OPSYNVI macitentan and tadalafil 10 mg; 20 mg Tablet, Film Coated, 30-count

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: ERAs cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated. ( 5.2 ) Hypotension: Vasodilatory effects may cause hypotension in susceptible patients.

( 5.3 ) Hemoglobin decrease. ( 5.4 ) Worsening Pulmonary Veno-Occlusive Disease: If pulmonary edema is confirmed, discontinue treatment. ( 5.5 ) Visual Loss: Sudden loss of vision could be a sign of non-arteritic ischemic optic neuropathy (NAION) and may be permanent.

( 5.6 ) Hearing Impairment: Cases of sudden decrease or loss of hearing have been reported in patients taking tadalafil. ( 5.7 ) Fluid Retention: Fluid retention may require intervention. ( 5.8 ) Combination with Other PDE5 Inhibitors: Avoid use with other PDE5 inhibitors.

( 5.9 ) Decreased Sperm Count: Decreases in sperm count have been observed in patients taking ERAs. ( 5.10 ) Prolonged Erection: Advise patients to seek emergency treatment if an erection lasts greater than 4 hours. ( 5.11 )

5.1Embryo-fetal Toxicity Based on data from animal reproduction studies, OPSYNVI may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for ERAs do not establish the presence or absence of major birth defects related to the use of OPSYNVI. Advise patients who can become pregnant of the potential risk to a fetus.

Obtain a pregnancy test prior to initiation of therapy with OPSYNVI. Advise patients who can become pregnant to use effective contraceptive methods prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with OPSYNVI. When pregnancy is detected, discontinue use as soon as possible [see Dosage and Administration (2.2) , Contraindications (4.1) , and Use in Specific Populations (8.1 , 8.3) ].

5.2Hepatotoxicity ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the double-blind and combined double-blind (DB)/open-label (OL) arms of the study of OPSYNVI in PAH are shown in Table 1. Table 1: Incidence of Elevated Aminotransferases in the A DUE Study OPSYNVI DB (N=107) OPSYNVI DB/OL (N=185) ≥3 × ULN 1.0% 3.4% ≥8 × ULN 1.0% 1.1% The overall incidence of treatment discontinuations for hepatic adverse events in the double-blind and combined double-blind/open-label arms study of OPSYNVI in PAH data were 0.9% and 2.2% respectively.

The incidence of elevated aminotransferases in the study of OPSUMIT (macitentan) in PAH is shown in Table 2. Table 2: Incidence of Elevated Aminotransferases in the SERAPHIN Study OPSUMIT 10 mg (N=242) Placebo (N=249) >3 × ULN 3.4% 4.5% >8 × ULN 2.1% 0.4% In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group vs. 1.6% for placebo.

Obtain liver enzyme tests prior to initiation of OPSYNVI and repeat during treatment as clinically indicated. Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSYNVI.

Consider re-initiation of OPSYNVI when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity. Do not initiate OPSYNVI in patients with elevated aminotransferases (> 3 × upper limit of normal [ULN]) at baseline. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, and, therefore, avoid use of OPSYNVI.

5.3Hypotension OPSYNVI tablets have vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing OPSYNVI tablets, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilato…

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Hypersensitivity [see Contraindications (4.2) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Hypotension [see Warnings and Precautions (5.3) ] Decrease in Hemoglobin [see Warnings and Precautions (5.4) ] Visual Loss [see Warnings and Precautions (5.6) and Patient Counseling Information (17) ] Hearing loss [see Warnings and Precautions (5.7) ] Fluid Retention [see Warnings and Precautions (5.8) ] Prolonged Erection [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥10%) are edema/fluid retention, anemia, and headache/migraine.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 overall safety profile of OPSYNVI is based on data from a double-blind, active-controlled, phase 3 clinical study (A DUE) and an open-label extension study, in patients with PAH [see Clinical Studies (14) ] . In the double-blind portion of the study, a total of 107 patients were treated with OPSYNVI 10 mg/40 mg, 35 patients were treated with 10 mg macitentan monotherapy, and 44 patients were treated with 40 mg tadalafil monotherapy.

