Aprocitentan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar.Doraghi, M.D.[2]
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Black Box Warning
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WARNING: EMBRYO–FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
TRYVIO can cause major birth defects if used by pregnant patients and is contraindicated in pregnancy.
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Overview
Aprocitentan is an endothelin receptor antagonist that is FDA approved 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema/fluid retention and anemia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
The recommended dosage of TRYVIO is 12.5 mg orally once daily, with or without food. TRYVIO, used with other antihypertensive drugs, treats hypertension in adults not adequately controlled by other medications. Lowering BP reduces the risk of strokes and heart attacks, although no trials have specifically shown these benefits with TRYVIO.
- Comprehensive Cardiovascular Risk Management
High BP control should be part of a broader cardiovascular strategy, including managing lipids, diabetes, and lifestyle factors. Most patients need multiple drugs to reach BP goals, following guidelines like those from the JNC.
- Efficacy of BP Reduction
Lowering BP, rather than specific drug properties, reduces cardiovascular risks, especially strokes, with consistent benefits also seen for heart attacks and cardiovascular mortality.
- Risk and Benefit of BP Reduction
Higher BP levels increase cardiovascular risk significantly. Reducing BP, even modestly in severe cases, offers substantial benefits, especially for high-risk patients (e.g., those with diabetes or hyperlipidemia), who benefit from more aggressive treatment and lower BP targets.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Aprocitentan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
- Pregnancy
- Hypersensitivity
Warnings
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WARNING: EMBRYO–FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
TRYVIO can cause major birth defects if used by pregnant patients and is contraindicated in pregnancy.
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- ERAs cause hepatotoxicity and liver failure.
- Measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and repeat periodically during treatment and as clinically indicated.
- Fluid retention may require intervention
- Decreases in hemoglobin Decreased sperm counts
- Embryo-Fetal Toxicity
TRYVIO, an endothelin receptor antagonist (ERA), can cause fetal harm based on animal studies and is contraindicated during pregnancy. Prior to initiating treatment, ensure patients are not pregnant and are using effective contraception. Advise patients of childbearing potential about the risks and to avoid pregnancy during treatment and for one month after. If pregnancy occurs, discontinue TRYVIO immediately. TRYVIO REMS
- TRYVIO is available only through the restricted TRYVIO REMS program due to embryo-fetal toxicity risks. Requirements include certification and training for prescribers and pharmacies.
- Hepatotoxicity
ERAs, including TRYVIO, can cause elevations in aminotransferases and hepatotoxicity. Clinical trials showed rare cases of significant ALT or AST elevation but no liver failure. Before starting TRYVIO, and periodically during treatment, monitor liver function tests. Do not start TRYVIO in patients with elevated aminotransferases or significant hepatic impairment. If symptoms of hepatotoxicity arise, stop TRYVIO and seek medical attention. Discontinue TRYVIO if significant liver enzyme elevations or symptoms occur.
- Fluid Retention
Fluid retention and peripheral edema are common effects of ERAs, including TRYVIO. In clinical trials, 9% of TRYVIO-treated patients experienced edema, compared to 18% with a higher dose of aprocitentan and 2% with placebo, sometimes requiring diuretics. Risk factors include older age and chronic kidney disease. TRYVIO has not been studied in severe heart failure patients and is not recommended for them. Monitor patients for fluid retention, weight gain, and worsening heart failure. If significant fluid retention occurs, treat appropriately and consider discontinuing TRYVIO.
- Hemoglobin Decrease
TRYVIO can cause decreases in hemoglobin and hematocrit, usually occurring early and stabilizing over time. In trials, 7% of TRYVIO patients had hemoglobin drops greater than 2 g/dL compared to 1% of placebo patients. Hemoglobin levels below 10.0 g/dL were seen in 3% of TRYVIO patients. Avoid initiating TRYVIO in patients with severe anemia and monitor hemoglobin levels periodically during treatment.
