Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
(Subsection title
revised; Additions and/or revisions underlined)
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 trials of another drug and may not reflect the rates
observed in practice.
Pulmonary Arterial Hypertension
In a 12-week, placebo-controlled study (TRIUMPH I)
of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class
III), the most commonly reported adverse reactions on Tyvaso included cough and
throat irritation, headache, gastrointestinal effects, muscle, jaw or bone
pain, dizziness, flushing, and syncope. Table 1 lists the adverse
reactions that occurred at a rate of at least 4% and were more frequent in
patients treated with Tyvaso than with placebo.
Table
1: Adverse Events in ?4% of PAH
Patients Receiving Tyvaso and More Frequenta than Placebo in
TRIUMPH I
…
Pulmonary Hypertension Associated with ILD
In a 16-week, placebo-controlled study (INCREASE) of
326 patients with PH-ILD (WHO Group 3), adverse reactions were similar to the
experience in studies of PAH.
6.2 Post-marketing Experience
(Subsection title
revised; Additions and/or revisions underlined)
The adverse reaction of angioedema has been
identified during the post-approval use of Tyvaso. Because this reaction is
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate the frequency or establish a causal relationship
to drug exposure.
7
Drug Interactions
7.4 Effect of Other Drugs on Treprostinil
(Additions and/or
revisions underlined)
Drug interaction studies have been carried out with
treprostinil (oral or subcutaneous) co-administered with acetaminophen (4
g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in
healthy volunteers. These studies did not show a clinically significant effect
on the pharmacokinetics of treprostinil. Treprostinil does not affect the
pharmacokinetics 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 unaffected by continuous
subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or
revisions underlined)
Across
clinical
studies used to establish the effectiveness of Tyvaso in patients
with PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were
enrolled. The treatment effects and safety profile observed in geriatric
patients were similar to younger patients. In general, dose selection for
an elderly patient should be cautious, reflecting the greater frequency of
hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other
drug therapy.
8.7 Patients with Renal Impairment
(Subsection title
revised; Additions and/or revisions underlined)
No
dose adjustments are required in patients with renal impairment.
Treprostinil is not cleared by dialysis [see
Clinical Pharmacology (12.3)].
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Adverse Reactions Identified in Clinical Trials
(Additions and/or revisions are underlined)
In a 12-week
placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and
nearly all NYHA Functional Class III), the most commonly reported adverse
reactions on Tyvaso included: cough and
throat irritation, headache, gastrointestinal effects, muscle, jaw or bone
pain, dizziness, flushing and syncope.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
Limited case
reports of treprostinil use in pregnant women are insufficient to inform a
drug-associated risk of adverse developmental outcomes. However, there are
risks to the mother and the fetus associated with pulmonary arterial
hypertension (see Clinical Considerations). In animal studies, no adverse reproductive
and developmental effects were seen for treprostinil at ?9 and ?145 times the
human exposure when based on Cmax and AUC following a single treprostinil dose
of 54 mcg, respectively.
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 is associated with an increased risk of maternal and
fetal mortality.
Data
Animal reproduction
studies have been conducted with treprostinil via continuous
subcutaneous administration and with treprostinil diolamine administered
orally. In pregnant rats, continuous subcutaneous infusions of treprostinil
during organogenesis and late gestational development, at doses as high as
900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous
infusion rate, on a ng/m2 basis and about 16 times the average rate achieved in
clinical trials), resulted in no evidence of harm to the fetus. In pregnant
rabbits, effects of continuous subcutaneous infusions of treprostinil during
organogenesis were limited to an increased incidence of fetal skeletal
variations (bilateral full rib or right rudimentary rib on lumbar 1)
associated with maternal toxicity (reduction in body weight and food
consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the
starting human subcutaneous infusion rate, on a ng/m2 basis, and 5 times the
average rate used in clinical trials). In rats, continuous subcutaneous
infusion of treprostinil from implantation to the end of lactation, at doses of
up to 450 ng treprostinil/kg/min, did not affect the growth and development of
offspring. In studies with orally
administered treprostinil diolamine, no adverse effect doses for fetal
viability / growth, fetal development (teratogenicity), and postnatal
development were determined in rats. In pregnant rats, no evidence of harm to
the fetus was observed following oral administration of treprostinil diolamine
at the highest dose tested (20 mg/kg/day), which represents about 154 and 1479
times the human exposure, when based on Cmax and AUC following a single Tyvaso
dose of 54 mcg, respectively… The dose at which no adverse effects were seen
(0.5 mg/kg/day) represents about 9 and 145 times the human exposure, when based
on Cmax and AUC following a single Tyvaso dose of 54 mcg, respectively…
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
There are no
data on the presence of
treprostinil in human milk, the effects on the
breastfed infant, or the effects on milk production.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Advise the
patient to read the
FDA-approved patient labeling (Patient Information and Instructions for
Use).
Train patients in the administration process for Tyvaso…
In the event that a
scheduled treatment session is missed or interrupted, resume therapy as
soon as possible.
PATIENT INFORMATION
(Additions and/or revisions are underlined)
Before taking
Tyvaso, tell your healthcare provider about all of your medical conditions,
including if you:
Tell your
healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements…
Especially tell
your healthcare provider if you take:
How should I
take Tyvaso?
See
the detailed “Instructions for Use Manual” that comes with your Tyvaso
Inhalation System for instructions on how to take Tyvaso the right way.
Tyvaso must be used only with the Tyvaso
Inhalation System.
Do
not mix Tyvaso with other medicines in the Tyvaso Inhalation System.
Do not swallow Tyvaso inhalation solution.
If you
miss a dose of Tyvaso, take your usual dose as soon as possible.
If
you take too much Tyvaso, call your healthcare provider or go to the nearest
hospital emergency room right away.
To
avoid a possible delay in your Tyvaso treatment, you should always have access
to a back-up Tyvaso Inhalation System device.
What are the possible side effects of
Tyvaso?
Tyvaso can cause serious side effects,
including:
The most common side effects of Tyvaso
include:
Call your doctor
for medical advice about side effects.
How should I
store Tyvaso?
Store at
25°C (77°F), with excursions permitted to 15°C to 30°C (59°F to 86°F) [see
USP Controlled Room Temperature].
Store
Tyvaso ampules in the unopened foil pouch and out of the light until you are
ready to use them.
If
unopened and stored in the foil pouch, Tyvaso ampules can be used until the
expiration date printed on the pouch. Do not use Tyvaso ampules past the
expiration date printed on the pouch.
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