TRYVIO - Idorsia Pharmaceuticals Ltd

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.

Exclude pregnancy before initiating treatment with TRYVIO in females of reproductive potential [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.1), Use in Specific Populations (8.3)].

Use of TRYVIO is contraindicated in patients who are pregnant [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

TRYVIO is contraindicated in patients who are hypersensitive to aprocitentan or any of its excipients [see Adverse Reactions (6.1)].

Based on data from animal reproduction studies with endothelin receptor antagonists (ERAs), TRYVIO may cause fetal harm when administered during pregnancy and is contraindicated for use in patients who are pregnant. The available human data for endothelin receptor antagonists do not establish the presence or absence of fetal harm related to the use of TRYVIO. Counsel patients who can become pregnant about the potential risk to a fetus. Obtain a pregnancy test prior to initiation of treatment with TRYVIO. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment with TRYVIO, during treatment, and for one month after the final dose of TRYVIO. When pregnancy is detected, discontinue TRYVIO as soon as possible [see Dosage and Administration (2.2), Contraindications (4.1), Use in Specific Populations (8.1, 8.3)].

Elevations of aminotransferases and hepatotoxicity are known effects of ERAs, including TRYVIO. 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. 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 TRYVIO-treated patients in the clinical trials. 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.

Do not initiate TRYVIO in patients with elevated aminotransferases (>3 × ULN) or moderate to severe hepatic impairment.

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 TRYVIO and seek medical attention.

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 TRYVIO.

Fluid retention and peripheral edema are known effects of ERAs, including TRYVIO [see Adverse Reactions (6.1)]. Edema/fluid retention was reported in 9% of TRYVIO-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. Older age and chronic kidney disease are risk factors for edema/fluid retention with TRYVIO. TRYVIO 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. TRYVIO is not recommended in these patients.

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

Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in the clinical trial with TRYVIO. Hemoglobin decreases usually presented early, stabilized thereafter, and were reversible after discontinuation. A decrease in hemoglobin of >2 g/dL from baseline was observed in 7% of patients compared to 1% of placebo patients. A decrease to below 10.0 g/dL was observed in 3% of TRYVIO-treated patients compared to 0 patients taking placebo. Initiation of TRYVIO is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and periodically during treatment as clinically indicated [see Adverse Reactions (6.1)].

TRYVIO, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of TRYVIO was evaluated in a placebo-controlled phase 3 clinical study (PRECISION, NCT03541174) in adults with uncontrolled BP (systolic blood pressure [SBP] ≥140 mmHg) despite the use of at least three antihypertensive medications.

In this study, 724 patients received any dose of aprocitentan, with 633 patients treated for at least 26 weeks, 192 patients for at least 47 weeks, and 99 patients for at least 48 weeks.

The most frequently reported adverse reactions to TRYVIO during the 4-week double-blind placebo-controlled treatment period (part 1) of the PRECISION study are presented in Table 1.

Hypersensitivity Reactions

During the initial 4-week double-blind placebo-controlled treatment period (part 1), 0.8% of patients experienced an adverse reaction of hypersensitivity (i.e., rash, erythema, allergic edema) on TRYVIO compared to no reports in patients treated with placebo. One patient experienced allergic dermatitis requiring hospitalization while receiving aprocitentan 25 mg.

Laboratory Tests

Initiation of TRYVIO may cause an initial small decrease in estimated glomerular filtration rate (eGFR) that occurs within the first 6 weeks of starting therapy and then stabilizes.

In the initial 4-week double-blind treatment period, TRYVIO 12.5 mg caused a mean decrease of about 0.8 g/dL in hemoglobin compared to no change in the placebo patients.

Risk Summary

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 [see Contraindications (4.1)]. Available data from post-marketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as TRYVIO have not identified an increased risk of fetal harm; however, these data are limited. Methodological limitations of these post-marketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. Administration of macitentan, where approximately ≥50% of total exposure was to aprocitentan, was teratogenic in rats and rabbits at all doses tested (see Data). Available data from reports of pregnancy in clinical trials with TRYVIO are insufficient to rule out a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Advise pregnant patients of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Data

Animal Data

In embryo-fetal development toxicity studies in pregnant rats and rabbits given macitentan (for which aprocitentan is a major metabolite) during the period of major organogenesis, cardiovascular and mandibular arch fusion malformations were observed at all doses studied. The lowest doses in rats and rabbits produced aprocitentan exposures that were equivalent to and 15-fold, respectively, the clinical exposures at the maximum recommended human dose (MRHD) based on area under the curve (AUC).

In pre- and post-natal development studies, female rats given macitentan (for which aprocitentan is a major metabolite) from late pregnancy through lactation showed reduced pup survival and impairment of the male fertility of the offspring at all doses. The lowest dose produced aprocitentan exposures approximately 2-fold the clinical exposures at the MRHD based on AUC.

Risk Summary

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

Data

A single ¹⁴C-radiolabeled macitentan dose of 3 mg/kg was given orally to lactating Wistar rats. Aprocitentan was consistently observed in milk samples across all collection times after oral administration.

