Aprocitentan (Monograph)

Brand name: Tryvio
Drug class: Endothelin Receptor Antagonists

Introduction

Aprocitentan is an endothelin receptor antagonist.¹

Uses for Aprocitentan

Aprocitentan has the following uses:

Aprocitentan is indicated for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs.¹ Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.¹

Aprocitentan Dosage and Administration

General

Aprocitentan is available in the following dosage form(s) and strength(s):

Tablets: 12.5 mg¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• The recommended dosage of aprocitentan is 12.5 mg orally once daily, with or without food.¹

Cautions for Aprocitentan

Contraindications

• Pregnancy.¹

• Hypersensitivity.¹

Warnings/Precautions

Embryo-fetal Toxicity

Based on data from animal reproduction studies with endothelin receptor antagonists (ERAs), aprocitentan can cause fetal harm when administered during pregnancy and is contraindicated for use in patients who are pregnant.¹ Exclude pregnancy and ensure use of acceptable contraceptive methods prior to initiation of treatment with aprocitentan.¹ Counsel patients who can become pregnant about the potential risk to a fetus.¹ Patients should monitor for pregnancy monthly during treatment and one month after discontinuation of treatment and avoid pregnancy by using acceptable contraception methods prior to initiation of treatment with aprocitentan, during treatment, and for one month after the final dose of aprocitentan.¹ If pregnancy is detected, discontinue aprocitentan.¹

REMS Program

Aprocitentan is available only through a restricted program under a REMS called the Tryvio REMS because of the risk of embryo-fetal toxicity.¹

Important requirements of the REMS include the following: ¹

• Prescribers must be certified with the Tryvio REMS by enrolling and completing training.¹

• Pharmacies that dispense aprocitentan must be certified with the Tryvio REMS.¹

Further information is available at www.TryvioREMS.com or 1-866-429-8964.¹

Hepatotoxicity

Elevations of aminotransferases and hepatotoxicity are known effects of ERAs, including aprocitentan.¹ Elevations in alanine transaminase (ALT) or aspartate aminotransferase (AST) of greater than 5-fold upper limit of normal (ULN) were observed rarely in patients treated with aprocitentan in the clinical trial, including cases with positive rechallenge.¹ There were no reports of patients with ALT and/or AST >3 × ULN and total bilirubin >2 × ULN or cases of liver failure observed in aprocitentan-treated patients in the clinical trials.¹ To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and repeat during treatment periodically and as clinically indicated.¹

Do not initiate aprocitentan in patients with elevated aminotransferases (>3 × ULN) or moderate to severe hepatic impairment. ¹ Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, scleral icterus, jaundice, dark urine, fever, or itching) to immediately stop treatment with aprocitentan and seek medical attention.¹ 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.¹

Fluid Retention

Fluid retention and peripheral edema are known effects of ERAs, including aprocitentan.¹ Edema/fluid retention was reported in 9% of aprocitentan-treated patients compared with 18% of patients receiving aprocitentan 25 mg (twice the recommended dose) and 2% on placebo in the clinical trial, requiring additional diuretic use in some patients.¹ Older age and chronic kidney disease are risk factors for edema/fluid retention with aprocitentan.¹ Aprocitentan has not been studied in patients with heart failure New York Heart Association stage III–IV, unstable cardiac function, or with NTproBNP ≥500 pg/mL.¹ Aprocitentan is not recommended in these patients.¹

Monitor for signs and symptoms of fluid retention, weight gain, and worsening heart failure.¹ If clinically significant fluid retention develops, treat appropriately, and consider discontinuation of aprocitentan.¹

Hemoglobin Decrease

Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in the clinical trial with aprocitentan.¹ Hemoglobin decreases usually presented early, stabilized thereafter, and were reversible after discontinuation.¹ A decrease in hemoglobin of >2 g/dL from baseline was observed in 7% of patients compared to 1% of placebo patients.¹ A decrease to below 10.0 g/dL was observed in 3% of aprocitentan-treated patients compared to 0 patients taking placebo.¹ Initiation of aprocitentan is not recommended in patients with severe anemia.¹ Measure hemoglobin prior to initiation of treatment and periodically during treatment as clinically indicated.¹

Decreased Sperm Counts

Aprocitentan, like other ERAs, may have an adverse effect on spermatogenesis.¹ Counsel men about potential effects on fertility.¹

Specific Populations

Pregnancy

Based on animal reproduction studies with other ERAs, aprocitentan can cause embryo-fetal toxicity, including birth defects and fetal death when administered to a pregnant patient and is contraindicated during pregnancy.¹ Administration of macitentan, where approximately ≥50% of total exposure was to aprocitentan, was teratogenic in rats and rabbits at all doses tested.¹ Available data from reports of pregnancy in clinical trials with aprocitentan are insufficient to rule out a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.¹ Advise pregnant patients of the potential risk to a fetus.¹

