Approved Drug Label (PDF)
Boxed Warning
(Additions and/or
revisions are underlined)
Because of the risks of hepatotoxicity and birth defects, Tracleer is available
only through a restricted
program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program.
5
Warnings and Precautions
5.3 Prescribing and Distribution Program for Bosentan
(Revised Subsection
Title; Additions and/or revisions are underlined)
Because of the risks of hepatotoxicity and birth defects,
Tracleer is available only through
a restricted
program called the Bosentan REMS Program. As a component of the
Bosentan REMS, prescribers, patients, and pharmacies
must enroll in the program.
Required
components of the Bosentan REMS are:
- Healthcare
professionals who prescribe Tracleer must review the
prescriber educational materials,
enroll in the Bosentan REMS Program and comply with
its
requirements.
- Healthcare
professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree
to order and monitor these tests monthly; and
(2) for females of reproductive potential, confirm
that the patient is not pregnant,
and agree to order and monitor
pregnancy tests monthly.
- To receive Tracleer,
all patients must
understand the risks and benefits,
complete a patient enrollment form.
- Pharmacies
that dispense Tracleer must
enroll in the program and agree to comply
with the Bosentan REMS Program requirements.
Further information about Tracleer and the Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Newly added section; please refer to label for complete information.
PATIENT COUNSELING INFORMATION
Bosentan replaces Tracleer throughout this subsection.
Patients must sign the Bosentan REMS Program
Patient Enrollment Form …
(Additions and/or
revisions are underlined)
Restricted
access
Advise the
patient that Tracleer is only available
through a restricted access
program called the Bosentan REMS Program.
As a component
of the Bosentan REMS,
prescribers must review the contents of the Tracleer Medication Guide
with the patient before initiating
Tracleer.
Advise the patient
that Tracleer is available
only from specialty pharmacies that are enrolled
in the
Bosentan REMS
Program.
Patients must sign the Bosentan REMS Program Patient Enrollment Form to confirm that they understand
the risks of Tracleer.
Other
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Hepatotoxicity
(Additions and/or revisions are underlined)
…In a pooled analysis of four pediatric studies conducted
in PAH (n =100), elevations in liver aminotransferases greater than or equal to
3 × ULN were observed in 2% of patients…
Avoid initiation of Tracleer in patients with elevated
aminotransferases (> 3 x ULN) prior to drug initiation because monitoring
hepatotoxicity in these patients may be more difficult.
In WHO Functional Class II patients, consider whether the
benefits of Tracleer are sufficient to offset the risk of hepatotoxicity, which
may preclude future use as their disease progresses.
5.2 Embryo-fetal Toxicity
(Newly added subsection)
Based on data from animal reproduction studies, Tracleer may
cause fetal harm when administered to a pregnant female and is contraindicated
in females who are pregnant. Advise females of reproductive potential of the
potential risk to a fetus. Obtain a pregnancy test prior to Tracleer treatment,
monthly during treatment and for one month after stopping treatment. Advise
females of reproductive potential to use two reliable forms of contraception
during treatment with Tracleer and for at least one month after the last dose.
Tracleer is only available for females through a restricted
program under REMS.
6
Adverse Reactions
(Additions and/or revisions are underlined)
The following important adverse reactions are described
elsewhere in the labeling:
- Hepatotoxicity
- Embryo-fetal Toxicity
- Fluid Retention
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
Safety data on Tracleer were obtained from 13 clinical
studies (9 placebo-controlled and 4 open- label) in 870 adult patients
with PAH and other diseases…
Treatment discontinuations due to adverse events other than
those related to pulmonary hypertension during the clinical trials in adult patients
with PAH were more frequent on Tracleer (6%; 15/258 patients) than on placebo
(3%; 5/172 patients)…
Table 3. (The footnote below has been added to this
table)
** Respiratory
Tract Infection combines the terms "Nasopharyngitis", "Upper
Respiratory Tract Infection" and "Respiratory Tract Infection".
Tracleer was evaluated for safety in 119 pediatric
patients in uncontrolled studies. The safety profile was similar to that
observed in adult patients with PAH.
Decreases in Hemoglobin and Hematocrit
The overall mean decrease in hemoglobin concentration for adult
Tracleer-treated patients was 0.9 g/dL (change to end of treatment)…
In a pooled analysis of pediatric patients (N=100) with
PAH treated with Tracleer, a decrease in hemoglobin levels to < 10 g/dL from
baseline was reported in 11% of patients. There was no decrease to < 8 g/dL.
