Brand name: Tryvio
Drug class: Endothelin Receptor Antagonists

Medically reviewed by Drugs.com on Jan 10, 2025. Written by ASHP.

[Web]

Introduction

Antihypertensive agent; an endothelin receptor antagonist.

Uses for Aprocitentan

Hypertension

Used in combination with other classes of antihypertensive agents for treatment of hypertension in adults not adequately controlled on other drugs.

Preferred pharmacological agents for the treatment of hypertension include thiazide diuretics, calcium channel blockers, and ACE inhibitors or angiotensin II receptor antagonists. Additional antihypertensive agents that may be used in resistant hypertension include beta-blockers, alpha-beta-blockers, alpha-agonists, hydralazine, and minoxidil. Specific place in therapy for aprocitentan not yet established.

Aprocitentan Dosage and Administration

General

Pretreatment Screening

• Exclude the possibility of pregnancy and ensure use of acceptable contraceptive methods prior to initiating aprocitentan.

• Assess serum aminotransferase levels and total bilirubin. Do not initiate aprocitentan in patients with elevated transaminases (ALT or AST >3 times ULN) or moderate to severe hepatic impairment (Child-Pugh class B and C).

• Assess hemoglobin. Do not initiate aprocitentan if severe anemia is present.

Patient Monitoring

• In patients who may become pregnant, exclude pregnancy monthly during therapy and 1 month after stopping aprocitentan.

• Monitor serum aminotransferase levels and total bilirubin periodically during therapy and as clinically indicated.

• Monitor hemoglobin periodically during therapy as clinically indicated.

• Monitor for signs and symptoms of fluid retention, weight gain, and worsening heart failure during treatment.

REMS Program

• Because of the risk of embryo-fetal toxicity, aprocitentan is only available through a restricted distribution program called the Tryvio Risk Evaluation and Mitigation Strategy (REMS). Prescribers and pharmacies must enroll in the program and agree to its requirements before prescribing and dispensing aprocitentan. Clinicians must counsel patients about pregnancy testing recommendations, the use of acceptable contraception, and the need to report suspected pregnancy immediately. To obtain additional information or to enroll in the program, clinicians may call 1-866-429-8964 or visit [Web].

Other General Considerations

• Aprocitentan is indicated for use with other antihypertensive agents.

• Blood pressure control should be part of a comprehensive cardiovascular risk management plan, including (as appropriate) lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

• Avoid using aprocitentan in patients with NYHA heart failure stage III–IV, unstable cardiac function, or with N-terminal pro-B-type natriuretic peptide (NTproBNP) levels of ≥500 pg/mL, as the drug has not been studied in these patients.

Administration

Oral Administration

Available as tablets containing 12.5 mg of aprocitentan.

Administer with or without food. Swallow tablets whole.

If a dose is missed, skip missed dose and take next dose at regularly scheduled time; do not double doses to make up for missed dose.

Dosage

Adults

Hypertension

Oral

12.5 mg once daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Use not recommended; patients may be at increased risk for poor outcomes from hepatotoxicity.

Renal Impairment

Mild to severe renal impairment (eGFR ≥15 mL/minute): No dosage adjustment necessary.

Renal failure (eGFR <15 mL/minute) or receiving dialysis: Use not recommended.

Patients with renal impairment at increased risk for edema and fluid retention.

Geriatric Patients

No dosage adjustment necessary, although edema/fluid retention reported more frequently in geriatric patients compared to younger adults.

Cautions for Aprocitentan

Contraindications

• Pregnancy.

• Hypersensitivity to aprocitentan or any of its excipients.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Based on animal findings, may cause fetal harm. (See Boxed Warning.)

Teratogenicity demonstrated in animals. Contraindicated during pregnancy. May impair fertility in males of reproductive potential.

Prior to initiating, exclude possibility of pregnancy in patients who can become pregnant and ensure use of acceptable contraceptive methods. Advise patients of reproductive potential about potential fetal hazard. In patients who can become pregnant, monitor for pregnancy monthly during therapy and for 1 month after discontinuing aprocitentan. Avoid pregnancy by using acceptable contraception methods during treatment and for 1 month after discontinuing aprocitentan. If pregnancy detected, discontinue aprocitentan.

Because of risk of embryo-fetal toxicity, aprocitentan available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. (See REMS under Dosage and Administration.)

