CONTINUING EDUCATION
Administration: Aprocitentan is dosed as a 12.5 mg oral tablet once daily with or without food. The efficacy of 25 mg in PRECISION was similar to that of the 12.5 mg dose, but with greater adverse events, and is therefore not an approved dose. Counsel patients to swallow the tablet whole; do not cut, crush or chew. 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. Safety: The most common side effects observed in patients using aprocitentan in clinical trials were edema/fluid retention and anemia (decreased hemo- globin). Fluid retention and peripheral edema are known effects of ERAs; patient should be monitored for signs of fluid retention, weight gain, and wors- ening HF during treatment. Aprocitentan carries a boxed warning for major birth defects in pregnant patients and is therefore contraindicated in preg- nancy. It will only be available through a restricted TRYVIO Risk Evaluation and Mitigation Strategies (REMS) program. Elevations of aminotransferases and hepatotoxic- ity are also known effects of ERA; measure serum aminotransferases and bilirubin prior to initiating aprocitentan and repeat testing during treatment as clinically indicated. ERAs can decrease sperm count, so men should be counseled on the poten- tial effects on fertility. Concomitant administration of aprocitentan with UGT inducers may decrease aprocitentan exposure. How Supplied: Aprocitentan will be available as a 12.5 mg film-coated tablet in packages of 30 tablets (either in 10-pill blister cards or in bottles of 30). It should be stored at room temperature and must be dispensed in the original container. Additional Notes: Counsel patients to continue therapeutic lifestyle changes to help lower high blood pressure. These can include: • Doing regular physical activity • Following a healthy diet low in sodium and fats • Getting adequate sleep every night • Decreasing stress
patients with hypertension who are not adequately controlled. As a dual ERA, aprocitentan inhibits the binding of endothelin (ET)-1 to ETA and ETB recep- tors. ET-1, via its receptors (ETA and ETB), mediates a variety of damaging effects such as vasoconstric- tion, fibrosis, cell proliferation, and inflammation. In hypertension, ET-1 can cause endothelial dys- function, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.
Aprocitentan was studied as monotherapy in a Phase II study 19 in patients with hypertension, and as an add-on therapy in a Phase III study (PRECISION) 20 in patients with medication-resistant hypertension. In PRECISION, adults with systolic blood pressure (SBP) greater than or equal to 140 mmHg who were prescribed at least three antihy- pertensive medications were randomized to receive either aprocitentan 12.5 mg, 25 mg, or placebo. The primary efficacy endpoint was the change in sitting SBP from baseline to week 4. The key secondary endpoint was the change in sit- ting SBP from week 36 to week 40. Aprocitentan at a dose of 12.5 mg was statistically superior to pla- cebo in reducing sitting SBP at week 4. The most blood pressure lowering effect occurred within the first 2 weeks of treatment. Lowering blood pressure reduces the risk of fatal and non-fatal CV events, primarily strokes and myo- cardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes; however, there are no controlled trials demonstrating reduc- tion of risk of these events with aprocitentan.
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