The background risk of major birth defects and miscarriage for the indicated population is unknown.¹ All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.¹ In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.¹

There is a Pregnancy Safety Study that monitors pregnancy outcomes in women exposed to aprocitentan during pregnancy.¹ Healthcare providers should report any prenatal exposure to aprocitentan by calling 1-866-429-8964.¹

Lactation

There are no data on the presence of aprocitentan in human milk, the effects on the breastfed infant, or the effect on milk production.¹ In rats, aprocitentan was excreted into milk during lactation.¹ When a drug is present in animal milk, it is likely that the drug will be present in human milk.¹ Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with aprocitentan.¹

Females and Males of Reproductive Potential

Based on data from animal reproductive toxicity studies with other ERAs, aprocitentan can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy.¹

Verify the pregnancy status of patients prior to initiating aprocitentan.¹ Patients who can become pregnant should exclude pregnancy with a negative pregnancy test monthly during treatment, and one month after discontinuation of treatment with aprocitentan.¹ The patient should contact their physician immediately if onset of menses is delayed or pregnancy is suspected.¹ If the pregnancy test is positive, the physician and patient must discuss the risks to the patient, the pregnancy, and the fetus.¹

Patients using aprocitentan who can become pregnant should use acceptable contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with aprocitentan.¹

Other ERAs have shown an adverse effect on spermatogenesis in humans and/or animals.¹ Aprocitentan, like other ERAs, may impair fertility in males of reproductive potential.¹ It is not known whether effects on fertility would be reversible. ¹

Pediatric Use

The safety and efficacy of aprocitentan in pediatric patients have not been established.¹

Geriatric Use

Of the total number of subjects in the PRECISION study of aprocitentan, 321 (44%) were 65 years and older, while 72 (10%) were 75 years and older.¹ Edema/fluid retention was more common in these patients than younger patients.¹

No dose adjustment is required in patients older than 65 years of age.¹

Renal Impairment

Aprocitentan is not recommended in patients with kidney failure (eGFR <15 mL/min) or on dialysis.¹ The effect of kidney failure (eGFR <15 mL/min) or dialysis on aprocitentan pharmacokinetics is unknown.¹ Patients with renal impairment are at increased risk of edema/fluid retention.¹

No dose adjustment is required in patients with mild to severe renal impairment (eGFR ≥15 mL/minute).¹

Hepatic Impairment

Aprocitentan is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh class B and C) because these patients may be at increased risk for poor outcomes from hepatotoxicity. ¹

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A).¹

Common Adverse Effects

Most common adverse reactions (more frequent than placebo and ≥ 2% in aprocitentan-treated patients) are edema/fluid retention and anemia.¹

Related/similar drugs

amlodipine, lisinopril, metoprolol, losartan, furosemide, hydrochlorothiazide

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Aprocitentan is an ERA that inhibits the binding of endothelin (ET)-1 to ET_A and ET_B receptors.¹

ET-1, via its receptors (ET_A and ET_B), mediates a variety of deleterious effects such as vasoconstriction, fibrosis, cell proliferation, and inflammation.¹ In hypertension, ET-1 can cause endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis. ¹

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).¹

• Counsel patients who can become pregnant to use acceptable methods of contraception before treatment with aprocitentan, during treatment, and for one month after treatment discontinuation.¹ Acceptable forms of contraception include, but are not limited to, IUD, contraceptive implants, tubal sterilization, or a combination of methods (either one hormone method with a barrier method or two barrier methods).¹ Alternatively, if a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method.¹ Patients who can become pregnant should have pregnancy tests prior to initiation of aprocitentan, monthly during treatment, and one month after aprocitentan discontinuation.¹ Patients should be instructed to contact their healthcare provider if they suspect they may be pregnant.¹ Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.¹

• Because of the risk of birth defects, aprocitentan is only available through a restricted distribution program called the Tryvio REMS.¹ Prescribers and pharmacies must enroll in the REMS.¹

• Educate and counsel patients who can become pregnant on the use of emergency contraception in the event of unprotected sex or contraceptive failure.¹ Advise pre-pubertal females and/or their guardian(s) to report any changes in their reproductive status immediately to their prescriber.¹

• Review the Medication Guide and REMS educational materials with patients.¹

• Advise females not to breastfeed during treatment with aprocitentan.¹

• Educate patients on signs of hepatotoxicity.¹ Advise patients that they should contact their healthcare provider if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.¹

• Educate patients on signs of fluid retention.¹ Advise patients that they should contact their healthcare provider if they have unusual weight increase or swelling of the ankles or legs.¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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