Macitentan And Tadalafil

1 INDICATIONS AND USAGE OPSYNVI is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, indicated for chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients of WHO functional class (FC) II–III. ( 1.1 ) Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability. ( 1.1 , 14 ) 1.1 Pulmonary Arterial Hypertension OPSYNVI is the combination of macitentan and tadalafil indicated for the chronic treatment of adults with pulmonary arterial hypertension (PAH, WHO Group I and WHO Functional Class (FC) II–III). Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability [see Clinical Studies (14.1) ] .

2 DOSAGE AND ADMINISTRATION One 10 mg/20 mg or 10 mg/40 mg tablet taken orally once daily with or without food. ( 2.1 ) 2.1 Recommended Dosage OPSYNVI is taken orally once daily with or without food. Swallow the tablets whole, with water. Do not cut, crush, or chew tablets. If the patient misses a dose of OPSYNVI, tell the patient to take it as soon as possible and then take the next dose at the regularly scheduled time. Tell the patient not to take two doses at the same time if a dose has been missed. For patients who are treatment-naïve to any PAH specific therapy or transitioning from ERA monotherapy The recommended starting dose of OPSYNVI is one 10 mg/20 mg tablet taken orally once daily with or without food for one week. If tolerated, up titrate OPSYNVI to one 10 mg/40 mg tablet taken orally once daily with or without food as the maintenance dose. For patients transitioning from PDE5 inhibitor monotherapy or PDE5 inhibitor and ERA therapy in combination The recommended dose of OPSYNVI is one 10 mg/40 mg tablet taken orally once daily. 2.2 Pregnancy Testing in Females of Reproductive Potential Exclude pregnancy before initiating treatment with OPSYNVI in females of reproductive potential [see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ].

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. 6.1 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 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. 6.2 Postmarketing 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 exposure. Macitentan: liver injury, symptomatic hypotension, hypersensitivity reactions (angioedema, pruritus, and rash). Tadalafil: Cardiovascular and cerebrovascular events including myocardial infarction, sudden cardiac death, stroke, and tachycardia; Nervous system events including, seizure, transient amnesia; Hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis; visual field defect, NAION, retinal vascular occlusion; sudden hearing loss, priapism.

12.3 Pharmacokinetics Macitentan The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration. A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects. Tadalafil Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 50% greater AUC was observed indicating a less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within 5 days, and exposure was approximately 30% higher than after a single dose. Absorption Macitentan After a single oral administration of OPSYNVI, the maximum plasma concentration of macitentan is achieved in about 10 hours. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. OPSYNVI may therefore be taken with or without food. Tadalafil After a single oral-dose administration of OPSYNVI, the maximum observed plasma concentration (C max ) of tadalafil is achieved in about 3 hours. Absolute bioavailability of tadalafil following oral dosing has not been determined. Food intake does not significantly alter the rate and extent of absorption of tadalafil and OPSYNVI may be taken with or without food. Distribution Macitentan Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects. Tadalafil The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Metabolism Macitentan Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with minor contributions of CYP2C8, CYP2C9, and CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. Tadalafil Tadalafil is predominantly metabolized by CYP3A to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. Elimination Macitentan In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces. Tadalafil Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean effective half-life is 11 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). Population Pharmacokinetics Tadalafil In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers. Specific Populations Renal Impairment Macitentan Exposure to macitentan and its active metabolite in patients with severe renal impairment (creatinine clearance 15–29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant. Tadalafil In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, C max doubled and AUC was 2.7 to 4.1 times as high following single-dose administration of 10 or 20 mg tadalafil, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2 to 4-times as high in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24-and 30-hours post-dose) contributed negligibly to tadalafil or metabolite elimination. Hepatic Impairment Macitentan Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant. Tadalafil In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was similar to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) . Geriatric Patients Macitentan There are no clinically relevant effects of age on the pharmacokinetics of macitentan and its active metabolite. Tadalafil In healthy male elderly subjects (65 years or over) after a 10 mg dose, a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on C max was observed relative to that in healthy subjects 19 to 45 years of age. Patients with Diabetes Mellitus Tadalafil In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and C max was 5% lower than that observed in healthy subjects. No dose adjustment is warranted. Race and gender There are no clinically relevant effects of race or gender on macitentan, its active metabolite, or tadalafil. Drug Interactions No clinical study evaluating drug interactions has been performed using OPSYNVI. Interactions that have been identified in studies with individual components of OPSYNVI (macitentan or tadalafil) determine the interactions that may occur with OPSYNVI. Co-administration of macitentan (10 mg once daily) and tadalafil (40 mg once daily) had no clinically relevant effect on the pharmacokinetics of either macitentan or tadalafil. Macitentan The metabolism of macitentan to its active metabolite is catalyzed mainly by CYP3A4, with minor contributions from CYP2C8, CYP2C9, and CYP2C19. Macitentan and its active metabolite do not have relevant inhibitory or inducing effects on CYP enzymes. Macitentan and its active metabolite are not substrates of the multi-drug resistance protein (P-gp, MDR-1) or organic anion transporting polypeptides (OATP1B1 and OATP1B3). Macitentan and its active metabolite are not inhibitors of hepatic or renal drug transporters at clinically relevant concentrations. Tadalafil Tadalafil is a substrate of and predominantly metabolized by CYP3A. Effects of other drugs on macitentan or tadalafil Strong CYP3A4 inducers or inhibitors Macitentan Concomitant treatment with rifampicin 600 mg daily, a potent inducer of CYP3A4, reduced the steady-state exposure to macitentan by 79% but did not affect the exposure to the active metabolite [see Drug Interactions (7.2) ]. Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (7.3) ] . A moderate dual inhibitor of CYP3A4 and CYP2C9 such as fluconazole (400 mg once daily) is predicted to increase macitentan exposure approximately 4-fold without relevant effect on the exposure to its active metabolite [see Drug Interactions (7.4) ] . Tadalafil Rifampin (600 mg daily), a CYP3A inducer, reduced tadalafil 10 mg single-dose exposure (AUC) by 88% and C max by 46%, relative to the values for tadalafil 10 mg alone [see Drug Interactions (7.2) ] . Bosentan, a substrate of CYP2C9 and CYP3A and a moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil systemic exposure following multiple-dose coadministration. Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure [see Drug Interactions (7.2) ]. Ketoconazole increased tadalafil exposure relative to the values for tadalafil alone. Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure [see Drug Interactions (7.3) ]. Ritonavir increased tadalafil 20-mg single-dose exposure relative to the values for tadalafil alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in a time-dependent manner. The initial inhibitory effect of ritonavir on CYP3A may be mitigated by a more slowly evolving induction effect so that after about 1 week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Drug Interactions (7.3) ] . Effects of macitentan or tadalafil on other medicinal products Macitentan Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR). At steady state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant. Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 µg). Macitentan 10 mg once daily did not affect the pharmacokinetics of concomitant use of a BCRP substrate drug (riociguat 1 mg and rosuvastatin 10 mg). Tadalafil Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Exposure changes of drugs following co-administration with tadalafil are shown in Figure 1. Figure 1: Impact of Tadalafil on the Pharmacokinetics of Other Drugs a A small augmentation (increase of 3 beats per minute) in heart rate was observed with theophylline. b Tadalafil (40 mg qd) had no clinically significant effect on exposure (AUC and C) of bosentan metabolites. c 95% CI Figure 1