Macitentan and Tadalafil

OPSYNVI is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, indicated for chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients of WHO functional class (FC) II–III. Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability.

Macitentan Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro. The clinical impact of dual endothelin blockage is unknown.

One 10 mg/20 mg or 10 mg/40 mg tablet taken orally once daily with or without food. Recommended Dosage OPSYNVI is taken orally once daily with or without food. Swallow the tablets whole, with water. Do not cut, crush, or chew tablets. If the patient misses a dose of OPSYNVI, tell the patient to take it as soon as possible and then take the next dose at the regularly scheduled time. Tell the patient not to take two doses at the same time if a dose has been missed. For patients who are treatment-naïve to any PAH specific therapy or transitioning from ERA monotherapy The recommended starting dose of OPSYNVI is one 10 mg/20 mg tablet taken orally once daily with or without food for one week. If tolerated, up titrate OPSYNVI to one 10 mg/40 mg tablet taken orally once daily with or without food as the maintenance dose.

Pregnancy. Hypersensitivity. Concomitant Organic Nitrates. Concomitant Guanylate Cyclase (GC) Stimulators Pregnancy OPSYNVI may cause fetal harm when administered to a pregnant woman. OPSYNVI is contraindicated in females who are pregnant. Macitentan was consistently shown to have teratogenic effects when administered to animals. If OPSYNVI is used during pregnancy, advise the patient of the potential risk to a fetus. Hypersensitivity OPSYNVI is contraindicated in patients with a history of a hypersensitivity reaction to macitentan, tadalafil, or any component of the product. Hypersensitivity reactions have been reported.

Boxed warning (embryo-fetal toxicity opsynvi): is contraindicated for use during pregnancy because it may cause fetal harm based on animal data. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with OPSYNVI. Advise use of effective contraception before the initiation of treatment, during treatment, and for one month after stopping treatment with OPSYNVI. Hepatotoxicity: ERAs cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated. Hypotension: Vasodilatory effects may cause hypotension in susceptible patients. Hemoglobin decrease. Worsening Pulmonary Veno-Occlusive Disease: If pulmonary edema is confirmed, discontinue treatment. Visual Loss: Sudden loss of vision could be a sign of non-arteritic ischemic optic neuropathy (NAION) and may be permanent.

Clinically significant adverse reactions that appear in other sections of the labeling include: Hypersensitivity Embryo-fetal Toxicity Hepatotoxicity Hypotension Decrease in Hemoglobin Visual Loss Hearing loss Fluid Retention Prolonged Erection Most common adverse reactions (≥10%) are edema/fluid retention, anemia, and headache/migraine.

Strong CYP3A4 Inducers/Inhibitors: Avoid concomitant use. Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors: Avoid concomitant use

Store at 20ºC to 25ºC (68ºF to 77ºF), excursions are permitted between 15°C and 30°C (59°F and 86°F). Store and dispense in the original package to protect from moisture.