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General Information
Tryvio (aprocitentan) is an endothelin receptor antagonist.
Tryvio is specifically indicated for use in combination with other antihypertensive drugs for the treatment of hypertension, to lower blood pressure (BP) in adult patients who are not adequately controlled on other drugs. Lowering BP reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating reduction of risk of these events with Tryvio.
Tryvio is supplied as tablets for oral administration. The recommended dosage of Tryvio is 12.5 mg orally once daily. Swallow tablets whole. Tryvio may be taken with or without food. If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses on the same day.
Mechanism of Action
Tryvio (aprocitentan) is an endothelin receptor antagonist (ERA) that inhibits the binding of endothelin (ET)-1 to ETA and ETB receptors. ET-1, via its receptors (ETA and ETB), mediates a variety of deleterious effects such as vasoconstriction, fibrosis, cell proliferation, and inflammation. In hypertension, ET-1 can cause endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.
Side Effects
Adverse effects associated with the use of Tryvio may include, but are not limited to, the following:
- edema/fluid retention
- anemia
The Tryvio drug label comes with the following Black Box Warning: Tryvio can cause major birth defects if used by pregnant patients and is contraindicated in pregnancy. Patients who can become pregnant: Exclude pregnancy prior to initiation of treatment, monthly during treatment, and for one month after stopping Tryvio. Patients who can become pregnant: Use acceptable contraception prior to initiation of treatment, during treatment, and for one month after stopping Tryvio. Tryvio is only available through a restricted distribution program called the TRYVIO REMS.
Clinical Trial Results
The FDA approval of Tryvio was based on a monotherapy Phase 2 study in patients with hypertension, and as an add-on therapy in a Phase 3 study called PRECISION in patients with confirmed resistant hypertension.
The efficacy of Tryvio (aprocitentan) was evaluated in a multipart, Phase 3 multicenter study (PRECISION) in adults with systolic blood pressure (SBP) ≥140 mmHg who were prescribed at least three antihypertensive medications. The trial included a placebo run-in period, which was followed by three parts as described below. Prior to the placebo run-in period, all patients were switched to standard background antihypertensive therapy, which was continued throughout the study. Patients with concomitant use of beta‑blockers continued this treatment throughout the study.
Following the 4-week placebo run-in period, 730 patients were randomized equally to aprocitentan at either 12.5 mg, 25 mg, or placebo once daily during the initial 4-week double-blind (DB) treatment period (part 1). At the end of 4 weeks, all patients entered the single-blind treatment period (part 2) where they received 25 mg aprocitentan once daily for 32 weeks. At the end of the 32 weeks, patients were re-randomized to receive either 25 mg aprocitentan or placebo, once daily, during a 12-week DB-withdrawal period (part 3).
The primary efficacy endpoint was the change in sitting SBP (SiSBP) from baseline to Week 4 during part 1.
Aprocitentan 12.5 mg was statistically superior to placebo in reducing SiSBP at Week 4 (part 1). The treatment effect was consistent for sitting diastolic BP (SiDBP).
The persistence of the BP-lowering effect of aprocitentan was demonstrated in part 3 of the trial, in which patients on aprocitentan were re-randomized to placebo or 25 mg aprocitentan following a period during which all patients were treated with 25 mg. In patients re-randomized to placebo, the mean SiSBP increased, whereas in patients re-randomized to 25 mg aprocitentan the mean effect on SiSBP was maintained and was statistically superior to placebo at Week 40. The treatment effect was consistent for SiDBP.
he efficacy for the 25 mg aprocitentan dose as measured in the primary end point of change in sitting SBP (SiSBP) from baseline to Week 4 in part 1, was similar to the 12.5 mg dose and thus aprocitentan 12.5 mg is the approved dose.