CLINICAL
NEWS JACC in a FLASH
Surgical Management of Obesity and
Clinical Manifestations of HF
In heart failure (HF) patients, bariatric surgery is associated with fewer
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
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 PAH Sympt
mptoms upon Abrupt Withdrawal —
Abrupt discontinuation or sudden large reductions
in dosage of Orenitram may result in worsening of
PAH symptoms.
Risk of Blee
Bleed
ding—Orenitram
ng
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
hospitalizations and visits to the
emergency department due to HF
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.
department were included in the study.
During the follow-up period of 13-24
months before surgery, 16.2% (95% CI:
13.1% to 19.4%) of patients had at least
one visit to the emergency department
due to HF exacerbation and the rate did
not change substantially (15.3%; 95%
CI: 12.2% to 18.4%) during the following 1-12 months prior to surgery.
However, there was a nonsignificantly reduced rate of emergency department visits or hospitalization for HF
exacerbation during the 12 months
post-bariatric surgery (12.0%; 95%
CI: 9.2% to 14.8%). In the 13 to 24
months after surgery, the rate was
significantly lower (9.9%; 95% CI:
7.4% to 12.5%).
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
Antihyper tens
nsiive Agents or
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.
Dru
ugs on Orenitram —Based on
Eff
ffeec t of
of O ther Dr
human pharmacokinetic studies, no dose adjustment
of Orenitram is recommended when co-administered
or esomeprazole.
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.
exacerbation. These findings were
published Feb. 22 in JACC.
A total of 524 obese patients
with heart failure who underwent
bariatric surgery and had at least one
subsequent visit to the emergency
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.
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.
USE IN SPECIFIC POPULATIONS
Pregna
gnan
nc y—Pregnancy Category C. Animal
reproductive studies with treprostinil diolamine have
OVERDOSAGE
Signs and symptoms of overdose with Orenitram
adequate and well-controlled studies in humans.
nausea, vomiting, diarrhea, and hypotension. Treat
supportively.
Labor and Deliver y
labor and delivery in humans is unknown.
These data translate to a 40%
reduction in the rate of emergency
department visits or hospitalizations for HF exacerbation in
patients who underwent bariatric
surgery. The observed decrease in
United Therapeutics Corporation, Research Triangle Park, NC 27709
Rx only
January 2016
www.orenitram.com
7618-2_JournalAd_Carido_Source_WorldNews_Resize_M1.indd 2
These data
translate to a 40%
reduction in the
rate of emergency
department
visits for HF
exacerbation in
patients who
underwent
bariatric surgery.
2/29/16 12:53 PM
March 2016