7
Drug Interactions
7.1 Cytochrome P450 Drug Interactions
(Additions and/or revisions are underlined)
Figure 1. CYP3A
induction-mediated effect of bosentan on other drugs
(Figure has been added; please refer to
label)
Figure 2. Effect of other drugs on bosentan
(Figure has been added; please refer to
label)
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
Based on data from animal reproduction studies, Tracleer
may cause fetal harm, including birth defects and fetal death, when
administered to a pregnant female and is contraindicated during pregnancy.
There are limited data on Tracleer use in pregnant women. In
animal reproduction studies, oral administration of bosentan to
pregnant rats at 2- times the maximum recommended human dose (MRHD) on a mg/m2
basis caused teratogenic effects in rats, including malformations of
the head, mouth, face, and large blood vessels. Advise pregnant women of the
potential risk to a fetus.
The estimated background risk of major birth defects and
miscarriage for the indicated population 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 2-4% and 15-20%,
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 bosentan in human milk,
the effects on the breastfed infant, or the effect on milk production.
Because of the potential for serious adverse reactions, such as fluid retention
and hepatotoxicity, in breastfed infants from Tracleer, advise women
not to breastfeed during treatment with Tracleer.
8.3 Females and Males of Reproductive Potential
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Pregnancy Testing
Verify the pregnancy status of females of reproductive
potential prior to initiating Tracleer, monthly during treatment and one month
after stopping treatment with Tracleer…
Contraception
…Females of reproductive potential using Tracleer must use
two acceptable methods of contraception during treatment and for 1 month
after treatment with Tracleer…
Infertility
Males
Decreased sperm counts have been observed in patients
receiving Tracleer. Based on these findings and findings in animals, Tracleer
may impair fertility in males of reproductive potential.
It is not known whether effects on fertility would be
reversible.
8.4 Pediatric Use
(Additions and/or revisions are underlined)
The efficacy of Tracleer in patients <18 years is
supported by data from an uncontrolled trial in which 19 pediatric patients
were treated with Tracleer. In this study, cardiopulmonary hemodynamic
improvements were similar to those seen in adults treated with Tracleer. Safety in pediatric patients is supported
by data from 100 pediatric patients treated with Tracleer for a median of 17
months.
Juvenile Animal Toxicity Data
In a juvenile rat toxicity study, rats were treated from
Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights,
absolute weights of testes and epididymides, and reduced number of sperm in
epididymides were observed after weaning. No effect on testis histology or
sperm morphology and function was seen. The NOAEL was 4 times (at Day 4
postpartum) and 2 times (Day 69 postpartum) the human therapeutic exposure,
respectively.
No effects on general development, sensory, cognitive
function and reproductive performance were detected at the highest dose tested
in juvenile rats, 7 times the therapeutic exposure in children with PAH.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17. PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Advise women not to breastfeed during treatment with
TRACLEER
Advise males of reproductive potential that TRACLEER may
impair fertility
Tracleer dispersable tablets contain phenylalanine, a
component of aspartame. Each dispersible tablet contains 1.87 mg of
phenylalanine.
Medication Guide
(Additions and/or
revisions are underlined)
What is the most important information I should know
about Tracleer?
Tracleer 32 mg dispersible tablets contain Aspartame.
Phenylketonurics: Contains Phenylalanine 1.87 mg per 32 mg dispersible tablet.
How should I take Tracleer?
- If necessary, the 32 mg
dispersible tablet can be divided into halves by breaking along the lines
cut into the surface. Hold the tablet between the thumb and index finger
on either side of one of the lines, with the line facing upwards, and
break the tablet along the line (see figure below). The dispersible tablet
should not be broken into quarters.
(Figure has been added; please refer to
label)
- Each 32 mg dispersible
tablet, or tablet part, can be dispersed in a minimal amount of water to
make a liquid medicine immediately before administration. When the tablet
has fully dispersed, the liquid should be administered to the patient.
How should I store
Tracleer?
- Dispersible tablets
that have been broken to adjust the dose of medicine can be stored at room
temperature, between 68oF to 77oF (20oC
to 25oC), and should be used within 7 days of having been
broken. Tablet pieces may be returned to the opened blister and stored
there out of reach of children for up to 7 days.
What are the ingredients in Tracleer?
Inactive ingredients in 62.5 mg and 125 mg film-coated
tablets: corn starch, pregelatinized starch, ….
Inactive ingredients in 32 mg dispersible tablets:
cellulose microcrystalline, calcium hydrogen, phosphate anhydrous,
croscarmellose sodium, silica colloidal anhydrous, tartaric acid, tutti frutti
flavor, aspartame (E951), acesulfame potassium, and magnesium stearate.
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