.91e94 Those patients most likely to successfully Inhaled treprostinil should be administered 4 times daily, transition from parenteral epoprostenol or treprostinil 4 h apart during waking hours using the Tyvaso Inhalation therapy to bosentan or sildenafil had better hemodynamics System. Patients should be initiated on 18 mg of inhaled at the time of the transition.92,94 Patients successfully tran- treprostinil (3 mg/breath), which should be increased to sitioned may have to go back on parenteral prostacyclin or 54 mg (9 breaths) within 6 weeks, provided the increased prostaglandin analog therapy as their disease progresses.93 dose is tolerated. However, it may be worth considering transitioning care- Inhaled treprostinil is supplied in 2.9 mL ampules at fully selected patients to an oral therapy due to decreased a concentration of 0.6 mg/mL (Table 2). It should be used adverse events reported on transitioned patients.91e94 undiluted. Unopened ampules should be stored at room 68 temperature and protected from light. Conclusions

Oral prostaglandin analogs Administration of prostacyclin and prostaglandin analogs in patients with PAH requires attention to detail due to Oral formulations of prostaglandin analogs are currently in numerous differences among the drugs. These differences development for use in the United States. An oral formulation include package size, concentration or dose, route of of treprostinil has been developed by United Therapeutics; administration, ease of use, cost, availability, and admin- however, this formulation has not yet been approved in the istration device. Thus, the clinician should not only weigh United States and is currently undergoing assessment in the pharmacological benefits of prostacyclin and prosta- clinical trials.16,71e73 Similarly, beraprost (Procyclin) has glandin analogs when deciding on treatment in patients launched in Japan and Korea by Kaken Pharmaceuticals and is with PAH but also whether the patient can comply with drug also undergoing assessment in the United States.74e85 storage requirements, route of administration, and use of the administration device. Switching between PAH therapies Competing interests The challenges of administration and adverse events associated with parenteral epoprostenol or treprostinil therapy Dr Safdar is on advisory boards and consultant committees (particularly the IV route) occasionally necessitate switch- for Actelion Pharmaceuticals US, Inc. Gilead, and United ing therapy, either from one analog to another or from Therapeutics. prostaglandin analog therapy to another drug class, such as endothelin receptor antagonists or phosphodiesterase type- Author contributions 5 inhibitors. The literature on switching between prostacyclin and Dr Safdar conceived the manuscript topic, helped to draft prostaglandin analogs mainly documents switching from IV the manuscript, and approved the final manuscript. epoprostenol to IV or SC treprostinil86e90; in all of these studies, switching from epoprostenol to treprostinil was successful in that it did not cause any clinical deterioration Acknowledgements or change in functional status and generally resulted in an improvement in treatment-related adverse events. Evidence for transitioning patients from parenteral to The author thanks Jennifer M. Kulak, PhD, Sheridan Hen- inhaled therapies is primarily anecdotal with few controlled ness, PhD, and Sohita Dhillon, PhD, of inScience Commu- studies.88 Practice patterns for transitioning patients vary nications, a Wolters Kluwer business, for medical writing greatly from transitioning over a period of weeks, to over and editorial support. Preparation of this manuscript was hours, and often with an overlap period. supported by Actelion Pharmaceuticals US, Inc. Although functional tests (eg, 6MWD and Borg dyspnea index) generally remain the same after transitioning from epoprostenol to treprostinil,86e90 the effect upon hemody- Conflict of interest statement namics is more variable; one study reported increases in mPAP and PVR and a decrease in cardiac index,86 but two Dr Safdar is on advisory boards and consultant committees others reported no change in hemodynamics,87,89 and for Actelion Pharmaceuticals US, Inc. Gilead, and United Prostacyclin and prostaglandin analogs in the treatment of PAH 825

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