- Decreased Sperm Counts
TRYVIO may adversely affect spermatogenesis. Counsel men about potential fertility impacts.
Adverse Reactions
Clinical Trials Experience
- Embryo-fetal toxicity
- Hepatotoxicity
- Fluid retention
- Hemoglobin decrease
- Decreased sperm counts
Adverse reaction rates from clinical trials may vary and might not reflect real-world rates. The safety of TRYVIO was assessed in the PRECISION phase 3 study (NCT03541174) in adults with uncontrolled blood pressure despite at least three antihypertensive medications. A total of 724 patients received aprocitentan, with extended treatment durations for many. During the initial 4-week double-blind, placebo-controlled period, adverse reactions in TRYVIO-treated patients (12.5 mg) versus placebo included:
- Edema/fluid retention: 9.1% vs. 2.1%
- Anemia: 3.7% vs. 0%
- Hypersensitivity Reactions
In the same period, 0.8% of TRYVIO patients experienced hypersensitivity reactions (rash, erythema, allergic edema) compared to none on placebo. One patient on a higher dose experienced allergic dermatitis requiring hospitalization.
- Laboratory Tests
TRYVIO initiation may cause a small, initial decrease in eGFR within the first 6 weeks, which then stabilizes. A mean hemoglobin decrease of about 0.8 g/dL was observed in TRYVIO 12.5 mg patients during the 4-week period, compared to no change in placebo patients.
Postmarketing Experience
There is limited information regarding Aprocitentan Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Aprocitentan Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
Based on animal reproduction studies with other ERAs, TRYVIO can cause embryo-fetal toxicity, including birth defects and fetal death when administered to a pregnant patient and is contraindicated during pregnancy
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aprocitentan in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Aprocitentan during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Aprocitentan in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Aprocitentan in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Aprocitentan in geriatric settings.
Gender
There is no FDA guidance on the use of Aprocitentan with respect to specific gender populations.
Race
There is no FDA guidance on the use of Aprocitentan with respect to specific racial populations.
Renal Impairment
TRYVIO is not recommended in patients with kidney failure (eGFR <15 mL/min) or on dialysis. The effect of kidney failure (eGFR <15 mL/min) or dialysis on aprocitentan pharmacokinetics is unknown
Hepatic Impairment
TRYVIO is not recommended in patients with moderate and severe hepatic impairment
Females of Reproductive Potential and Males
Verify the pregnancy status of patients prior to initiating TRYVIO. Patients who can become pregnant should exclude pregnancy with a negative pregnancy test monthly during treatment, and one month after discontinuation of treatment with TRYVIO. The patient should contact their physician immediately if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to the patient, the pregnancy, and the fetus
Immunocompromised Patients
There is no FDA guidance one the use of Aprocitentan in patients who are immunocompromised.
Administration and Monitoring
Administration
The recommended dosage of TRYVIO is 12.5 mg orally once daily.
- Swallow tablets whole. TRYVIO may be taken with or without food.
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.
- Pregnancy Testing in Females of Reproductive Potential
Initiate treatment with TRYVIO in females of reproductive potential only after confirmation of a negative pregnancy test. Patients should exclude pregnancy with negative pregnancy tests monthly during treatment and one month after discontinuation of treatment with TRYVI.
Monitoring
There is limited information regarding Aprocitentan Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Aprocitentan and IV administrations.
Overdosage
TRYVIO has been administered as a single dose of up to 600 mg, and as multiple doses of up to 100 mg daily, to healthy subjects (48 and 8 times the recommended dose, respectively). Adverse events of headache, nasal congestion, nausea, and upper respiratory tract infection were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because aprocitentan is highly protein-bound.
Pharmacology
There is limited information regarding Aprocitentan Pharmacology in the drug label.
Mechanism of Action
Aprocitentan is an ERA 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.
