Last updated Jan. 31, 2023, by Lindsey Shapiro, PhD
Fact-checked by José Lopes, PhD
What is Orenitram for PH?
Orenitram is an extended-release oral formulation of treprostinil that is used to improve exercise capacity and delay clinical worsening in people with pulmonary arterial hypertension (PAH).
The treatment is marketed by United Therapeutics.
How does Orenitram work?
In PAH, the arteries that carry blood to the lungs, called the pulmonary arteries, are narrowed. This leads to increased blood pressure and reduced oxygen transport in the body.
The mechanisms underlying PAH progression are thought to include activation of platelets, involved in blood clotting, and dysfunction of the endothelial cells that line the inner surface of blood vessel walls . Both are linked to a reduction in prostacyclin levels.
Prostacyclin is a naturally occurring lipid molecule that helps the pulmonary arteries relax and widen, a process called vasodilation. It also inhibits platelet activation, preventing them from building up and blocking arteries.
Orenitram’s active ingredient, treprostinil, is a synthetic version of prostacyclin. By mimicking the activity of the naturally occurring molecule, Orenitram is thought to promote vasodilation, thereby making it easier to pump blood through the lungs.
In addition to Orenitram, which is given as an extended-release oral tablet, United markets two other versions of treprostinil — Remodulin and Tyvaso. Remodulin is given as an into-the-vein (intravenous) or under-the-skin (subcutaneous) infusion, while Tyvaso is an inhaled version of the medication.
Who can take Orenitram?
The U.S. Food and Drug Administration approved Orenitram in 2013 as a monotherapy or single therapy to improve exercise capacity for PAH patients in World Health Organization (WHO) group 1.
The label was updated in 2019 to indicate the treatment’s use to delay disease progression when given in combination with an approved background oral PAH therapy.
The clinical studies that backed these approvals included predominately patients with WHO functional class II-III symptoms.
Who should not take Orenitram?
Patients with severe liver impairments should not take Orenitram.
How is Orenitram administered?
Orenitram comes as extended release oral tablets in five strengths:
- 0.125 mg: white tablet imprinted with UT 0.125
- 0.25 mg: green tablet imprinted with UT 0.25
- 1 mg: yellow tablet imprinted with UT 1
- 2.5 mg: pink tablet imprinted with UT 2.5
- 5 mg: red tablet imprinted with UT 5.
There is no established daily dose of Orenitram, rather the dose is titrated or adjusted up as needed and as tolerated for each individual. Patients should start treatment by taking 0.125 mg three times daily, or o.25 mg or 0.5 mg twice daily. This can be titrated up, not more frequently than every three to four days, until the highest tolerated dose is reached.
If patients are transitioning to Orenitram from Remodulin, the Orenitram dose should be increased while the dose of Remodulin is simultaneously decreased.
Patients with mild liver impairments or who are using certain medications may need to start at the lower 0.125 mg dose and increase more slowly. All patients should discuss their course of treatment with their healthcare team before starting the therapy.
Orenitram should be taken with food. Tablets should be swallowed whole and should not be split, crushed or chewed. Treatment should not be discontinued abruptly, and the dose should be gradually reduced until tapered off.
Orenitram in clinical trials
Orenitram’s initial U.S. approval was backed by data from the global Phase 3 FREEDOM-M trial (NCT00325403), which enrolled 349 PAH patients, ages 12–75, who were not receiving an approved PAH therapy.
Participants were randomly assigned to receive oral Orenitram or a placebo twice daily for 12 weeks, or about three months, with the dose titrated up to a maximum of 12 mg twice daily. The trial’s main goal was to evaluate Orenitram’s effects on exercise capacity, as assessed by the six-minute walk distance (6MWD), which tests the distance a person can walk in six minutes.
Results showed that those in the Orenitram group experienced a median 23-meter (about 75 feet) improvement in 6MWD compared with the placebo group after 12 weeks of treatment, a statistically significant improvement.
