Last Updated April 2009
What is treprostinil?
Treprostinil is a subcutaneous (under the skin) or intravenous (in the veins) medication used for the treatment of pulmonary arterial hypertension (PAH). It is a synthetic (not obtained from other humans or animals) analogue of prostacyclin (see epoprostenol fact sheet for more information about prostacyclin). Treprostinil was approved by the FDA in 2002 for subcutaneous use, and subsequently in 2004 for intravenous use for the treatment of PAH in patients with New York Heart Association Class II, III, or IV symptoms.
How does treprostinil work?
The major actions of treprostinil are vasodilatation of the pulmonary and systemic vascular beds (widening of narrowed blood vessels in the lung and other parts of the body), and inhibition of platelet clumping (aggregation). These effects appear to be similar to the effects of epoprostenol (Flolan). Improved exercise capacity has been demonstrated in a short-term (3 month) study of subcutaneous treprostinil. The improvement was dose related, meaning that that those patients in the clinical trial achieving the highest doses had the greatest improvement in exercise capacity. Two long-term studies of subcutaneous treprostinil involving patients with a variety of causes of pulmonary hypertension showed efficacy out to 2-4 years.
Trials with intravenous treprostinil have been open-label involving limited numbers of patients. These studies showed improvement in exercise capacity as well cardiac function. Other small studies have transitioned patients on a stable dose of epoprostenol to treprostinil displaying maintainence of exercise capacity. The dose of treprostinil needed to be higher than the previous epoprostenol dose. Whether intravenous treprostinil is as effective as intravenous epoprostenol is unknown as there are no comparative studies.
How is treprostinil given?
The half-life of treprostinil is about four and a half hours; although symptoms due to drug interruption can occur in less than one hour. This means that after stopping the infusion, about half the drug is still in the patient's system four and a half hours later. Treprostinil is stable at room temperature for 48 hours when mixed with sterile solution (this means it does not have to be refrigerated).
Subcutaneous treprostinil is delivered via the CADD MS3 portable infusion pump. Infusion sites are placed in the fat tissue, generally in the abdominal area, and are changed on average every 3-5 weeks. Intravenous treprostinil must be administered via a surgically placed central venous catheter. Intravenous treprostinil is delivered via the CADD Legacy pump (the same pump that is used for intravenous epoprostenol administration).
Dosing of treprostinil
Treprostinil is usually initiated at 1.25 – 2.5 ng/kg/min and the dose is gradually increased to achieve symptomatic relief. It is not uncommon for some patients to be on a dose of 100 ng/kg/min, or more, to achieve optimal benefit with a tolerable safety profile. The dose of treprostinil is the same for subcutaneous and intravenous delivery systems. Patients converted from epoprostenol to treprostinil typically require 1.5-2.5 times the original dose of epoprostenol to maintain clinical stability.
What are the main side effects with treprostinil?
The major side effect with subcutaneously administered treprostinil is the development of infusion site pain (which often improves after 1-2 months or longer of therapy) and/or redness at the site of the subcutaneous infusion. This occurs in up to 80% of patients. The occurrence of site pain is not dose-related and often improves the longer an infusion site is left in place. Cellulitis and bleeding can also occur at the infusion site. There are various remedies used to treat this problem, and patients differ in their response to these remedies. The other side effects of treprostinil are similar to those seen with epoprostenol and include flushing, nausea, jaw pain, diarrhea, headache, extremity pain, and skin rash. Side effects related to the intravenous use of treprostinil, such as catheter infections, are similar to those with intravenous epoprostenol.
How is treprostinil supplied?
Treprostinil is supplied in four concentrations (1.0 mg/ml, 2.5 mg/ml, 5.0 mg/ml, and 10.0 mg/ml), each containing 20 ml of solution in a multidose accessible vial. A single vial should be used no more than 14 days after the initial opening and usage of the vial, provided that the proper storage procedures are followed.
How do patients obtain treprostinil?
Treprostinil must be prescribed by a physician and insurance approval must be obtained prior to starting therapy. The cost of treprostinil is $100,000 per year or more depending upon patient dose. Most insurance, as well as Medicaid and Medicare, will pay for treprostinil. The drug is provided directly from specialty pharmacies (Accredo, Caremark, and Curascript) whom provide a team of clinical pharmacists and nurses. They assist with all aspects involved in the long term usage of treprostinil including insurance issues, dose titration, providing pumps and supplies, and technical troubleshooting with 24 hour hotlines.
How is treprostinil initiated?
Patients started on intravenous treprostinil require admission to the hospital for a few days similar to epoprostenol initiation. Teaching of Hickman catheter care, CADD pump specifics, and administration of treprostinil are taught before leaving the hospital by specialty nurses. Subcutaneous treprostinil can be started in the hospital or at home. For home initiation, pre-teaching by specialty nurses occurs whose presence during the start-up of drug delivery is often required.
Could a patient be allergic to treprostinil?
There are no reports of allergies to treprostinil. It is unlikely that this would occur since prostacyclin is naturally made by the body. However, any medication can cause side effects, which are listed above. No medications are prohibited with the use of treprostinil.
Pregnant and nursing women
Treprostinil has not been studied in pregnant women. It has not been shown to cause birth defects or other problems in animals. It is not known whether this drug is excreted in breast milk.
Use in children
Treprostinil has been used in children. Clinical studies of treprostinil did not include sufficient numbers of patients 16 years of age and under to determine its safety and efficacy in children.
New modes of delivery of treprostinil
Two recent studies of treprostinil have been performed looking at easier methods of drug delivery. One study evaluated an inhaled formulation of treprostinil taken four times a day with the results demonstrating an improvement in exercise capacity over placebo. Some patients in this study were also taking an endothelin receptor antagonist, bosentan (Tracleer), or a phosphodiesterase 5 inhibitor, sildenafil (Viagra, Revatio). Based on the positive results, the Food and Drug Administration (FDA) is currently reviewing inhaled treprostinil for usage in patients with PH in WHO group I with an expected answer in 2009.
Another study involved an oral, sustained release preparation of treprostinil. Unfortunately, there was no statistical difference in exercise capacity found between patients taking oral treprostinil and those receiving placebo at 16 weeks. There also were many side effects noted with the oral preparation that limited the ability to give higher doses. Future trials involving oral treprostinil will likely take place to try and alleviate the difficulties discovered during this study and improve drug delivery.