Structure
TRYVIO (aprocitentan) is an ERA. The chemical name of aprocitentan is N-[5-(4-bromophenyl)-6- [2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide. It has a molecular formula of C16H14Br2N6O4S and a molecular weight of 546.2 g/mol.
The structural formula is:
Aprocitentan is a white to off-white powder that is insoluble in water.
TRYVIO is available as film-coated 12.5 mg strength tablets for oral administration. The inactive ingredients in TRYVIO are croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.
The film coating contains the following inactive ingredients: hydroxypropyl cellulose, iron oxide black, iron oxide red, iron oxide yellow, polyvinyl alcohol, silica colloidal hydrated, talc, titanium dioxide, and triethyl citrate.
Pharmacodynamics
Aprocitentan exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.
- Cardiac Electrophysiology
At eight times the recommended dose, clinically significant QTc interval prolongation was not observed.
Pharmacokinetics
Peak Concentration: Mean Cmax is 1.3 mcg/mL following a single 25 mg dose. Exposure: Mean AUC0-tau is 23 mcg·h/mL following a single 25 mg dose.
- Dose-Proportionality: Plasma concentrations increase proportionally with doses from 5 to 100 mg.
- Steady State: Reached by Day 8 with a 3-fold accumulation.
- Plasma Unchanged: Aprocitentan remains primarily unchanged in plasma.
Absorption:
- Bioavailability: Unknown.
- Time to Peak: 4-5 hours post-dose.
Effect of Food:
- No Significant Impact: High-fat, high-calorie meals do not affect pharmacokinetics.
Distribution:
- Volume: 20 L.
Protein Binding: >99%, primarily to albumin; unaffected by renal/hepatic impairment.
- Blood-to-Plasma Ratio: 0.63.
Elimination:
- Half-Life: 41 hours.
- Clearance: 0.3 L/h.
Metabolism:
- Pathways: UGT1A1 and UGT2B7-mediated N-glucosidation, non-enzymatic hydrolysis.
Excretion:
- Urine: 52% (0.2% unchanged).
- Feces: 25% (6.8% unchanged).
Specific Populations:
- No Significant Differences: Based on age, sex, race, body weight, renal, or mild to moderate hepatic impairment.
- Unknown Effects: Kidney failure (eGFR <15 mL/min), dialysis, severe hepatic impairment.
Drug Interaction Studies:
- No Significant Differences: With midazolam (CYP3A4 substrate) or rosuvastatin (BCRP substrate).
In Vitro Studies:
- UGT Inducers: May decrease exposure.
- CYP450 Enzymes: Inhibits CYP3A4 and CYP2C family; induces CYP3A4.
UGT Enzymes: Substrate and inhibitor of UGT1A1 and UGT2B7.
- Transporters: Substrate of P-gp and BCRP; inhibitor of BCRP, BSEP, and NTCP. Does not inhibit P-gp, OCT1, OCT2, MATE1, MATE2K, OAT1, OAT3, OATP1B1, or OATP1B3.
Nonclinical Toxicology
- Carcinogenesis
Two-year carcinogenicity studies with macitentan (for which aprocitentan is a major metabolite) did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, which produced aprocitentan exposures approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.
- Mutagenesis
Aprocitentan did not induce mutagenicity or genotoxicity in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, a chromosome aberration test in human lymphocytes, and an in vivo bone marrow micronucleus test in rats.