Other Warnings/Precautions

Hepatotoxicity

Increased aminotransferases and hepatotoxicity reported.

To reduce risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiating aprocitentan and periodically during treatment and as clinically indicated.

Do not initiate aprocitentan in patients with elevated transaminases (ALT or AST >3 times ULN) or moderate to severe hepatic impairment (Child-Pugh class B and C). Advise patients with symptoms of hepatotoxicity (e.g., nausea, vomiting, right upper quadrant pain, fatigue, anorexia, scleral icterus, jaundice, dark urine, fever, itching) to immediately stop aprocitentan and seek medical attention.

If sustained or unexplained clinically important aminotransferase elevations observed, or if elevations accompanied by increase in bilirubin >2 times ULN, or if clinical symptoms of hepatotoxicity are present, discontinue aprocitentan.

Fluid Retention

Fluid retention and peripheral edema reported. Risk factors include older age and chronic kidney disease.

Not recommended in patients with NYHA heart failure stage III–IV, unstable cardiac function, or with N-terminal pro-B-type natriuretic peptide (NTproBNP) levels ≥500 pg/mL.

Monitor for signs and symptoms of fluid retention, weight gain, and worsening heart failure during treatment. If clinically important fluid retention occurs, treat appropriately, and consider discontinuing aprocitentan.

Hemoglobin Decrease

Decreased hemoglobin and hematocrit concentrations reported.

Do not initiate aprocitentan in patients with severe anemia. Assess hemoglobin prior to initiation and periodically during therapy as clinically indicated.

Decreased Sperm Counts

May cause decreased sperm counts.

Counsel men about potential effects on fertility.

Specific Populations

Pregnancy

Based on animal findings with other endothelin receptor antagonists (ERAs), may cause embryo-fetal toxicity (including birth defects and fetal mortality).

Teratogenicity demonstrated in animals. Available data in pregnancy insufficient to rule out drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Pregnancy Safety Study available that monitors pregnancy outcomes in women exposed to aprocitentan; healthcare providers should report prenatal exposure by calling 1-866-429-8964.

Counsel patients who can become pregnant that acceptable methods of contraception must be used before treatment, during treatment, and for 1 month after treatment discontinuation.

In patients who can become pregnant, exclude pregnancy with negative pregnancy test prior to initiating aprocitentan, monthly during treatment, and 1 month after treatment discontinuation.

Advise pregnant patients of potential fetal risk.

Lactation

No data available on presence in human milk, effect on breast-fed infant, or effect on milk production. Excreted into milk of lactating rats; therefore, likely will be excreted into human milk.

Because of potential for serious adverse reactions in breast-fed infants, advise women not to breast-feed during treatment with aprocitentan.

Females and Males of Reproductive Potential

Animal data indicate may cause fetal harm.

Verify pregnancy status prior to initiating aprocitentan. In patients who can become pregnant, exclude pregnancy monthly during treatment and for 1 month after discontinuation of aprocitentan. If delay in menses onset or if pregnancy suspected, instruct patients to contact their clinician immediately. If pregnancy test is positive, discuss risks to patient, pregnancy, and fetus.

Advise patients who can become pregnant that acceptable methods of contraception must be used before treatment, during treatment, and for 1 month after treatment discontinuation. Inform patients that acceptable forms of contraception include, but are not limited to, intrauterine devices, contraceptive implants, tubal sterilization, or a combination of methods (either 1 hormone method with a barrier method or 2 barrier methods). If partner's vasectomy is chosen method of contraception, inform patients that a hormone or barrier method must be used along with this method.

Adverse effect on spermatogenesis demonstrated with other ERAs. May impair fertility in males of reproductive potential; unknown whether these effects are reversible.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

PRECISION trial included patients ≥65 years of age. Edema/fluid retention reported more frequently in geriatric patients compared to younger adults.

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): No clinically important differences in pharmacokinetics observed.

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics not studied.

Moderate or severe hepatic impairment (Child-Pugh class B or C): Use not recommended; patients may be at increased risk for poor outcomes from hepatotoxicity.

Renal Impairment

Mild to severe renal impairment (eGFR ≥15 mL/minute): No clinically important differences in pharmacokinetics observed.

Kidney failure (eGFR <15 mL/minute) or receiving dialysis: Pharmacokinetics not studied.

