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IMPORTANT SAFETY INFORMATION
BOXED WARNING: EMBRYO-FETAL TOXICITY
Do not administer OPSUMIT®
to a pregnant female because it may cause fetal harm.
Females of reproductive potential: Exclude pregnancy before
the start of treatment, monthly during treatment, and 1
month after stopping treatment. Prevent pregnancy during
treatment and for one month after stopping treatment by
using acceptable methods of contraception.
For all female patients, OPSUMIT®
is available only through a restricted program called the
Evaluation and Mitigation Strategy (REMS).
OPSUMIT® is an endothelin receptor antagonist (ERA)
indicated for the treatment of pulmonary arterial hypertension
(PAH, WHO Group I) to reduce
the risks of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH
patients with predominantly WHO Functional Class II-III symptoms
treated for an average of 2 years. Patients had idiopathic and
heritable PAH (57%), PAH caused by connective tissue disorders
(31%), and PAH caused by congenital heart disease with repaired
Pregnancy: OPSUMIT® may cause fetal harm when administered to a
pregnant woman. OPSUMIT® is contraindicated in females who are
pregnant. If OPSUMIT® is used during pregnancy, advise the
patient of the potential risk to a fetus.
Hypersensitivity: OPSUMIT® is contraindicated in patients with a
history of a hypersensitivity reaction to macitentan or any
component of the product.
WARNINGS AND PRECAUTIONS
Embryo-fetal Toxicity and OPSUMIT®
Due to the risk of embryo-fetal toxicity, OPSUMIT® is available
for females only through a restricted program called the
OPSUMIT® REMS Program. For females of reproductive potential,
exclude pregnancy prior to initiation of therapy, ensure use of
acceptable contraceptive methods, and obtain monthly pregnancy
Notable requirements of the OPSUMIT® REMS Program include:
Prescribers must be certified with the program by enrolling and
All females, regardless of reproductive potential, must enroll in
the OPSUMIT® REMS Program prior to initiating OPSUMIT®.
Male patients are not enrolled in the REMS.
Females of reproductive potential must comply with the pregnancy
testing and contraception requirements.
Pharmacies must be certified with the program and must only
dispense to patients who are authorized to receive OPSUMIT®.
ERAs have caused elevations of aminotransferases, hepatotoxicity,
and liver failure. The incidence of elevated aminotransferases in
the SERAPHIN study >3 x ULN was 3.4% for OPSUMIT® vs
4.5% for placebo, and >8 x ULN was 2.1% vs 0.4%,
respectively. Discontinuations for hepatic adverse events were
3.3% for OPSUMIT® vs 1.6% for placebo.
Obtain liver enzyme tests prior to initiation of OPSUMIT® and
repeat during treatment as clinically indicated.
Advise patients to report symptoms suggesting hepatic injury
(nausea, vomiting, right upper quadrant pain, fatigue, anorexia,
jaundice, dark urine, fever, or itching).
If clinically relevant aminotransferase elevations occur, or if
elevations are accompanied by an increase in bilirubin
>2 x ULN, or by clinical symptoms of hepatotoxicity,
discontinue OPSUMIT®. Consider re-initiation of OPSUMIT®
when hepatic enzyme levels normalize in patients who have not
experienced clinical symptoms of hepatotoxicity.
Peripheral edema and fluid retention are known consequences of PAH
and ERAs. In the pivotal PAH study SERAPHIN, edema was reported in
21.9% of the OPSUMIT® group vs 20.5% for placebo.
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 pulmonary
hypertension due to left ventricular dysfunction, more patients in
the OPSUMIT® group developed significant fluid retention and
had more hospitalizations due to worsening heart failure compared
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 and the possible need
to discontinue OPSUMIT®.
Decreases in hemoglobin concentration and hematocrit have occurred
following administration of other ERAs and in clinical studies
with OPSUMIT®. These decreases occurred early and stabilized
In the SERAPHIN study, OPSUMIT® caused a mean decrease in
hemoglobin (from baseline to 18 months) of about 1.0 g/dL vs
no change in the placebo group. A decrease in hemoglobin to below
10.0 g/dL was reported in 8.7% of the OPSUMIT® group vs
3.4% for placebo. Decreases in hemoglobin seldom require
Initiation of OPSUMIT® is not recommended in patients with
severe anemia. Measure hemoglobin prior to initiation of treatment
and repeat during treatment as clinically indicated.
Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
Should signs of pulmonary edema occur, consider the possibility of
associated PVOD. If confirmed, discontinue OPSUMIT®.
Decreased Sperm Counts
OPSUMIT®, like other ERAs, may have an adverse effect on
spermatogenesis. Counsel men about potential effects on fertility.
Most common adverse reactions (more frequent than placebo by ≥3%)
were anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%),
bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%),
and urinary tract infection (9% vs 6%).
Strong inducers of CYP3A4 such as rifampin significantly reduce
macitentan exposure. Concomitant use of OPSUMIT® with strong
CYP3A4 inducers should be avoided.
Strong inhibitors of CYP3A4 like ketoconazole approximately double
macitentan exposure. Many HIV drugs like ritonavir are strong
inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT® with
strong CYP3A4 inhibitors. Use other PAH treatment options when
strong CYP3A4 inhibitors are needed as part of HIV treatment.
Moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole
and amiodarone are predicted to increase macitentan exposure.
Avoid concomitant use of OPSUMIT® with moderate dual
inhibitors of CYP3A4 and CYP2C9.
Concomitant treatment of both a moderate CYP3A4 inhibitor and
moderate CYP2C9 inhibitor with OPSUMIT® should also be
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated
for the treatment of pulmonary arterial hypertension (PAH,
WHO Group I) to reduce the risks
of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients
with predominantly WHO Functional Class II-III symptoms treated
for an average of 2 years. Patients had idiopathic and heritable
PAH (57%), PAH caused by connective tissue disorders (31%), and
PAH caused by congenital heart disease with repaired shunts (8%).
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Prescribing Information, including BOXED WARNING.