ACC . org / CSWN vol 5 , no 5 / MAY 2016

Innovators : Promoting Cardiovascular Health Worldwide | A COGENT Argument for More Use of PPIs with DAPT

EXPERT COMMENTARY

fred bove : Observations and Inferences … p . 8

steve nissen : Interpreting the ACC . 16 Prevention Trials … p . 58

CLINICAL NEWS Long-lasting Survival Benefits of Guideline-directed Care in Older MI Patients … p . 16

Statement Calls for More Clinical Trials that Include Elderly Adults … p . 16

Earlier Follow-up Improves Medication Adherence … p . 21

Biomarker-based ABC-bleeding Risk Score for AF … p . 21

The Tension Between Appropriate Screening and Appropriate Revascularization … p . 22

CardioSource

A

WorldNews publication of the American College of Cardiology

The Fading Bright Line of

The Conundrum of Cost-effective but Unaffordable Care … p . 26

The Debate Over Statistical Significance

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 .

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 .

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 . 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 .

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