CLINICAL
NEWS JACC in a FLASH
found that women had a greater
number of risk factors for heart
disease than men, yet these women
were more likely to be characterized
as lower risk.
The Prospective Multicenter
Imaging Study for Evaluation of
Chest Pain (PROMISE) examined
BRIEF SUMMARY
The following is a brief summary of the full prescribing
information for Orenitram® (treprostinil) ExtendedRelease 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
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
a background of another vasodilator is probably less
than this.
CONTRAINDICATIONS
Severe hepatic impairment (Child Pugh Class C).
WARNINGS AND PRECAUTIONS
Worsening PAH Symptoms upon Abrupt Withdrawal—
Withdrawal
Abrupt discontinuation or sudden large reductions
in dosage of Orenitram may result in worsening of
PAH symptoms.
Risk of Bleeding—Orenitram
Bleeding
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
Experience
clinical trials ar e
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.
10,003 patients, of whom 5,200
were women. Half of the patients
were randomly selected to undergo
a CT scan while the other received a
stress test.
The researchers, led by Kshipra
Hemal, found that, compared with
men, women were older, more often
non-white, less likely to smoke or be
overweight, and more likely to have
high blood pressure, high cholesterol, a history of stroke, a sedentary
lifestyle, a family history of earlyonset heart disease and a history
of depression. Chest pain was the
primary symptom for 73.2% of
Table 1. Adverse Reactions with Rates at Least 5% Higher on Orenitram Monotherapy than on Placebo
Treatment (%)
Reaction
Orenitram (N=151)
Placebo (N=77)
Headache
63%
19%
Diarrhea
30%
16%
Nausea
30%
18%
Flushing
15%
6%
Pain in jaw
11%
4%
Pain in extremity
14%
8%
Hypokalemia
9%
3%
Abdominal discomfort
6%
0%
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—
Vasodilator
Concomitant administration of Orenitram with
diuretics, antihypertensive agents or other
vasodilators increases the risk of symptomatic
hypotension.
Anticoagulants
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
Orenitram
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
Pregnancy
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
Mothers
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
Impairment
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
Impairment
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
7618-7_FullSpreadResize_CardioSourceWorldNews_M1.indd 2
women and 72.3% of men. Men and
women, however, described this pain
differently. While women were more
likely to describe it as “crushing,”
“pressure,” “squeezing” or “tightness,”
men were more likely to describe it
as “aching,” “dull,” “burning” or “pins
and needles.” Equal proportions of
women and men (15%) reported
shortness of breath. Although
women were more likely than men to
have back pain, neck or jaw pain, or
palpitations as their primary symptom, the percentage of patients of
both sexes reporting these symptoms
was very small.
Women had lower scores than
men on heart disease risk-assessment
scores, suggesting a lower risk of
heart disease, and before any diagnostic tests were conducted, health care
providers were more likely to consider that women probably did not have
heart disease. Women were more
likely than men to be referred for a
stress echocardiogram or nuclear
stress test and less likely than men
(9.7% vs. 15.1%) to have a positive
test. Factors predicting a positive test
differed for women compared with
men. In women, body mass index
and score on one of five risk-assessment questionnaires (the Framingham risk score) predicted a positive
test, whereas in men scores on two
risk-assessment questionnaires (the
Framingham and modified DiamondForrester risk scores) predicted a
positive test.
“The most important take-home
message for women from this study
is that their risk factors for heart
disease are different from men’s, but
in most cases symptoms of possible
blockages in the heart’s arteries are
the same as those seen in men,” Hemal wrote. “For health care providers,
this study shows the importance of
taking into account the differences
between women and men throughout the entire diagnostic process for
suspected heart disease. Providers
also need to know that, in the vast
majority of cases, women and men
with suspected heart disease have the
same symptoms.”
Hemal added that the next step
is to examine how these differences
influence outcomes.
Hemal K, Pagidipati NJ, Coles A, et al. J
Am Coll Cardiol Img. 2016;doi:10.1016/j.
jcmg.2015.10.022.
3/8/16 12:00 PM
April 2016