The duration of exposure to OPSYNVI during the double-blind portion was 16 weeks. The most common adverse reactions (occurring in ≥ 10% of the OPSYNVI-treated patients) from the double-blind study data were edema/fluid retention (21%), anemia (19%), and headache/migraine (18%). The incidence of treatment discontinuations due to adverse events among patients receiving OPSYNVI in the double-blind phase of the study was 8%.

The most frequent adverse reactions leading to discontinuation were anemia and hemoglobin decreased (2% grouped) and peripheral edema and peripheral swelling (2% grouped). Table 3 presents adverse reactions seen in patients treated for 16 weeks during the double-blind portion of A DUE. Table 3: Adverse Reactions Occurring in 3% or More of Patients Treated with OPSYNVI During the 16-week Double-blind Study Portion of A DUE Adverse Reaction OPSYNVI N=107 % Macitentan Monotherapy N=35 % Tadalafil Monotherapy N=44 % Edema/fluid retention 21 14 16 Anemia 19 3 2 Headache 18 17 14 Abdominal pain 7 3 14 Hypotension 7 0 0 Myalgia 6 0 5 Nasopharyngitis 6 3 0 Nausea 6 0 7 Increased uterine bleeding 5 0 0 Back pain 5 3 9 Flushing 4 6 0 Vomiting 4 0 5 Palpitations 4 3 5 Pain in extremity 3 0 7 Epistaxis 3 0 0 One-hundred eighty-five patients received OPSYNVI in the double-blind or open-label phase of the study.

The median exposure to OPSYNVI during the combined double-blind/open-label extension was 59.9 weeks with a mean exposure of 63.2 weeks. Adverse reactions from the combined double-blind/open-label study data were similar to those observed in the double-blind study. The following adverse reactions have been reported during clinical trials with the individual components of OPSYNVI but were not observed in 3% or more of subjects treated with OPSYNVI in the A DUE clinical trial: Macitentan: bronchitis, pharyngitis, transaminases increased, influenza, urinary tract infection.

Tadalafil: lower respiratory tract infection, prolonged erections, gastroesophageal reflux disease, vision blurred, tinnitus, swelling face, chest pain.

6.2Postmarketing Experience Additional adverse reactions have been identified during post-approval use of tadalafil. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug e…

7 DRUG INTERACTIONS Strong CYP3A4 Inducers/Inhibitors: Avoid concomitant use ( 7.2 , 7.3 ) Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors: Avoid concomitant use ( 7.4 )

7.1Nitrates Administration of nitrates within 48 hours after the last dose of OPSYNVI is contraindicated [see Contraindications (4.3) ] .

7.2Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Use of OPSYNVI with strong CYP3A4 inducers should be avoided [see Clinical Pharmacology (12.3) ].

7.3Strong CYP3A4 Inhibitors Concomitant use of strong CYP3A4 inhibitors like ketoconazole increase exposure to both macitentan and tadalafil. Avoid concomitant use of OPSYNVI with strong CYP3A4 inhibitors such as ritonavir, ketoconazole and itraconazole. Use other PAH treatment options when strong CYP3A4 inhibitors are needed [see Clinical Pharmacology (12.3) ].

7.4Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold. Avoid concomitant use of OPSYNVI with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3) ]. Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSYNVI should also be avoided [see Clinical Pharmacology (12.3) ].

7.5Alpha-Blockers PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. In patients who are taking alpha 1 blockers, concomitant administration of tadalafil may lead to symptomatic hypotension in some patients. Therefore, the combination of OPSYNVI and doxazosin is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2) ].

7.6Antihypertensives PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood–pressure–lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo [see Clinical Pharmacology (12.2) ].

7.7Alcohol Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure–lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with OPSYNVI can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations [see Clinical Pharmacology (12.2) ].