Additions and/or revisions underlined:
In a 12-week, placebo-controlled, monotherapy study (Study 1; WHO Group 1; functional class II-III),
and an event-driven, placebo-controlled,
combination therapy study (Study 4; WHO
Group 1; functional class
I-III), the most commonly
reported adverse reactions
that occurred in patients receiving Orenitram included: headache, diarrhea,
nausea, and flushing.
Orenitram patients
in Study 1 (N=151) had
access to 0.25 mg tablets
at randomization. Approximately 91% of such patients in Study 1 experienced an adverse reaction, but only 4% discontinued
therapy for an adverse reaction (compared
to 3% receiving placebo). Study
4 enrolled a total of 690 patients,
346 received Orenitram and 344
received placebo.
Overall, 19% of patients
treated with Orenitram discontinued treatment in Study 4 due to
an adverse
event (compared to 4% of patients receiving placebo). The
exposure to Orenitram in Study 4 was
up to 5.1 years with a median
duration of exposure of 1.2 years. Table 1 summarizes
adverse events with rates
at least 5% higher on Orenitram therapy than on placebo that were reported in either Study
1 or 4.
Changes to Table 1 with additional data; please see
label for complete information
PLLR conversion for below 2 subsections; as below:
Additions and/or revisions underlined:
Risk Summary
Limited published data
from
case reports with Orenitram use in pregnant women
are not sufficient to
assess for a drug-associated risk of major birth
defects, miscarriage, or adverse
maternal or fetal outcomes.
There are risks to
the mother and
the fetus associated with pulmonary
arterial hypertension. Animal reproductive
studies with treprostinil diolamine administered
orally have shown an
adverse effect on the
fetus. In rats, administration of treprostinil to pregnant rats
during the period of organogenesis
at
doses greater than or equal
to 10 mg/kg/day
(approximately 15 times the
human exposure at the
dose of 3.5 mg BID on
an AUC
basis) resulted in decreased
pregnancy rate,
increased post-implantation loss, and
decreased fetal viability and growth.
In rabbits,
teratogenicity and decreased fetal viability
and growth were observed at doses greater than or equal to 1.5 mg/kg/day
(approximately 7 times
the human exposure at the dose
of 3.5 mg BID on an AUC basis).
The estimated background risk of major birth defects
and miscarriage for the indicated
populations is unknown. All pregnancies have
a background risk of birth defect, loss,
or
other adverse outcomes.
In the U.S. general population,
the
estimated background risk of major birth defects
and miscarriage in clinically recognized
pregnancies is 2 to 4% and 15
to 20%, respectively.
Clinical Considerations
Disease-associated maternal and embryo-fetal risk
Pulmonary arterial hypertension in pregnancy increases
the risk of maternal
heart failure, stroke
and death, preterm delivery,
low birth weight, and stillbirth.
Data
Animal Data
In pregnant rats,
reversible, dose-dependent decreases
in body weight gain
and food consumption were
observed during the first four days of
dosing in animals administered 10, 20, and 30 mg/kg/day
treprostinil diolamine. In
a dose range-finding study,
there was a 17% decrease in the
pregnancy rate in the
animals administered 20 and 30 mg/kg/day. One
dam in each of the 20 and 30 mg/kg/day had litters with no
viable fetuses. In the definitive
study (0, 5, 10, and 20 mg/kg/day),
there were four treatment-related
deaths, and a 32% decrease in the pregnancy
rate for rats
administered 20 mg/kg/day. There
was
an 8% decrease in the pregnancy rate in the animals administered 10 mg/kg/day. Across
both studies, an increase in post-implantation loss was
observed in animals administered
10 to 30 mg/kg/day, and a significant decrease in the mean number of live
births was seen at dose levels ?10 mg/kg/day. The no observed adverse
effect level was 5 mg/kg/day (maternal,
fetal viability and growth),
and 20 mg/kg/day (teratogenicity), the highest dose tested in
the definitive study. The exposures at 5 and 20 mg/kg/day doses represent 8 and 33
times, respectively, the human exposure
at the dose of 3.5
mg
BID on an AUC basis.
For F1 progeny, a decreased
copulation index was observed
at the 5 and 10 mg/kg/day
treprostinil diolamine
dose levels in rats. The
no observed
effect levels for physical
development, reflex
development, exploratory behavior, learning and memory,
and sexual maturation was 10 mg/kg/day. The no observed effect level for F1 progeny general development (based on body
weight) was 10 mg/kg/day
for females and ?2.5
mg/kg/day for males; the
no observed
effect level for F1 reproductive performance
was 2.5 mg/kg/day (approximately 4 times the human exposure at the dose
of
3.5 mg BID on an AUC basis).
In pregnant rabbits,
the primary maternal adverse effect was
gastrointestinal disturbance;
dose-dependent decreases
in mean
body weight, body weight gain, and
food consumption were observed. During the
post-dose phase, the effect was reversed. In
a dose range-finding study,
there was a 17% decrease
in the pregnancy
rate for animals administered 4 mg/kg/day. A dose-dependent increase
in post-implantation loss
was
observed. Two dams administered
4 mg/kg/day had litters
with no viable fetuses; the
mean fetal weight was slightly
decreased in animals
administered 4 mg/kg/day. In the definitive
study, mean fetal weights were
significantly decreased in animals
administered 0.5 to 3 mg/kg/day
of treprostinil diolamine. At doses
of 1.5 and 3 mg/kg/day, external fetal and soft tissue
malformations were observed in
a few fetuses, and the total fetal skeletal malformations
were significantly increased. The
no observed adverse effect level was less than
0.5 mg/kg/day (maternal), 1.5 mg/kg/day (fetal viability and growth), and 0.5 mg/kg/day (teratogenicity). The
0.5 mg/kg/day dose represents about 3 times
the human exposure at the dose
of
3.5 mg BID on an AUC basis.
Additions and/or revisions underlined:
What is Orenitram?
• Orenitram
is a prescription medicine used to treat pulmonary arterial hypertension (PAH)
which is high blood pressure in the arteries of your lungs.
• Orenitram
can help slow down the progression of your disease and improve your
ability to exercise. It is not known if Orenitram is safe and effective in
children.
Before taking Orenitram, tell your healthcare provider about
all of your medical conditions, including if you:
• are
breastfeeding or plan to breastfeed. It is not known if Orenitram passes into
your breast milk. Talk to your healthcare provider about the best way
to feed your baby during treatment with Orenitram.
Especially tell your healthcare provider if you take another
medicine that contains treprostinil, such as Remodulin® or Tyvaso®.
What are the possible side effects of Orenitram?
Orenitram can cause serious side effects, including worsening
of PAH symptoms.
• Stopping
Orenitram suddenly may cause worsening of your PAH symptoms. Do not change your
dose or suddenly stop taking Orenitram without first talking to your healthcare
provider.
The most common side effects of Orenitram include:
• headache • flushing
• diarrhea • pain
in arms and legs
• nausea • jaw pain
• vomiting
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