JERAYGO: Uses, Dosage & Side Effects

What Is JERAYGO and What Is It Used For?

JERAYGO contains the active substance aprocitentan, a small-molecule dual endothelin receptor antagonist (ERA) that blocks both endothelin A (ET_A) and endothelin B (ET_B) receptors. It was developed by Idorsia Pharmaceuticals and received marketing authorization from the European Medicines Agency (EMA) in June 2024, making it the first ERA approved specifically for the treatment of resistant hypertension. In the United States, the same active substance is marketed under the brand name Tryvio, approved by the U.S. Food and Drug Administration (FDA) in March 2024.

Resistant hypertension is defined as blood pressure that remains above target (typically 140/90 mmHg for most adults) despite the use of three or more antihypertensive medications from different classes, including a diuretic, all at optimal or maximally tolerated doses. This condition affects approximately 10–15% of all patients with hypertension and is associated with a significantly increased risk of cardiovascular events including stroke, heart attack, heart failure, chronic kidney disease, and premature death. Patients with resistant hypertension often have elevated levels of endothelin-1 (ET-1), a 21-amino acid peptide that is one of the most potent vasoconstrictors known in human physiology.

Endothelin-1 is produced primarily by vascular endothelial cells and exerts its effects through two receptor subtypes: ET_A and ET_B. ET_A receptors are found predominantly on vascular smooth muscle cells and mediate vasoconstriction, cell proliferation, and inflammation. ET_B receptors are located on both endothelial cells (where they promote vasodilation through nitric oxide and prostacyclin release) and smooth muscle cells (where they contribute to vasoconstriction). In resistant hypertension, the endothelin system is overactivated, leading to sustained vasoconstriction, sodium and water retention, vascular remodeling, and fibrosis — all of which contribute to persistently elevated blood pressure.

Aprocitentan blocks both ET_A and ET_B receptors, thereby inhibiting the vasoconstrictive, pro-inflammatory, and pro-fibrotic actions of endothelin-1. This dual blockade results in vasodilation, reduced peripheral vascular resistance, decreased sodium retention, and ultimately a clinically meaningful reduction in blood pressure. Importantly, aprocitentan represents a fundamentally different mechanism of action from existing antihypertensive drug classes (ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, diuretics, and beta-blockers), making it a valuable addition to the armamentarium for patients who do not achieve blood pressure control with standard therapies.

The efficacy and safety of JERAYGO were established primarily through the PRECISION (PREvention and Control of Blood Pressure with Aprocitentan in Resistant Hypertension — Prospective, International, Phase 3) trial. This landmark study was a multicenter, blinded, randomized, parallel-group trial that enrolled 730 adults with resistant hypertension across multiple countries. The trial design included three parts:

• Part 1 (4 weeks, double-blind): Patients were randomized to receive aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo, added to their existing triple antihypertensive therapy. The primary endpoint was change in unattended automated office systolic blood pressure (SBP) at 4 weeks. Aprocitentan 12.5 mg reduced SBP by 15.3 mmHg compared to 11.5 mmHg for placebo (difference: −3.8 mmHg; p = 0.0042). The 25 mg dose showed a reduction of 15.2 mmHg (difference: −3.7 mmHg; p = 0.0046).
• Part 2 (4 weeks, withdrawal): All patients were switched to aprocitentan 25 mg for 32 weeks, then re-randomized to either continue aprocitentan or switch to placebo for 4 weeks. Patients switched to placebo experienced a significant increase in office SBP of 5.8 mmHg compared to those continuing aprocitentan, confirming the sustained blood pressure-lowering effect.
• Part 3 (open-label extension): Patients could continue treatment with aprocitentan 25 mg for up to 48 weeks, demonstrating durable blood pressure reduction and long-term tolerability.

In the PRECISION trial, 24-hour ambulatory blood pressure monitoring (ABPM) confirmed that aprocitentan 12.5 mg reduced mean 24-hour systolic blood pressure by 4.2 mmHg more than placebo (95% CI: −6.2 to −2.1), providing objective evidence of sustained blood pressure lowering throughout the full dosing interval. This consistent 24-hour efficacy is clinically important because it reduces the risk of early morning blood pressure surges, which are associated with an increased risk of cardiovascular events.

Aprocitentan is a metabolite of macitentan (Opsumit), an ERA previously approved for pulmonary arterial hypertension. However, JERAYGO was specifically developed and studied for resistant hypertension, a distinct clinical indication with different patient populations, dosing strategies, and risk-benefit considerations. The pharmacological profile of aprocitentan was optimized for once-daily oral administration in the hypertension setting, with properties that minimize drug-drug interactions and allow for straightforward combination with existing antihypertensive regimens.

