Approved Drug Label (PDF)
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions
and/or revisions underlined)
The following adverse reactions have been identified during
post-approval use of OPSUMIT. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Immune
system disorders: hypersensitivity reactions (angioedema, pruritus
and rash)
Vascular
disorders: flushing
Approved Drug Label (PDF)
4
Contraindications
4.2 Hypersensitivity
(Newly added
subsection)
OPSUMIT
is contraindicated in patients with a history of a hypersensitivity reaction to
macitentan or any component of the product [see
Adverse Reactions (6.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
Who should not
take OPSUMIT?
Do not take
OPSUMIT if you are pregnant, plan to become pregnant, or become pregnant during
treatment with OPSUMIT. OPSUMIT can cause serious birth defects (see the
Medication Guide section above called “What is the most important information I
should know about OPSUMIT?”).
Do not take
OPSUMIT if you are allergic to macitentan or any of the ingredients in OPSUMIT.
See
the end of this Medication Guide for a complete list of ingredients in OPSUMIT.
Tell your
healthcare provider about all your medical conditions and all the medicines you
take, including prescription and over-the-counter medicines, vitamins, and
herbal supplements.
OPSUMIT
and other medicines may affect each other causing side effects. Do not start
any new medicine until you check with your healthcare provider.
Especially
tell your healthcare provider if you take an HIV medicine.
…
Approved Drug Label (PDF)
7
Drug Interactions
7.3 Moderate Dual
or Combined CYP3A4 and CYP2C9 Inhibitors
(Newly Added Subsection)
Concomitant use of moderate dual inhibitors of CYP3A4 and
CYP2C9 such as fluconazole is predicted to increase macitentan exposure
approximately 4-fold based on physiologically based pharmacokinetic (PBPK)
modelling. Avoid concomitant use of OPSUMIT with moderate dual inhibitors of
CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3)].
Concomitant treatment of both a moderate CYP3A4
inhibitor and moderate CYP2C9 inhibitor with OPSUMIT should also be avoided
[see Clinical Pharmacology (12.3)]
Approved Drug Label (PDF)
4
Contraindications
4.1 Pregnancy
(Additions and/or revisions
are underlined)
OPSUMIT may cause fetal harm when administered to a
pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT
was consistently shown to have teratogenic effects when administered to
animals. If OPSUMIT is used during pregnancy, advise the patient of the
potential risk to a fetus.
5
Warnings and Precautions
5.7 Decreased Sperm Counts
(Additions and/or revisions are underlined)
OPSUMIT, like other ERAs, may have an adverse effect on spermatogenesis.
Counsel men about potential effects on fertility.
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, OPSUMIT may cause embryo-fetal
toxicity, including birth defects and fetal death, when administered to a
pregnant female and is contraindicated during pregnancy. There are risks
to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy. There are limited data on OPSUMIT use in
pregnant women. Macitentan was teratogenic in rabbits and rats at all dosestested.
If this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, advise the patient of the 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.
Clinical Considerations
Disease-associated
maternal or embryo/fetal risk
In patients with pulmonary arterial hypertension,
pregnancy is associated with an increased rate of maternal and fetal morbidity and
mortality, including spontaneous abortion, intrauterine growth restriction and premature
labor.
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
macitentan in human milk, the
effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions
in breastfed infants from OPSUMIT advise women not to breastfeed
during treatment with OPSUMIT.
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions are underlined)
Females
Pregnancy Testing:
Verify the pregnancy status of females of reproductive potential prior to initiating OPSUMIT,
monthly during treatment and one month after stopping treatment with OPSUMIT.
The patient should contact her physician immediately for pregnancy testing
if onset of menses is delayed or pregnancy is suspected. If the pregnancy
test is positive, the physician and patient must discuss the risks to her,
the pregnancy, and the fetus.
Males
Infertility
Based on findings in animals, OPSUMIT
may impair fertility in males of reproductive potential. It is not known whether
effects on fertility would be reversible.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Advise patient to read FDA-approved patient labeling (Medication Guide).
Embryo-Fetal Toxicity
Counsel female patients of reproductive potential about the
need to use reliable methods of contraception during treatment with OPSUMIT
and for one month after treatment discontinuation. Females of reproductive potential
must have monthly pregnancy tests and must use reliable methods of contraception
while taking OPSUMIT and for one month after discontinuing OPSUMIT.
OPSUMIT REMS Program
Patients may choose one highly effective
form of contraception (intrauterine devices (IUD), contraceptive implants or tubal
sterilization) or a combination of methods (hormone method with a barrier
method or two barrier methods).
Patients should be instructed to contact
their physician if they suspect they may be pregnant. Patients should seek additional
contraceptive advice from a gynecologist or similar expert as needed.
Advise women not to breastfeed during
treatment with OPSUMIT.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.4 Fluid Retention
(Newly added subsection)
Peripheral edema
and fluid retention are known clinical consequences of PAH and known effects of
ERAs. In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema
was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.
Patients with
underlying left ventricular dysfunction may be at particular risk for developing
significant fluid retention after initiation of ERA treatment. In a small study
of OPSUMIT in patients with pulmonary hypertension because of left ventricular
dysfunction, more patients in the OPSUMIT group developed significant fluid
retention and had more hospitalizations because of worsening heart failure
compared to those randomized to placebo. Postmarketing cases of edema and fluid
retention occurring within weeks of starting OPSUMIT, some requiring
intervention with a
diuretic or hospitalization for decompensated heart
failure, have been reported.
Monitor for signs
of fluid retention after OPSUMIT initiation. If clinically significant fluid
retention develops, evaluate the patient to determine the cause, such as
OPSUMIT or underlying heart failure, and the possible need to discontinue
OPSUMIT.
6
Adverse Reactions
(Additions and/or revisions are underlined)
Clinically
significant adverse reactions that appear in other sections of the labeling
include:
Embryo-fetal
Toxicity
Hepatotoxicity
Fluid
Retention
Decrease
in Hemoglobin
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
Gastrointestinal disorders: Elevations of liver aminotransferases (ALT,
AST) and liver injury have been reported with Opsumit use; in most cases
alternative causes could be identified (heart failure, hepatic congestion,
autoimmune hepatitis). Endothelin receptor antagonists have been associated
with elevations of aminotransferases, hepatotoxicity, and cases of liver failure
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Fluid Retention
Educate patients
on signs of fluid retention. Advise patients that they should contact their
doctor if they have unusual weight increase or swelling of the ankles or legs.
Medication Guide
(Additions and/or revisions are underlined)
What are the
possible side effects of Opsumit? Opsumit can cause serious side effects,
including:
6
Adverse Reactions
6.2 Postmarketing Experience
Addition of the following:
Gastrointestinal disorders: Elevations of
liver aminotransferases (ALT, AST) and liver injury have been reported with
Opsumit use; in most cases alternative causes could be identified (heart
failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor
antagonists have been associated with elevations of aminotransferases,
hepatotoxicity, and cases of liver failure.
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