TRYVIO

WARNING: EMBRYO-FETAL TOXICITY TRYVIO is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant patients. Therefore in patients who can become pregnant, exclude pregnancy prior to initiation of TRYVIO. Advise use of effective contraception before the start of TRYVIO, during treatment and for one month after stopping treatment. When pregnancy is detected, discontinue TRYVIO as soon as possible [see Dosage and Administration (2.2) , Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] . WARNING: EMBRYO–FETAL TOXICITY See full prescribing information for complete boxed warning. Based on animal data TRYVIO may cause fetal harm if used by pregnant patients and is contraindicated in pregnancy. ( 4.1 , 5.1 , 8.1 ) For patients who can become pregnant, exclude pregnancy prior to initiation of treatment with TRYVIO. ( 2.2 , 5.1 , 8.3 ) Use effective contraception prior to initiation of treatment, during treatment, and for one month after stopping TRYVIO. ( 2.2 , 4.1 , 5.1 , 8.3 ) When pregnancy is detected, discontinue TRYVIO as soon as possible ( 5.1 )

5 WARNINGS AND PRECAUTIONS 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. ( 5.2 ) Fluid retention may require intervention ( 5.3 ) Decreases in hemoglobin ( 5.4 ) Decreased sperm counts ( 5.5 ) 5.1 Embryo-Fetal Toxicity 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) ] . 5.2 Hepatotoxicity 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. 5.3 Fluid Retention 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. 5.4 Hemoglobin Decrease 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) ] . 5.5 Decreased Sperm Counts 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) ] .

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal toxicity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Fluid retention [see Warnings and Precautions (5.3) ] Hemoglobin decrease [see Warnings and Precautions (5.4) ] Decreased sperm counts [see Warnings and Precautions (5.5) ] Most common adverse reactions (more frequent than placebo and ≥ 2% in TRYVIO-treated patients) are edema/fluid retention and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Idorsia Pharmaceuticals Ltd at 1-833-400-9611 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Table 1 Adverse reactions reported with a frequency of ≥2% in TRYVIO-treated patients and greater (≥1%) than in placebo-treated patients during the initial 4-week double-blind placebo-controlled treatment (part 1) Adverse Reaction 12.5 mg N = 243 % Placebo N = 242 % Edema/fluid retention 9.1 2.1 Anemia 3.7 0 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.

<table width="90%" ID="Table1"><caption>Table 1 Adverse reactions reported with a frequency of &#x2265;2% in TRYVIO-treated patients and greater (&#x2265;1%) than in placebo-treated patients during the initial 4-week double-blind placebo-controlled treatment (part 1) </caption><col width="28%" align="left" valign="top"/><col width="24%" align="center" valign="top"/><col width="24%" align="center" valign="top"/><col width="24%" align="center" valign="top"/><tbody><tr><td styleCode="Toprule Botrule" valign="bottom"><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Toprule Botrule" valign="bottom"><content styleCode="bold">12.5 mg</content> <content styleCode="bold">N = 243</content> <content styleCode="bold">%</content></td><td styleCode="Toprule Botrule" valign="bottom"> </td><td styleCode="Toprule Botrule" valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">N = 242</content> <content styleCode="bold">%</content></td></tr><tr><td styleCode="Toprule">Edema/fluid retention</td><td styleCode="Toprule">9.1</td><td styleCode="Toprule"> </td><td styleCode="Toprule">2.1</td></tr><tr><td styleCode="Botrule">Anemia</td><td styleCode="Botrule">3.7</td><td styleCode="Totrule"> </td><td styleCode="Botrule">0</td></tr></tbody></table>