What Should You Know Before Taking JERAYGO?

Contraindications

JERAYGO must not be used in the following situations:

• Pregnancy: Endothelin receptor antagonists are known to cause serious birth defects in animal studies. JERAYGO is strictly contraindicated during pregnancy. A pregnancy test must be performed before starting treatment to confirm that the patient is not pregnant.
• Breastfeeding: It is not known whether aprocitentan passes into human breast milk. Due to the potential for serious adverse effects in breastfed infants, JERAYGO must not be used during breastfeeding.
• Women of childbearing potential not using reliable contraception: Women who could become pregnant must use reliable contraception during treatment with JERAYGO and for at least one month after stopping the medication. The interaction between aprocitentan and hormonal contraceptives has not been fully studied; therefore, women using hormonal contraceptives should add a barrier method (such as a condom or diaphragm).
• Severe hepatic impairment: JERAYGO is contraindicated in patients with severe liver disease (Child-Pugh class C) due to the risk of hepatotoxicity and altered drug metabolism.
• Hypersensitivity: Do not use JERAYGO if you are allergic to aprocitentan or any of the other ingredients in the tablet (see the section on composition below).

Warnings and Precautions

Before and during treatment with JERAYGO, your healthcare provider should be aware of the following important precautions:

• Hepatotoxicity (liver damage): Endothelin receptor antagonists as a class are associated with liver injury. Although clinically significant liver damage was rare in clinical trials of aprocitentan, elevations in liver enzymes (ALT and AST greater than 5 times the upper limit of normal) were observed in a small number of patients, including cases with positive rechallenge. Your doctor should check your liver function (blood tests for liver enzymes and bilirubin) before starting JERAYGO, monthly for the first year, and periodically thereafter. If you develop unexplained nausea, vomiting, right upper abdominal pain, fatigue, loss of appetite, jaundice (yellowing of the skin or eyes), or dark urine, contact your doctor immediately.
• Fluid retention and edema: JERAYGO can cause fluid retention, manifesting primarily as peripheral edema (swelling of the ankles, feet, or legs). In the PRECISION trial, edema occurred in approximately 9.1% of patients taking the 12.5 mg dose and 18.4% of those taking 25 mg, compared to 2.1% with placebo. Risk factors for edema include older age and chronic kidney disease. If you develop significant swelling, weight gain, or shortness of breath, inform your doctor promptly. The dose may need to be adjusted or a diuretic may be added or increased.
• Decreased hemoglobin: Aprocitentan can cause a mild decrease in hemoglobin and hematocrit levels, consistent with the hemodilutional effect of fluid retention. In clinical trials, a mean decrease of approximately 0.8 g/dL in hemoglobin was observed with the 12.5 mg dose over the first 4 weeks. Your doctor will monitor your blood counts during treatment. This effect is generally mild and does not usually require treatment discontinuation.
• Decreased sperm count: Endothelin receptor antagonists may impair male fertility by reducing sperm count. Although the reversibility of this effect has been demonstrated in animal studies, men who wish to father children should discuss this with their doctor before starting treatment.
• Renal function: An initial small decrease in estimated glomerular filtration rate (eGFR) may occur within the first 6 weeks of treatment with JERAYGO, which then typically stabilizes. This is likely related to hemodynamic changes rather than structural kidney damage. Your doctor will monitor your kidney function during treatment.

Pregnancy and Breastfeeding

JERAYGO is strictly contraindicated during pregnancy. Endothelin receptor antagonists have been shown to cause teratogenic effects (birth defects) in animal studies, including craniofacial, cardiovascular, and mandibular malformations. There are no adequate human data, but the potential risk to the fetus is considered unacceptable. A pregnancy prevention program is mandatory for all women of childbearing potential prescribed JERAYGO. This includes:

• A negative pregnancy test before starting treatment.
• Monthly pregnancy testing during treatment.
• Reliable contraception throughout treatment and for at least one month after stopping JERAYGO.
• Since hormonal contraceptive interactions have not been fully evaluated, a barrier method should be used in addition to hormonal contraception.

If pregnancy is confirmed during treatment, JERAYGO must be discontinued immediately and the patient should be referred to an obstetrician for counseling and monitoring. The long elimination half-life of aprocitentan (approximately 44 hours) means that the drug may remain in the body for several days after the last dose.

It is not known whether aprocitentan is excreted in human breast milk. Given the potential for serious adverse effects in the nursing infant, breastfeeding is contraindicated during treatment with JERAYGO.

