SUMMARY

• For patients who are treatment-naïve to any pulmonary arterial hypertension (PAH)-specific therapy or transitioning from endothelin receptor antagonist (ERA) monotherapy: the recommended starting dose of OPSYNVI is one macitentan 10 mg/tadalafil 20 mg tablet taken orally once daily with or without food for 1 week. If tolerated, uptitrate OPSYNVI to one macitentan 10 mg/tadalafil 40 mg tablet taken orally once daily with or without food as the maintenance dose.¹
• For patients transitioning from phosphodiesterase type-5 inhibitor (PDE5i) monotherapy or PDE5i and ERA therapy in combination: the recommended dose of OPSYNVI is one 10 mg/40 mg tablet taken orally once daily.¹
• The dosages recommended in section 2 of the OPSYNVI prescribing information are based on dosages administered in the phase 3 A DUE study^2,3 and further supported by phase 1 bioequivalence studies.^4,5

PRESCRIBING INFORMATION

OPSYNVI is taken orally once daily with or without food. Swallow the tablets whole, with water.¹

• 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 for 1 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 PDE5i monotherapy or PDE5i and ERA therapy in combination
  • The recommended dose of OPSYNVI is one 10 mg/40 mg tablet taken orally once daily.

CLINICAL DATA

The A DUE Study

A DUE was a prospective, multicenter, double-blind, randomized, active-controlled, triple-dummy, parallel group, group-sequential, adaptive phase 3 study (NCT03904693) that evaluated the efficacy and safety of OPSYNVI as a single tablet combination therapy (STCT) vs macitentan 10 mg and tadalafil 40 mg monotherapies in patients with PAH, including treatment-naïve patients and patients on prior ERA or PDE5i monotherapy at baseline.²

Study Design/Methods

The double-blind treatment had 2 phases: a 2-week tadalafil titration phase followed by a maintenance phase. In week 1 of the titration phase, patients were given macitentan 10 mg, tadalafil 20 mg, or both once daily (as separate tablets), along with relevant placebos (to maintain blinding). In week 2, tadalafil was uptitrated to 40 mg once daily; patients on baseline PDE5i therapy (tadalafil 40 mg, sildenafil 60-120 mg, or vardenafil 10 mg daily) were administered tadalafil 40 mg once daily from day 1. The maintenance phase spanned from day 15 to the end of week 16, when patients received macitentan 10 mg, tadalafil 40 mg, or OPSYNVI once daily, along with the relevant placebos. Downtitration of tadalafil to 20 mg was permitted for tolerability issues, while downtitration of macitentan was not.^2,3 During the titration phase, if a participant could not tolerate tadalafil 40 mg daily (or placebo), the dose was to be decreased back to 20 mg daily. Within the first 2-3 weeks after decreasing the dose (up to and including week 4/visit 5) and with the investigator’s approval, the participant was allowed to be re-uptitrated to the tadalafil 40 mg daily dose (or its matching placebo equivalent). If the participant could not tolerate the 40 mg dose again on the second attempt to uptitrate the tadalafil dose (or its matching placebo equivalent), then they were to stay on the 20 mg tadalafil daily dose (or its placebo equivalent) for the remainder of the double-blind treatment period. During the maintenance phase, the tadalafil dose was only adjusted for participants in the OPSYNVI group. The tadalafil dose decreased from 40 mg to 20 mg once in 3 participants (2 due to an AE, and 1 for an unspecified reason).⁶ On completion of the 16-week double-blind treatment, patients were enrolled in a 24-month open-label treatment where all patients received a single tablet of OPSYNVI (see Figure: Study Design and Table: Study Treatments).^2,3

Phase 1 Pharmacokinetic Studies

Three phase 1 pharmacokinetic studies in healthy adult subjects established the bioequivalence between a single OPSYNVI 10/40 film-coated tablet and the free combination of macitentan plus tadalafil administered together as 3 separate tablets. In these studies, macitentan 10 mg was provided as one OPSUMIT^® 10 mg film-coated tablet for oral administration, and tadalafil 40 mg was provided as two ADCIRCA^® 20 mg film-coated tablets for oral administration.^4,5

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 March 2024.