Patients with renal impairment at increased risk for edema/fluid retention.

Common Adverse Effects

Adverse effects reported in ≥2% of patients receiving aprocitentan include edema/fluid retention and anemia.

Drug Interactions

Inhibits CYP3A4 and all members of the CYP2C family. Does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1.

Induces CYP3A4. Does not induce CYP1A2 or CYP2C9.

Substrate and inhibitor of UGT1A1 and UGT2B7.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); Inhibitors of P-gp and BCRP not expected to affect aprocitentan pharmacokinetics.

Inhibits BCRP, bile salt export pump (BSEP), and sodium taurocholate co-transporting polypeptide (NTCP). Does not inhibit P-gp, organic cation transporter (OCT) 1, OCT2, human multidrug and toxin extrusion (MATE) 1, or MATE2K. Does not inhibit organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3 at therapeutic concentrations.

UGT Inducers

Based on in vitro studies, concomitant administration of aprocitentan with UGT inducers may decrease aprocitentan exposure.

Specific Drugs

Aprocitentan Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability unknown.

Plasma concentrations increase in dose-proportional manner following once-daily administration of aprocitentan 5 mg, 25 mg, and 100 mg (0.4–8 times the recommended dosage).

Following oral administration of aprocitentan 25 mg (2 times the recommended dosage), peak plasma concentrations attained in 4–5 hours.

Steady state concentrations achieved by day 8 with approximately 3-fold accumulation.

Food

Administration with high-fat, high-calorie meal did not substantially affect pharmacokinetics.

Distribution

Extent

Unknown if excreted into human milk.

Plasma Protein Binding

>99%; primarily bound to albumin.

Protein binding not affected by renal or hepatic impairment.

Elimination

Metabolism

Metabolized principally by UGT1A1 and UGT2B7-mediated N-glucosidation and non-enzyme mediated hydrolysis.

Elimination Route

Urine: 52% (0.2% as unchanged drug).

Fecal: 25% (6.8% as unchanged drug).

Half-life

Approximately 41 hours.

Special Populations

Age (18–84 years), sex, race/ethnicity, and body weight (44–196 kg) did not demonstrate clinically important impact on pharmacokinetics.

Stability

Storage

Oral

Tablets, Film-Coated

20–25°C in original package; excursions permitted to 15–30°C.

Dispense to patient in original container only. Replace cap securely each time after opening; do not discard dessicant. Protect from light and moisture.

Actions

• Endothelial receptor antagonist; inhibits binding of endothelin (ET)-1 to ET_A and ET_B receptors.

• Endothelin-1 causes vasoconstriction, fibrosis, cell proliferation, and inflammation via the ET_A and ET_B receptors.

• Activation of ET-1 in hypertension can cause endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Inform patients that, because of the risk of birth defects, aprocitentan is only available through a restricted distribution program called the Tryvio REMS. Inform patients of the REMS requirements, and that their clinician will review the Medication Guide and REMS educational materials with them.

• Counsel patients who can become pregnant that acceptable methods of contraception must be used before treatment with aprocitentan, during treatment, and for 1 month after treatment discontinuation. Inform patients that acceptable forms of contraception include, but are not limited to, intrauterine devices, contraceptive implants, tubal sterilization, or a combination of methods (either 1 hormone method with a barrier method or 2 barrier methods). Alternatively, if a partner's vasectomy is the chosen method of contraception, inform patients that a hormone or barrier method must be used along with this method. Advise patients to seek additional contraceptive advice from a gynecologist or similar expert as needed.

• Inform patients of reproductive potential of the risk of fetal harm, and the need to have pregnancy tests prior to initiation of aprocitentan, monthly during treatment, and 1 month after treatment discontinuation. Instruct patients to contact their clinician if they suspect they may be pregnant.

• Educate and counsel patients who can become pregnant on the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise pre-pubertal females and/or their guardian(s) to report any changes in their reproductive status immediately to their clinician.

• Advise patients not to breast-feed during treatment with aprocitentan.

• Inform patients of the signs of hepatotoxicity. Advise patients that they should contact their clinician if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.

• Inform patients of the signs of fluid retention. Advise patients that they should contact their clinician if they have unusual weight increase or swelling of the ankles or legs.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of aprocitentan is restricted. (See REMS under Dosage and Administration)

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