Pulmonary Arterial Hypertension (PAH)


Vasodilators have served as the foundation for pulmonary arterial hypertension (PAH) treatment since 1996. They target the vasculature systemically rather than the pulmonary vessels specifically.1 Vasodilators decrease systemic blood pressure and pulmonary arterial pressure and resistance by reversing vasoconstriction, improving systemic circulation and oxygenation, and decreasing cardiac load.2 

Flolan (Epoprostenol)

Flolan® (epoprostenol sodium) is an injectable vasodilator produced by GlaxoSmithKline. It was approved by the US Food and Drug Administration (FDA) on April 14, 2000 for the long-term intravenous treatment of patients with PAH categorized in the scleroderma disease spectrum, particularly for class III and IV patients on the New York Heart Failure Association’s (NYHA) functional classification scale who are unresponsive to conventional treatments.3-5 

Epoprostenol performs 2 major pharmacological actions—direct vasodilation of pulmonary and systemic arterial vasculature and reduction of platelet aggregation. The sodium salt is packaged in glass vials containing 0.5 mg or 1.5 mg of the white to off-white powder, in addition to 3.76 mg of glycine, 2.93 mg of sodium chloride, and 50 mg of mannitol. Epoprostenol requires reconstitution for intravenous injection using a sterile diluent.5 

The initial recommended dosage is 2 ng/kg/min via an intravenous infusion pump over a 24- to 48-hour period; it may require adjustment to a lower dose if the patient does not tolerate the initial dose. If the patient tolerates the initial dosage, titration of subsequent doses by 1 to 2 ng/kg/min every 15 minutes or longer is recommended until the drug achieves the desired effect or side effects limit further dose increases.4

Frequently reported adverse effects of epoprostenol include flushing, jaw pain, headache, myalgia, diarrhea, nausea, vomiting, flu-like symptoms, hypotension, anxiety, nervousness, and dermatological problems such as rash, urticaria, and eczema.4 

Contraindications for use include congestive heart failure due to severe left ventricular systolic dysfunction, chronic pulmonary edema developed during dose initiation, and hypersensitivity to epoprostenol or structurally related drugs.4,5 

The efficacy and safety of epoprostenol were demonstrated in 2 prospective, open, randomized controlled trials lasting 8 and 12 weeks in duration, respectively. These trials compared epoprostenol plus standard therapy to standard therapy alone. Standard therapy included varying combinations of anticoagulants, oral vasodilators, diuretics, digoxin, and supplemental oxygen treatments. Compared to controls, patients receiving epoprostenol infusions had increased stroke volume, cardiac index, and arterial oxygen saturation and decreased mean pulmonary artery pressure, systemic vascular resistance, mean right atrial pressure, and total pulmonary resistance. These patients also exhibited improved exercise tolerance as measured by the 6-minute walk test. Additionally, none of the patients treated with epoprostenol in the 12-week trial died, while 8 of the 40 (20%) patients treated only with standard therapies died.5

Ventavis (Iloprost)

Ventavis® (iloprost) is an inhaled vasodilator produced by CoTherix, Inc that is a synthetic analog of prostacyclin.6 It was approved by the FDA on December 29, 2004 for the treatment of patients with PAH categorized in World Health Organization (WHO) group I with NYHA class III or IV symptoms.6,7 

Iloprost works by dilating systemic and pulmonary arterial vasculature and inhibiting platelet aggregation.7

It is packaged in 1-mL ampules with 2 concentrations, 10 mcg/mL and 20 mcg/mL, and it is delivered directly into the patient’s lungs via inhalation using one of two nebulizers: the I-neb® AAD® System or the Prodose® AAD® System.7,8

The recommended initial dose is 2.5 mcg, with gradual titration to a maintenance dose of 5 mcg if tolerated by the patient. Patients should have 6 to 9 doses/inhalations administered daily as needed, with a minimum of 2 hours between doses.7,8 

Frequently reported adverse events include flushing, increased cough, headache, trismus, nausea, vomiting, hypotension, insomnia, flu-like symptoms, muscle cramping, fainting, heart palpitations, back and tongue pain, hemoptysis, pneumonia, and increased concentrations of alkaline phosphatase and gamma-glutamyl transferase.7

There are no contraindications for the use of iloprost; however, vital signs should be monitored during administration and the treatment should be stopped quickly in patients showing signs of pulmonary edema, bronchospasm, or syncope and in those with a systolic blood pressure lower than 85 mmHg.7 

The efficacy and safety of iloprost were demonstrated by 2 controlled clinical trials lasting 12 weeks and 2 long-term extensions, which showed that it improved exercise tolerance, decreased symptoms, and stabilized disease progression, with patients showing a lack of further deterioration.7 

Remodulin/Orenitram (Treprostinil)

Remodulin® (treprostinil sodium) is an injectable vasodilator produced by United Therapeutics Corporation. It was approved by the FDA on May 21, 2002 for the reduction of exercise-associated symptoms in patients with PAH in WHO group 1 categorized in NYHA functional classes II through IV and in patients no longer responding to epoprostenol as indicated by clinical deterioration.9,10 Orenitram® is the oral, extended-release tablet version of Remodulin with the same indications.11