Combined improvements in the 6MWT and a test of shortness of breath also were observed in the Orenitram group compared with the placebo group.
FREEDOM-C and FREEDOM-C2 trials
The international FREEDOM-C (NCT00325442) and FREEDOM-C2 (NCT00887978) Phase 3 trials were designed to assess the efficacy and safety of Orenitram in PAH patients who were receiving background PAH therapy. Treatments consisted of a phosphodiesterase-5 inhibitor and/or an endothelin receptor antagonist.
The participants were randomized to receive Orenitram or a placebo for 16 weeks, or about four months.
As in FREEDOM-M, the main goal of both trials was to evaluate improvements in the 6MWD test with treatment. However, this goal was not met in either FREEDOM-C or FREEDOM-C2.
The multicenter, Phase 3b FREEDOM-EV trial (NCT01560624) evaluated Orenitram’s effects against a placebo in PAH patients who were using a single oral background PAH therapy.
A total of 690 patients, ages 18 to 75, were randomly assigned to receive oral Orenitram, or a placebo, three times per day.
FREEDOM-EV’s main goal was to assess the time to clinical PAH worsening, defined as death from any cause, hospitalization due to PAH, disease progression, starting inhaled or infused therapies, or a generally unsatisfactory long-term clinical response.
After six months, the results demonstrated that 26% of patients given Orenitram had experienced a clinical worsening event, compared with 36% of those in the placebo group, reflecting a reduced risk of clinical worsening. Clinical worsening was significantly delayed by a median of nine weeks in the Orenitram group compared with the placebo group, which was mainly due to a reduction in disease progression in the Orenitram group.
Other measures of disease status, including blood levels of N-terminal pro–brain natriuretic peptide, breathlessness measures, and changes in WHO functional classification, also favored Orenitram after six months.
While those in the Orenitram group had a significantly higher mortality risk at baseline, meaning at the start of the study, their risk profile decreased from weeks 12 to 60 of the trial.
A total of 470 participants in FREEDOM-EV were transitioned to an open-label extension trial (NCT01560637) after experiencing a clinical worsening event or study completion. All participants received Orenitram.
These results showed that patients experienced continued improvements or stabilizations after nearly a year in the extension trial, and no new safety signals were observed.
Participants from FREEDOM-M, FREEDOM-C, FREEDOM-C2, or other prior Phase 2 clinical trials of Orenitram (NCT01104870, NCT01477333, and NCT01588405) were eligible to opt in to the FREEDOM-EXT open-label extension trial.
In that trial (NCT01027949), a total of 894 participants received Orenitram twice or three times daily for at least a year, and up to six years. The median treatment duration was two years. Trial results demonstrated that Orenitram led to improvements in exercise capacity among the 522 people who completed a year of treatment.
A six-month, open-label Phase 2 trial (NCT01588405) evaluated the safety and tolerability of transitioning to Orenitram from Remodulin among 33 PAH patients on a stable dose of Remodulin.
Among them, 31 people completely transitioned to Orenitram within five days. After six months of using Orenitram, performance on 6MWD test, blood flow and heart function remained stable.
Common side effects of Orenitram
The most common side effects associated with Orenitram include:
- jaw pain
PAH worsening with abrupt withdrawal
Sudden discontinuation or large dose decreases in Orenitram may lead to a worsening of PAH symptoms. If a treatment discontinuation is needed, the dose of Orenitram should be gradually lowered under the supervision of a healthcare professional.
The outer shell of Orenitram tablets does not dissolve inside the body. In patients with diverticulitis, a condition in which small bulging pouches (diverticulum) develop in the lining of the digestive tract, the tablets may lodge inside the diverticulum.
Pregnancy and breastfeeding
Limited data exist on the effects of Orenitram in pregnant patients, but animal studies indicate the treatment may have adverse effects on a developing fetus at high doses.
No data are available on the presence of Orenitram in human breastmilk.
Patients who are pregnant, wish to become pregnant, are nursing or plan to breastfeed while using Orenitram should discuss the issue with their healthcare provider.
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