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 )
1.1Pulmonary 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) ] .
OPSYNVI may cause fetal harm when administered to a pregnant woman. OPSYNVI is contraindicated in females who are pregnant. Macitentan was consistently shown to have teratogenic effects when administered to animals. If OPSYNVI is used during pregnancy, advise the patient of the potential risk to a fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] .
4.2Hypersensitivity
OPSYNVI is contraindicated in patients with a history of a hypersensitivity reaction to macitentan, tadalafil, or any component of the product. Hypersensitivity reactions have been reported. Stevens-Johnson syndrome and exfoliative dermatitis have been reported with tadalafil [see Adverse Reactions (6.2) ].
4.3
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OPSYNVI is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of OPSYNVI. Tadalafil potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2) ].
4.4 Concomitant Guanylate Cyclase (GC) Stimulators Coadministration of GC stimulators such as riociguat with OPSYNVI is contraindicated. Tadalafil may potentiate the hypotensive effects of GC stimulators.
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 vasodilatory effects. Patients with pre-existing hypotension, with autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators [see Clinical Pharmacology (12.2) ].
5.4Hemoglobin Decrease Decreases
in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSYNVI and OPSUMIT. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group.
Similar results were observed in the trial with OPSYNVI. Decreases in hemoglobin seldom require transfusion. Initiation of OPSYNVI is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated [see Adverse Reactions (6.1) ].
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of OPSYNVI tablets to patients with veno-occlusive disease, administration of OPSYNVI tablets to such patients is not recommended. Should signs of pulmonary edema occur when OPSYNVI tablets are administered, the possibility of associated PVOD should be considered.
If confirmed, discontinue OPSYNVI.
5.6Visual Loss
Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, has been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking.
Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged greater than or equal to 50 in the general population. Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use of OPSYNVI in these patients is not recommended.
5.7Hearing Impairment Cases
of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.
5.8Fluid Retention
Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs and heart failure has been reported in patients taking OPSYNVI. In the active-controlled and combined double-blind/open-label arms of the study of OPSYNVI in PAH, the incidence of peripheral edema/fluid retention was 20.6% in the active-controlled and 17.3% in the double-blind/open-label arm [see Adverse Reactions (6.1) ] .
In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group. Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of OPSUMIT in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the OPSUMIT group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo.
Postmarketing cases of edema and flu
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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) ].
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on data from animal reproduction studies, OPSYNVI is contraindicated during pregnancy. Macitentan, a component of OPSYNVI, may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female. Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as OPSYNVI have not identified an increased risk of major birth defects; however, these data are limited.
Methodological limitations of these postmarketing 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 ERA use. Macitentan was teratogenic in rabbits and rats at all doses tested. Available data from a randomized controlled trial, observational studies, and case series with tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In tadalafil animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats and mice during organogenesis at exposures 7 times the maximum recommended human dose (MRHD) of 40 mg/day (see Data ) . There are risks to the mother and the fetus associated with PAH in pregnancy (see Clinical Considerations ) . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise pregnant women of the potential risk to a fetus [see Contraindications (4.1) and Warnings and Precautions (5.1) ].
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 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with PAH, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including heart failure, stroke, spontaneous abortion, intrauterine growth restriction, premature labor, and preterm birth.
Data Animal Data Macitentan In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested. Tadalafil Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC.
In one of two perinatal/postnatal developmental studies in rats, a reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed-effect-level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately 5 times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than 8 times the exposure at the MRHD.
Surviving offspring had normal development and reproductive performance.
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.
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.
Composition
Active ingredients
MACITENTAN 10MG; TADALAFIL 20MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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