Treprostinil works by dilating systemic and pulmonary arterial vasculature and inhibiting platelet aggregation.10

Remodulin is packaged with 4 concentrations, 1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10 mg/mL, and it is administered by continuous subcutaneous or intravenous injection. Undiluted continuous subcutaneous infusion is the preferred mode of administration; however, if the patient does not tolerate this method, diluted intravenous infusion is recommended.10,11

The recommended initial dose of Remodulin is 1.25 ng/kg/min via continuous infusion, with subsequent titrations no greater than 1.25 ng/kg/min every week for the first 4 weeks and then no greater than 2.5 ng/kg/min every week thereafter.10,11 

The recommended initial dose of Orenitram is 0.125 mg orally 3 times a day or 0.25 mg orally twice a day, with subsequent titrations every 3 to 4 days of 0.125 mg three times daily or 0.25 mg or 0.5 mg twice daily until the highest tolerated dosage is achieved.11 

Frequently reported adverse events include subcutaneous infusion site pain and reaction, headache, diarrhea, nausea, jaw pain, flushing, dizziness, edema, pruritus, and hypotension.10

There are no contraindications for the use of treprostinil.10 

The efficacy and safety of treprostinil were demonstrated in two 12-week, randomized, double-blind, controlled clinical trials comparing the continuous subcutaneous infusion of Remodulin with placebo in 470 patients with PAH. Although Remodulin did not significantly improve walking distance, it decreased dyspnea, fatigue, and signs and symptoms of PAH.10 

In another study, Remodulin prevented further clinical deterioration compared to placebo after patients transitioned to it following the use of epoprostenol.10

Uptravi (Selexipag)

Uptravi® (selexipag) is a prostacyclin receptor agonist produced by Actelion Pharmaceuticals US, Inc. It was approved by the FDA on June 29, 2018 for the reduction of exercise-associated symptoms in patients with PAH in WHO group 1 for the purposes of delaying disease progression and reducing hospitalization risk.12,13 

Selexipag works by dilating systemic and pulmonary arterial vasculature and inhibiting platelet aggregation.13,14

Selexipag comes in 200-mcg, 400-mcg, 600-mcg, 800-mcg, 1000-mcg, 1200-mcg, 1400-mcg, and 1600-mcg tablets. Selexipag may also be administered as an injection, which is packaged as 1800 mcg of lyophilized powder in a single-dose vial requiring reconstitution and dilution.13

The recommended initial dose for selexipag is 200 mcg twice daily, increasing the dose by 200 mcg twice daily at weekly intervals until reaching the maximum dose of 1600 mcg twice daily as tolerated. If hepatic impairment is present, increase the dose by 200 mcg once daily at weekly intervals until reaching the highest tolerated dose up to 1600 mcg.13 

Frequently reported adverse events include headache, diarrhea, nausea, jaw pain, flushing, vomiting, myalgia, and extremity pain.13

Contraindications for the use of selexipag include hypersensitivity and simultaneous administration of strong CYP2C8 (cytochrome P450, family 2, subfamily C, polypeptide 8) inhibitors. Discontinuation of the treatment is suggested if pulmonary edema is present.13 

The efficacy and safety of selexipag were demonstrated by a multicenter, double-blind, placebo-controlled clinical trial of 1156 patients with PAH. Treatment with selexipag reduced death, hospitalization, disease progression, and the initiation of supplemental oxygen therapy by 40% compared to the placebo.13 

References

  1. Rich S. The effects of vasodilators in pulmonary hypertension: pulmonary vascular or peripheral vascular? Circ Heart Fail. 2009;2(2):145-150. doi:10.1161/CIRCHEARTFAILURE.108.805374
  2. Vasodilators. Mayo Clinic. September 25, 2021. Accessed May 25, 2022.
  3. Drug appr-oval package: Flolan (epoprostenol sodium) injection. US Food and Drug Administration (FDA). Accessed May 25, 2022. 
  4. Epoprostenol (Rx). Medscape. Accessed May 25, 2022. 
  5. Flolan. Prescribing information. GlaxoSmithKline; 2008. Accessed May 25, 2022.
  6. Drug approval package: Ventavis (iloprost) inhalation solution. US Food and Drug Administration (FDA). Accessed May 25, 2022. 
  7. Ventavis. Prescribing information. Actelion Pharmaceuticals US, Inc; 2010. Accessed May 25, 2022.
  8. Iloprost (Rx). Medscape. Accessed May 25, 2022.
  9. Drug approval package: Remodulin (treprostinil sodium) injection. US Food and Drug Administration (FDA). Accessed May 25, 2022.
  10. Remodulin. Prescribing information. United Therapeutics Corp; 2011. Accessed May 25, 2022.
  11. Treprostinil (Rx). Medscape. Accessed May 25, 2022.
  12. Drug approval package: Uptravi. US Food and Drug Administration (FDA). October 27, 2021. Accessed May 25, 2022.
  13. Uptravi. Prescribing information. Actelion Pharmaceuticals US, Inc; 2021. Accessed May 25, 2022.
  14. Uptravi (selexipag). Actelion Pharmaceuticals US, Inc. Accessed May 25, 2022.

Reviewed by Kyle Habet, MD, on 5/31/2022.