Based on data from animal reproductive toxicity studies with other ERAs, TRYVIO can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1), Use in Specific Populations (8.1)].

Pregnancy Testing

Verify that patients who can become pregnant, are not pregnant prior to initiating 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 should discuss the risks to the patient, the pregnancy, and the fetus [see Warnings and Precautions (5.1), Dosage and Administration (2.2), Contraindications (4.1)].

Contraception

Patients using TRYVIO who can become pregnant should use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with TRYVIO to prevent pregnancy [see Warnings and Precautions (5.1)].

Infertility

Other ERAs have shown an adverse effect on spermatogenesis in humans and/or animals. TRYVIO, like other ERAs, may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.5), Nonclinical Toxicology (13.1)].

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

Of the total number of subjects in the PRECISION study of TRYVIO, 321 (44%) were 65 years and older, while 72 (10%) were 75 years and older. Edema/fluid retention was more common in these patients than younger patients [see Warnings and Precautions (5.3)].

No dose adjustment is required in patients over the age of 65 years [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of edema/fluid retention [see Warnings and Precautions (5.3)].

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

TRYVIO 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.

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology (12.3)].

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

ET-1, via its receptors (ET_A and ET_B), 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.

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.

The aprocitentan mean (%CV) C_max is approximately 1.3 mcg/mL (19) following a single 25 mg dose (twice the recommended dose). The mean (%CV) aprocitentan AUC to the dosing interval (AUC_0-tau) is approximately 23 mcg∙h/mL (17) following a single 25 mg dose. Aprocitentan plasma concentrations increased in a dose-proportional manner following once-daily administration of 5, 25, and 100 mg (0.4 times the recommended dose to 8 times the recommended dose). Aprocitentan steady state is reached by Day 8 with approximately 3-fold accumulation following once daily administration. Aprocitentan is primarily unchanged in plasma following oral TRYVIO administration.

Absorption

The absolute oral bioavailability of aprocitentan is unknown. The time to reach C_max is between 4 and 5 hours after administration of 25 mg aprocitentan (twice the recommended dose).

Effect of Food

No clinically significant differences in aprocitentan pharmacokinetics were observed following administration of a high-fat, high-calorie meal (approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) in healthy subjects.

Distribution

The apparent volume of distribution of aprocitentan is approximately 20 L. Aprocitentan is >99% bound to plasma proteins, primarily albumin. Protein binding is not affected by renal or hepatic impairment. The aprocitentan blood-to-plasma ratio is 0.63.

Elimination

The aprocitentan effective half-life is approximately 41 hours, and the apparent clearance is approximately 0.3 L/h.

Metabolism

Aprocitentan is primarily metabolized by UGT1A1- and UGT2B7-mediated N-glucosidation and non-enzymatic hydrolysis.

Excretion

After a single dose of radiolabeled aprocitentan, approximately 52% of the dose was eliminated via urine (0.2% unchanged) and 25% via feces (6.8% unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of aprocitentan were observed based on age (18–84 years), sex, race/ethnicity, body weight (44–196 kg), between patients and healthy subjects, mild to severe renal impairment (eGFR ≥15 mL/min), or mild to moderate hepatic impairment (Child-Pugh class A to B). The effect of kidney failure (eGFR <15 mL/min), dialysis, or severe hepatic impairment (Child-Pugh class C) on aprocitentan pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with aprocitentan: midazolam (CYP3A4 substrate), rosuvastatin (breast cancer resistance protein [BCRP] substrate) or combined oral contraceptive (ethinyl estradiol and levonorgestrel).

In Vitro Studies

UDP-glucuronosyltransferase (UGT) inducers: Concomitant administration of aprocitentan with UGT inducers may decrease aprocitentan exposure.

CYP450 enzymes: Aprocitentan inhibits CYP3A4 and all members of the CYP2C family, but did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP2E1. Aprocitentan is an inducer of CYP3A4 but did not induce CYP1A2 or CYP2C9.

UGT enzymes: Aprocitentan is a substrate and inhibitor of UGT1A1 and UGT2B7.

Transporter systems: Aprocitentan is a substrate of P-glycoprotein (P-gp) and BCRP. However, inhibitors of these transporters are not anticipated to influence the PK of aprocitentan. Aprocitentan is an inhibitor of BCRP, bile salt export pump (BSEP), and sodium taurocholate co-transporting polypeptide (NTCP), but does not inhibit P-gp, organic cationic transporter (OCT)1, OCT2, human multi-drug and toxin compound extrusion (MATE)1, or MATE2K. Aprocitentan does not inhibit organic anion transporter (OAT)1, OAT3, OATP1B1, or OATP1B3 at therapeutic concentrations.

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.

TRYVIO tablets are available as:

• 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

Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original package. Dispense to patient in original container only. Replace cap securely each time after opening. Do not discard desiccant. Protect from light and moisture.