- Impairment of Fertility
In a fertility study in male rats given aprocitentan for 15 weeks at doses up to 250 mg/kg/day, no effect on fertility or spermatogenesis was observed at 52-fold the clinical exposure at the MRHD based on AUC. In repeated dose toxicity studies, treatment with aprocitentan resulted in testicular tubular degeneration/atrophy in male rats and dogs at high doses of 250 mg/kg/day and 25 mg/kg/day, respectively, which represents approximately 41- and 52-fold the clinical exposure at the MRHD, based on AUC, respectively. The testicular toxicity was not evident in male rats and dogs at 50 mg/kg/day and 5 mg/kg/day, respectively, which represents approximately 14- and 10-fold the clinical exposure at the MRHD based on AUC. In female rats given aprocitentan prior to mating, minimally increased pre-implantation loss was observed at doses ≥50 mg/kg/day, which represent ≥23-fold the clinical exposure at the MRHD based on AUC. No impact on fertility was observed at 10 mg/kg/day, which represents 5-fold the clinical exposure at the MRHD based on AUC.
Clinical Studies
The efficacy of TRYVIO (aprocitentan) was evaluated in the PRECISION phase 3 multicenter study involving adults with SBP ≥140 mmHg who were on at least three antihypertensive medications. The study included a placebo run-in period followed by three parts. Initially, all patients were switched to a standard background antihypertensive therapy, including an angiotensin receptor blocker, a calcium channel blocker, and a diuretic, and those using beta-blockers continued this treatment throughout the study.
- Following the 4-week placebo run-in, 730 patients were randomized to receive 12.5 mg or 25 mg aprocitentan, or placebo daily for 4 weeks (part 1). All patients then received 25 mg aprocitentan daily for 32 weeks (part 2). Subsequently, patients were re-randomized to receive either 25 mg aprocitentan or placebo daily for 12 weeks (part 3).
The primary efficacy endpoint was the change in sitting SBP (SiSBP) from baseline to Week 4 during part 1, measured by unattended automated office blood pressure (uAOBP). The key secondary endpoint was the change in SiSBP from Week 36 to Week 40. Patients had a mean age of 62 years, with a demographic breakdown of 60% male, 83% White, 11% African American, and 5% Asian, and 10% Hispanic. The mean BMI was 34 kg/m², and at baseline, 19% had an eGFR of 30-59 mL/min/1.73 m² and 3% had an eGFR of 15-29 mL/min/1.73 m². Additionally, 24% had a UACR of 30-300 mg/g and 13% had a UACR >300 mg/g. Approximately 54% had diabetes, 31% had ischemic heart disease, and 20% had congestive heart failure, with 63% reporting the use of four or more antihypertensive medications. TRYVIO 12.5 mg was statistically superior to placebo in reducing SiSBP at Week 4, with consistent effects observed for sitting diastolic BP (SiDBP).
The persistence of the blood pressure-lowering effect of TRYVIO was demonstrated in part 3 of the trial. Patients on aprocitentan were re-randomized to either placebo or 25 mg aprocitentan after all had been treated with 25 mg. Those switched to placebo showed an increase in mean SiSBP, while those continuing with 25 mg maintained their SiSBP levels, which were statistically superior to placebo at Week 40. The effect was consistent for SiDBP as well. Most of the BP-lowering effect occurred within the first two weeks of treatment.
TRYVIO is not approved at a 25 mg dose because it did not show a meaningful improvement in blood pressure reduction compared to the 12.5 mg dose and had a higher risk of edema/fluid retention. The BP-lowering effect of TRYVIO was consistent across subgroups defined by age, sex, race, BMI, baseline eGFR, baseline UACR, diabetes history, and different BP measurement methodologies.
How Supplied
12.5 mg: yellow to orange round, film-coated tablet, debossed with "AN" on one side and plain on the other side.
- NDC 80491-8012-8, each blister contains 10 tablets
- NDC 80491-8012-3, each bottle contains 30 tablets and has a child-resistant closure
Storage
Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF)
Images
Drug Images
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Package and Label Display Panel
NDC 80491-8012-3
TRYVIO™ (aprocitentan) tablets
12.5 mg
Attention: Dispense the enclosed Medication Guide to each patient.
Rx only
30 film-coated tablets
idorsia
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Patient Counseling Information
There is limited information regarding Aprocitentan Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Aprocitentan interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Aprocitentan Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Aprocitentan Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.