BRIEF SUMMARY The following is a brief summary of the full prescribing information for Orenitram ® ( treprostinil ) Extended- Release Tablets . Please review the full prescribing information before prescribing Orenitram .

INDICATIONS AND USAGE Orenitram is indicated for the treatment of pulmonary arterial hypertension ( PAH ) ( WHO Group 1 ) to improve exercise capacity . The study that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH ( 75 %) or PAH associated with connective tissue disease ( 19 %). When used as the sole vasodilator , the effect of Orenitram on exercise is about 10 % of the deficit , and the effect , if any , on a background of another vasodilator is probably less than this .

CONTRAINDICATIONS Severe hepatic impairment ( Child Pugh Class C ).

WARNINGS AND PRECAUTIONS Worsening ng PAH Symptoms upon Abrupt Withdrawal — Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms .

Risk of Blee eeding

— Orenitram inhibits platelet aggregation and increases the risk of bleeding .

Use in Patients with Blind-end Pouches — The tablet shell does not dissolve . In patients with diverticulosis , Orenitram tablets can lodge in a diverticulum .

ADVERSE REACTIONS Clinical Trials Experience — Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical

observed in clinical practice . In a 12-week placebocontrolled monotherapy study ( Study 1 ; WHO Group 1 ; functional class II-III ), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included : headache , diarrhea , nausea and flushing . Table 1 lists the adverse reactions that occurred at a rate on Orenitram at least 5 % higher than on placebo . Orenitram patients in Table 1 for Study 1 ( N = 151 ) had access to 0.25 mg tablets at randomization . Approximately 91 % of such patients experienced an adverse reaction , but only 4 % discontinued therapy for an adverse reaction ( compared to 3 % receiving placebo ). The overall discontinuation rate for any reason was 17 % for active and 14 % for placebo .

Orenitram was studied in a long-term , open-label extension study in which 824 patients were dosed for a mean duration of approximately 2 years . About 70 % of patients continued treatment with Orenitram for at least a year . The mean dose was 4.2 mg BID at one year . The adverse reactions were similar to those observed in the placebo-controlled trials .

DRUG INTERACTIONS Antihypertensive Agents or Other Vasodilator — Concomitant administration of Orenitram with diuretics , antihypertensive agents or other vasodilators increases the risk of symptomatic hypotension .

Anticoagulants — Treprostinil inhibits platelet aggregation ; there is increased risk of bleeding , particularly among patients receiving anticoagulants .

— Co-administration of Orenitram and the CYP2C8 enzyme inhibitor

exposure to treprostinil . Reduce the starting dose of Orenitram to 0.125 mg BID and use 0.125 mg BID increments every 3 to 4 days .

Effect of Other Drugs on Orenitram — Based on human pharmacokinetic studies , no dose adjustment of Orenitram is recommended when coadministered

or esomeprazole .

Warfarin — A drug interaction study was carried out with Remodulin co-administered with warfarin ( 25 mg / day ) in healthy volunteers . There was no

the pharmacokinetics of treprostinil . Additionally ,

or pharmacodynamics of warfarin . The pharmacokinetics of R- and S- warfarin and the international normalized ratio ( INR ) in healthy subjects given a single 25 mg dose of warfarin were

treprostinil at an infusion rate of 10 ng / kg / min .

USE IN SPECIFIC POPULATIONS Pregnancy — Pregnancy Category C . Animal reproductive studies with treprostinil diolamine have

adequate and well-controlled studies in humans .

Labor and Delivery labor and delivery in humans is unknown .

High doses of caffeine will not lead to arrhythmias in patients which chronic systolic heart failure ( HF ), according to a study published Oct . 17 in JAMA : Internal Medicine . It is currently recommended that patients

The safety of Orenitram was also evaluated in an open-label study transitioning patients from Remodulin . The safety profile during this study was similar to that observed in the three pivotal studies .

delivery were seen in animal studies .

Nursing Mothers — It is not known whether treprostinil is excreted in human milk or absorbed systemically after ingestion . Because many drugs are excreted in human milk , choose Orenitram or breastfeeding .

Pediatric Use patients have not been established .

Geriatric Use — Clinical studies of Orenitram did

years and over to determine whether they respond

selection for an elderly patient should be cautious ,

hepatic or cardiac function , and of concomitant disease or other drug therapy .

Patients with Hepatic Impairment — Plasma clearance of treprostinil is reduced in patients with hepatic

therefore be at increased risk of dose-dependent adverse reactions because of an increase in systemic exposure . Titrate slowly in patients with hepatic

exposed to greater systemic concentrations relative to patients with normal hepatic function . In patients with mild hepatic impairment ( Child Pugh Class A ) start at 0.125 mg BID with 0.125 mg BID dose increments every 3 to 4 days . Avoid use of Orenitram in patients with moderate hepatic impairment ( Child Pugh Class B ). Orenitram is contraindicated in patients with severe hepatic impairment ( Child Pugh Class C ).

Patients with Renal Impairment — No dose adjustments are required in patients with renal impairment . Orenitram is not removed by dialysis .

OVERDOSAGE Signs and symptoms of overdose with Orenitram

nausea , vomiting , diarrhea , and hypotension . Treat supportively . at risk for arrhythmias limit caffeine consumption .

Researchers from Brazil examined 51 heart failure patients who were randomized to take caffeine or a placebo . Participants drank 5 doses of 100 mL decaffeinated coffee mixed with 100 mg of either caffeine or lactose powder . Doses were consumed at 1-hour intervals and electrocardiogram ( ECG ) monitoring began with the first dose . A treadmill test was performed 1 hour after the final dose .

No significant differences in ventricular premature beats ( VBPs ) or supraventricular premature beats ( SVPBs ) were observed between the groups and mean heart rate was also similar . At least 1 nonsustained ventricular tachycardia episode was experience in 16 participants in the caffeine group and 19 in the placebo group , while 4 caffeine and 9 placebo participants recorded nonsustained supraventricular tachycardia episodes .

The treadmill test showed no differences in VPBs or SVBPs between groups . Duration of exercise and estimated peak oxygen consumption were also similar . The only significant differences were higher values of peak systolic and diastolic blood pressure in the caffeine group .

An analysis of arrhythmic events was conducted in the 31 enrolled patients that had an implantable cardioverter defibrillator ( ICD ). No therapies , including shocks or pacing , or other major arrhythmic events were identified during the study .

The authors wrote that these findings , “ challenge the intuitive notion that caffeine intake should be limited or prohibited in patients with heart disease and at risk for arrhythmia .”

However , the authors did caution that the findings should be interpreted with caution because of the small number of patients included and the relatively low prevalence of arrhythmias observed . ■

Zuchinali P , Souza GC , Pimentel M , et al . JAMA Intern Med . 2016 ; doi : 10.1001 / jamainternmed . 2016.6374

United Therapeutics Corporation , Research Triangle Park , NC 27709 Rx only January 2016 www . orenitram . com

November 2016