Driving and Operating Machinery

JERAYGO has no or negligible direct influence on the ability to drive or use machines. However, since JERAYGO lowers blood pressure, some patients may experience dizziness or lightheadedness, particularly at the start of treatment or after a dose increase. If you experience these symptoms, avoid driving or operating heavy machinery until you know how JERAYGO affects you.

How Does JERAYGO Interact with Other Drugs?

One of the practical advantages of JERAYGO in the management of resistant hypertension is its favorable drug interaction profile. Because resistant hypertension by definition requires treatment with multiple medications, the potential for drug-drug interactions is a critical consideration when adding a new agent. Aprocitentan is primarily eliminated through non-CYP enzyme-mediated metabolism and is not a substrate for BCRP (breast cancer resistance protein), distinguishing it from other endothelin receptor antagonists such as bosentan, which is a strong CYP enzyme inducer.

In pharmacokinetic studies, aprocitentan did not demonstrate clinically significant interactions with commonly used medications. The compound does not inhibit or induce major CYP enzymes (including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at therapeutic concentrations, and it is not a clinically relevant substrate, inhibitor, or inducer of major drug transporters including P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATPs).

The following table summarizes the interaction status of JERAYGO with commonly co-prescribed medication classes in hypertensive patients:

The most important interaction to be aware of involves hormonal contraceptives. Although no formal pharmacokinetic interaction study has been completed between aprocitentan and hormonal contraceptives, there is a theoretical concern based on the drug class. As a precaution, women using hormonal contraceptives should add a barrier method of contraception (such as a condom or diaphragm) while taking JERAYGO. This recommendation is particularly important given the strict contraindication of JERAYGO during pregnancy.

Additionally, while no specific interaction has been identified, the combination of JERAYGO with other medications that can cause fluid retention (such as non-steroidal anti-inflammatory drugs [NSAIDs], pioglitazone, or pregabalin) may theoretically increase the risk of peripheral edema. Your doctor may monitor you more closely if you take such medications concomitantly.

What Is the Correct Dosage of JERAYGO?

JERAYGO should always be used exactly as your doctor has instructed. The medication is available as film-coated tablets for oral use. Your doctor will determine the most appropriate dose based on your blood pressure response and tolerability. The goal is to achieve adequate blood pressure control while minimizing side effects, particularly edema.

Adults

The tablets should be swallowed whole with water and can be taken with or without food. It is recommended to take JERAYGO at approximately the same time each day to maintain consistent blood levels. The 12.5 mg tablet is a yellow to orange, round, biconvex film-coated tablet (6 mm diameter) debossed with “AN” on one side. The 25 mg tablet is a pink to light purple, oval, biconvex film-coated tablet (9.2 mm × 5.1 mm) debossed with “BN” on one side.

When increasing the dose from 12.5 mg to 25 mg, your doctor should evaluate your blood pressure response, monitor for edema and other side effects, and assess liver function. The decision to increase the dose should be based on the clinical judgment that the additional blood pressure lowering benefit outweighs the increased risk of side effects, particularly edema (which was approximately twice as common at the 25 mg dose compared to 12.5 mg in clinical trials).

Children and Adolescents

JERAYGO is not recommended for use in children and adolescents under 18 years of age. The safety and efficacy of aprocitentan have not been established in this age group. Resistant hypertension in the pediatric population is rare and typically requires specialized evaluation and management by a pediatric cardiologist or nephrologist.

Elderly Patients

No dose adjustment is required for elderly patients. In the PRECISION trial, patients aged 65 and older were included, and the efficacy and safety profile was generally consistent with the overall study population. However, elderly patients may be at increased risk for edema and fluid retention, so careful monitoring is advised. Blood pressure should be assessed regularly and the dose titrated based on individual tolerability.

Renal and Hepatic Impairment

Missed Dose

If you miss a dose of JERAYGO, take it as soon as you remember on the same day. If it is already the next day, skip the missed dose and take the next dose at your regular time. Do not take a double dose to make up for a forgotten dose. Consistent daily dosing is important for maintaining steady blood pressure control. Consider using a pill organizer, smartphone alarm, or other reminder system to help you take JERAYGO at the same time each day.

