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General Information
Opsynvi is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor.
Opsynvi is specifically indicated for chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients of WHO functional class (FC) II-III.
Dosage/Administration
- Opsynvi is supplied as tablets for oral administration.
- 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 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.
For patients transitioning from PDE5 inhibitor monotherapy or PDE5 inhibitor and ERA therapy in combination:
- The recommended dose is one 10 mg/40 mg tablet taken orally once daily
Mechanism of Action
Opsynvi is a combination of macitentan and tadalafil.
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.
Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). PAH is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.
Side Effects
Adverse effects associated with the use of Opsynvi may include, but are not limited to, the following:
- edema/fluid retention
- anemia
- headache/migraine
The Opsynvi drug label comes with the following Black Box Warning: Do not administer Opsynvi to a pregnant female because it may cause fetal harm. Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception. For all female patients, Opsynvi is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy.
Clinical Trial Results
The FDA approval of Opsynvi was based on the A DUE study. The double-blind, randomized, active-controlled, multi-center, adaptive, parallel-group study was designed to compare the efficacy and safety of Opsynvi to macitentan and tadalafil monotherapies in adult patients with PAH (WHO FC II or III). The three-arm trial enrolled patients from across 76 sites in 16 countries/territories worldwide who were treatment-naïve or on a stable dose of an endothelin receptor antagonist (ERA), or a phosphodiesterase 5 (PDE5) inhibitor, for at least three months. The primary endpoint was change from baseline in Pulmonary Vascular Resistance (PVR) at the end of double-blind treatment at 16 weeks and was considered met if macitentan and tadalafil fixed-dose combination (FDC) treatment was superior to both monotherapies. Following the treatment period, patients transitioned to the open-label treatment period for 24 months.
Opsynvi demonstrated greater reduction in PVR after 16 weeks. Treatment with Opsynvi resulted in a statistically significant treatment effect of 0.71, representing a 29% reduction in PVR as compared to macitentan, and of 0.72, representing a 28% reduction in PVR as compared to tadalafil.