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OPSUMIT® (macitentan)
Table 1: Incidence of Elevated Aminotransferases in the SERAPHIN Study
OPSUMIT 10 mg
(N=242)
Placebo
(N=249)
>3 × ULN
3.4%
4.5%
BRIEF SUMMARY
The following is a brief summary of the full Prescribing Information for OPSUMIT®
(macitentan). Please review the full Prescribing Information prior to prescribing
OPSUMIT.
>8 × ULN
2.1%
0.4%
WARNING: EMBRYO-FETAL TOXICITY
• Do not administer OPSUMIT to a pregnant female because it may cause
fetal harm [see Contraindications (Pregnancy), Warnings and Precautions
(Embryo-fetal Toxicity), Use in Specific Populations (Pregnancy)].
• 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 [see
Use in Special Populations (Females and Males of Reproductive Potential)].
• For all female patients, OPSUMIT is available only through a restricted
program called the OPSUMIT Risk Evaluation and Mitigation Strategy
(REMS) [see Warnings and Precautions (OPSUMIT REMS Program)].
INDICATIONS AND USAGE
Pulmonary Arterial Hypertension
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of
pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.
Disease progression included: death, initiation of intravenous (IV) or subcutaneous
prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance,
worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also
reduced 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 were
treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5
inhibitors or inhaled prostanoids. 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%).
CONTRAINDICATIONS
Pregnancy
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, apprise the patient of the potential hazard to a fetus [see Warnings and
Precautions (Embryo-fetal Toxicity) and Use in Specific Populations (Pregnancy)].
WARNINGS AND PRECAUTIONS
Embryo-fetal Toxicity
OPSUMIT may cause fetal harm when administered during pregnancy and is
contraindicated for use in females who are pregnant. In females of reproductive
potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable
contraceptive methods and obtain monthly pregnancy tests [see Dosage and
Administration section 2.2 in full Prescribing Information and Use in Specific Populations
(Pregnancy, Females and Males of Reproductive Potential)].
OPSUMIT is available for females through the OPSUMIT REMS Program, a restricted
distribution program [see Warnings and Precautions (OPSUMIT REMS Program)].
OPSUMIT REMS Program
For all females, OPSUMIT is available only through a restricted program called
the OPSUMIT REMS Program, because of the risk of embryo-fetal toxicity [see
Contraindications (Pregnancy), Warnings and Precautions (Embryo-fetal Toxicity), and
Use in Specific Populations (Pregnancy, Females and Males of Reproductive Potential)].
Notable requirements of the OPSUMIT REMS Program include the following:
• Prescribers must be certified with the program by enrolling and completing training.
• 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 [see Use in Specific Populations (Females and Males
of Reproductive Potential)].
• Pharmacies must be certified with the program and must only dispense to patients
who are authorized to receive OPSUMIT.
Further information is available at www.OPSUMITREMS.com or 1-866-228-3546.
Information on OPSUMIT certified pharmacies or wholesale distributors is available
through Actelion Pathways at 1-866-228-3546.
Hepatotoxicity
Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver
failure. The incidence of elevated aminotransferases in the study of OPSUMIT in PAH
is shown in Table 1.
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In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events
were 3.3% in the OPSUMIT 10 mg group 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 × 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.
Hemoglobin Decrease
Decreases in hemoglobin concentration and hematocrit have occurred following
administration of other ERAs and were observed in clinical studies with OPSUMIT.
These decreases occurred early and stabilized thereafter. In the placebo-controlled
study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin
from baseline to up to 18 months of about 1.0 g/dL compared to no change in the
placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of
the OPSUMIT 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin
seldom require transfusion. 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 [see Adverse Reactions (Clinical Trial Experience) ].
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
Other ERAs have caused adverse effects on spermatogenesis. Counsel men about
potential effects on fertility [see Use in Specific Populations (Females and Males
of Reproductive Potential) and Nonclinical Toxicology (Carcinogenesis, Mutagenesis,
Impairment of Fertility) ].
ADVERSE REACTIONS
Clinically significant adverse reactions that appear in other sections of the labeling
include:
• Embryo-fetal Toxicity [see Warnings and Precautions (Embryo-fetal Toxicity) ]
• Hepatotoxicity [see Warnings and Precautions (Hepatotoxicity)]
• Decrease in Hemoglobin [see Warnings and Precautions (Hemoglobin Decrease)]
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in 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 clinical practice.
Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical
study in 742 patients with PAH (SERAPHIN study). The exposure to OPSUMIT in this
trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year;
N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment
discontinuations because of adverse events was similar across OPSUMIT 10 mg and
placebo treatment groups (approximately 11%).
Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%.
Table 2: Adverse Reactions
OPSUMIT 10 mg
(N=242)
Placebo
(N=249)
Anemia
13%
3%
Nasopharyngitis/pharyngitis
20%
13%
Bronchitis
12%
6%
Headache
14%
9%
Influenza
6%
2%
Urinary tract infection
9%
6%
Adverse Reaction
Postmarketing Experience
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)
Respiratory, thoracic and mediastinal disorders: nasal congestion
ACTOP15438_BriefSumPI_Mv02-HR.pdf
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