Acronyms
- BP - Blood pressure
- CrCl - Creatinine clearance
- DBP - Diastolic blood pressure
- HCTZ - Hydrochlorothiazide
- LFTs - Liver function tests
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- ULN - Upper limit of normal
MECHANISM OF ACTION
- Aprocitentan is an endothelin receptor antagonist 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.
FDA-APPROVED INDICATIONS
- Aprocitentan, in combination with other antihypertensive drugs, is indicated for the treatment of hypertension, to lower blood pressure (BP) in adult patients who are not adequately controlled on other drugs
RESISTANT HYPERTENSION
- Resistant hypertension is defined as a clinic blood pressure > 130/80 mmHg in a patient taking ≥ 3 antihypertensives that include a long-acting calcium channel blocker, an ACE inhibitor or ARB, and a diuretic at maximal or maximally tolerated doses. Results from a study that evaluated the effects of adding aprocitentan to amlodipine, valsartan, and HCTZ in patients with resistant hypertension are presented in the table below.
Effects of Aprocitentan on BP in a 4-week trial | ||
---|---|---|
Aprocitentan 12.5 mg once daily (N=243) |
Placebo (N=244) |
|
Baseline BP | 153/88 | 153/87 |
SBP change | -15.4 | -11.6 |
DBP change | -10.4 | -6.4 |
SIDE EFFECTS
- Fluid retention and peripheral edema
- Aprocitentan can cause fluid retention and peripheral edema. In trials, fluid retention/edema occurred in 9.1% of aprocitentan-treated patients compared to 2% of placebo-treated patients. Older patients and those with chronic kidney disease were at greater risk. Patients with heart failure were excluded from clinical trials, and aprocitentan is not recommended in these patients. Monitor patients for fluid retention and discontinue aprocitentan if significant symptoms develop.
- Hemoglobin decrease
- In trials, a decrease in hemoglobin of 2 g/dl or more was observed in 7% of aprocitentan-treated patients compared to 1% in the placebo group. Decreases typically occurred early after treatment initiation, stabilized over time, and were reversible upon discontinuation. Since aprocitentan causes fluid retention, the effect may be secondary to hemodilution. Do not give aprocitentan to patients with significant anemia. Check hemoglobin levels prior to therapy and periodically thereafter.
- Hepatotoxicity
- Endothelin receptor antagonists, including aprocitentan, have been associated with hepatotoxicity. In trials, ALT or AST elevations greater than 5 X ULN were rare in aprocitentan-treated patients, and there were no reports of patients with ALT and/or AST >3 X ULN and total bilirubin >2 X ULN or cases of liver failure. Check liver enzymes before therapy and periodically thereafter, as clinically indicated. Advise patients to stop aprocitentan and seek care if they experience symptoms of hepatotoxicity (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine). If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or if clinical symptoms of hepatotoxicity occur, discontinue aprocitentan.
- Decreased sperm count
- Endothelin receptor antagonists have been shown to adversely affect spermatogenesis in humans and/or animals. Aprocitentan may reduce spermatogenesis, and it is unknown if the effects are reversible upon discontinuation.
- Hypersensitivity reactions
- In trials, hypersensitivity reactions, including rash, erythema, and allergic edema, were reported in 0.8% of aprocitentan-treated patients compared to none in the placebo group.
CONTRAINDICATIONS
- Pregnancy - may cause birth defects and fetal death
- Hypersensitivity to aprocitentan or any of its excipients
PRECAUTIONS
- Kidney disease
- CrCl ≥ 15 ml/min: no dose adjustment necessary. Patients with renal disease are at greater risk of fluid retention.
- CrCl < 15 ml/min or dialysis: Not recommended
- Liver disease
- Child-Pugh A: No dose adjustment necessary
- Child-Pugh B or C: Not recommended. Risk of hepatotoxicity is increased.
- Pregnancy
- Aprocitentan may cause fetal harm and is contraindicated in pregnancy. Women of childbearing potential should receive contraception before and during aprocitentan therapy. Exclude pregnancy before initiation and monitor for pregnancy monthly during treatment and for one month after discontinuation. If pregnancy is detected, discontinue aprocitentan. Because of the potential risk, pharmacies and providers must register with the Tryvio REMS program (TRYVIO REMS) before prescribing aprocitentan.
- Heart failure
- Aprocitentan causes fluid retention and should not be used in patients with heart failure (see fluid retention)
- Anemia
- Aprocitentan causes a decrease in hemoglobin and should not be used in patients with significant anemia (see hemoglobin decrease)
DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- No clinically relevant drug interactions have been identified
- Metabolism and clearance
- Aprocitentan is primarily metabolized by UGT1A1- and UGT2B7-mediated N-glucosidation and non-enzymatic hydrolysis
DOSING
- Dosage form
- 12.5 mg tablet
- No generic / > $700 for 30 tablets
- Dosing
- Dosing: 12.5 mg once daily. Swallow tablets whole. May take without regard to food.
- Missed doses: 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.
- Before starting therapy, rule out pregnancy and start contraception in women of childbearing potential (pregnancy and Tryvio REMS). Check liver function tests (hepatotoxicity) and hemoglobin levels (hemoglobin decrease).
LONG-TERM SAFETY
- Aprocitentan was FDA-approved in 2024, and long-term safety data is not available
BIBLIOGRAPHY
- 1 - Tryvio prescribing information