Overdose

If you take more JERAYGO than prescribed, contact your doctor, pharmacist, or poison control center immediately. In clinical development, doses up to 50 mg were studied in phase II trials without dose-limiting toxicities. The most likely clinical manifestation of overdose would be an exaggeration of the known pharmacological effects, particularly hypotension (dangerously low blood pressure), fluid retention, and edema. There is no specific antidote for aprocitentan overdose. Treatment should be supportive and symptom-directed, which may include intravenous fluids for hypotension and diuretics for fluid overload. Given the long elimination half-life of approximately 44 hours, patients may require extended monitoring.

What Are the Side Effects of JERAYGO?

Like all medicines, JERAYGO can cause side effects, although not everyone who takes it will experience them. The safety profile of JERAYGO has been characterized through the PRECISION phase III trial (730 patients), its open-label extension, and additional post-marketing surveillance. Understanding the potential side effects and their frequency helps patients and healthcare providers make informed treatment decisions and recognize adverse reactions early.

The most frequently reported adverse reactions are related to the pharmacological mechanism of endothelin receptor blockade: fluid retention (manifesting as peripheral edema) and a mild decrease in hemoglobin (related to hemodilution). These effects are generally dose-dependent, meaning they are more common at the higher 25 mg dose than at the recommended starting dose of 12.5 mg.

Peripheral edema is the most clinically relevant side effect and warrants detailed discussion. In the PRECISION trial, edema was reported in 9.1% of patients receiving aprocitentan 12.5 mg, 18.4% of patients receiving 25 mg, and only 2.1% of patients receiving placebo during the initial 4-week double-blind period. The edema was typically mild to moderate in severity, presented as swelling of the ankles or lower legs, and was manageable in most cases with dose adjustment or the addition or increase of diuretic therapy. Risk factors for developing edema include older age, pre-existing chronic kidney disease, and higher doses. In most cases, edema resolved or improved upon dose reduction or treatment discontinuation.

The decrease in hemoglobin observed with JERAYGO is a pharmacological class effect of ERAs and is primarily related to fluid retention causing hemodilution rather than true bone marrow suppression or blood loss. The mean decrease was approximately 0.8 g/dL with the 12.5 mg dose, which is generally clinically insignificant. However, patients with pre-existing anemia should be monitored more closely. No cases of clinically significant anemia requiring transfusion were reported in the PRECISION trial.

Hepatotoxicity is a known class effect of endothelin receptor antagonists. In the PRECISION trial and its extension, elevations in ALT or AST greater than 5 times the upper limit of normal were observed rarely, including isolated cases with positive rechallenge (recurrence of liver enzyme elevations upon re-exposure). No cases of fulminant liver failure (Hy’s law cases) were observed. Nevertheless, liver function monitoring is mandatory: baseline testing before treatment, monthly during the first year, and periodically thereafter.

How Should You Store JERAYGO?

Proper storage of medications is essential to maintain their effectiveness and safety throughout the treatment period. JERAYGO film-coated tablets should be stored at room temperature, not exceeding 30°C (86°F). Keep the tablets in the original blister packaging until use to protect them from moisture. Do not remove tablets from the blister until you are ready to take them.

Store JERAYGO in a safe place out of the sight and reach of children. This is particularly important because JERAYGO can cause serious harm if accidentally ingested by children or by women who are pregnant. Consider storing the medication in a locked medicine cabinet if young children are present in the household.

Do not use JERAYGO after the expiry date stated on the carton and blister packaging (marked “EXP”). The expiry date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

If you notice any change in the appearance of the tablets (such as discoloration, chipping, or unusual texture), do not take them and consult your pharmacist. Medications that appear damaged or different from their usual appearance may have been compromised by exposure to heat, moisture, or other environmental factors.

What Does JERAYGO Contain?

Active Ingredient

Each JERAYGO 12.5 mg film-coated tablet contains 12.5 mg of aprocitentan. Each JERAYGO 25 mg film-coated tablet contains 25 mg of aprocitentan. Aprocitentan (chemical name: 5-(4-bromophenyl)-4-(2-((5-bromo-2-pyrimidinyl)amino)-2-oxoethyl)-4-methyl-1,3-dioxol-2-ylidene]sulfonamide) is a synthetic, small-molecule dual endothelin receptor antagonist with a molecular formula of C₁₆H₁₄Br₂N₆O₄S.

Excipients

In addition to the active ingredient, JERAYGO tablets contain the following inactive ingredients:

• Tablet core: Lactose monohydrate (54 mg per 12.5 mg tablet; 45.7 mg per 25 mg tablet), microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and sodium lauryl sulfate.
• Film coat: Hypromellose, titanium dioxide (E171), iron oxide yellow (E172) [for 12.5 mg tablets], iron oxide red (E172) [for 25 mg tablets], and triacetin.

Tablet Description