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PAH is a progressive disease

Patients with PAH may experience only mild symptoms at first. However, due to the progressive nature of PAH, patients will continue to get worse and will eventually require treatment.1-3

There are 3 primary pathways in PAH that affect symptomatology and progression1,2

Prostacyclin, endothelin, and nitric oxide are the 3 main pathways in PAH. Abnormalities in these pathways result in proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with PAH. These 3 pathways correspond to important therapeutic targets in the treatment of PAH.1,2


The endothelin pathway

Elevated levels of endothelin correlate with disease severity and prognosis3:
  •   Endothelin-1 (ET-1) and its receptors (ETA and ETB) mediate a variety of deleterious effects such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation4
  •   In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and organ damage4
  •   ET-1 secretion from the endothelial cell layer is directional, with 80% released from the side adjacent to the smooth muscle layer, while the remaining 20% is released from the side facing the bloodstream5

The effects of endothelin

In PAH, levels of endothelin are significantly increased in the bloodstream and in the lungs.3,6 Excess levels of endothelin have been linked to:

  •  Vascular inflammation7
  •   Vasoconstriction2
  •   Cellular proliferation (smooth muscle cells and fibroblasts)7,8
  •   Vascular smooth muscle hypertrophy7,8
OPSUMIT acts on the endothelin pathway, 1 of 3 principal pathways involved in PAH.2,4

The prostacyclin pathway

Please note, OPSUMIT is not associated with the prostacyclin pathway.2,4

Prostacyclin is a potent vasodilator that has antiproliferative properties and inhibits platelet activation.9 Reduced levels of prostacyclin synthase are found in patients with IPAH.3,10

Prostacyclin levels are lower in PAH and this has been implicated in9:

  •   Vasoconstriction
  •   Thrombosis
  •   Cellular proliferation

Prostacyclin may play a role in:

  •   Vasodilation11
  •   Platelet aggregation inhibition11,12
  •   Cardiac contractility13-15
  •   Anti-inflammatory effects16


The nitric oxide pathway

Please note, OPSUMIT is not associated with the nitric oxide pathway.2,4

Patients with PAH have evidence of decreased nitric oxide synthase, which generates nitric oxide.3

The role of nitric oxide in PAH:

  •   Nitric oxide is a potent vasodilator and inhibitor of platelet activation and vascular smooth muscle cell proliferation3,9
  •   Decreased levels of the endothelial isoform of nitric oxide synthase have been observed in the pulmonary vascular tissue of patients with pulmonary hypertension3,9
  •   Endothelial nitric oxide synthase is increased in the plexiform lesions of idiopathic pulmonary arterial hypertension, where it may promote pulmonary endothelial cell proliferation9


Long-term outcome studies are useful to assess the effect of therapy on disease progression

  •   PAH disease progression represents the long-term deterioration of a patient’s condition
  •   To assess impact of treatment on disease progression, it is important to design a clinical study that:
  • —  Measures a range of clinically significant events
  • —  Collects a sufficient number of events over a long-term treatment period



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Important Safety Information

Boxed Warning:
Embryo-fetal Toxicity

  • Do not administer OPSUMIT® (macitentan) 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 OPSUMIT Risk Evaluation and Mitigation Strategy (REMS).

INDICATION

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. If OPSUMIT is used during pregnancy, apprise the patient of the potential hazard to a fetus.

WARNINGS AND PRECAUTIONS

Embryo-fetal Toxicity and OPSUMIT REMS Program

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 tests.

Notable requirements of the OPSUMIT REMS Program include:

  • 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.
  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT.

Hepatotoxicity

  • ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the SERAPHIN study >3 × ULN was 3.4% for OPSUMIT vs 4.5% for placebo, and >8 × 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 × 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.

Fluid Retention

  • 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.

Hemoglobin Decrease

  • 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 thereafter.
  • 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 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.

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.

ADVERSE REACTIONS

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%).

DRUG INTERACTIONS

  • 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.

INDICATION

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%).

View full Prescribing Information for OPSUMIT® (macitentan), including BOXED WARNING for embryo-fetal toxicity.