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Primary EndpointImpact earlier with Orenitram to delay the time to clinical worsening1
The risk of clinical worsening decreased by 25% compared with placebo1
Patients on Orenitram were at a higher risk at baseline vs placebo (P=0.0017)2‡
- As part of a post hoc analysis, when adjusted for baseline risk stratification, patients on Orenitram had a 39% reduction in the risk of a clinical worsening event (P=0.0006*; HR=0.61; 95% CI, 0.46-0.81; P=0.0006†)2
- Using the French methodology2,3§:
- 25.2% of patients on Orenitram had 0 low-risk factors, 33.2% had 1 low-risk factor, 30.3% had 2 low-risk factors, and 11.3% had 3 low-risk factors
- 17.7% of patients on placebo had 0 low-risk factors, 32.9% had 1 low-risk factor, 28.1% had 2 low-risk factors, and 21.3% had 3 low-risk factors
Delayed disease progression
Clinical Worsening Event Category as the First Event, n (%)1,2
|All adjudicated events||90 (26%)||124 (36%)|
|Unsatisfactory long-term clinical response||19 (5.5%)||20 (5.8%)|
|Disease progression||19 (5.5%)||50 (14.5%)|
|Initiation of inhaled or infused prostacyclin||2 (0.6%)||5 (1.5%)|
|Hospitalization due to PAH||35 (10.1%)||35 (10.2%)|
|Death (all causes)||15 (4.3%)||14 (4.1%)|
|HR (95% CI)†|
(Orenitram – Placebo)
- P-value was calculated with log-rank test stratified by background PAH therapy and baseline 6MWD category.
- Hazard ratio and 95% CI were calculated with proportional hazard model with treatment, background PAH therapy, and baseline 6MWD as explanatory variables.
Important Safety Information
- Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.
Warnings and Precautions
- Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
- The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.
- In the 12-week, placebo-controlled, monotherapy study, and an event-driven, placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.
- Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.
- Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
- It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
- Safety and effectiveness of Orenitram in pediatric patients have not been established.
- Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
- There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.
Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).
6MWD=6-minute walk distance; CI=confidence interval; ERA=endothelin receptor antagonist; HR=hazard ratio; ITT=intent-to-treat; NT-proBNP=N-terminal pro–B-type natriuretic peptide; PAH=pulmonary arterial hypertension; PDE-5i=phosphodiesterase type 5 inhibitor; sGCS=soluble guanylate cyclase stimulator; WHO=World Health Organization.
References: 1. Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2019. 2. Data on file. United Therapeutics Corporation. Research Triangle Park, NC. 3. Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1700889.